Note: Descriptions are shown in the official language in which they were submitted.
H-208
1067080
The present invention concerns new 4-amino-quinoline
derivatives, a process for their preparation and pharmaceutical
compositions containing them.
The invention provides new`4-aminoquinoline derivatives of
the general formula
CONR R
N~ ~ (Il
10 X~
and their acid addition salts, where X is halogen atom or a
trifluoromethyl group; Z is hydrogen; Rl represents hydrogen
Gr lower alkyl; and R represents [mono(lower alkyl)amino]
(lower alkyl), [di(lower alkyl)amino](lower alkyl),
[phenyl(lower)alkyl]-piperidyl or l-(lower alkyl)piperidyl
or -NRlR2 represents [mono(lower alkyl)amino]piperidino or
,~ [dl(lower alkyl)aminolpiperidino. Preferably R2 represents
[di(lower alkyl)amino](lower alkyl) or l-(lower alkyl)piperidyl
or -NRlR2 represents Idi(lower alkyl)amino]piperidino. We
~ particularly prefer those compounds where R2 is [di(lower alkyl)
;~ aminol(lower alkyl) whilst Rl is lower alkyl and those where
R2 is l-(lower alkyl)piperidyl.
The term "lower" as used herein in connection with such
groups as "alkyl" or "alkoxy" denotes that the group contains
; up to 4 carbon atoms. By the term "ar(lower)alkyl" there
~ is meant lower
:::
~ 2 -
7~'
J'~
~067080 H-208
alkyl substituted by aryl. The aryl group may be unsubstituted
or substituted with one or more substituonts conventional~y
used in medicinal chemistry. Preferably the aryl group is
phenyl.
It will be apparent to those skilled in the art that
the above definition of R2 includes moieties possessing an
asymmetric carbon atom, especially for instance, in
the ca~es where R2 represents a 1-[ar(lower~alkyl]-3-piperidyl
or l-(lower alkyl)-3-piperidyl group. It i9 to be understood
that general formula I is intended to encompass both
enantiomers where the compound contains an asymmetric carbon
atom and mixtures of the enantiomers, for instance, a racemic
~ixture of the enantiomers. General methods are recorded
in the literature for the resolution of enantiomers.
; 15 In the compoùnds of the invention, X preferably
represents a halogen atom, for example, a chlorine or
bromine atom, but may aloo represent a trifluoromethyl
group. Illustrative meanings of Z include hydrogen,
chlorine, bromine atoms and trifluoromethyl, lower alkyl or
2û alkoxy (for example, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy and butoxy), hydroxyl, nitro, amino, methyl-
- amino, athylamino, dimethylamino and diethylamino groups.
Z is preferably hydrogen.
As illustrative meanings of Rl there may be mentioned
hydrogen, methyl, ethyl, propyl, butyl and hexyl. As
illustrative meanings of [mono(lower alkyl)amino](lower
alkyl) there may be mentioned (methylamino)methyl and (ethyl-
amina)ethyl. As illustrative meanings of [di(lower alkyl)
; amino](lower alkyl) there may be mentioned [di(methyl)
amino]methyl, [di(ethyl)-amino]ethyl, [N-methyl-N-ethylamino]
propyl, [di(ethyl)amino]butyl and [di(butyl)amino]ethyl.
-- 3 --
~0670~ . H-208
Piperidyl may be 3-piperidyl or 4-piperidyl. As
illustrative meanings of l-(lower alkyl)piperidyl there
may be mentioned l-ethyl-2-piperidyl, 1-ethyl-3-piperidyl,
1 1-ethyl-4-piperidyl, 1-methyl-4-piperidyl, 1-methyl-3-piperidyl,
;~ 5 1-propyl-3-piperidyl, 1-butyl-4-piperidyl and 1-pentyl-3-
piperidyl. As illustrativ~ meanings of l-[ar(lower)
alkyl]pi~erldyl there may be mentioned l-benzyl-3-piperidyl,
l-benzyl-4-piperidyl, 1-phenethyl-3-piperidyl and l-phenethyl-
4-piperldyl. ~s illustrative meanings of [di(lower alkyl)
amlno3piperidino snd [mono(lower alkyl)amino]piperidino
there may be mentioned 4-(dimethylamino)piperidino, and
3-(dibutylamino)-piperidino, 4-(methylamino)piperidino
and 3-(ethylamino)piperidino.
