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Патент USA US3085104

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3,985,094
Patented Apr. 9, 1963
2
lower alkyl-Nphenyl-lower alkyl-amino, in which lower
3,985,094
alkyl contains from one to four carbon atoms, e.g. N
HETEROCYCLIC C(BMPGUNDS
benzyl-N-methyl-amino, N-benzyl-N-ethyl-amino, N
methyl-N—( 1-phenylethyl)-amino, N-methyI-N-(Z-phenyl
Charles Ferdinand Huehner, Chatharn, N.J., assignor to
Ciba Corporation, a corporation of Delaware
No Drawing. Filed Feb. 9, 1961, Ser. No. 88,031
6 Claims. (Cl. 260-495)
ethyl)-amino and the like, or any other N,N-di-hydro
carbon-amino group. The hydrocarbon radicals, particu
larly lower alkyl, may also contain functional groups,
such as hydroxyl, lower alkoxy, e.g. methoxy, ethoxy and
The present invention relates to N-oxides of tertiary
amino-lower alkyl-indenes. Primarily, it concerns N
the like, lower alkyl-mercapto, e.g. methylmercapto, ethyl
oxides of 3-(pyridyl-lower alkyl)-2—(tertiary amino 10 mercapto and the like, or any other suitable group as
lower alkyD-indenes and the salts thereof.
substituents.
N,N-di-hydrocarbon-amino groups, in
A pyridyl group in the above compounds represents
which hydrocarbon contains functional groups as sub
primarily 2-pyridyl, but may also stand for 3-pyridyl or
stituents are, for example, N-hydroxy-‘lower alkyl alkyl
4-pyridyl. These pyridyl radicals are preferably unsub
N-lower alkyl-amino, e.g. N-(Z-hydroxy-ethyl)-N-methyl
stituted or may be substituted by lower alkyl, e.g. methyl,
amino and the like, N,N-di-hydroxy-lower alkyl-amino,
ethyl and the like.
Other substituents may be, for ex
e.g. N,N-di-'(2-hydroxy-ethyl)-amino and the like.
The disubstituted amino group may also be represented
ample, lower alkoxy, e.g. methoxy, ethoxy and the like,
or halogeno, e.g. ?uoro, chloro, bromo and the like, or
by 1-N,N-a-lkylene-imino or by l-N,N-aza-alkylene
imino groups, in which the alkylene portions contain
any other suitable functional groups.
The lower alkyl portion of the pyridyl~lower alkyl 20 from four to six carbon atoms, as well as by l-N,N-oxa
alkylene-imino and by 1-N,N-thia-alkylene-imino, in
radical, which connects the pyridyl group with the indene
nucleus, may be represented by a lower alkylene radical
having from one to seven, especially from one to three,
carbon atoms, e,g. methylene, l,l-ethylene, 1,2»ethylene,
I-methyI-LQ-et-hylene, 2-methyl-1,2-ethylene, 1,1-propyl
ene, 1,3-propylene or 2,2-propylene, as well as l,1-butyl
ene, 2,2-butylene, 2,3-butylene, 1,4-butylene, 1,5-pentyl
ene and the like.
(The lower alkyl portion of the tertiary amino-lower
25
,which alkylene contains preferably four carbon atoms.
Together with the nitrogen atom such alkylene, aza
alkylene, oxa-alkylene or thia-alkylene radicals represent,
for example, 1-N,N-alkylene-imino, in which alkylene
contains from four to six carbon atoms, such as l-pyr
rolidino radicals, e.g. l-pyrrolidino, Z-methyl-l-pyrroli
dino and the like, l-piperidino radicals, e.g. l-piperidino,
Z-methyl-l-piperidino, 4-methyl-l-piperidino, B-hydroxy
alkyl group attached to the 2-position of the indene 30 l-piperidino, 3~acetoxy-1-piperidino, 3-hydroxymethyl-1
nucleus, ‘may be represented by a lower alkylene radical
piperidino and the like, 1-N,N-1,6-hexylene-imino and
containing from one to seven, preferably from two to
the like, l-N,N-(aza-alkylene)-irnino, in which alkylene
three, carbon atoms; such radicals are, for example, 1,2
contains from four to six carbon atoms, particularly
ethylene, 1-methyl-1,2-ethylene, 2-methyl-1,2-ethylene or
1,3-propylene, as Well as methylene, 1,1-ethylene, 1
,l-N,N-r(N-lower alkyl-aza-alkylene)-imino, in which
alkylene contains from four to six carbon atoms, such
as 1-N,N-(3-aza-l,5-pentylene)-imino, particularly 1
ene, 1,5-pentylene and the like. The lower alkylene
N,N-(3-aza-3-lower alkyl-1,5-pentylene)-imino, e.g. 4
radical or a portion of it may also be part of a hetero
methyl-l-piperazino, 4-ethyl-l-piperazino and the like, as
cyclic ring system, such as a saturated or partially satu
well as 4-hydroxyethyl-l-piperazino, 4-acetoxyethyl-1
rated azacyclic ring system, containing the tertiary amino 40 piperazino and the like, l-N,N-(3-aZa—l,6-hexylene)
group as the aza-ring member. Preferably, the lower
imino, particularly l-N,N-(3-aza-3-lower alkyl-l,6~hexyl
alkyl portion of the tertiary amino-lower alkyl group con
ene)-imino, e.g. 1-N,N-(3-aza-3-methyl-l,6-hexylene)
tains from two to three carbon atoms and separates the
imino and the like, or 1-N,N-(4-aza-1,7-heptamethylene)
tertiary amino group from the 2-position of the indene 45 irnino, particularly 1-N,N-‘(4-aza-4-lower alkyl-1,7-hepta
nucleus by from two to three carbon atoms.
