U.S. patent number 3,696,120 [Application Number 05/058,985] was granted by the patent office on 1972-10-03 for 4-(2-hydroxy-3-amino propoxy)-indole derivatives.
Invention is credited to Franz Troxler.
United States Patent |
3,696,120 |
Troxler |
October 3, 1972 |
4-(2-HYDROXY-3-AMINO PROPOXY)-INDOLE DERIVATIVES
Abstract
The present invention concerns new indole derivatives of the
formula: ##SPC1## Wherein R.sub.1 is lower alkyl of one to six
carbon atoms, preferably of three to five carbon atoms, cycloalkyl
of three or four carbon atoms or 3-phenylpropyl, R.sub.2 is methyl,
hydroxymethyl, methoxymethyl, alkoxycarbonyl wherein the alkoxy
group is of one to four carbon atoms or carboxyl. The compounds are
useful in the treatment of angina pectoris and heart rhythm
disorders.
Inventors: |
Troxler; Franz (4103
Bottmingen, Basel-Land, CH) |
Family
ID: |
27509196 |
Appl.
No.: |
05/058,985 |
Filed: |
July 28, 1970 |
Foreign Application Priority Data
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Aug 5, 1969 [CH] |
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11918/69 |
Oct 24, 1968 [CH] |
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15866/69 |
Jun 24, 1970 [CH] |
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9536/70 |
Oct 24, 1969 [CH] |
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15865/69 |
Mar 24, 1970 [CH] |
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4383/70 |
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Current U.S.
Class: |
548/492; 548/467;
548/503; 548/469; 548/509 |
Current CPC
Class: |
C07D
209/42 (20130101); C07D 209/12 (20130101); C07D
209/08 (20130101) |
Current International
Class: |
C07D
209/00 (20060101); C07D 209/08 (20060101); C07D
209/42 (20060101); C07D 209/12 (20060101); C07d
027/56 () |
Field of
Search: |
;260/326.15,326.14R |
References Cited
[Referenced By]
U.S. Patent Documents
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3471515 |
October 1969 |
Troxler et al. |
|
Primary Examiner: Mazel; Alex
Assistant Examiner: Narcavage; Joseph A.
Claims
What is claimed is:
1. A compound of the formula: v,.sup.1/8
wherein
R.sub.1 is lower alkyl of one to six carbon atoms, cycloalkyl of
three to four carbon atoms or 3-phenylpropyl,
R.sub.2 is methyl, hydroxymethyl, methoxymethyl, alkoxycarbonyl
wherein the alkoxy group is of one to four carbon atoms or
carboxyl,
or a pharmaceutically acceptable acid addition salt thereof.
2. The compound of claim 1, which is
2,3-dimethyl-4-(2hydroxy-3-isopropylaminopropoxy)indole.
3. The compound of claim 1, which is
4-[2-hydroxy-3-(3-pentylamino)propoxy]-3-methylindole-2-carboxylic
acid ethyl ester.
4. The compound of claim 1, which is
4-(2-hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl
indole.
5. The compound of claim 1, which is
4-(3-cyclopropylamino-2-hydroxypropoxy)-3-methylinole-2-carboxylic
acid ethyl ester.
6. The compound of claim 1, which is
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic
acid methyl ester.
7. The compound of claim 1, which is
4-(3-tert.butylamino-2-hydroxypropoxy)-3-methylindole-2-carboxylic
acid ethyl ester.
8. The compound of claim 1, which is
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic
acid.
Description
The present invention relates to new indole derivatives of formula
I, ##SPC2##
wherein
R.sub.1 is lower alkyl of one to six carbon atoms, preferably of
three to five carbon atoms, cycloalkyl of three or four carbon
atoms or 3-phenylpropyl,
R.sub.2 is methyl, hydroxymethyl, methoxymethyl, alkoxycarbonyl
wherein the alkoxy group is of one to four carbon atoms or
carboxyl,
As well as to processes for the production thereof.
The preferred compounds of formula I, wherein R.sub.1 is lower
alkyl, are those wherein the alkyl radical is branched or compact,
especially those which are branched on the .alpha. carbon atom,
e.g. the isopropyl, sec.butyl, tert.butyl, or 3-pentyl radical.