Examples of acid addition salts are those formed from
, ~ .
inorganic and organic acids and in particular pharmaceutically
acceptable acid addition salts such as the sulphate, hydrochlor-
ide, h~drobromide, hydroiodide, nitrate, phoqphate, sulphonate
; (such a~ the methanesulphonate and Q-toluene-sulphonate),
acetate, maleate, fumarate, tartrate, malonate,
citrate and formate.
,1 ~
The compounds of the invention may be made by
building the compound up by known reactions. In
. - . - , .
~ particular the amide linkage shown in formula I as
c -CONR1R2 may be formed by acylation of an appropriate
amine, and a primary amino-substituted benzamide may
be converted to the seconary amine by introducing
the 7-(halo or trifluoromethyl)-4-quinolyl group in
known manner.
- H-208
106~080
The invention provides a method of making compounds of.
- ` :;theformula I and their acid addition salts, wherein
(a) a compound of the formula HNR1R2 where R1
and R are defined in connection with fDrmula I,
or a corresponding compound with an activatsd
amino group, is acylated with a compound of formula
(II) COOH
NH ~
¦ ~ (II)
) ~ 7
(wherein X and Z are as defined above in connection
with formula I), or a corresponding compound with
a protecting group, or a reactive derivative of the -
~ compound of formula (II) or its corresponding
:~ compound with a protecting group;
or (b) a compound of the formula (III)
, CONR1R2
NH2 ~ (III)
Z
(where R1, R2 and Z are as defined in connection
with formula I) or a corresponding compound with a
protecting group, is reacted with a compound of
~ormula (IV)
X ~ (iV)
~ _ 5 _
~ 2a8
1067080
;~ (where X is a6 definzd above in connection with
formula I and Y denotés~ a group or atom replaceable
by nucleophilic attack by compound of formula'III)-.-
Y is for example, an iodine atom, a bromine atom
or a chlorine atom or an organosulphonyloxy group,
for instance, p-toluenasulphonyloxy. ~here
necessary or if de~ired, the process may also
include removal of a protecting group and, if
' desired, conversion of a free bsse form of compound
. .
~10 of formula I into an acid addition salt form or
conversion of an acid addition salt form of a
compound of formula I into the corresponding free
,.
base form.
Starting materials of formula HNR1R2 and formulae
'15 II, III and IV are known compounds or, if new, are
sccessible by conventional methods.
The acylation method may be carried out by reacting
the compound'of formula II with the compound of formula
HNR1R2 or - correspondin~g compound ~ith a protecting
~ group, in the presence of a condensing agent, for in~tance,
a carbodiimide. Alternatively the acid of formula II may
be-~r-;cted~ith a compound of formula Q_R2 ~here Q is an
activated amino~group. The amino group may be aetivated
for example, by forming the phosphazo derivative. The
-, ~
~ reactive acylating derivatives of the compound of formula
II may be employed, for example, active esters, acyl halides,
simple or mixed anhydrides and the acid azide. The acid
halides, particularly the acid chloride are e~pecially
suitable. Preferably the compound of formula HNR1R2 is
' acylated ~ith a reactive derivative'of the acid of formula II.
- 6 -
~0 67 0 ~ H-20~
The acylation product may be recovered from the reaction
mixture by standard isolation procedures. Acylating derivatives
of the acid of formula II may include protection for a
group Z sensitive to acylation. For e~ample, a final product
in which Z is an amino function can be formed by ucing
an acylating derivat~ive of the acid of formula
CI
x ~ 3 (v)
and converting the phthalimido group to an -NH2group
by reaction with hydrazine. The new compounds of the
invention are normally quite stab~e to hydroly9is under
; lO acid condition5 and therefore favour protecting groups
.
that are readily hydrolysed off under acid conditions.
