close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3084179

код для вставки
3,084,167
United States Patent O?ice
Patented Apr. 2, 1963
2
1
The products of the present invention may be prepared
by reacting a dialkylaminoalkylamine or heterocyclic
3,084,167
ISOINDOLES
alkylamine with a molecular equivalent of the corre
Leonard M. Rice, Baltimore, Md., assignor to The
Gesehickter Fund for Medical Research, Inc., Wash
ington, D.C., a corporation of New York
No Drawing. Filed Dec. 9, 1954, Scr. No. 474,288
9 Claims. (Cl. 260-319)
this invention are phthalic; tetrahydrophathalic; endo
methyleno tetrahydrophthalic; 5 - methyl tetrahydro
sponding acid anhydride. The acid anhydrides used in
phthalic; 3,5-dirnethyl tetrahydrophthalic; endomethylene
hexahydrophthalic; S-methyl hexahydrophthalic; 3,5
dimethyl hexahydrophthalic; 3-methy1 tetrahydrophthalic;
The present invention relates to organic compounds,
particularly new, substituted isoindole derivatives and 10 and 3-methyl hexahydrophthalic; as well as those derived
from hexahydrophthalic, anhydride, dichlorophthalic an
their quaternary salts with various hydrogenation states
hydride, and tetrachlorophthalic anhydride and halogen
and to methods of producing such compounds.
substituted derivatives such as by chlorine, bromine, and
According to the present invention, generally stated,
iodine and the hydrogenated derivatives of these phthalic
new products which are of outstanding value in the treat
ment of various diseases are made by preparing N-sub 15 anhydrides.
The resulting N-substituted dialkylaminoalkyl imide is
stituted isoindoles, of varying degrees of hydrogenation
of the type represented by the formula
C
then reduced by suitable means, for example, with lithium
aluminum hydride or sodium in alcohol, or catalytically
or electrolytically, to the corresponding isoindole deriva
tive which is then methylated to the quaternary salt. The
following examples illustrate this synthesizing process of
the present invention and exemplary compounds resulting
a
therefrom.
These examples are to be construed as merely
illustrative and not limiting the scope of the present
B
and conversion to their corresponding di-methionium 25 invention.
salts, having the formula:
EXAMPLE I
N-Diethylaminoethyl Octahydroisoindole
Dimethyl Quaternary Iodide
30
In the above Formulae 1 and 2, the six membered ring
A, of the isoindole nucleus, B, represents a cyclic hydro 35
carbon ring, substituted or unsubstituted and in various
stages of hydrogenation, being selected from the follow
ing group:
Phenyl
Cyclohexene
Endomethylene-cyclohexene
S-methyl-cyclohexene
S-methyl-cyclohexene
3,5-dimethy1-cyclohexene
Cyclohexane
B-methyl-cyclohexane
S-methyl-cyclohexane
3,5-dimethyl-cyclohexane
Endomethylene-cyclohexane
A mixture of 116 grams (1 mole) of diethylamino
ethylamine and 154 grams (1 mole) of hexahydrophthalic
anhydride was heated in a bath at 160-170° C. for 4
40 hours. The mixture was allowed to cool and then
vacuum distilled. The distillation yielded 220 grams
of N-diethylaminoethyl hexahy-drophthalimide boiling at
132-135“ C. at 2 mm. pressure.
With stirring 110 grams of the N-diethylaminoethyl
45 hexahydrophthalimide was added dropwise to 36 grams
of lithium aluminum hydride dissolved in 1000 ml. of
anhydrous ether at such a rate as to maintain a gentle
re?ux of the ether.
50
Also, in the general formulae,
After all the material was added,
the reaction mixture was decomposed with a minimum
amount of cold water. This was determined by the
liberation of hydrogen and re?uxing of the other. When
N
R
V
gas was no longer evolved, the mixture was stirred for
25 hours and then ?ltered. The ethereal ?ltrate was
represents (1) a dialkylamlno group or radical having
from 1 to 6 carbon atoms in the alkyl chains or (2) 55 concentrated to give the isoindole derivative which, when
distilled at a pressure of 2 mm., boiled at 93-96° C. and
a heterocyclic alkylamino group or ring such as mor
pholine, pyrrolidine or piperidine; n represents a num
ber from 2 to 6 and x represents a halogen ion such as
chloride, bromide or iodide or the methylsulfate ion.
weighed 85 grams.