In accordance with the invention an indole derivative of formula I
is obtained by
A. reacting a compound of formula IIa, ##SPC3##
Wherein
R.sub.2 ' is methyl, hydroxymethyl, methoxymethyl or alkoxycarbonyl
wherein the alkoxy group is of one to four carbon atoms, or a
compound of formula IIb, ##SPC4##
Wherein
Y is halogen, and
R.sub.2 ' is as defined above,
Or a mixture of the compounds of formulas IIa and IIb, hereinafter
referred to as compounds of formula II, with a compound of formula
III,
H.sub.2 NR.sub.1 III
wherein R.sub.1 is as defined above, to obtain a compound of
formula Ia, ##SPC5##
Wherein R.sub.1 and R.sub.2 ' are as defined above, or
B. debenzylating a compound of formula IV, ##SPC6##
wherein R.sub.1 and R.sub.2 ' are as defined above,
To obtain a compound of the above formula Ia, or
C. reducing a compound of formula V, ##SPC7##
wherein
R.sub.2 ' is as defined above,
R.sub.1 ' is lower alkyl of one to six carbon atoms, preferably of
three to five carbon atoms, cycloalkyl of three or four carbon
atoms, or 3-phenylpropyl when R.sub.2 ' is methyl, hydroxymethyl or
methoxymethyl, and
R.sub.1 ' is methyl, ethyl, propyl, isopropyl or cyclopropyl when
R.sub.2 ' is alkoxycarbonyl, and
R and R' are lower alkyl,
In an inert organic solvent, to obtain a compound of formula Ib,
##SPC8##
Wherein R.sub.1 ' and R.sub.2 ' are as defined above, or
D. reducing a compound of formula VI, ##SPC9##
wherein
R.sub.1 " is methyl, ethyl, propyl, isopropyl or cyclopropyl,
R.sub.3 is methyl or ethyl, and
R and R' are as defined above,
In the presence of a catalyst and a lower alkanol of the formula
AlkOH, wherein Alk is lower alkyl of one to four carbon atoms, to
obtain a compound of formula Ic, ##SPC10##
Wherein R.sub.1 " and Alk are as defined above, or
E. reducing a compound of formula VII, ##SPC11##
wherein R, R' and R.sub.2 ' are as defined above, and R.sub.1 "' is
isopropyl, cyclopropyl, tert.butyl or tert.pentyl, in an inert
organic solvent, to obtain a compound of formula Id, ##SPC12##
wherein R.sub.1 "' and R.sub.2 ' are as defined above, or
f. reducing a compound of formula VIII, ##SPC13##
wherein R.sub.1 "' , R.sub.3, R and R' are as defined above, in the
presence of a catalyst and a lower alkanol of the formula AlkOH,
wherein Alk is as defined above, to obtain a compound of formula
Ie, ##SPC14##
wherein R.sub.1 "' and Alk are as defined above, or
g. reducing an imine of formula IX, ##SPC15##
wherein R.sub.2 ' is as defined above, and either each of
R.sub.4 and R.sub.5 is lower alkyl of one to three carbon atoms,
or
R.sub.4 and R.sub.5 together are trimethylene, or
R.sub.4 is hydrogen and
R.sub.5 is phenethyl,
to obtain a compound of formula If, ##SPC16##
wherein R.sub.2 ', R.sub.4 and R.sub.5 are as defined above, and,
where a free carboxyl group is required in the 2 position of the
indole structure, the corresponding 2-alkoxycarbonyl compound is
hydrolyzed, and where a hydroxymethyl group is required in the
2-position of the indole structure, the corresponding 2-carboxyl or
2-alkoxycarbonyl compound is reduced.
Acid addition salts or salts of resulting free bases may be
produced in conventional manner by reaction with an acid, and free
bases may be liberated from salts by treatment with a base.
The production of the new compounds may, for example, be effected
as follows:
a. The reaction of a compound of formula II with a compound of
formula III is preferably effected in an inert organic solvent,
e.g. an aromatic hydrocarbon such as benzene or toluene, or in a
cyclic ether such as dioxane, and has a duration of about 2 to 24
hours. The reaction temperature may range between 20.degree. and
15.degree. C; the reaction is preferably effected at the boiling
temperature of the reaction mixture under reflux. In the compounds
of formula IIb, Y preferably signifies chlorine or bromine.
b. The debenzylation of the compounds of formula IV is conveniently
effected by hydrogenation in the presence of a catalyst, preferably
a palladium catalyst, in an inert organic solvent, e.g. ethyl
acetate, a cyclic or open chain ether such as tetrahydrofuran, or a
lower alkanol such as methanol or ethanol. Hydrogenation if
preferably effected at room temperature and normal pressure. After
hydrogenation is complete, the catalyst is filtered off.
c. The reduction of compounds of formula V may be effected as
described in embodiment b) above. It should, however, be pointed
out that an interchange of ester radicals my occur in the case of
hydrogenation of a compound of formula VI, (which is a special case
of a compound of formula V), when a lower alkanol is used as
solvent. This interchange of ester radicals can be avoided when
reduction is effected in an alkanol R.sub.3 OH, wherein R.sub.3 is
identical to the significance of R.sub.3 in formula VI.
d. The reduction of a compound of formula VI to a compound of
formula Ic is likewise preferably effected in the presence of a
palladium catalyst, conveniently at room temperature and normal
pressure.
e. The reduction of a compound of formula VII can likewise be
effected in a manner analogous to embodiment b) above. In this case
an interchange of ester radicals, as indicated in section c), may
likewise take place when a lower alkanol is used as solvent, it
being possible to avoid this interchange in the same way as
indicated in section c) above.
f. The reaction of a compound of formula VIII to obtain a compound
of formula Ie may be effected as described in embodiment d).
g. The reduction of an imine of formula IX may, for example, be
effected by hydrogenation in the presence of a suitable metal
catalyst, preferably a palladium catalyst, in an inert organic
solvent, e.g. ethyl acetate, or a lower alkanol such as methanol.
Hydrogenation is preferably effected at normal pressure and room
temperature. After hydrogenation is complete, the catalyst is
filtered off. In accordance with an alternative method of
embodiment g), reduction is effected with a complex borohydride.