methylene)-imino, e.g. 1-N,N-(4-aza-4-n1ethyl-1,7-hepta
Disubstituted amino groups, which represent tertiary
methylene)-imino and the like, 1-N,N-(3-oxa-1,5-pentyl
methyl-1,3-propylene, 1,4-buty1ene, 1-methyl-1,4-butyl
amino, are, for example, N,N-di-hydrocarbon-amino
ene)-imino, e.g. 4-morpholino and the like, 1-N,N-(3
groups, in which hydrocarbon represents, for example,
thia-1,5-pentylene)-imino, e.g. l~thiamorpholino and the
lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower 50 like.
alkly, monocyclic carbocyclic aryl, such as phenyl, or
{The tertiary amino-lower alkyl radical may also be
monocyclic carbocyclic aryl-lower alkyl, such as phenyl
represented by a heterocyclic or a heterocyclic-lower
lower alkyl.
Such radicals contain from one to ten car
bon atoms, and may be represented, for example, by
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second
ary butyl, pentyl, neopentyl, allyl, methylallyl, cyclo
pentyl, cyclohexyl, cyclopentyl-methyl, phenyl, benzyl, l
phenylethyl, 2-phenylethyl and the like. These hydro
carbon radicals may contain further substituents; tree
alkyl radical, in which the disubstituted amino group is
part of the heterocyclic nucleus. Such nucleus may be
55 connected through one of its ring carbon atoms or
through a lower alkylene radical, e.g. methylene, 1,2
ethylene and the like, with the 2-position of the indene
ring. Such radicals are represented, for example, by
1-methyl-3-pyrrolidinomethyl, 1-methyl-3-piperidinometh
hydroxyl, lower alkoxy, e.g. methoxy, ethoxy and the 60 yl, 1-methyl-4-piperidino and the like.
like, or any other suitable functional group may be at
tached to such hydrocarbon radicals. N,N-di-lower hy
drocarbon-amino groups are primarily represented by
N,N-di-lower alkyl-amino, in which lower alkyl contains
The 1~position of the indene nucleus is preferably un
substituted, or, if substituted, contains primarily a hydro
carbon radical, particularly lower alkyl, e.g. methyl, ethyl
and the like, or monocyclic carbocyclic aryl-lower alkyl,
from one to four carbon atoms, e.g. N,N-dimethylamino, 65
e.g. benzyl and the like.
N-methyl-N-ethylamino, N,N-diethylamino, N,N-di-n
propylamino, N,N-di-isopropylamino and the like, by N
cycloalkyl-N-lower alkylamino, in which cycloalkyl con
The six-membered carbocyclic aryl portion of the in
dene nucleus is preferably unsubstituted or may contain
one or more than one substituent, which may be located
tains from ?ve to seven ring carbon atoms and lower
alkyl contains from one to four carbon atoms, e.g. 70 in any of the four positions available for substitution;
whenever at least two substituents are present, these may
N~cyclopentyl-N-methyl-amino, N-cyclohexyl-N-methyl
be of the same or of different nature. Such substituents
amino, N~cyclohexyl-N-ethyl-amino and the like, or N
3,085,094
a
s3
may be, for example, lower alkyl, e.g. methyl, ethyl and
the like, halogeno~lower alkyl, e.g. triiluoromethyl, ether
i'?ed hydroxyl, such as lower alkoxy, e.g. methoxy, ethoxy
and the like, or lower alkylenedioxy, e.g. methylenedioxy,
propionic acid and the like, monocyclic or bicyclic carbo
cyclic aryl carboxylic or car-bocyclic aryl-lower aliphatic
carboxylic acids, e.g. benzoic, dihydrocinnamic, cinnamic,
mandelic, salicylic, 4-aminosalicylic, Z-phenoxy-benzoic,
esteriiied hydroxyl, such aslower alkoxy-carbonyloxy,
e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the
like, lower alkanoyloxy, e.g. acetyloxy, propionyloxy and
Z-acetoxybenzoic acid and the like, or monocyclic or bi
like, nitro, amino, for example, unsubstituted amino,
nine, aspartic, glutamic, hydroxyglutamic acid and the