The isoindole derivative was dissolved in absolute al
cohol and treated with a 10% excess of methyl iodide.
At this juncture, it is pointed out that the naming of
these compounds is in conformity with the Patterson
Ring Index as illustrated in the following examples in
The quaternary salt crystallized out of the solution and
after recrystallization from alcohol melted at 224
which numbers 8 and 9 had to be assigned to the two
EXAMPLE II
225° C.
carbon atoms at the ring junctions.
65
43
/O\
or
670/
1
Octahydrolsoindole
\NH
04
Isotdoline or
dihydroisolndollne
N-Dierhylaminoethyl-4,7,8,9-Tetrahydrozlsoindoline
Dimethyl Quaternary Iodide
H2
CH3
(3
l
‘13H3
a2 I
I.
>I;*——eH.———
0 a
N<
2 5
l
C
8,084,167
4
EXAMPLE v
A mixture of 116 grams of diethylaminoethyl amine
and 152 grams of cis-A‘Ltetrahydrophthalic anhydride was
N-Dimethylamin0ethyl-6-Methyl-4,7,8,9
maintained at 160~170° C. for 4 hours. After cooling,
the mixture was vacuum distilled whereupon it yielded
Tetrahydroisoindoline Dinzethiodide
210 grams of N-diethylaminoethyl - cis - A4 - tetrahydro
phthalimide boiling at 132-134“ C. at 2 mm.
110 grams of the above imide was added, at such a
rate as to just maintain re?ux, to 36 grams of lithium
aluminum hydride dissolved in 1000 ml. of anhydrous
ether.
When all the material had been added, the re
10
action mixture was decomposed with a minimum amount
of cold water. The solution was ?ltered and the ?l
standing. After recrystallization from alcohol the qua
The imide was prepared from S-methyl cis-A4-tetra
hydrophthalic anhydride as in Example I and boiled at
ternary salt of the isoindoline melted at 218-220° C.
106-112” C. at 0.2 mm.
Reduction by means of lithium aluminum hydride as
The isoindoline derivative was dissolved in absolute 15
in Example I yielded the base boiling at 78—85° C. at
alcohol and treated with a 10% excess of methyl iodide.
0.1 mm.
The quaternary salt precipitated from the solution on
Conversion to the quaternary salt as in Example I
standing. After recrystallization from alcohol the quater
gave the product which, after recrystallization, melted at
nary salt of the isoindoline melted at 218-220° C.
20 203—205‘‘ C.
EXAMPLE VI
EXAMPLE III
N-Dimethylaminoethyl-4,6-Dimethyl-4,7,8,9
Tetrahydroisoindoline Dimelhiodide
N-Diethylaminoethyl-I-3-Dihydroisoindole Dimethiodide
25
H,
011,
CH; 02H»
llI+-—GiH4—N+
30
The imide was prepared from 3,5-dimethyl cis-M
A mixture of 116 grams of diethylaminoethylamine
tetrahydrophthalic anhydride as in Example I and boiled
and 148 grams of phthalic anhydride was heated at 160 35 at 101—105° C. at 0.1 mm. The base was obtained by
170° C. for 4 hours. When cool, the mixture was vac
reduction as in Example I and boiled at 87-94° C. at
uum distilled and yielded 215 grams of N-diethylarnino
0.1 mm. Conversion to the dimethiodide as in Exam
ethyl phthalirnide boiling at 140-143° C. at 2 mm.
ple I yielded the salt with a melting point of 194-197° C.