I ~ Compounds of the formula III are accessible in
standard manner, for example, by acylation of a compound
of ~ormula NHR1R2 where R1 and R2 have the meanings given
lS~ i~n connection ~ith formula I with an-acylating derivative
ofan o-nitrobenzoic acid or 2-(protected amino) benzoic
, . .
acid and subsequent reduction of the nitro group or
removal of the amino protecting group. The reaction
of the primary amine III with the compound of formula
IV may be carrled out in conventional manner for
amination of 4-substituted quinolines. The reaction
products may be recovered from the reaction mixtures by
standard isolation procedureo. In certain cases it
!
,f '
` 10670~ H-208
is e~pedient to incorporete a protecting group for
amino in the compound of formula III to reduce or
preclude undesired reaction of the compounds of formula
IV with an amino function as Z. The protected amino
group may be a phthalimido group. In such cases the
protecting group is removed after the reaction with
the compound of formula IV.
The compounds of the pr~sent invention may be
isolated in free base form or as an acid addition salts.
Acid addition salts may be converted into the free ba~es
in conventional manner. The free base forms may be
converted into acid addition salts in conventional
manner, for instance, by adding ethereal hydrogen chloride
to a solution of the free base where a hydrochloride
salt is desired.
The compounds of the present invention are
indicated for pharmacological usage and, in particular,
generally demonstrate anti-inflammatory activity. A
literature reference for testing for anti-inflammatory
activity is Newbould, B.~., Brit. Bour. Pharm.Chemoth.,
2I: 127-136 (1963). Some of the new compounds of the
invention also show anti-hypertensive activity.2-(7-
chloro-4-quinolylamino)-N-(2-diethylaminoethyl)-N-
ethylbenzamide demonstrates activity as a blood
platelet aggregation inhibLtor.
The invention also includes pharmaceutical
compositions containing as active ingredients a compound
of formula (I) or a pharmaceuticalLy acceptable acid
addition salt thereof, which may be micronised if
desired. In addition to the active ingredient, said
compositions also contain a non-toxic carrier. Any
-- 8 --
H-208
1067080
suitable carrier known in the art can be used to prepare
the pharmaceutical compositions. In such a composition,
the carrier may be a solid, liquid or mixture of a solid
and a liquid. Solid ~orm compositions include powders,
tablets and capsules. A solid carrier can be one or
more substances which m~ay also act as flavouring agents,
lubricants, solubilizers, suspending agents, binders,
or tablet-disIn~egrating agents; it can also be an
~ -encapsulating material. In pow~ers the carrier is a
; 10 finely divided solid which is in admixture with the
~ ~inely divided active ingredient.
-` In tablets the active ingredient is mixed with a
.
carrier having the necessary binding propertie~
in suitable proportions and compacted in the shape
and size desired. The po~der~ and tablets preferably
~. .
~' contain from 5 to 99, preferably 10-~0% of the
,
~ active ingredient. Suitable solid carriers are
. .
~; magnesium carbonate, magnesium stearate, talc,
sugar, lactoie, pectin, dextrin, starch, gelatin,
2;0 tragacanth, methyl cellulose, 90dium ~carboxymethyl
. .
cellulose, a low melting wax, and cocoa butter. The
term "composition" is intended to include the formation
of an active ingredient with encapsulating material as
carrier to give a capsule in which the active ingredient
(with or without other carriers) is surrounded by
carrier, which is thus in association with it.
Similarly cachets are included.
Sterile liquid form compositions include sterile
solutions, suspensions, emulsions, syrups and exilirs.
_ g _
~0670~UV H-208
The active ingredient can be dissolved or suspended in
a pharmaceutically acceptable sterile liquid carrier,
such as sterile water, sterile organic solvent or a
mixture of both. Preferably a liquid carrier is one
suitable for parenteral injection. Where the active
ingredient is sufficiently soluble it can be dissolved
in normal saline as a carrier;ifit is too insoluble
~,
for this it can often be dissolved in a suitable
organic solvent, for instance aqueous propylene glycol
or polyethylene glycol solutions. Aqueous propylene
glycol containing from 10 to 75% o~ the glycol by
weight is generally suitable.
