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Патент USA US3025298

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3&25238
¥at~ented Mar. 13, 1962
2
1
wherein R1 and R2 have the meanings given above, the
reaction possibly being performed in the presence of a
halogen hydracid binding agent.
3,025 !283
NEW AZEPINE DEREVATHVES
The reaction can be performed in an inert solvent such
Walter Schindler, Riehen, near Basel, Switzerland, assign
or to Geigy Chemical Corporation, Saw Mill River
Road, Ardsley, N.Y., a corporation of Delaware
No Drawing. Filed June 16, 1958, Ser. No. 742,018
as for example benzene or homologues thereof. An ex
cess of the amine used in the reaction can serve to bind
the halogen hydracid liberated in the reaction, which
amine at the same time can also be the sole solvent.
However, also an organic tertiary base such as dimethyl
aniline or pyridine, or inorganic acid binding substances
Claims priority, application Switzerland June 25, 1957
6 Claims. (Cl. 260-239)
The present invention concerns new amino-acylated 10 such as, for example, sodium or potassium carbonate
can be used to bind the halogen hydracid.
Compounds of the general Formula I can also be pro
salts and quaternary ammonium compounds as well as
duced by reacting a dibenzo[b.f]azepine of the general
processes for the production thereof.
'
azepines having valuable pharmacological properties, their
S-dibenzo [b.f] azepine and derivatives thereof have not
been known up to now.
formula
It has now been found that 15
N-substituted dibenzo [b.f] azepines of the general formu
. ?g}.
N/
la de?ned below
20
(V)
H
B:
with an amino-alkanoyl chloride of the general formula
R:
(I)
25
possess valuable pharmacological properties, for exam
ple strong local anaesthetic activity, whereas the corre
R2
sponding quaternary ammonium salts of the general
formula
X1-(\<\ oo~onH,n-N£Rl
X:
it R;
have spasmolytic properties.
or the hydrochloride of such an amino-alkanoyl chloride,
30
the reaction possibly being performed in the presence
of an acid binding agent. In these formulae X1, X2, R1,
R2 and n have the meanings given above.
In addition, compounds of the general Formula I are
Br
N
(v1)
35 obtained by reacting a possibly ring substituted N-amino
alkanoyl~dibenzo[b.f]azepine of the general formula:
(11)
In the two formulae given
above :
Xtl
X1 and X2 represent hydrogen or halogen atoms,
R1, R2 and R3 represent low molecular alkyl or alkenyl
l
Xi
R1
‘groups, or
the nitrogen atom represent an
R1 and R2 together withhaving
5—6 ring members or the
alkylenimino radical
morpholino radical,
H
(VII)
45
Y represents a monovalent anion, in particular a halogen
hydracid, a low molecular alkyl sulphuric acid or an
with a reactive ester
la
aryl sulphonic acid, and
n represents a low whole number.
la
R2—-OH
(VIII)
the reaction possibly being performed in the presence of an
acid binding agent, or reacting the dibenzo[b.f]azepine
compound of the general Formula VII with another al
The new compounds of the general Formula I can be
produced by reacting a possibly ring substituted N-halo
gen alkanoyl-dibenzo[b.f] azepine of the general formu
of an alcohol of the general formu
lcylating agent such as for example formaldehyde or a
homologue thereof in the presence of formic acid. In
55 these formulae X1, X2, R1, R2 and n have the meanings
given above.
Derivatives of dibenzo[b.f]azepine and 3.7-clichloro
dibenzo[b.f]azepine substituted in 5-position by a lower
N/
m-dialkylamino-alkanoyl, a-pyrrolidino-alkanoyl or a-pi
radical, in particular a lower a-dialkyl
wherein Hal represents chlorine or bromine and X1, X2 60 peridino-alkanoyl
amino-, u-pyrrolidino- or u-piperidino- acetyl or ~propionyl
and n have the meanings given above, with an amine
radical, are of special value because of their good local
of the general formula:
anaesthetic action and low toxicity.