N-mono-substituted amino, such as N-lower alkyl-amino,
e.g. N-rnethylamino and the like, or preferably N,N-di
like, organic sulfonic acids, such as lower alkane sulfonic
acids, e.g. methane sulfonic, ethane sulfonic acid and the
cyclic carbocyclic aryl-dicarboxylic acids, e.g. phthalic
acid, and the like, monocyclic or bicyclic heterocyclic
aryl carbocyclic acids, e.g. nicotinic, isonicotinic, 6-quin
the like, or halogeno, e.g. ?uoro, chloro, bromo and the
like, acyl, such as lower alkanoyl, e.g. acetyl, propionyl
oline carboxylic, thienoic, furoic acid and the like, or any
and the like, etheri?ed mercapto, such as lower alkyl 10 other suitable carboxylic acid. In addition, amino car
mercapto, e.g. methylmercapto, ethylmercapto and the
boxylic acids, e.g. methionine, tryptophane, lysine, argi
substituted amino, for example, N,N-di-lower alkyl 15 like, lower hydroxy-alkane sulfonic acids, e.g. 2~hydroxy
amino, e.g. N,N-dimethylamino and the like. The six
membered carbocyclic aryl portion of the indene ring
ethane sulfonic acid and the like, carbocyclic aryl sul
fonic acids, such as monocyclic carbocyclic aryl sulfonic
acids, e.g. p-toluene sul-fonic acid and the like or mixtures
may, therefore, be represented, for example, by an un
substituted, a lower alkyl-substituted, a halogeno-lower
of acids, such as the mixture known as tannic acid, are
alkyl-substituted, a lower alkoxy-substituted, a lower 20 suitable for salt formation. Particularly useful are acid
alkylenedioxy-substituted, a lower alkoxy-carbonyloxy
addition salts with mineral acids, lower alkene dicarbox
substituted, a lower alkanoyloxy-substituted, a halogeno
ylic acids, e.g. maleic, citraconic acid and the like, lower
hydroxy-alkane dicarboxylic acids, e.g. malic, tartaric acid
Substituted, a lower alkanoyl-substituted, a lower alkyl
mercapto-substituted, a nitro-substituted, an amino-sub
stituted, an N-lower alkyl-amino-substituted or an N,N
di-lower alkyl-amino substituted six-membered carbocy
clic aryl portion.
Salts of the N-oxide compounds of this invention are
primarily therapeutically acceptable acid addition salts
with inorganic or organic acids. Suitable inorganic acids
are, for example, mineral acids, such as hydrohalic acids,
e.g. hydrochloric, hydrobromic acid and the like, or sul
furic, phosphoric acids and the like. Organic acids are
organic carboxylic acids, such as lower aliphatic mono
carboxylic acids, for example, lower alkane monocarbox
ylic acids, e.g. formic, acetic, propionic, pivalic acid and
and the like, hydroxy-lower alkene dicarboxylic acids, e.g.
hydroxymaleic, dihydroxymaleic acid and the like, or
hydroxy-lower alkane tricarboxylic acid, e.g. citric acid
and the like.
Salts, which may be prepared primarily for identi?ca~
tion purposes, are, for example, those with acidic organic
nitro compounds, e.g. picric, picrolonic, flavianic acid and
the like, or metal complex acids, e.g. phosphotungstic,
phosphomolybdic, chloroplatinic, Reinecke acid and the
like.
Mono- or poly-salts may be ‘formed depending on the
number of salt-forming groups and/or the conditions used
for the salt formation.
Depending on the number of asymmetric carbon atoms,
the indene compounds of this invention may be obtained
the like, lower alkene monocarboxylic acid, e.g. 3~butene
carboxylic acid and the like, hydroxy-lower alkane mono
as mixtures of racemates, racemates or antipodes, the sep
carboxylic acids, e.g. glycolic, lactic acid and the like,
lower alkoXy-lower alkane monocarboxylic acids, e.g. 40 aration and resolution of which will be discussed and
illustrated hereinbelow.