In other instances compositions can be made by dispersing
the fineIy-divided active ingredient in aqueous starch
. .
or-sodium carboxymethyl cellulose solution, or in a
~;~ 3uitable oil, for instance arachis oil. Liquid pharmf-
aceutical compo itions ~hich are sterile or suspensions
cab be utilised by intramuscular, intraperitoneal or
. .i~ .
~ ubcutaneous injection. In many:instances-a compound
~ :
is orally active and can be admihi~tered orally either
in liquid or solid composition form.
- Preferably the pharmaceutical composition is in
unit dosage form. In such form, the composition is
sub-divided in unit do~es containing appropriate
quantities of the active ingredient; the unit dosage
form can be a packaged composition, the package containing
specific quantities of compositions, for example packeted
po~ders or vials or ampoules. The unit dosage form can
be a capsule, cachet or tablet itself, or it can be the
appropriate number of any of these in package form.
- 10 -
H-208
~067080
The quantity of active ingrsdient in a unit dose of
compo~ition may be varied or adjusted from 5 mg. or less
to 500 or more, according to the particular need and the
activity of the active ingredient. The invention also
; S includes the compounds in the absence of carrier where
1 ths compounds are in unit dosage form.
~ .
~ The invention is illustrated b~ the follo~ing Examples:-
: ,
EXAMPLE 1
2-(7-Chloro-4-quinolvlamino)-N-(l-ethYl-3-piperidYl)benzamide
i~ ; 10 A~'~olution of 10.05 grams-of 2-(1-chloro-4-quinolylamino)
'~ ~ benzoic acid hydrochloride in 60 millilitres of thionyl
'~ chloride was refluxed for two hours. After evaporation
of the thionyl chIoride 50 millilitres of benzene Were
added and the mixture re-evaporated to give the acid
chloride as a pinkish solid. This was then added in
portions'to a stirred, ice-cooled solution of 3.84 grams
. ~ , ,
of 3-amino-1-eth'yl-piperidine-in 60 millilitres of
chloroform with 80 millilitre~ of water and 31.8 grams
of sod~ium carbonate. After the addition was complete
the mlxture was stirred at room temperature overnight,
- filtered and the filtrate (chloroform-water) separated,
, ~:~: : -
' the aqueous layer~further extracted with chloroform,
the chloroform extract~ comblned, dried over magnesium
sulphate and evaporated to give a brown gum.
Trituration uith n-hexane gave 8.9 grams of the title
compound as the hemihydrate.
~elting point: lB7-188'C
Analysis: Found C, 66.5%; H, 6.23~; N, 13.4%
- C23H2sClN4o-~H2o requires C, 66.1%; H, 6.27~; N, 13.4%.
-- 11 -
H-208
1067080
EXAMPLE 2
2-(7-Chloro-4-quinolvlamino)-N-(2-diethylaminoethyl)-
N-ethYlbenzamide.
A solution of lO.OS grams of 2-(7-chloro-4-qaDnolylamino)
benzoic acid hydrochloride in 60 millilitres of thionyl
chloride was refluxed for two hours. After evaporation
of the thionyl chloride 50 millilitrss of benzene were added
and the mixture re-evaporated to give ths acid chloride as
a yellouish solid. This ~as then added in portions to a
~ ~ "
~ 10 stirred, ice-cooled solution of 4.33 grams of N,N,N'-
:`
triethylethylenediamine in 60 millilitres of chlorofo~m
,
~ith 100 millilitres of water and 31.8 grams of sodium
carbonate. After the addition was complete the mixture
was stirred at room temperature overnight, filt-red and the
filtrate (chloro-~m-Jater) separated, the aqueous layer
further extracted ~ith chloroform, the chloroform extracts
l combined, dried over magnesium sulphate and evaporated to
... .
give 16 grams of a bro~n gum. Thi~ ~as dissolved in
250 millilitres of ether and ethereal hydrogen chloride
added to precipitate 14.4 grams of the title compound
as the hydrochloride dihydrate.