The quaternary ammonium compounds of the general
6
Ra
(1v)
Formula II are obtained from tertiary amines of the gen
8,025,288
4
eral Formula I by treating these ‘with a reactive ester
of an aliphatic or araliphatic alcohol of the general
Quaternary ammonium compounds of the general For
formula
R3—OH
mula II are obtained from the tertiary amines of the gen
eral Formula I by the ?rst or second process above men
(IX)
tioned ‘for example by adding methyl chloride, methyl
in particular with a halide, sulphate or aryl sulphonic acid
ester and if desired, then replacing an anion arising from
bromide, methyl iodide, ethyl chloride, ethyl bromide,
ethyl iodide, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl,
isoamyl and n-hexyl chlorides or bromides, dimethyl sul
10
R1
(X)
wherein R1, R2 and R3 have the meanings given above,
to form a quaternary ammonium compound of the gen
eral Formula II.
The following example further illustrates the produc
The N-halogen alkanoyl-dibenzo[b.f]azepines neces
tion of the new compounds. Where not otherwise stated,
parts are given as parts by weight and their relationship
to parts by volume is as that of grammes to cubic centi
metres. The temperatures are in degress centigrade.
sary as starting materials are easily obtained by acylating
the corresponding dibenzo[b.f] azepines with halogen fatty
acid halides or also corresponding anhydrides in the
presence or absence of agents which bind halogen hy
dracid such as ‘for example pyridine or dimethyl aniline.
The dibenzo[b.f]azepines are obtained from the corre
sponding
'
'
'
The halides, alkyl sulphates or aryl
sulphonates obtained direct on using these starting ma
terials can, if desired, be converted by double decomposi
tion for example of quaternary halides with silver salts
of other acids or by liberation of the quaternary bases and
neutralisation with other acids, into quaternary salts with
other anions.
NZR.
\Ra
ester, allyl bromide, allyl iodide,
Example
19.3 parts of dibenzo[b.f]azepine are dissplved in 100
'
parts by volume of abs. benzene and 11.5 parts of chlor
acetyl chloride are added. The solution is boiled for 4
hours under re?ux and then the solvent is completely
distilled .01? in the vacuum. On adding ether, the residue
derivatives
example with bromosuccinimide, splitting olf hydrogen
halide and hydrolysis.
Examples of N-halogen alkanoyl-dibenao[b.fJazepines
are N-chloracetyl-, N-bromacetyh, N-(a-chloropropion
crystallises; the N-ehloracetyl-dibenzo[b.f]azepine so ob
30 tained melts at 147-148".
yl)-, N-(u-bromopropionyl)-, N-(a-brompbutyryly, N
12.5 parts of N-chloracetyl-dibenzo[bf] azepine are re
(11 ~ bromovaleryl)-, N - (oz - bromo - isovaleryl)-, N - (a
bromocaproyl)-, N-(B-chloropropionyl)-, N-(?-bromo
propionyl)-, N-(p-bromobutyryl)-, N-(B-bromovaleryl)-,
N- ('y-chlorobutyryl)-, and -N-('y-chlor0valeryl) -dibenz0
35
[b.f]-azepine, -3.7-dichloro-dibenzo[b.fJazepine, -2.8-di
chloro-dibenzo[b.f]-azepine,
and -3.7-dibromo-dibenzo
[b.flazepine.
are made alkaline and again ethered out. On adding abs.
These N-halogen alkanoyl-dibenzo[b.tf] azepines can be
alcoholic hydrochloric acid to the ethereal solution, the
reacted for example in the ?rst process mentioned with di
hydrochloride of N-(diethylaminoacetyl)-dibenzo[b.f]
azepine crystallises. On recrystallising from isopropanol,
amine, di-isppropylamine, dibutyl and diamyl amines,
it melts at 217-220".
On adding excess methyl iodide to the free base in
methylallylamine, diallylamine, methyl-methallylamine,
bis-methallylamine, pyrrolidine, piperidine, C-alkylated
ethyl acetate and allowing to stand, the metho-iodide of
45 N-diethylaminoacetyl-dibenzo[b.f]
azepine crystallises out.
pyrrolidines or piperidines or morpholine.
To produce the quaternary ammonium salts of the gen
On recrystallising from ethanol, it melts at 215-216 °.
The ethereal solutions of further tertiary bases can be
eral Formula II direct the N~halogen alkanoyl-dibenzo
[b.f] azepines given above can be reacted for example with
obtained in the manner described above.
trimethylamine or triethylamine.
Amino alkanoyl chlorides of the general Formula VI
50
can be obtained as hydrochlorides for example by treat
'
'
to the residue and the mixture is
thoroughly shaken out with ether. The basic portions
are removed from the ethereal solution by ‘shaking out
four times with 2 N-hydrochloric acid. The acid extracts
tion of their ethereal solutions, the free bases given below
crystallise as such and can be recrystallised for example
from ether or ether/pentane:
carboxylic acids with
phosphorus pentachloride in acetyl chloride.
N-(piperidino-acetyl)-dibenzo[b.f]azepine ___
The N'-mono-substituted N-(amino-alkanoyl)-dibenzo
55
[b.fJazepines necessary in the last process for the pro
M.P.
104°
N - (or - piperidino - propionyl) - dibenzo
[b.fjazepine ____________ _'_ __________ __ 124-125”
N - (a - pyrrolidino-propionyl) - 3.7 - dichloro
dibenzo[b.f]azepine
_________________ __ 167-168“
N - (a - diethylamino - propionyl) - dibenzo
60
in the same step as the alkylation to form the end prod
uct having a tertiary amino group, for example by treat
88-89°
acetate, the metho-iodide of N-(a-diethylamino-pro
ing N-amino-acetyl-dibenzo[b.f]azepine with excess for
maldehyde or with another alkanal in formic acid. The
[b.f] azepine ________________________ __
On adding excess methyl iodide to the base in ethyl
pionyl)-dibenzo[b.f]azepine also precipitates in amor
phous form. It crystallises from acetone and then melts
65 at 212—2l4°.
The ethobromide and the allylobromide and N-(a-di
ethylamino-propionyl)-dibenzo[b.f]azepine and N-(di
ethylamino-acetyl-dibenzo[b.f]azepine are obtained in an
70
analogous manner.
The hydrochlorides of N-(diethylamino-acetyl)-3.7
dibromo-dibenzo[b.f]azepine, N-(diallylamino-acetyl)
with an almost neutral reaction.
dibenzo-[b.f]azepine and N-(a-dipropylamino-butyryl)
hydrochloride of N-(diethylamino-acetyl)-dizenzo[b.f]
azepine.
dibenzo[b.f]azepine are obtained in the same way as the
75
8,025,288
5
What I claim is:
1. A member selected from the group consisting of an
azepine derivative of the formula:
____
X1
\
\
X2
members and the morpholino radical,
N/
R
l
Y represents an anion of a halogen hydroacid, and
‘
CO-—-C nH1n——N \R:
n represents a whole number from 1 to 3 inclusive.
(I) 10
muqa:
and the quaternary ammonium salt thereof of the for_--—
X
\N
2. The hydrochloride of N-(diethylamino-acetyl)-di
beyogllgli] agglrllgliodide of N_ (diethylamino-acetyl) ~d1
benzo [b.f] azepine.
4. N-(piperidino-acetyl) -dibenzo [b.?-azepine.
X
‘
6
R1, R2 and R3 when taken separately represent a member
selected from the group consisting of lower alkyl and
lower alkenyl groups, and R1 and R2 together with the
nitrogen atom represent a member selected from the
5
group consisting of alkylenimino having 5 to 6 ring
5. N - (a - pyrrolidino-propionyl) - 3.7 - dichloro - di
’
benzo[b.f] azepine.
R1
6. N-(a-diethylamino-propionyl-dibenzo[b.f]-azepine.
References Cited in the ?le of this patent
wherein each of
Y R!
(11)
X1 and X2 represent a member selected from the group
consisting of hydrogen, chlorine and bromine,
UNITED STATES PATENTS
2,309,200
Schindler 6t a1~ -------- -- 06L 3, 1957
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