For example, an imine of formula IX is taken up in an inert organic
solvent, e.g. a lower alkanol such as methanol, and solid sodium
borohydride is added portionwise.
Hydrolysis of a 2-alkoxycarbonyl compound of formula I to the
corresponding 2-carboxyl compound of formula I may, for example, be
effected with aqueous alcoholic solutions of an excess of an alkali
metal or alkaline earth metal hydroxide, e.g. sodium, potassium or
barium hydroxide. Lower alkanols such as methanol or ethanol are
preferably used as alcohols.
Hydrolysis may, for example, likewise be effected with an alkaline
ion exchange resin.
Reduction of a 2-alkoxycarbonyl compound of formula I to the
corresponding 2-hydroxymethyl compound may, for example, be
effected with a complex aluminum hydride such as lithium aluminum
hydride or sodium dihydro-bis-(2-methoxyethoxy)aluminate, in an
inert organic solvent, e.g. a cyclic or open chain ether such as
tetrahydrofuran, preferably at the boiling temperature of the
reaction mixture, and has a duration of one-half to several hours.
The reaction mixture may be worked up by adding, e.g. water or a
lower alkanol, removing the resulting precipitate by filtration and
separating the organic phase. The precipitate is subsequently
washed out with an inert organic solvent, and the combined organic
phases are dried, e.g. over sodium sulphate. Upon concentrating the
organic phase by evaporation, the 2-hydroxymethyl compound of
formula I is obtained as residue.
The reduction may, for example, likewise be effected in accordance
with the procedure of Bouveault-Blanc with sodium in alcohol.
The reaction mixture obtained in accordance with the above
embodiments of the process may, for example, be worked up by
concentrating it by evaporation, shaking out the residue between an
aqueous acid, e.g. 1 N tartaric acid or 1 N hydrochloric acid, and
a inert organic solvent which is not miscible with the acid, such
as ethyl acetate, making the acid aqueous phase neutral, e.g. with
an aqueous sodium carbonate solution, taking up the liberated basic
product in an inert organic solvent such as methylene chloride,
separating and drying the organic phase and finally concentrating
the same by evaporation, preferably at reduced pressure.
The compounds of formula II are new. A compound of formula II may,
for example, be produced by reacting a compound of formula X,
##SPC17##
wherein R.sub.2 ' is as defined above,
with an epihalohydrin, preferably epichlorhydrin or epibromhydrin.
The compound of formula X is preferably employed in the reaction in
the form of its ammonium or alkali metal salt, e.g. as sodium salt,
with the epihalohydrin, conveniently in the absence of oxygen or
alternatively in the presence of a base such as piperidine.
After removing the excess epihalohydrin by distillation or
completely concentrating the reaction mixture by evaporation,
optionally in a vacuum, the residue (mixture of the compounds of
formulas IIa and IIb) can be used for the next reaction without
further purification.
Since epihalohydrin molecules have two reactive sites, a mixture of
the compounds of formulas IIa and IIb is obtained, which, however,
yields the same final product when used in embodiment a) of the
process. Therefore, it is not necessary to effect a separation of
the mixture, although this may be readily effected (e.g. by
chromatography).
The compounds of formula IV are likewise new. A compound of formula
IV may, for example, be produced by reacting a compound of formula
XIa, ##SPC18##
wherein R.sub.1 is as defined above,
or a compound of formula XIb,
wherein R.sub.1 and Y are as defined above,
or a mixture of the compounds of formulas XIa and XIb, hereinafter
referred to as compounds of formula XI, with a compound of formula
X.
This reaction may, for example, be effected as follows:
One to three equivalents of a compound of formula XI are added to a
solution or a suspension of a compound of formula X or its alkali
metal or ammonium salt, e.g. the sodium salt of a compound of
formula X. The reaction may, for example, be effected by stirring
the mixture for an extended period, e.g. about 1 to 24 hours, while
heating to 20.degree. to 120.degree. C, preferably in the absence
of oxygen.
The compounds of formula XIa may be produced in accordance with
known processes, e.g. by treatment of a compound of formula XIb
with an alkali. The compounds of formula XIb may, for example, be
obtained by reacting an amine of formula XIII,
R.sub.1 --NH--CH.sub.2 C.sub.6 H.sub.5 XIII
wherein R.sub.1 is as defined above,
with an epihalohydrin, preferably at a temperature of about
20.degree. to 120.degree. C, in an inert organic solvent, e.g. an
aromatic hydrocarbon such as benzene or toluene.
A compound of formula V (including the compounds of formula VI) may
be produced by reacting a compound of formula XII, ##SPC19##
wherein R.sub.2 ' is as defined above,
with a compound of formula XI, and aminomethylating the resulting
reaction product, e.g. under the conditions of a Mannich
reaction.
The reaction of a compound of formula XII with a compound of
formula XI may be effected in a manner analogous to that described
for the production of compounds of formula IV.
The compounds of formula VII (including the compounds of formula
VIII) are likewise new. A compound VII may be obtained in a manner
analogous to the method for obtaining a compound of formula V, by
aminomethylation of a compound of formula XIV, ##SPC20##
wherein R.sub.1 "' and R.sub.2 ' are as defined above.