methoXy-acetic, ethoXy-acetic acids and the like, lower
The new compounds of this invention show antihista
alkanoyl-lower alkane monocarboxylic acids, e.g. pyruvic
acid and the like, halogeno-lower alkane monocarbcxylic
acids, e.g. chloroacetic, dichloroacetic, trichloroacetic,
minic effects and are intended to be used as antihistaminic
succinic, glutaric, a-methylglutaric, a,a-dimethylglutaric,
tion, compounds of this invention have a central nervous
agents to relieve allergic disorders, especially those caused
bromoacetic acid and the like, lower aliphatic dicarbox 45 by an excess of histamine; such allergic conditions are,
for example, hay fever, urticaria, allergies caused by food,
ylic acids, for example, lower alkane dicarboxylic acids,
plant pollen or medicinal agents, and the like. In addi
e.g. oxalic, malonic, succinic, methyl-succinic, dimethyl
system depressing effect, thus exert sedative and quiet
B-methylglutaric acid and the like, lower alkane dicar
boxylic acid halfesters with lower alkanols, e.g. succinic 50 ing properties; they can, therefore, be used as sedative
agents to counteract states of nervousness, anxiety, stress
acid monomethyl ester, glutaric acid monoethyl ester and
or shock, as well as local anesthetic eifects, which render
the like, lower alkene dicarboxylic acids, e.g. itaconic,
these compounds useful as local anesthetics, for example,
homoitaconic, maleic, citracom'c, homocitraconic, pyro
in connection with minor surgery and the like.
cinchonic, xeronic, fumaric acid and the like, lower
alkene dicarboxylic acid halfesters with lower alkanols, 55 {Compounds with particularly outstanding antihista
minic properties are N-oxides, particularly mono-N
e.g. maleic acid monoethyl ester and the like, hydroxy
oxides, of compounds of the formula:
lower alkane dicarboxylic acids, e.g. malic, tartaric acid
and the like, as well as their optically active forms, lower
alkoxy-lower alkane dicarboxylic acids, e.g. a,[3-di
methoxysuccinic and the like, lower alkoxy-lower alkene 60
dicarboxylic acid, e.g. ethoxy-maleic acid and the like,
halogeno-lower alkane dicarboxylic acids, e.g. chlorosuc~
cinic, bromosuccinic acid and the like, lower aliphatic
tricarboxylic acids, for example, lower alkane tricarbox
ylic acids, e.g. tricarballylic acid and the like, lower alkene
tricarboxylic acids, e.g. aconitic acid and the like, hy
in which R1, attached to any of the positions available
droxy-lower alkane tricarboxylic acids, e.g. citric acid and
for substitution, represents hydrogen, lower alkyl con
the like, cycloaliphatic monocarboxylic acids, such as
taining from‘ one to ‘four carbon atoms, e.g. methyl, ethyl,
cycloalkane monocarboxylic acids, e.g. cyclohexane car
n-propyl, isopropyl, n-butyl and the like, lower alkoxy
boxylic acid and the like, cyclo-aliphatic dicarboxylic
containing from one to four carbon atoms, e.g. methoxy,
‘acids, such as cycloalkene dicarboxylic acids, e.g. tetra~
ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the
hydrophthalic acid and the like, cycloaliphatic-hydrocar
like, or halogeuo having an atomic weight below 80,
hon-lower aliphatic monocarboxylic acids, such as cyclo
e.g. ?uoro, chloro or bromo, R2 represents hydrogen or
alkyl-lower alkane monocarboxylic acids, e.g. cyclopentyl 75 lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and
7'3,085,094
5
the like, A1 stands for alkylene containing from one to
three carbon atoms, e.g. methylene, 1,1-ethylene, 1,2
lower alkyl of (4-pyridyl)-lower alkyl and (3-pyridyl)
lower alkyl, respectively, contains from one to three car
ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene or
bon atoms, and in which lower alkyl, separating the N,N
di-lower alkyl-amino group from the 2-position of the
2,2Jpropylene, Py represents pyridyl or lower alkyl-sub
stituted pyridyl, A2 stands for lower alkylene containing
indene nucleus by from two to three carbon atoms,
stands for an alkylene radical having from two to three
carbon atoms, and the N-oxide oxygen atom is attached
from one to three canbon atoms, particularly for lower
alkylene, which contains from two to three carbon atoms
and separates the group Am from ‘the 2-position of the
indene nucleus by from two to three carbon atoms, i.e.
to the nitrogen atom of the N,N-di-lower alkyl-amino
group, and ‘their therapeutically acceptable acid addition
salts; these compounds show remarkable antihistaminic
eifects.