Melting point: 155C
Analysis: Found C, 54.0%; H, 6.30%; N, 10.2%
C24H29ClN40.2HCl.2H20 requires C, 54.0%; H, 6.61%;
N, 10.5%.
- 12 -
10 67 0 ~ H-208
EXAMPLE 3
2-(7-Chloro-4-quinolylamino)-N-(2-diethvlaminoethyl)benzamide
A solution of 6.7 grams of 2-(7-chloro-4-quinolylamino)
benzoic acid hydrochloride in 40 millilitres of thionyl
chloride was refluxed for two hours. After evaporation
of the thionyl chloride 50 millilitres of benzene were
added and the mixture re-evaporsted to give the acid
chloride as a pinki~h solid. This was then added in
; ~ portions to a stirred, ice-cooled solution of 2.32 grams
of N,N-diethylet'hylenediamine in 40 millilitres of
chloroform with 100 millilitres of water and 21.2 grams of
odium'carbonate. After the addition was complete the
l . ;
t, mixture was stirred at room temperature overnight,
filtered and the filtrate (chLoroform-water) separated,
the aqueous layer further extracted' with chloro'form, the
~ l~S chloroform extracts combined, dried over magnesium
j~ ~ulphate and evaporated to give an oil. This was
' dis~olved in 200 millilitres of ether and ethereal
hydrogen chloride added to precipitate 7.4 grams of
the titlo compound as the dihydrochloride hydrate.
Melting point: ' 225C.
Analysi's: Found C, 51.2%; H, 5.99%; N, 10.6%
C22H25ClN40.2HCl.2~H20 requires C, 51.3%; H, 6.26%;
N, 10.9%
'
- 13 _
: ' .
-
~0 6q 0 ~ H-208
EXAMPLE 4
l-r2-(7-chloro-4-quino~amino)-benzoyll-4-dimeth~laminopiperidine_
A solution of 8 grams (0.024 mole? of 2-(7-chloro-4-quinolyl-
amino)-benzoic acid hydrochloride in 60 millilitres of thionyl
'~ S chloride ~a~''.re~Iuxed ~or :t~o:.. hours.;.E.vaporationi.~.'oll~wed,by;,~he
addition of dry benzene (2 x 50 ml) and re-evaporation gave the
acid chloride as a pinkish solid. This was added in portions
to a stirred, ice-cooled solution of 4.8 grams (0.0239 mole)
of 4-dimethylamino piperidine dihydrochloride in 60 millilitres
of chloroform ~ith 100 millilitres of ~ater and 31.8 grams of sod-
. ium carbonate.The'mixtu.re.,was stlrred at room temperature over-
night. The mixture ~as then filtered, the filtrate ~as
separated and the chloroform layer ~as evaporated to give an
oil. The oil was converted to the hydrochloride in isopropyl
alcohol-ether. This ~as dissolved in ~ater and saturated
sodium carbonate solution added to precipitate the free
base as a yello~ solid. Reconversion to the hydrochloride
and back to the free base again gave 2.5 grams of
title compound as a hemihydrate. Melting point: 111-112C.
Analysis: Found C,66l%; H'~ 6............ '21%; N, 13.3%.
Calculated for C23H2sClN4 ~H20: C, 66.1%; H, 6.27%; N, 13.4%.
EXAMPLE 5
2-(7-Chloro-4-quinolYlamino)-N-r2-(dimethYlamino)ethY
N-methylbenzamide
A.solution of 10.05 grams (0.03 mole) of
2-(7-chloro-4-quinolylamino) benzoic acid hydrochloride
in 60 millilitres of thionyl chloride ~as refluxed ~or two
hours. Evaporation follo~ed by the addition of dry benzene
(2 x 50ml) and re-evaporation gave the acid chloride as a
pinkish solid. This ~as added in portions to a stirred,
ice-cooled solution of 3.1 grams (0.03 mole) of N,N,N~
- 14 -
~067080 H-200
trimethylethylenediamine in 60 millilitres of chloroform with
; 120 millilitres of water and 31.8 grams of sodium
carbonate.The~mixture-~as stirred at room temperature over-
night. The mixture was then filtere'd, the filtrate was sep-
arated and the chloroform layer was evaporated to give an oil.