With stirring, 110 grams of the above imide was
EXAMPLE VII
added, at such a rate as just to maintain re?ux, to 36 40
grams of lithium aluminum hydride dissolved in 1000
N-Dialky lamin0alkyl-4,5 ,6 ,7,8,9-Hexahyidro-4,7
ml. of dry ether. When all the imide was added the
Endomethano lsoindolines
reaction mixture was decomposed with a minimum
A. These isoindolines and their derivatives were pre
amount of cold water. The solution was ?ltered and
the ?ltrate was concentrated to give the isoindole which, 45 pared in the manner illustrated by the foregoing exam
when distilled at a pressure of 2 mm., boiled at 101
ples, the starting anhydride being endomethylene hexa
104° C.
The isoindole derivative was dissolved in absolute a1
cohol and a 10% molar excess of methyl iodide was
hydrophthalic anhydride which recently has become corn
mercially available. The imide resulting when this anhy
dride is reacted with diethylaminoethyl amine is N-di
added. The product which separated after recrystalli 50
ethylaminoethyl - endomethylene - hexahydrophthalimide,
zation from alcohol melted at 193-194° C.
which has a boiling point of 130—135° C. at 2 mm. pres
sure. The hydrochloride salt of this imide has a melt
EXAMPLE IV
ing point of 205—206° C. Reduction of the imide gives
55 the corresponding isoindoline having a boiling point of
110°-114° C. at 1 mm. The dimethiodide, obtained by
methylation of this isoindoline as hereinbefore described,
has a melting point of 213—214° C.
B. With the same anhydride and dimethylaminoethyl
N-Diethylaminoethyl-4,7,8,9-Tetrahydr0-4,7
Endomethano-Isoindoline Dimethiodide
60 amine, the corresponding compounds were obtained and
are characterized as follows:
Imide: N - dimethylaminoethyl-endomethylene - hexahy
drophthalimide, boiling point, 120-123 at 2 mm.
65
The imide may be prepared by reacting 116 grams of
diethylaminoethylamine with 164 grams of 3,6-endometh
ylene-cis-M-tetrahydrophthalic anhydride as in Example
I.
4,7-cndomethano-isoindoline, boiling point, 103408“
C. at 2 mm.
This imide boils at 142—144° C. at 2 mm. pres
sure.
Reduction of the imide as in Example I yielded 109
grams of the isoindoline direvative boiling at 122-124”
at 2 mm. pressure.
Conversion into the methionium salt as in Example I
yielded the quaternary salt melting at ZOE-210° C.
Imide hydrochloride: Melting point, 201-203” C.
Isoindoline: N-dimethylaminoethyl-4,5,6,7,8,9-hexahydro
70
llsoindoline dirncthiodide: Melting point, 220~-221D C.
The following tabulation presents further examples
of compounds embraced by the invention, which were
prepared according to the procedure set forth herein
75 above.
3,084,167
TABLE II—~Continued
N-DIALKYLAMINOALKYLISOINDOLINES
Analysis, percent
Dimcthiodide
B.P.,
R
Formula
° C.
1101
Mn.
Carbon
Hydrogen
Nitrogen
T
‘‘ C
Calcd. Found Calcd. Found Calcd.
Diothylamincethyl ______ __
DirnethylaminopropyL. _
blowliolinopropyl _____ _.
CnllnNz ____ __
cmllmN? ____ ._
CHIHQNQOUH
1014104
120-123
1li4—l08
2
3
3
77.01
70. 42
T3. l3
76. 87
76. 12
T2. 97
10. 15
‘.1. B7
9. U0
9. 76
0. 40
8. 70
12. 83
13. 71
ll. 37
i
Ml’.,
#
Found
12. 54
13. ~11
11.57
—
Nitrogen
M.P.,
° C.
Galcd.
234-235
2464247
247*248
193-194
237~238
230*231
5. 58
5. T4
5. 2
Found
5. 5]
.5. 88
5. 2i)
N'DIA LRYLA MINOALKYL OCTAILYDROISOINDO LES
Dirnolllylanlinoetllyl_____|
Dicthylaminnethyl_._
__
C
Dimctllylatnlnoilrojby]. _.