1,2-ethylene, 1-methyl-l,2-ethylene, 2-methyl-l,2-ethylene
or 1,3-propylene, and Am represents N,N-di-lower alkyl
arnino, in which lower ‘alkyl contains from one to four
The new compounds of this invention may be used as
" medicaments in the form of pharmaceutical preparations,
carbon atoms, e.g. N,N-dimethylamino, N-ethyl~N
methyl-amino, N,N-diethylamino, N,N-di-n-propylamino,
N,N-di-isopropylamino, N,N-di-n-butylamino and the like,
N-cycloalkyl-N-lower alkyl-amino, in which cycloalkyl
which contain ‘the new indene N-ox-ide derivatives, in-,
15
contains from ?ve to seven ring carbon atoms and lower
alkyl contains from one to ‘four carbon atoms, e.g. N-cy
clopentyl-N-methyl-amino, N - cyclopenty-l-‘N-n-propyl
amino, N - cyclohexyl-N-ethyl-amino, N - cycloheptyl-N
methyl-amino and the like, N-lower alkyl-Nephenyl-lower
alkyl amino, in which lower alkyl contains from one to
four carbon atoms, e.g. N-benzyl-N-methyl-amino, N-ben
zyl-N-ethyl-amino, N-methyl-N~(l-phenylethyl)-amino, N
methyl-N- ( 2-phenylethyl) -amino, N-methyl~N- ( 3-phenyl
propyl)-amino and the like, >1-N,N-lower alkylene-imino,
in which lower alkylene contains from four .to seven car
bon atoms, e.g. l-pyrrolidino, l-piperidino, 1-N,N-(1,6
hexylene)~imino and the like, 4~morpholino, 1-N,N-(N
lower alkyl-aza-alkylene)-imino, in which alkylene con
tains from four to six carbon atoms, particularly 4-lower
alkyl-l-piperazino, e.g. 4-methyl-1-piperazino, 4-ethyl-1
piperazino, and the like, as well as l-N,N-(3-aza-3-methyl
l,6-hexylene)—imino, l-N,N-(4-aza-4-methyl-l,7 - heptyl
ene)-imino and the like, and in which the N-oxide oxygen
is preferably attached to the nitrogen atom of the tertiary
amino group Am, and the therapeutically acceptable acid’
addition salts thereof.
This group of compounds may be represented by the
mono-N-oxides of 2-(N,N-di-lower alkyl-amino-lower
alkyl)-3-[~(2-pyridyl)-lower alkyl]-indenes, in which lower
alkyl of the N,N-di-lower alkyl-amino group contains
from one to four carbon atoms, lower alkyl, separating
the N,N-di-lower alkyl-amino group from the 2-position
of the indene nucleus by from two to three carbon atoms,
contains from two to three carbon atoms, and lower alkyl
of the (2-pyridyl)-lower alkyl portion contains from one
to three, preferably from one to two, carbon atoms, and
in which the N-oxide oxygen is attached to the nitrogen
atom of the N,N-di-lower alkyl-amino group, and the
cluding racemates, .antipodes, and the therapeutically
acceptable acid addition salts thereof in admixture with
a pharmaceutical organic or inorganic, solid or liquid
vehicle suitable for enteral or parenteral administration.
To relieve allergic skin troubles, the new indene com
20
pounds may also be employed topically.
For making
up the preparations there may be used substances, which
do not react with the new compounds, such as water,
gelatine, lactose, starches, lactic acid, stearic acid, mag
nesium stearate, stearyl alcohol, talc, vegetable oils, benzyl
25
alcohols, gums, propylene glycol, polyalkylene glycols
or any other carrier used in the art of manufacturing
medicaments. The pharmaceutical preparations may be
in solid form, for example, as capsules, tablets, dragees,
and the like, in liquid form, for example, as solutions,
suspensions, emulsions and the like, or in the form of
salves, creams, lotions and the like for topical admin
istration. If desired, they may contain auxiliary sub
stances, such as preserving, stabilizing, wetting, emulsify
ing agents and the like, salts for varying the osmotic
pressure, buffers, etc. They may also contain, in com
bination, other therapeutically useful substances.
The compounds of the present invention may be pre
pared by treating a S-(pyridyl-lower aJkyD-Z-tentiary
amino-lower alkyl-indene or a salt thereof with an N
oxidation reagent, ‘and, if desired, converting a resulting
salt into the free compound, and/or, if desired, convert
ing a resulting free compound into a salt thereof.
The treatment with an N-oxidation reagent is carried
out according to known methods. For example, a solu
tion of ‘the starting material in an inert solvent is treated
with the N-oxidation reagent. Suitable reagents are, for
example, ozone, hydrogen peroxide, inorganic pera'cids,
e.g. persulfuric acid and the like, organic per-sulfonic
acids, e.g. p-toluene persu-lfonic acid and the like, or
therapeutically acceptable acid addition salts thereof. 50 primarily organic percarboxylic acids, e.g. peracetic acid,
perbenzoic acid, monoperphthalic acid and the like.
Outstanding properties are exhibited by 2—(2-N,N-di
Inert solvents are, for example, halogenated lower ali
methylaminoethyl) - 3 - [1 - (2-pyridyl)-ethyl] -indene N
phatic hydrocarbons, e. g. methylene chloride, chloroform,
oxide of the formula:
ethylene chloride and the like, monocyclic carbocyclic
aryl hydrocarbons, e.g. benzene, toluene and the like, or
any other suitable, inert solvent employed in N-oxida
tion reactions.
HaC-EHQ
/ \\
\
CH:
O
either in the form of its racemate or the optically active
forms, particularly the levo-rotatory l-form, and salts
of these compounds with therapeutically acceptable acids,
such as mineral acids, e.g. hydrochloric, hydrogromic,
sulfuric, phosphoric acids and the like, lower alkene di
The reaction is preferably carried out at room tem
perature, or, if necessary, while cooling; it may also be
performed in the atmosphere of an inert gas, erg. nitrogen
and the like.