The oil was dissolved in ether and ethereal HCl added to prec-
ipitate the hydrochloride. This was dissolved in water
and saturate~ sodium carbonate solution added to precipitate
the free base as a gummy solid. Reconversion to the
hydrochloride gave a grams of the title compound as its
dihydrochloride dihydratejm.p. 190-91C.
Analysis: Found C, 53.2%; H, 5.29%; N, 12.0%; C21H23ClN40.2HCl.
2H20 requires: C, 53.2%; H, 5.74%; N, 11.8%
EXAMPLE 6
N~ 8enzyI-4-piperidYl)-2-(7-chloro-4-quinolylaminoLbenzamide
A solution of 10.05 grams (0.03 mole) of
2-~7-chIoro-4-quinolylamino)benzoic acid hydrochloride in
6~ millilitres of thionyl chloride was refluxed for two hours.
Evaporation followed by the addition of dry benzene (20 x 50ml)
,:.
- 20 and re-evaporation gave the acid chloride as a pinkish solid.
This wa~ added in portions to a stirred, ice-cooled solution
of 5.71 grams (û.03 mole) of 4-amino-1-benzyl piperidine
in 60 mi~'i~`tr'es of chloroform with 120 millilitres of ~ater and
31.8 grams of sodium carbonste a'nd thè mix'ture ' ' ~-
stirred at room temperature overnight. The mixture wasthen filtersd, the filtrate was separated and the chloroform
layer was evaporated to give a sticky solid. This solid
was triturated with ether to give the title compound~m.p.
171-72C .
Analysis: Found: C,7p.5%; H, 5.83%; N,11.5%; C28H27ClN40.~H20
requires C, 70.7%; H, 5.82%; N,11.8%.
-15-
~06708~
H-208
EXAMPLE 7
2-(7-Chloro-4-quinolylamino~-N-(2-dimethylaminoethyl)-N-ethvl
benzamide
A solution of 10.5 grams (0.03 mole) of
2-(7-chloro-4-quinolylamino) benzoic acid hydrochloride
in 60 millili~res of thionylc~oride was refluxed for
two hours. Evaporation followed by the addition of dry
benzene (2 x 50 ml) and re-evaporation gave the acid
chloride as a pinkish solid. This was added in portions
to a stirred ice-cooled solution of 3.5 grams (0.03 mole) o~
N,N -dimethyl-N-ethylethylenediamine in 60 millilitres of
chloroform with 120 millilitres o~ water and 31.8 grams of
~odium carbonate and the mixturé stirred at room temperature
overnight. The mixture was then filtered, the filtrate
was separated and the chloroform layer was evaporated to
give an oil. The oil was dissolved in ether and ethereal HCl
added to precipitate 11.8 grams of the title compound as its
dihydrochloride dihydrate, m.p. 175-180C.
Analy~is: Found: C~ 51.8%; H, 5.73%;N, 10.9%; C22H25ClN40.
2HCl.2H20 requires: C, 52.5%; H, 6.17%; N, 11.1%.
EXAMPLE 8
.2-(7-Ehloro-4-quinolv~anino)-N-(l-ethYl-4-pipsridyl)benzamide
A solution of 15.1 grams (0.045 mole) of
2-(7-chloro-4-quinolylamino) benzoic acid hydrochloride
in 90 millilitres of thionyl chloride was refluxed for two
hours. Evaporstion followdd by the addition of dry benzene
(2 x 75 ml) and re~evaporation gave the acid chloride as
a pinkish solid. This was added in portions to a stirred
- 16 -
1067080
H-208
ice-cooled solution of 5.75 grams (0.045 mole) of
4-amino-N-ethyl piperidine in 90 millilitr~s of chloroform
with 200 millilitres of water and 47.7 grams of sodium
carbonate and the mixture was stirred at room temperature
, 5, overnight. The mixture was then filtered, the filtrate was
separated and the chloroform layer was evaporatad to give
a sticky solid which was triturated with ether to give
a yellow solid. This was recrystallised from ethanol to
give 4.7 grams o~ 2-(7-chloro-4-quinolylamino)-N-(l-ethyl-
4-pip~ri,dyl)ben~amide, m.p. 239-240C.