Dietllyluminotrroilylr
1\’lor}\l10lin0cth_v]r
1M1orpl1olinopmpy Dibutylanilnoproliy _
77730
2
T3. 41
l2. 19
14.27
14.02
276078
5. S3
5. 88
934.16
2
74. 33
75. (ll
12.55
12.21
14.43
12. 23
177478
5. 5i
5. 24
H5485
2
74. 22
74.10
12.40
12. ‘.10
13.32
2
5
‘2
0. 1
74. 5t‘)
70. 54
71.38
77. ~18
4. 9i)
70. 11
71. 24
77, $1
l2. 6??
10.99
11. 18
13. 01
12.30
10.63
10. 93
12. 81
11.75
11.75
ll. 10
U. 51
105*107
1474119
132*135
ll?wlll
73.10
12.32
' .
‘
0. 08
5. 71
5. 30
I 7. 3R
5. 27
4.1%
56
T. 40
5. 3S
5. O1
Dihoxylarninoethyl?
140445
0. l
78. 50
77. 05
13. l8
13. 23
8. 32
4. 52
4. 4S
Dlethylamlnohoxyl. _
Piperdinoethyl _____ __
Diethylnrnlnobutyl ____ _.
1104120
103*10?
83 >87
(1.1
(l. l
0. 02
77. [)7
70. ?]
76. 12
76. 99
76.29
76.50
12. 92
11.94
12. 78
12.03
11.69
12. 64
9. 00
11.85
11. 10
4. 0|‘)
5. 3S
47. 33
5. (l2
5. 32
4G. 98
3»dlcthylaminopropanal-2
105*115
0. l
70. 81
71. 30
11. 89
11. 96
11.01
47. 15
110. 89
5. 69
5. 58
1 Monomethiodide.
Dimethylaminoethyl.____
N-DIALKYLAMINOALKYL-B-METHYLAJ .8 .Q-TETRAHYDROISOINDOLINE
C 13}I71Nu ____ __
78485
0. 1
74. 94
74. 65
11.61
11. 38
13. 45
13. 48
262-263
203-205
Following the same general procedure, the trimethoniurn
salt of isoindole has been prepared having the following
formula:
rather severe, rapid action which may result in fainting
on standing (postural hypotension) and the action is
relatively brief, being ‘from about 3 to 20 hours. Bistrium
and Apresoline also, in certain cases, exhibit side reac
tions such as headache, palpitation, nausea and ‘fainting,
35 and Apresoline apparently has a damaging effect on the
‘blood and bone marrow when given over a long period
of time which has, in some cases, been fatal. The effect
The imide was prepared from cis n'i-tetrahydrophthalic
predictable and overdoses can reduce blood pressure to
of Bistrium or Apresoline on the blood pressure is un
anhydride and N-methyl piperazine propylamine and had
40 shock or coma levels.
a boiling point of 160° to 165° C. at 0.2 mm.
In some cases the blood pressure
may even drop to zero.
The hydrochloride of the above imide had a melting
point of 258° to 259° C. and ‘gave the following analytical
The isoindoles of the present invention have a slower
and more prolonged or sustained effect in lowering blood
‘pressure and seem to have a saturation or plateau e?ect
?gures:
45
so that overdosage is not serious. Even if an overdose
Calculated
Found
is administered, the blood pressure is not reduced to
shock or coma levels. None of the side reactions of
Carbon _____________________________________ __
52. 75
52. 84
Bistrium and Apresoline have been observed with the use
7. 47
7. 77
11. 53
11. 26
of isoindoles and the isoindoles seem to have a relaxing
50
Chlorine ____________________________________ __
19.
19. 41
effect on nervous as well as hypertensive individuals. The
effect of these isoindoles lasts 48 hours or more in ob
The isoindole base obtained as described above had a
served cases.
boiling point of 136° to 142° C. at 0.1 mm. and gave the
The compound may be administered intramuscularly
following analytical ?gures:
k Calculated \ Found
Carbon“ . __________________________________ __
72. 95
72. 90
Hydrogen“--.