The starting materials used in the above N-oxidation
reaction may be prepared according to the procedure
described in my patent application Serial No. 18,815,
?led March 31, 1960, of which the present application is
a continuation-in-part application.
'
. carboxylic acids, eg. itaconic, maleic acid and the like,
Compounds of the present invention, as well as the
hydroxy-lower alkane dicarboxylic acids e.g. tartaric acid
starting materials, which contain more than one asym
and the like, and the optically active forms of such acids,
metric tatom, may be obtained in the ‘form of mixtures
particularly the d-form of tartaric acid.
- 70 of tracemates. Such mixtures of racemates may be
‘Other compounds representing the above group are
separated into individual racernic compounds or salts
the mono-N-oxides of 2-('N,N-di-lower alkyl-amino-lower
alkyl) -3~[i(4-pyridyl) ~lower alkyl]-indenes and the mono
thereof, using known methods, which may be, for exam
ple, based on physico-chemical differences, such as solu
bility. Thus, mixtures of racenia-tes may be separated
N-oxides of 2~(N,N-di-lower alkyl-amino-lower alkyl)-3
[(3-pyridyl)-lower alkylJ-indenes, in which compounds 75 by fractionate crystallization, if necessary, by using a
3,085,094
7
derivative, e.g. a salt, of a mixture of racemates, by frac
tionated distillation and the like.
Separated raccmiates or racemates of compounds which
contain one asymmetric carbon atom only, may be re
8
with ether. ‘The ether is evaporated to dryness leaving
a?ree base, which is dissolved in 2 ml. of ethanol and treated
with 0.5 ml. of 30% hydrogen peroxide. After stand
ing 24 hours at room temperature, the excess hydrogen
solved into the optically active ‘forms, the levo-rotatory
l-form and the dextro-rotatory d-form. Such resolution
peroxide is destroyed by adding a catalytic amount of
platinum oxide. The latter is removed by ?ltration and
procedure may be carried out according to methods which
the ?ltrate evaporated to dryness. 0.5 g. of maleic acid
in 3 ml. of ethanol is added to the residue, containing
are suitable for the separation of a racernate. For exam
ple, to a solution of the free base of a racemate (a d,l
the 2- ( 2-N,N-dimethylaminoethyl) -3-[ 1- (2-pyridyl) ~eth
compound) in an inert solvent or a mixture of solvents, 10 yl]-indene N-oxide of the formula:
is added one of the. optically active forms of an acid,
containing an asymmetric carbon atom, or a solution
thereof. Especially useful as optically active forms of
saltaforming acids, having an asymmetric carbon atom,
are the d-tartaric acid (L-tartaric acid) and the l-tartaric 15
acid (D-tartaric acid); the optically active forms of di-
/
benzoyl tartaric, di-p-toluyl-tartaric, malic, mandelic, 10‘
camphor sulfonic acid, quinic acid and the like, may
also be used. The salts, which are formed by the op
\o-bmomrlrwnm
\(J g
0
and the solution evaporated to dryness leaving the 2-(2
tically active forms of the base with the optically active 20 N,N-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl] - indene
N-oxide maleate as a noncrystalline powder. The corre
form of the acid may then be isolated, primarily on the
sponding picrate melts at 160°.
basis of their different solubilities. The free and optically
Other N-oxides, such as the l-2-(2-N,N-dimethylamino
active base may be obtained from a resulting salt ac
ethyl) -3- [ l-(2spyridyl ) -ethyl] -indene N-oxide, 2- (2-N,-N
cording to methods known for the conversion of a salt
into a base, for example, as is outlined here-inbelow. An 25 dimethylaminoethyl) ~3- [ Z-pyridyl) -et-hyl] -indene N-oxide,
2-(2-N,N-dirnethylamino-2-rnethyl-ethyl)-3-[l-(2 - pyri
optically active base may be converted into a therapeu
dyl) -ethyl] ~indene, 2- (2-N,N-dimethylaminoethyl) -3- [ (4
tically useful acid addition salt with one of the acids men
pyridyl) -methyl] -indene, 2- (2-N,N-dimethylaminoethyl) tioned hereinbefore, for example, according to the meth
3-[(3-pyridyl)-methyl]-indene and the like, may be pre
ods described hereinbelow. The optically active forms
30 pared according to the above procedure using the ap
may also be isolated by biochemical methods.
propriate starting materials.