Analysis: Found: C,67.55%; H, 6.22%; N, 13.7%; C23H25ClN40
requires C, 67.55%; H, 6.16%; N, 13.7%.
'EXAMPLE 9
2-(7-Chloro-4-quinolylamino)-N-(2-diethYlaminoethYl)-N-methY
benzamide
A solution of 10.05 grams (0.03 mole) of
2-(7-chloro-4-quinolylamino)benzoic acid hydrochloride in
60 millilitres of thionyl chloride was refluxsd for two
hours. Evaporation followed by the addition of dry benzene
(2 x 50 ml) and re-evaporation gave the acid chloride as a
pinkish solid. This was added in portions to a stirred
ice-coolsd solution of 3.91 grams (0.03 mole) o~
N,N-diethyl-N1-~ethyl-ethylenediamine in 60 millilitres of
chloroform with 120 millilitres of water and 31.B grams-of
sodium carbonate and the mixture was stirred at room
tsmperature overnight. The mixture was then filtered,
the filtrate was separatsd and ths chloroform laysr was
svaporatsd to give an oil. The oil~was dissolved in ether
and ethereal HCl added to precipitate the hydrochloride. This
7 0~D H-208
.
was dissolved in ~ater and saturated sodiùm carbonate solution
added to precipitate the free base as a gummy solid.
Reconversion to the hydrochloridegave 9.0 grams of
2-(7-chloro-4-quinolylamino)-N-(2-diethylaminoethyl)-N-
methyl benzamide dihydrochloride trihydrate, m.p. 90-95C.
Analysis: Found: C, 51.2%; H, 6.42%; N, 10.3%; C23H27ClN40.
2HEl.3H20 requires: C, 51.35%; H, 6.56%; N, 10.4%.
:i
- EXAMPLE 10
N-(l-n-8utYl-4-piperidYl)-2-(7-chloro-4-quinolylamino)benzamide
A solution of 10.05 grama (0.03 mole) of
` I :
2-(7-chloro-4-quinolylamino)benzoic acid hydrochloride
in 60 millilitres of thionyl chloride wa~ refluxed for two
hours. Evaporation followed by the addition of dry benzene
(2 x 50 ml) and re-evaporation gave the acid chloride as
a pinkish solid. This was added in portions to a stirred
.:
$ce-cooled solution of 4.7 grams (0.03 mole) of 4-amino-1-n-butyl
piperidine in 60 millilitres of chloro~orm with 120 millilitres
of~ater and 31.8 grams of sodium carbonate. The mixture
was atirred at room temperature overnight. The mixture ~as
~ then filtered, the filtrate ~as separated and the chloroform
- ~ - layer ~as evaporated to give a yellow solid which ~as
~ ~ triturated ~ith ether. Recrystallisation from absolute
, . ,
; alcohol gave 4.2 grams of N-(l-n-butyl-4-piperidyl)-2-
(7-chloro-4-quinolylamino) benzamide, m.p. 231-32C.
Analysis: Found: C, 69.0%;~H, 6.82%; N, 12.7%; C25H29ClN40
requires C, 68.7%; H, 6.69%; N, 12.8%.
~ ' ' '- .
:
.
_ 18 -
~06708Q
H-20a-Canada
EXAMPLE 11
?-(7-Chloro-4-quinolylamino)-N-(1-ethyl-3-piperidyl~
benzamide
0.2~6 Gram of 4,7-Dichloroquinoline and 0.356
gram of 3-(o-aminobenzamido)-1-ethyl-piperidine are
heated together under re~lux in glacial acetic acid
for five minutes and then heated on a steam bath for
two hours. The resulting mixture is pourad into
uater, ~iltered, and oasification of the filtrate gives
the title compound.
- 19 -