A compound of formula XIV, used as starting material for this
reaction, may be produced from a compound of formula XII by
reaction with an epihalohydrin (in a manner analogous to the
production of a compound of formulas IIa and IIb) and treatment of
the resulting reaction product with the corresponding amine (in a
manner analogous to embodiment a) above).
The compounds of formula IX are likewise new. A compound IX may,
for example, be produced by debenzylating a compound of formula XV,
##SPC21##
wherein
R.sub.2 ' is as defined above, and
R.sub.7 is hydrogen or benzyl,
and reacting the resulting compound of formula XVI, ##SPC22##
wherein R.sub.2 ' is as defined above,
with the corresponding ketone or the corresponding aldehyde. After
removing the excess aldehyde or the excess ketone by distillation,
the resulting imine of formula IX is used as such for the next
reaction without further purification.
The removal of the benzyl radical(s) may, for example, be effected
in a manner analogous to process b). A compound of formula XV may
be produced from a compound of formula X as described in process
a).
The compounds of formula X are new, and such compound may, for
example, be produced by aminomethylation of a compound of formula
XVII, ##SPC23##
wherein R.sub.2 ' is as defined above,
and subsequent hydrogenation of the resulting Mannich base of
formula XVIII, ##SPC24##
wherein R, R' and R.sub.2 ' are as defined above.
Aminomethylation may be effected under the conditions of a Mannich
reaction. Hydrogenation of a compound of formula XVIII may, for
example, be effected as described in process b).
A compound of formula XII may, for example, be obtained by
hydrogenolytic debenzylation of a compound of formula XVII.
The compounds of formula XVII are new with the exception of
4-benzyloxy-2-methyl indole.
4-Benzyloxy-2-hydroxymethyl indole may be produced by reduction of
4-benzyloxyindole-2-carboxylic acid, e.g. with lithium aluminum
hydride or sodium dihydro-bis-(2-methoxyethoxy) aluminate, in an
inert organic solvent such as dioxane or benzene.
4-Benzyloxy-2-methoxymethyl indole may, for example, be obtained by
etherifying 4-benzyloxy-2-hydroxymethyl indole with diazomethane in
the presence of boron trifluoride in an inert organic solvent, e.g.
a cyclic or open chain ether such as diethyl ether.
The corresponding esters may be obtained by esterification of
4-benzyloxyindole-2-carboxylic acid, in accordance with
conventional processes.
Insofar as the production of the starting materials is not
described, these are known or may be produced in accordance with
known processes or in a manner analogous to the processes described
herein or to known processes.
The compounds of formula I and pharmaceutically acceptable acid
addition salts thereof are useful because they possess
pharmacological activity in animals. More particularly, the
compounds are useful in the treatment of angina pectoris and heart
rhythm disorders, including tachycardia, as indicated by their
.beta.-blocking activity (blocking effect on the vascular,
adrenergic .beta.-receptors). The activity is illustrated by an
inhibition of the positive inotropic adrenalin effect on the
spontaneously beating guinea pig atrium and also by an inhibition
of the hypotension caused by isoproterenol
[1-(3,4-dihydroxyphenyl)-2-isopropylamino-ethanol] in the
narcotized cat.
For the abovementioned use, the dosage administered will naturally
vary depending on the compound employed, the mode of administration
and the treatment desired. However, in general, satisfactory
results are obtained at doses between about 0.004 and 0.6 mg/kg
animal body weight. For the larger mammals, the total daily dose is
in the range of from about 5 to about 100 milligrams of the
compound. The daily dose may be given in divided doses two to three
times a day, or in sustained release form. Dosage forms suitable
for oral administration comprise from about 1.5 to about 50
milligrams of the compound admixed with a solid or liquid
pharmaceutical carrier or diluent.
In the following examples which illustrate the invention without in
any way limiting its scope, all temperatures are indicated in
degrees Centigrade and are uncorrected.
EXAMPLE 1
2,3-dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole indole
[process a)]
A solution of 8.1 g of 2,3-dimethyl-4-hydroxyindole in 35 cc of
dioxane is added to a solution of 2.01 g of sodium hydroxide in 35
cc of water, in an atmosphere of nitrogen and while stirring, and
subsequently 9.3 g of epichlorhydrin diluted with 25 cc of
dioxane/water (1:1) are added. The reaction mixture is stirred at
room temperature for a further 24 hours, is extracted four times
with methylene chloride, and the combined organic layers which have
been dried over magnesium sulphate are concentrated by evaporation
at reduced pressure. The resulting oily residue of
2,3-dimethyl-4-(2,3-epoxypropoxy)indole, without characterization,
is heated to the boil for 15 hours with 30 cc of isopropylamine in
70 cc of absolute dioxane. The reaction mixture is subsequently
evaporated to dryness at reduced pressure, the residue is shaken
out thrice between ethyl acetate and a 1 N tartaric acid solution,
and 5 N sodium hydroxide solution is added to the combined tartaric
acid phases until an alkaline reaction is obtained. Extraction is
subsequently effected 4 times with methylene chloride, and the
combined organic layers which have been dried over magnesium
sulphate are concentrated by evaporation at reduced pressure. The
title compound crystallizes as maleate from ethanol/ethyl acetate
and has a M.P. of 151.degree.-153.degree..
The 2,3-dimethyl-4-hydroxyindole, required as starting material, is
obtained as follows:
4-Benzyloxy-2-methyl gramine is quaternized with methyl iodide
(M.P. 203.degree.-205.degree.) and subsequently reduced with
lithium aluminum hydride in dioxane at 90.degree. to give
2,3-dimethyl-4-benzyloxyindole (prisms from ethyl acetate with a
M.P. of 125.degree.-127.degree.). Debenzylation of
2,3-dimethyl-4-benzyloxyindole with hydrogen in the presence of a 5
percent palladium catalyst on aluminum oxide yields
2,3-dimethyl-4-hydroxyindole which crystallizes from benzene in
prisms having a M.P. of 100.degree.-104.degree..
The 4-benzyloxy-2-methyl gramine, required as starting material, is
obtained as follows:
4-Benzyloxyindole-2-carboxylic acid dimethyl amide is reduced in
boiling tetrahydrofuran with lithium aluminum hydride to
4-benzyloxy-2-dimethylaminomethyl indole (M.P.
116.degree.-118.degree.). Quaternization of this compound with
methyl iodide and subsequent deamination with lithium aluminum
hydride in boiling dioxane yields 4-benzyloxy-2-methyl indole
(prisms from ether/petroleum ether with a M.P. of
88.degree.-90.degree.), which is converted with formaldehyde
solution and dimethyl amine in alcohol/glacial acetic acid into
4-benzyloxy-2-methyl gramine, the hydrochloride of this compound
having a M.P. of 185.degree.-187.degree. after crystallization from
ethanol.
EXAMPLE 2
2,3-dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole [process
a)]
10 g of 2,3-dimethyl-4-hydroxyindole and 75 cc of epichlorhydrin
are heated to the boil for 5 hours after the addition of 2 drops of
piperidine. The excess epichlorhydrin is removed by distillation at
reduced pressure and the resulting residue is reacted with
isopropylamine as described in Example 1.
EXAMPLE 3
4-[2-hydroxy- 3-(3-pentylamino)propoxy]-
3-methylindole-2-carboxylic acid ethyl ester [ process a)]
The title compound is obtained as a viscous oil in a manner
analogous to that described in Example 1 or 2, from
4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester, using
3-pentylamine in place of isopropylamine; the hydrogen maleate of
the title compound crystallizes from ethanol/ether in cubes having
a M.P. of 153.degree.-155.degree. .
The 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester, used as
starting material, is produced as follows:
Esterification of 4-benzyloxyindole-2-carboxylic acid with ethanol
yields the corresponding ethyl ester (M.P.
168.degree.-170.degree.). 4-Benzyloxyindole-2-carboxylic acid ethyl
ester is converted with formaldehyde, dimethyl amine and glacial
acetic acid in ethanolic solution into
4-benzyloxy-3-dimethylaminomethylindole-2-carboxylic acid ethyl
ester (M.P.115.degree.-117.degree. from benzene/petroleum ether,
M.P. of the hydrochloride 205.degree.-207.degree. from ethanol),
and 4-hydroxy-3-methylindole- 2-carboxylic acid ethyl ester is
either produced directly with hydrogen in the presence of a
palladium catalyst (5 percent Pd on charcoal), or the methiodide of
the above Mannich base is reduced in ethanolic solution with sodium
borohydride to give 4-benzyloxy-3-methylindole-2-carboxylic acid
ethyl ester (M.P. 149.degree.-150.degree. from benzene in cubes),
and this is subsequently debenzylated with hydrogen in the presence
of a palladium catalyst (5 percent Pd on charcoal), to give
4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester (M.P.
160.degree.-162.degree. from ethanol).
EXAMPLE 4
2,3-dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole [ process
b)]
4.8 g of 1-(N-benzylisopropylamino)-3-chloro-2-propanol are added
to a solution of 1.61 g of 2,3-dimethyl-4-hydroxyindole and 0.4 g
of sodium hydroxide in 150 cc of methanol, and the mixture is
heated to the coil for 20 hours. The solvent is evaporated at
reduced pressure, the residue is triturated several times with
petroleum ether and shaking out is finally effected between water
and ethyl acetate. The combined ethyl acetate phases which have
been dried over magnesium sulphate are concentrated by evaporation
at reduced pressure.
The resulting amorphous 4-[3-(N-benzylisopropylamino)-2
-hydroxypropoxy]-2,3-dimethyl indole is taken up in 100 cc of
methanol and after the addition of 1 g of a palladium catalyst (5
percent Pd on aluminum oxide), shaking is effected with hydrogen
until the taking up of hydrogen is complete.
The catalyst is filtered off, the filtrate is evaporated to dryness
at reduced pressure and worked up as described in Example 1 to
obtain the compound of the heading.
1-(N-Benzylisopropylamino)-3-chloro-2-propanol may, for example, be
produced as follows:
A mixture of 18.4 g of epichlorhydrin and 29.8 g of
N-benzylisopropylamine in 100 cc of benzene is heated to the boil
at reflux for 24 hours, the solvent is removed by evaporation and
the residue is distilled in a high vacuum.
1-(N-Benzylisopropylamino)-3-chloro-2-propanol, having a B.P. of
110.degree.-115.degree. 10.2 mm of Hg, is obtained.
EXAMPLE 5
2,3-dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole [ process
g)]
4-(3-Dibenzylamino-2-hydroxypropoxy)-2,3-dimethyl indole is
obtained as viscous oil in a manner analogous to that described in
Example 1, using dibenzylamine in place of isopropylamine.
5 g of a palladium catalyst (5 percent Pd on charcoal) in 75 cc of
methanol are added to 5 g of this crude product without further
purification, and shaking is effected with hydrogen until the
taking up of hydrogen is complete. The catalyst is filtered off and
the solvend is evaporated at reduced pressure. The resulting
amorphous 4-(3-amino-2 -hydroxypropoxy)-2,3-dimethyl indole is
taken up in 50 cc of acetone and is allowed to stand at room
temperature for 24 hours. The solution is subsequently evaporated
to dryness at reduced pressure and the title compound is isolated
as described in Example 1. The residue is again dissolved in 50 cc
of methanol, and after the addition of 5 g of a palladium catalyst
(5 percent Pd on aluminum oxide), shaking is effected with hydrogen
until the taking up of hydrogen is complete. The catalyst is
filtered off, the solution evaporated to dryness at reduced
pressure and working up as described in Example 1 is effected to
obtain the compound of the heading.
EXAMPLE 6
4-[2-hydroxy-3-(3-pentylamino)propoxy] -3-methylindole-
2-carboxylic acid ethyl ester [ process g)]
The title compound (M.P. 153.degree.-155.degree.) is produced in a
manner analogous to the process described in Example 5, from
4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester (M.P.
160.degree.-162.degree.).
EXAMPLE 7
4-(2-hydroxy-3-isopropylaminopropoxy- 2-hydroxymethyl-3-methyl
indole [ process c)]
55.5 g of 4-(2-hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl
indole are heated to the boil for 8 hours with 38 g of benzyl
bromide and 22.3g of triethylamine in 1.3 liters of
tetrahydrofuran. The reaction mixture is evaporated to dryness and
the residue is shaken out between methylene chloride and a 1 N
tartaric acid solution. The pH of the combined tartaric acid phases
is adjusted to 8 to 9 with a 10 percent soda solution, while
cooling with ice, and are extracted 4 times with 200 cc amounts of
methylene chloride. After drying the methylene chloride phases over
magnesium sulphate, these are concentrated by evaporation at
reduced pressure. The crude product is subsequently crystallized
with ethanol and yields
4-(3-benzylisopropylamino-2-hydroxypropoxy)-2-hydroxymethyl indole
having a M.P. of 133.degree.-136.degree. .
13.2 g of glacial acetic acid are added to a solution of 27 g of
4-(3-benzylisopropylamino-2-hydroxypropoxy)-2-hydroxymethyl indole
in 600 cc of methanol, 11.9 g of a 33 percent solution of
dimethylamine in ethanol are first added dropwise at +2.degree.,
and subsequently 7.35 g of a 36 percent aqueous formaldehyde
solution are added dropwise at the same temperature, and the
reaction mixture is allowed to stand at room temperature for 16
hours. The reaction mixture is evaporated to dryness at reduced
pressure and the residue is shaken out between ethyl acetate and a
1 N tartaric acid solution. The combined tartaric acid extracts are
made alkaline with a 5 N sodium hydroxide solution, while cooling
with ice, and are extracted with methylene chloride. The
evaporation residue of the methylene chloride extracts is
crystallized with ethanol/petroleum ether, whereby
3-dimethylaminomethyl-4-(3-benzylisopropylamino-2-hydroxypropoxy)-
2-hydroxymethyl indole is obtained in the form of crystals having a
M.P. of 139.degree.-140.degree. .
10 g of 3-dimethylaminomethyl-4-(3-benzylisopropylamino-
2-hydroxypropoxy)-2-hydroxymethyl indole in 350 cc of methanol are
shaken with hydrogen in the presence of 10 g of a palladium
catalyst (5 percent Pd on charcoal) until the taking up of hydrogen
is complete. The catalyst is filtered off, the filtrate is washed
well with hot methanol and concentration is effected until
crystallization of the title compound commences. M.P.
150.degree.-152.degree., needles.
The 2-hydroxymethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole,
used as starting material (M.P. 145.degree.-148.degree.), may, for
example, be produced as described in Example 1, from
4-hydroxy-2-hydroxymethyl indole by reaction with epichlorhydrin
and subsequent reaction of the reaction product with
isopropylamine.
4-Hydroxy-2-hydroxymethyl indole (M.P. 112.degree.-114.degree. from
benzene/ethyl acetate) is obtained by debenzylation of 4-benzyloxy-
2-hydroxymethyl indole with hydrogen in the presence of a 5 percent
palladium catalyst on aluminum oxide. 4-Benzyloxy-2-hydroxymethyl
indole (M.P. 109.degree.-111.degree. from benzene) is produced by
reduction of 4-benzyloxyindole-2-carboxylic acid with lithium
aluminum hydride in boiling dioxane.
EXAMPLE 8
4-(3-cyclopropylamino-2-hydroxypropoxy)-
3-methylindole-2-carboxylic acid ethyl ester [ process c)]
4-(3-Benzylocyclopropylamino-2-hydroxypropoxy)-3-dimethylaminomethylindole-
2-carboxylic acid ethyl ester is obtained in a manner analogous to
that described in Example 7 by aminomethylation from
4-(3-benzylcylopropylamino-2-hydroxypropoxy)indole- 2-carboxylic
acid ethyl ester (M.P. 125.degree.-127.degree. from benzene), the
compound is isolated by chromatography (silica gel with methylene
chloride and 2 percent of methanol) and is taken up in 70 cc of
ethanol without further purification and is shaken with hydrogen in
the presence of 2 g of a palladium catalyst (5 percent Pd on
charcoal) until the taking up of hydrogen is complete. The catalyst
is filtered off, the filtrate is acidified with an excess of a 2 N
solution of hydrochloric acid in ethanol and is concentrated by
evaporation at reduced pressure until crystallization commences.
The hydrochloride of the title compound crystallizes in fine
needles having a M.P. of 228.degree.-231.degree. .
4-(3-Benzylcyclopropylamino-2-hydroxypropoxy)indole- 2-carboxylic
acid ethyl ester (M.P. 125.degree.-127.degree. from benzene) is
obtained in accordance with Example 3, by using
4-hydroxyindole-2-carboxylic acid ethyl ester in place of
4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester and
benzylcyclopropylamine in place of 3-pentylamine.
4-Hydroxyindole-2-carboxylic acid ethyl ester (M.P.
159.degree.-160.degree.) is obtained by catalytic debenzylation
with palladium/hydrogen of 4-benzyloxyindole-2-carboxylic acid
ethyl ester.
EXAMPLE 9
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole- 2-carboxylic
acid methyl ester [ process d)]
14.9 g of 4-(3-benzylisopropylamino-2-hydroxypropoxy)-indole-
2-carboxylic acid ethyl ester are dissolved in methanol, an excess
of a 2 N solution of hydrochloric acid in methanol is added and the
solution is concentrated by evaporation. The resulting
hydrochloride is heated to the boil while stirring for 4 hours with
2 g of paraformaldehyde, 3 g of dimethylamine hydrochloride and 3
drops of concentrated hydrochloric acid in 25 cc of isopropanol.
The reaction mixture is subsequently evaporated to dryness at
reduced pressure and the evaporation residue is recrystallized from
ethanol.
4-(3-Benzylisopropylamino-2-hydroxypropoxy)-3-dimethylaminomethylindole-
2 -carboxylic acid ethyl ester hydrochloride has a M.P. of
168.degree.-172.degree. with foaming.
The base is liberated in the usual manner from 8 g of this Mannich
base, is taken up in 200 cc of methanol and shaken with hydrogen in
the presence of 5 g of a palladium catalyst (5 percent Pd on
charcoal) until the taking up of hydrogen is complete. The catalyst
is removed by filtration, the solvent is evaporated at reduced
pressure and the crude title compound is crystallized from ether.
M.P. 122.degree.-124.degree., needles from ether.
4-(3-Benzylisopropylamino-2 -hydroxypropyl)indole1 2-carobxylic
acid ethyl ester (M.P. 103.degree.-105.degree.) is obtained as
indicated in Example 8 for the production of
4-(3-benzylcyclopropylamino-2-hydroxypropoxy)indole-2-carboxylic
acid ethyl ester, except that benzylisopropylamine is used in place
of benzylcyclopropylamine.
EXAMPLE 10
4-(3-tert.butylamino-2-hydroxypropoxy)-3-methylindole- 2-carboxylic
acid ethyl ester [ process e)]
5.7 g of glacial acetic acid are added to a solution of 10.8 g of
4-(3-tert.butylamino-2-hydroxypropoxy)indole-2-carboxylic acid
ethyl ester in 500 cc of ethanol, while stirring and cooling with
ice, 8.8 g of a 33 percent solution of dimethylamine in ethanol are
then added and 4.0 g of a 36 percent aqueous solution of
formaldehyde are finally added. The reaction mixture is allowed to
react at room temperature for 4 days, is then concentrated by
evaporation at reduced pressure, and the basic components are
isolated in the usual manner by extraction between ether/1 N
tartaric acid. Chromatography on 50 parts of water-saturated silica
gel with methylene chloride and 0.5 percent of methanol yields
4-(3tert.butylamino-2-hydroxypropoxy)-3
-dimethylaminomethylindole-2-carboxylic acid ethyl ester (M.P.
139.degree.-140.degree. from ethyl acetate.
3.0 g of the above compound are taken up in 150 cc of ethanol and
shaking is effected with hydrogen in the presence of 5 g of a
palladium catalyst (5 percent Pd on charcoal) until the taking up
of hydrogen is complete. The catalyst is removed by filtration, the
filtrate is evaporated to dryness at reduced pressure, and the
title compound is crystallized as hydrogen maleate from
ethanol/ethyl acetate. M.P. 96.degree.-100.degree. .
4-(3-tert.butylamino-2-hydroxypropoxy)indole-2-carboxylic acid
ethyl ester (the N-cyclohexyl sulphate has a M.P. of
169.degree.-171.degree.) is obtained as indicated in Example 8 for
the production of
4-(3-benzylcyclopropylamino-2-hydroxypropoxy)indole-2-carboxylic
acid ethyl ester, except that tert.butylamine is used in place of
benzylcyclopropylamine.
EXAMPLE 11
4-(3-cyclopropylamino-2-hydroxypropoxy)-3-methylindole-
2-carboxylic acid ethyl ester [ process e)]
The title compound is obtained in a manner analogous to that
indicated in Example 10 by hydrogenation of
4-(3-cyclopropylamino-2-hydroxypropoxy)-3-dimethylaminomethylindole-2-carb
oxylic acid ethyl ester (the bishydrogen maleate thereof
crystallizes from ethanol in needle druses having a M.P. of
148.degree.); the hydrochloride of the title compound crystallizes
in needles having a M.P. of 228.degree.-231.degree. .
The ester used as starting material is obtained by reacting
4-hydroxyindole-2-carboxylic acid ethyl ester as indicated in
Example 1 or 2with epichlorhydrin, reacting the reaction product
with cyclopropylamine and aminomethylating the resulting
4-(3-cyclopropylamino-2-hydroxypropoxy)indole-2-carboxylic acid
ethyl ester (M.P. 145.degree.-147.degree.).
EXAMPLE 12
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole- 2carboxylic
acid (Hydrolysis of compound of Example 9)
4.6 g of 4-(2-hydroxy-3-isopropylaminopropoxy)-3
-methylindole-2-carboxylic acid methyl ester are heated to the boil
while stirring for 2 hours with 4.55 g of crystalline barium
hydroxide in 60 cc of methanol and 185 cc of water. 14.2 cc of 2 N
sulphuric acid are subsequently added, the reaction mixture is
filtered through talc until clear and is washed well with boiling
water. After concentrating the filtrate, the title compound
crystallizes in white crystals having a M.P. of
271.degree.-273.degree. (decomp.).
EXAMPLE 13
4-(2-hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl
indole [ process a)]
The title compound, having a M.P. of 150.degree.-152.degree., is
produced in a manner analogous to that described in Example 1 from
4-hydroxy-2-hydroxymethyl-3-methyl indole.
The 4-hydroxy-2-hydroxymethyl-3-methyl indole, used as starting
material, may, for example, be produced as follows:
4-Benzyloxy-2-hydroxymethyl indole is converted with formaldehyde,
dimethylamine and glacial acetic acid in ethanolic solution into
4-benzyloxy-2-hydroxymethyl gramine (M.P. 127.degree.-129.degree.,
crystallization from ethanol), and reduction is subsequently
effected with hydrogen in the presence of a palladium catalyst (5
percent Pd on charcoal), to give 4-hydroxy-2-hydroxymethyl-3-methyl
indole. M.P. 135.degree.-136.degree. from ethyl acetate.
4-Hydroxy-2-hydroxymethyl-3-methyl indole may likewise be obtained
by converting 4-benzyloxyindole-2-carboxylic acid ethyl ester in
accordance with the above Mannich process into 4-benzyloxy-3
-dimethylaminomethylindole-2-carboxylic acid ester (M.P. of the
hydrochloride 205.degree.-207.degree., crystallization from
ethanol), quaternizing the resulting ester with methyl iodide to
the methiodide, reducing this with lithium aluminum hydride in
tetrahydrofuran to 4-benzyloxy-2-hydroxymethyl-3-methyl indole
(M.P. 129.degree.-131.degree. from methylene chloride), and finally
debenzylating with hydrogen in the presence of a palladium catalyst
(5 percent Pd on aluminum oxide).
EXAMPLE 14
4-(2-hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl
indole.
A solution of 32 g of
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic
acid methyl ester in 250 cc of absolute tetrahydrofuran is added
dropwise while stirring and in an atmosphere of nitrogen within 15
minutes to a boiling suspension of 7.6 g of lithium aluminum
hydride in 200 cc of absolute tetrahydrofuran and stirring is
continued for a further 2 hours. The reaction mixture is then
cooled to 40.degree. and 20 cc of water are added dropwise. The
resulting precipitate is filtered off, washed well with
tetrahydrofuran, and the organic solution is dried over sodium
sulphate. The evaporation residue is recrystallized from ethanol,
whereby the title compound, having a M.P. of
150.degree.-152.degree., is obtained.
The
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic
acid methyl ester, required as starting material, is produced as
described in Example 9.
EXAMPLE 15
4-(2-hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl
indole.
The title compound which is identical with the compound produced in
Example 14, is obtained in a manner analogous to that described in
Example 14, except that 4-(2-hydroxy-3
-isopropylaminopropoxy)-3-methylindole-2-carboxylic acid is used in
place of
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic
acid methyl ester.
The
4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic
acid, required as starting material, is, for example, produced as
described in Example 12.
* * * * *