The indene N-oxide compounds of this invention may
The starting material used in the above procedure may
be obtained in the form iof the free bases or as the salts
be prepared as follows: 33.2 g. of dhydropyran is slowly
thereof. A salt may be converted into the free base, for
added to a stirred mixture of 50 g. of or-benzyl-malonic
example, by reaction with an alkaline reagent, such
acid and 0.1 g. of p-toluene sulfonic acid in 130 ml. of
as aqueous alkali metal hydroxide, e.g. lithium hydroxide,
sodium hydroxide, potassium hydroxide and the like,
diethylether kept at 30° during the addition of the dihydro
aqueous alkali metal carbonate, e.g. sodium or potassium
carbonate or hydrogen carbonate and the like, ammonia,
pyran. The mixture is stirred for an additional 15 min
utes and then poured onto ice. The ether phase is washed
such as aqueous ammonia, ammonia in a lower alkanol, ,
e.=g. methanol, ethanol, and the like, or any other suitable
basic reagent, such as, for example, an anion exchange
resin. A free base may be converted into its therapeu
tically useful acid addition salts by reacting the former
with one of the acids mentioned hereinbefore according
to known methods.
with aqueous potassium carbonate, then with water and
is dried over magnesium sulfate; the ether is evaporated
under reduced pressure by keeping the temperature below
30° to yield the ditetrahydropyranyl mabenzyl-malonate.
A toluene solution of this ester is ‘gradually given to a
solution of 4.86 g. of a 50% suspension ofnsodiurn hy
The salts may also be obtained as 45 dride in mineral oil while heating and stirring for six
the hemihydrates, monohydrates, sesquihydr-ates or poly<
hydrates depending on the conditions used in the forma
tion of the salts. Mono- or poly-salts may be formed
according to the conditions used in the procedure for the
preparation of the salts and/ or the number of salt-form
ing groups present.
This is a continuation-in-part application of my appli
cation Serial No. 18,815, ?led March 31, 1960, which
hours. A solution of 10.8 g. of 2-N,N-dimethylamino
ethyl chloride in toluene is added dropwise, and the re_
action mixture is re?uxed for an additional 48 hours.
The toluene layer is washed with water, dried over mag
nesium sulfate and evaporated to yield the di-tetrahydro
pyranyl
a-benzyl-ow(2-N,N-dimethylaminoethyl)-malo—
nate; yield: 32.2 ‘g. of crude material.
A mixture of the resulting di-tetr-ahydropyranyl oc
benzyl-a~(2-N,N-dimethylaminoethyl)~malonate in 180 g.
in turn is a continuation-in-part application of my applica
tion Serial No. 852,208, ?led November 12, 1959', now 55 of polyphosphoric acid is stirred at 110-120° during
thirty minutes, and then at 150° during an additional
abandoned, which in turn is a continuation-in-part appli
twenty minutes. The reaction mixture is cooled, poured
cation of my application Serial No. 825,886, ?led July
into ice-water, the acidic phase is neutralized with potas
9, 1959, now US. Patent No. 3,036,085, which in turn
sium carbonate and extracted with ether. The ether so
is a continuation-impart application of my application
Serial No. 810,998, ?led May 5, 1959‘, now US. Patent .60 lution is washed with 15 percent aqueous hydrochloric
acid solution, the aqueous layer is neutralized with po
No. 2,947,756, which in turn is a continuation-in-part
tassium carbonate and again extracted with ether. After
application of my application Serial No. 792,263, ?led
washing the ether layer with water and drying it over
February 10, 1959, which in turn is a continuation-in-part
magnesium ‘sulfate, the solvent is evaporated to yield the
application of my application Serial No. 771,225, ?led
2-(2-N,N-dimethylaminoethyl)-indan-1-one, yield: 8 g. of
November 3, 1958, now US. Patent No. 2,970,149, which
crude material. The hydrochloride of the base melts at
in turn is a continuation-in-part application of my appli
165° after recrystallization from a mixture of ethanol and
cation Serial No. 754,526, filed August 12, 1958.
et er.
The following example is intended to illustrate the in
26 g. of Z-ethyl-pynidine is added dropwise to a stirred
vention and is not to be construed as being a limitation
solution of ‘650 ml. of an 0.37 molar solution of phenyl
thereon. Temperatures are given in degrees Centigrade.
Example
1.75 g. of 2 - (2 - N,N - dimethylaminoethyl)-3-[1-(2
lithium benzene. The addition is carried out in an at
mosphere of nitrogen and while cooling to 20°. After
two hours a solution of 10‘ g. of 2-‘(2-N,N-dimethylamino
ethyl)-indan-1-one in 50 ml. of dry ether is added over
pyridyl)-ethyl]-indene maleate is suspended in 5 ml. of
water, made strongly basic with ammonia and extracted 75 a period of ?ve minutes while stirring and cooling to
3,085,094
10
room temperature. After standing for twenty-four hours
the organo-lithium compounds are decomposed by the
alkyl-N-phenyl-lower alkyl-amino, l-N,N-lower alkylene
addition of 50 ml. of water with external cooling. After
carbon atoms, 4-morpholino, 4-lower alkyl-l~piperazino,
l-N,N-(3-aza-3-methyl-1,6-hexylene)-imino and 1-N,N
(4-aza-4-methyl-1,7-heptylene)-imino, and therapeutically
imino, in which lower alkylene has from four to seven
separating the water phase from the organic solution, the
latter is washed several times with 50 ml. of water, and
then extracted with a mixture of 40 ml. of concentrated
hydrochloric acid and 100 ml. of water.
acceptable acid addition salts of such N-oxides.
2. The mono-N-oxide of 2-(N;N-di-lower alkyl-amino
The acidic solution, containing 2-(2-N,N-dimethylami
iower alkyl) -3-[(2-pyridyl)-lower alkylJ-indene, in which
lower alkyl, separating the N,N-di-lower alkyl-amino
noethyl)-1-[1-(2-pyridy1)-ethyl]-indan-l-ol, is heated ‘on
the steam hath for thirty minutes to effect complete de
hydration to the desired indene derivative. The solution
is cooled, made strongly basic with an aqueous solution
of ammonia and then extracted with ether. The ether
group from the 2-position of the indene nucleus by trom
two to three carbon atoms, has from two to three car
bon atoms, and lower alkyl of the (2-pyridyl)-lower
alkyl portion has from one to three carbon atoms, and
phase is dried ‘over sodium sulfate, ?ltered, evaporated,
in which the N-oxide oxygen is attached to the nitrogen
and the residue is distilled. At 15 mm. pressure, the 15 atom of the N,N-,di-lower alkyl-amino group.
excess of Z-ethyl-pyridine is removed, at l20°/0.5 mm.
3. Therapeutically acceptable acid addition salts of the
some unreacted 2-(2~N,N-dimethylaminoethyl)-indan-o
mono-N-oxide of 2-(N,N-di-lower alkyl-amino-lower al
one distills and at 165-l75/05 mm. the 2-(2-N,N-di
kyl)-3-[(2-pyridyl)-lower alkyl]-indene, in which lower
methylaminoethyl) -3-[ 1~(2-pyridyl) ethyl] -indene is col
Clected.
To a solution of 1.0 g. of 2-(2—N,N-dimethylamino
alkyl, separating the N,N-di-lower alkyl-amino group
20 from the 2~position ot the indene nucleus by from two to
three carbon atoms, has from two to three carbon atoms,
ethyl) -3-[l-(2—pyridyl) -ethyl]-indene in 10 ml. of ethanol
and lower alkyl of the (2-pyridyl)-iower alkyl portion has
is added while stirring and heating 0.4 g. of maleic acid.
{from one to three carbon atoms, and in which the N-oxide
oxygen is attached to the nitrogen atom of the N,N~di—'
*On cooling the 2~(2-N,N—dimethylaminoethyl)-3-[1-(2
pyridyl)-ethyl] -indene maleate crystallizes, is ?ltered off, 25 lower alkyl-amino group.
washed with a small amount of ethanol and recrystallized
4. The mono-N-oxide of 2-(2-N,N-dimethylaminoeth
yl)-3-[l~(2-pyridyl)-ethyl]-indene, in which the N-oxide
from ethanol, M.P. 158°.
What is claimed is:
oxygen atom is attached to the nitrogen atom of the
1. A member of the group consisting of N-oxides of a
N,N-dimethylamino group.
compound of the formula:
30
5. Therapeutically accptable acid addition salts of the
mono-N-oxide of 2-(2-N,N-dimethylaminoethyl)-3-[1
(2-pyridyl)-ethyl]-indcne, in which the N-oxide oxygen
A1-PY
/3
R1
2 C-A:—Am
atom is attached to the nitrogen atom of the N,N-dimethyl
amino vgroup.
35
6. The maleate of the mono-N-oxide of 2—(2-N,N-di
1
methylaminoethyD-3-[l-(2 - pyridyD-ethyl] - indene, in
R2
which the N-oxide oxygen atom is attached to the nitrogen
atom of the N,N-dimethy1amino group.
\t
in which "R1 represents a member of the group consisting 40
of hydrogen, lower alkyl, lower alkoxy and halogeno, R2
stands for a member of the group consisting of hydrogen
and lower alkyl, A1 stands for alkylene having from one
to three carbon atoms, Py represents a member of the
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,947,756
Huebner ______________ __ Aug. 2, 1960
OTHER REFERENCES
group consisting of pyridyl and lower alkyl-substituted 45
pyridyl, A2 stands for lower alkylene, and Am stands for
Sidgwick: “The Organic Chemistry of Nitrogen,” 2nd
a member of the group consisting of N,N-di-lower alkyl
edition, pages 166-7, Oxford (1937).
amino, N-cycloalkyl-N-lower alkyl-amino, in which cyclo
Noller: “Chemistry of Organic Compounds,” 2nd edi~
alkyi has from ?ve to seven ring carbon atoms, N-lower
tion, page 240 (Saunders) (1957).
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