-
11.10
10. 88
Nitrogen ___________________________________ -_
15. 95
16.21
55 or orally.
Doses of 10 to 30 mg. in sterile aqueous solu
tion may ‘be given intramuscularly every other day and
100 mg. tablets may be given once daily. Such dosages
are sufficient to reduce and hold blood pressure at safe
levels and no toxic or unpleasant side effects have been
observed.
60
The present application is a continuation-in-part of
The trihydrochloride had a melting point of 270° to
my application Serial No. 336,457, ?led February 11,
271° C. and analyzed for 28.54% chlorine, the theoreti
1953, now abandoned.
cal amount being 28.53%. The trimethonium compound
From the foregoing it will be apparent that I attained
obtained as above employing methyl iodide, melted at
213° to 215° C. and analyzed 54.94% iodine, the theo 65 the object of my invention and have provided new and
useful compounds for the treatment of hypertension.
retical amount being 55.24%.
I claim:
The compounds bis-methionium salts of the present
1. A compound selected from the group consisting of
invention have proven especially effective in the treat
(l) N-substituted isoindoles of the formula
ment of hypertension and are superior to any presently
11g
70
known remedies.
0
There are two compounds being presently used in the
A
treatment of hypertension, known under the proprietory
N_
names of “Bistrium" and “Apresoline,” and these com
pounds have been only recently introduced. These drugs
have certain de?nite disadvantages.
Both drugs have a 75
C
HI) n-N
R
3,084,167
10
wherein ring A is selected from the group consisting of
6. The therapeutically useful dimethonium salts of N
phenyl; cyclohexene; endomethylene cyclohexene; 3
methyl cyclohexene; S-methyl cyclohexene; 3,5-dirnethyl
cyclohexene; cyclohexane; 3-methyl cyclohexane; 5
methyl cyclohexane; 3,5-dimethyl cyclohexane; endo
methylene cyclohexane; 6-1nethyl cyclohexene; 6-rnethyl
cyclohexane; 4 methyl cyclohexene; 4-methyl cyclohex
dimethylaminoethyl dihydroisoindoline.
7. The therapeutically useful dimethonium salts of N
dimethylaminoethyl tetrahydroisoindoline.
[3
8. The therapeutically useful dimethonium salts of N
dimethylaminoethyl hexahydroisoindoline.
9. The therapeutically useful dimethoniurn salts of N
ane; 4,6»dimethyl cyclohexene; 4,6»dimethyl cyclohexane;
dimethylaminoethyl endomethanoisoindoline.
wherein n is a whole number from 2 to 6; and wherein
ll)
A
N
R
V
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,143,751
2,432,905
2,528,940
is an amino group selected from the group consisting
of morpholine, piperidine, pyrrolidine and dialkylamine
of from 1 to 6 carbon atoms in the alkyl chain; and (2)
the therapeutically useful dimethonium salts thereof.
2,541,211
Adkins ______________ __ Jan. 10,
Kharasch et ‘al _________ __ Dec 19,
Wright ______________ __ Nov. 7,
Cusic _______________ __ Feb. 13,
2,807,624
Grogan et a1. ________ __ Sept. 24, 1957
2. The compound N-dimethylaminoethyl dihydroiso
20
987,158
France ______________ __ Apr. 11, 1951
OTHER REFERENCES
Jour. Am. Chem. Soc., vol. 68, pp. 1657-58 (1946).
isoindoline.
4. The compound N-dimethylaminoethyl hexahydro
isoindoline.
Comptes Rendus, vol. 222, pp. 1443-44 (1946).
5. The compound N-dimethylaminoethyl endomethano~
isoindoline.
1951
FOREIGN PATENTS
indoline.
3. The compound N-dimethylaminoethyl tetrahydro
1939
1947
1950
25
Chem. Abstracts, vol. 45, pp. 5146 and 9527 (1951).
Beilstein, 4th ed., vol. XX, 2nd supp, page 172 (1953).
Документ
Категория
Без категории
Просмотров
2
Размер файла
528 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа