Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
63
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel 1(2H)-isoquino-
lone compounds and the acid addition salts thereof which
exhibit useful analgesic, gastric secretion inhibitory,
anti-depression, anti-histamine, anti-chlorinergic and
anti-ulcer activities.
~.
X
- 2 -
SU~ RY OF Tl-IE INVENTION
The present invention is thcrefore to provides
novel 1(2H)-isoquinolone compounds having the formula (I)
hereinafter described and the acid addition salts thereo~
which are useful as pharmaceutical agents.
BRIEF DESCRIPTION OF THE ~RAWINGS
Figures l(a) and l(b) are graphs showing effects
of the known compounds and Compound C of ~l1is ~vention
on the decrease in body temperature induced by administ-
ration of reserpine.
Figures 2(a) and 2(b) are graphs showing the
! anti-histamine activity and the anti- chlorineryic activi-ty
of Compound A of this invention.
Figures 3(a) and 3(b) are graphs showing the
anti histamine activity and the anti-chlorinergic activity
of Compound B of this invention.
Figures 4~a) and 4(b) are graphs showing the
anti-histamine activity and the anti-chlorinergic activity
of Gompound C of this invention.
DET~ILED DESCRIPTION OF TIIE INVENTION
- The 1(2~1)-isoquinolone compounds according to
the present invention are represented by the formula (I)
~ ~3~;33
y ~ f N Z N -~R
wherein Y represents hydrogen, chlorine or a methoxy
group, Z repres~nts a straight chain or branched chain
divalent saturated aliphatic hydrocarbon group having 2
to 4 carbon atoms, Rl represents a cyano group, a lower
alkoxycarbonyl group, a carbamoyl group, an N-substituted
carbamoyl group, a phenyl group or a substituted phenyl
group, R2 represents hydrogen or a lower alkyl group,
R3 represents a lower alkyl group~ or R2 and R3 can form,
when taken together with tlle nitrogen atom to which they
are attached, a heterocyclic group, and the acid addition
salts thereof.
The term "a straight chain or branched chain
divalent saturated alipha~ic hydrocarbon group" as used
herein means an alkylene group having 2 to 4 carbon atoms
which can be substituted with an alkyl group having 1 to
4 carbon atoms, for example, an ethylene group~ a trimethylene
group, a methylethylene group, a methyltrimethylene group
and the like.
The term "a lower alkoxycarbonyl group" as used
herein means an alkoxycarbonyl group having 1 to 4 carbon
7~3
atoms in the alkoxy moiety such as a methoxycarbonyl
group, an e-thoxycarbonyl group, propoxycarbon~l groups,
butoxycarbonyl groups and the like.
The term "N-substituted carbamoyl group" as used
herein means an N-alkylcarbamoyl group, an N,N-dialkyl-
carbamoyl group wherein each alkyl group has 1 to 4 carbon
atoms, a 4-methylpipera~inocarbonyl group, a morpholino-
carbonyl group and the like.
The term "substituted phenyl group" as used herein
means a halophenyl group such as a p-chlorophenyl group
or an alkoxyphenyl group having 1 to 4 caTbon atoms in the
,
alkoxy group, for example, a p-methoxyphenyl group.
The term "lower alkyl group" as used herein means
a straight chain or branched chain alkyl group having 1
to 4 carbon atoms such as methyl, ethyl, n-propyl, iso-
propyl, n-butyl, sec-butyl and the like.
Examples of the heterocyclic group formed by R2
and R3 together with the nitrogen atom to which they are
attached are a pyrrolidino group, a piperidino group,
a 4-methylpiperazino group9 a 4-~ydroxyethylpiperazino
group, a morpholino group, etc.
The term "acid addition salts" as used herein for
the compounds of the formula (I) means the salts with
pharmaceutically acceptable inorganic or organic acids
and preferred examples of the salts are hydrochloride,
sulfate~ hydrobrornide, methanesulfonate, maleate, tartarate,
7~
citrate, lactate and tl1e like.
fhe 1(2~ isoquinolone compounds of the formula (I)
can be prepared by reacting a substituted-1~2~ isoquinolone
having the formula ~II) Rl
y )`\~ ,/~
wherein Y and ~l are as defined above, with a substituted-
aminoalkyl halide of the formula ~III)
! .. X - Z N / (III)
R3
wherein X represents a halogen atom such as chlorine,
bromine ancl the like and Z, R2 and R3 are as defined above~
in the presence o a basic catalyst.
More particularly, the above reaction between the
compounds of the formulae (II) and (III) can be advantage-
ously carried out by dissolving the substituted l~2~
iso~uinolone of the formula (II) in an organic solvent
such as dimethylfoTmamide, dimethyl sulfoxi.de, toluene,
ethanol, etc., adding thereto a basic catalyst, for example,
alkali metal carbonates such as potassium carbonate,
sodium carbonate and the like, sodium hydride, sodium amide,
alkali metal alkoxides such as sodium methoxide, sodium
- 5 -
7~
ethoxide, potassiuln t-butoxide and the like, followed by,
optionally, heating; then adding to tl1e resulting reaction
mixture the substituted aminoalkyl halide of the -formula
~III) and heating thc mixture at a temperature of about
80 to about 140C for a period of about l to 5 hours.
In the above reaction~ the bas~c catalyst and the
substituted aminoalkyl halide can be used in at least an
equimolar amount to the substituted 1(21-1)-isoquinolone
of the formula (II). Also, the substituted aminoalkyl
halide ~III) can be used in the form of a salt with an
inOTganiC acid such as hydrochloride and the like and,
in such instance, the base is pre-Eera~ly used in
an excess amount over the equimolar amount to the
compound (II).
Most oE the substituted aminocllkyl halide of the
formula (III) are commercially available, but when the
desired aminoalkyl halides are not available, the compounds
of the formula (I) can also be prepared from the substituted
l~2H)-isoquinolone of the formula ~II) via an a~lternative
route using an amine according to the following procedures.
That is, the compounds of the -formula (I) can be prepared
by reacting the compound of the formula (II) with a hydroxy-
alkyl halide of the formula (IV)
X- Z- 0~1 ~IV)
wherein X and Z are as clefined above, to produce the corres-
~ ~5;~7~3
-- 7
ponding 2-(hydroxyalkyl)-l(211)-isoquinolone compound of
the formula (V)
R
~h (v)
y/~ ,N-- Z--011
O
l~herei.n Y, Z ancl Rl are as defined above, reacting the
compound of the formula (V) with a halogenating agent ~o
produce a 2-(haloalkyl)-1(211)-isoquinolone compound of
B the formula (~I)
, R
Y 1~N-- Z --X (VI)
wherein Y, Z, Rl ahd X are as defined above, and reacting
the compound of the formula (VI) with an amine of the
formula (VII)
~IN ~ R2
~ R3
wherein R2 and R3 are as defined above.
In the above alternative procedure~ the reaction
between the compounds of the formulae ~II) and (IV) can
be carried out using abou~ l ~o about l.5 mol of the
7~3
hydroxyalkyl halide of the formùla (IV) per mol of the
compound of the formula ~II) in an organic solvent such
as dimethylformamide~ toluene and the like, in the presence
o~ a base such as potassium charbonate, sodium
carbonate, sodium hydride and the like in an amount of
at least about Z mols per mol of the compound of the
formula (II), at a temperature of about 80 to about 140C
for a period of about 1 to 5 hours.
The reaction of the thus obtained 2-(hydroxyalkyl)-
- 10 1(2H)-isoquinolone compound of the formula (V) with a
halogenating agent can be carried out by heating at reflux
in the presence or absence of organic solvent for a period
of about 30 minutes to about 2 hours. Suitable examplcs
of halogenating agents are thionyl chloride, oxalyl chloride,
phosphorus oxychloride, phosphorus oxybromide ancl the like.
These halogenating agents may be used in a molar excess
amount so as to serve as a solvent and in such case the
organic solvent may not be used. Suitable examples of
organic solvents are benzene~ carbon tetrachloride~ etc.
The subsequent reaction of the thus obtained 2-
thaloalkyl)-1(2H)-isoquinolone oE the formula (VI) with
an amine of the formula (VII) can be conducted while heating
at reflux for a period of about 1 to 6 hours, optionally
in the presence of an inorganic base as exempli-
fied before for the reaction of the compounds of the
7~
formulae (II) and ~III). T11e rcaction can be advantage-
ously carried out using an organic solvent having a boiling
point higher than that of the amine (VII) used? for example,
xylene, tetralin~ ethylbenzene, etc. When the amine used
has a relatively lo~ boiling point, the reaction is advanta-
geously carried ou~ in a sealed reaction vessel.
The compounds of ~he formula (I) having a substituted
carbamoyl group at the 4-position can also be prepared by
heat-reacting thc ~-ester compound of the formula (I')
Rl
~ / ~ N- Z- N
y / ~ R3
o
wherein Rl is a lower alkoxycarbonyl group and Y, Z, R2
and R3 are as clcfined above, wi-th an aminc of the formula
(VII) in an alcohol solvent.
I~lternatively, the 4-carbamoyl compounds of the
lS formula (I') aboue can be obtained by hydrolyzing the
2-(hydroxyalkyl)-1(2~1)-isoquinolone compound of the formula
(V)
- R
q (V)
Y b~
37~3
- 10 -
wherein Rl reprcsents a lo~er alkoxycarbonyl group, and
Y and Z are as defined abovc, dissolved in an alkaline
alcohol to obtaln the corresponding 4-carboxy compound
of the formula (VIII)
COO~I
,~\,q
1 11 (VIII)
y / ~ ~ ~ N~ Z - 011
wherein Y and Z are as definecl above, reacting the thus
obtained 4-carboxy compound wi-th a halogenating agent
such as thionyl chloride, o~alyl chloride, phosphorus
oxychloride, phosphorus oxybromide and the like in the
presence.o:E an organic solvent such as benzene or carbon
tetrachloride, or in the absence of tlle organic solvent,
for a period of about 1 ~o 3 hours to obt~in the correspon-
ding 4-acid halide compound of the formula ~IX)
COX
y ~ N- Z - X ~IX)
wherein X, Y and Z are as defined above, reacting the
thus obtained 4-acicl halide compound ~IX) l~ith an amine
of the formula (VII) in an amount of at least about 2 mols
- lU -
7~
per mol of the 4-acid halide compound ~IX) in an organic
solvent such as benzene, chloroform, diethyl ether at
room temperature ~about 15 - 30C) for à period of about
1 to 5 hours to obtain the corresponcling 4-carbamoyl
compound of the formula ~X)
CON \ 2
q~ ~ z - x (X)
y
O
. wherein X, Y, Z, R2 and R3 are as defined above, and
reacti.ng the resulting 4-carbamoyl compound of the formula
(X) with an amine of the formula (VII) in an organic
solvent such as acetone, benzene, toluene at a temperature
of about 90 to about 150C for a period o:f about 1 to 6
hours to obtain the desired compound of the formula (I').
When the same amine is used in the ami(lation of the
4-acid halide compound (IX) and the amination of the 4-
carbamoyl compound (X~, these reactions are not necessaryto conduct in two steps, and the desired compound of the
formula (I') can be obtained in a single step by reacting
the compound of the formula ~IX) with an excess of the
amine (VII) according to the procedure as described above
for the reaction between the compounds of the formula (VI)
or (X) and the amine ~VII).
7~3
- 12 -
The object compounds of tlle formula (I) are
generally obtained in the form of free base and, if desired,
the free base can be easily converted into their acid
addition salts by a conventi.onal procedure ~ell known in
the art, for example, by reacting the free base with an
inorganic or organic acid in a solvent such as et1lanol,
ethyl acetate, acetone and the like or an aqueous acid
solution at room temperature or an elevated temperature.
The starting matcri.als of the :formula ~II) whercin
Rl represents a cyano group or a lower alkoxycarbonyl
group and Y represents chlorine or a methoxy group are
novel compounds and can be obtAined according to the
~ollowing reaction scheme:
1S ~ ~ 3
Y ~XI) Y ~XII)
(XIII) ~II)
where:i.n Y is Cl or -OC113, and Rl is -CN, -COOR ~R=C~-13,
C2~15, C3117 or C4119).
- 12 -
7~3
- 13 -
~ lore spcciEical~y, 1 mol of a p-substituted phenyl-
acetic acid lower alkyl ester of the formula (XI) (or an
acetonitrile compound), about 1 to 1.5 mol of a sodium
alkoxide and about 1.5 to 3 mols of ethyl formate are
mixed in diethy] ether, and the mixture is allowed to react
for about 10 to 24 llours at room temperature to obtain the
formyl compound of the formula (XII). Thc resulting formyl
compound and an equimolar amount of urethane are hea~-
refluxed in the presencc o:~ concentrated sulfuric acid
in toluene to obtain the ethoxycarbonylamino compound of
the formula ~XIII) which is then heated under reflux in diphenyl
ether to obt~in the starting material of the fo~mula (II).
The starting materials of the ormula ~II) having
a lower alkoxycarbonyl group of 1 to ~ carbon atoms at the
4-position are novel compounds regardless of the type of
substituent at the 7-position, and these compounds can be
easily prepared by esterification o-f 4-carboxy compounds
or transesterification of methoxy- or cthoxycarbonyl
compounds. rhese reactions can be achieved using a desired
alcohol in the presence of concentrated sulfuric acid
while heating at reflux for about 10 to 20 hours.
The object compounds of the formula (I) thus obtained
exhibit excellent analgesic, anti-reserpine ~anti-depressant),
anti-histaminic, anticholinergic, gastric secretion inhibiting
and anti-ulcer activities in mammals and, therefore~ are
- 13 -
b~6 3
useful as pharmaceutical ~gents.
The dose level of the compounds of the present
invention as pharmaceutical agents varies depending upon
the severity of conditions to be treated, the age of patients,
the ~ype of diseases or other factors, bu~ generally ranges
from 0.5 to 50 mg/kg of body weight per day in adult human
administcred as a single dose or multiple dose ~flivided
into 2 to 3 doscs).
lhe compounds o-f this invcntion can be~ administered
orally, parenterally or intrarectally in various dosnge
forms such as tablets, capsules, granules, powders, injections,
suppository, ointments and the like.
The above preparations are formulated as compositions
comprising suitable carriers or excipients by the procedure
generally used in preparing pharmaceutical compositions.
Tllc tablets, ca~sulcs, granules, powdcrs, etc. -~or
oral administration can be prepared from excipients generally
used in the art, for example, calcium carbonate, calcium
phosphate, starch, sucrose, lactose, talc 3 magnesium
stearate, geletin, polyvinylpyrrolidine, gum arabic, sorbitol,
cystalline cellulose, polyethylene glycol, carboxymethyl-
cellulose, silica and the like. Also, tablets and granules
can be coated according -to the method well known in the art.
Tlle injections can be aqueous or oily suspensions,
solutions, or powder filled in ampollles or rreeze-dried
- 14 -
~L5~763
-15-
1 preparation wh.ich is instantly dissolved in a liquid
medium jus-t before the use~ and these preparations can
be prepared according to the procedure well known in the
art.
The suppositories can contain well-known
carriers, for example, polyethylene glycol, lanolin, cacao
butter, fatty acid triglycerides and the like.
The ointments can be prepared from conventional
base materials by the procedure well known in the a.rt~
J~3
- 16 -
The present invention is further illustrated in
greater detail by the -following Examples and Re~erence
Examples, but they are not to be construed as limiting the
present invention. Unless otherwise indicated, all parts,
percents, rat;os ancl the like are by weight.
Example
22 g of 4-phenyl-1(21I)-isoquinolone and 30 g of
anhydrous potassium carl)onate were added to 100 ml of
dimethylformamide and the mixture was stirred for 2 hours
at 120C. 18 g of 3-N,N-dimethylaminopropyl chloride
was added to the solution and the mixturc was stirred for
3 hours at 100C. After completion of the reaction, the
solvent was distilled oEf and water and subsequently
dichloromethane were added to the residue, followed by
lS thoroughly shaking. The dichlorollIethane layer was separated,
washed ~/ith watcr and dricd ovcr anhydrous sodium sulfate.
The solvent was distilled off and the residue was recrystal-
lized from ligroin to obtain 23 g oE 2-(3-N,N-dimethylamino-
propyl)-4-phenyl-1(2II)-isoqunolone having a melting point
of 95C as colorless prisms.
Elementary Analysis:
Calcd for C20~I22N2o 306.411
C, 78.40; }I, 7.24; N, 9.14 t~)
Found: C, 78.36; II~ 7.32; N, 8.97 (%)
80 ml Or a solution of 16 g of 2-(3-N,N-climethylamino-
propyl)-4-phenyl-1(2I-I)-isoquinolone in ethyl ace~ate and
- 16 -
~154371Eii3
-17-
1 100 ml of a solution of 8 g of tartaric acid in ethyl
acetate were combined and the resulting mixture was warmed
with stirr1ng for a while. After allowing the mixture to
cool, the precipitated crystals were filtered and recrystal-
lized from a mixture of ethanol and petroleum ether toobtain 18 g of 2-(3-N,N-dimethylaminopropyl)-4-phenyl-
1(2H)-isoquinolone tartrate having a melting point of 114C
as colorless needles.
Elementary Analysis:
Calcd for C20EI22N2O C4H6 6
C, 63.15; H, 6.18; N, 6.14 (~)
Found: C, 63.29; ~1, 6.23; N, 6.06 (%)
Example 2
A mixture of 22.1 g of 4-phenyl-1(2H)-isoquino-
lone, 20 g of anhydrous potassium carbonate and 100 ml of
dimethylformamide was stirxed for 2 hours at 100C. Then,
11 g of 3-chloropropanol was added to the resulting solution
and the mixture was stirred at 110C for 5 hour A~ter
completion of the reaction, the solvent was distilled off,
and the residue was dissolved in dichloromethane. Water
was added to the resulting solution and, after thoroughly
stirring, the dichloromethane layer was separated and dried
over anhydrous sodium sulfate. The solvent was dis-tilled off,
and the resulting resi:due was recrystallized from a mixture
of ethyl acetate and petroleum ether to ob-tain 23 g of 2-
(3-hydroxypropyl)-4-phenyl-1(2H-isoquinolone having a
melting point of 84C as colorless prisms~
~ ' .
7~i3
- 18 -
Elementary Analysis:
for Cl8 l7N2 279.342.
C, 77.40; ~I, 6.13; N, 5.01 (%)
Found: C, 77.47; ~1, 6.09; N, 5.11 (%)
Then,23;g of 2-(3-hydroxypropyl)-4-phenyl-1~2H)-
isoquil1olone was added to a mixture of 60 ml of benzene
and 25 ml of thionyl chloride and the mixture was heated at
reflux for l hour. The solvent was distilled off and the
residue was dissolved in dichloromethane. The soltuion was
washed with water and dried, and then the solvent was distilled
off. The resulting crystals were recrystallized from a
mixture of ethyl acetate and petroleum ether to obtain
23.3 g of 2- (3-chloropropyl)-4-phenyl-l(21l)-isoqllinolone
having a melting point of 138C as colorless prisms.
Elementary Analysls:
Calcd for Cl811l6ClN0 297.787:
C, 72.60; ~1, 5.42; N, 4.70 (%)
Iound: C, 72.64; H, 5.40; N, 4.77 (%)
Then, ]4.9 g of 2-~3-chloropropyl)-4-phenyl-1(211)-
isoquinolone, 7 g oE anhydrous potassium carbonate and
40 ml o-f piperidine were mixed an;l heated at reflux for 5
hours. Thereafter, any excess of piperidine was distilled
off and the residue was dissolved in dichloromethane. The
solution was washed with water, dried and the solvent was
distilled off. 'lhe resulting crystals were recrystallized
- 18 -
~S,~7~
- 1 9 -
1 from a mixture oE die-thyl ether and p~troleum ether to
obtain 15.6 g of 2-(3 piperidinopropyl)-4-phenyl-1(2H)-
isoquinolone having a melting point of 117.5C as color
less prisms.
S Elementary Analysis:
Calcd for C23H26N2 = 346-476;
C, 79.73; H, 7.56; N, 8.09
Found: C, 79.85; H, 7.55; N, 8.00
Then, 10.4 g of 2-(3-piperidinopropyl)-4-phenyl-
1(2H~-isoquinolone was dissolved in 80 ml of ethyl acetate
and 4 g-of maleic acid was added to the solution, followed
by stirring while warming. After cooling, the precipitated
crystals were filtered and recrystallized from a mixture
of diethyl ether and petroleum ether to obtain 12.2 g of
2-(3-piperidinopropyl)-4-phenyl-1(2H)-isoquinolone maleate
having a melting point of 160.5C as colorless prisms.
Elementary Analysis:
calcd for C23H26N2 C4H404
C, 70.11; H, 6.54; N, 6.~6 ~)
Found: C, 70.05; H, 6.58; N, 6.02 (%)
The corresponding hydrobromic acid salt was
obtained by the following procedure:
10.4 g of 2-(3-piperidinopropyl)-4-phenyl-1~2H)-
isoquinolone was dissolved in 50 ml of acetone and 10 ml
of a 47~ aqueous solution of hydrobromic acid was added
-thereto and the mixture was warmed. After cooling, the
~,~L5~P763
- 20 -
precipitated crystals were filtered and recrystallized
from a mixture of methanol and petroleum ether to obtain
11.6 g of 2-(3-piperidinopropyl)-4-phenyl-1(2~ isoqu;inolone
hydrobro~;de having a melting point of 300C as colorless
needles.
Elementary ~nalysis:
Calcd for C23ll26N2 ~lBr = 427.393
C9 64.64; }I, 6.37; N, 6.55 (%)
Found: C, 64.75; 1-1, 6.37; N, 6.46 (%)
Example 3
22 g of 7-chloro-4-ethoxycarbonyl-1(2H)-isoquinolone
and 0.5 g of sodium hydr;de were added to 100 ml of toluene 7
and the mixture was heatcd at reflux. I`hereafter, 20 g of
N,N-dimethylamillopropyl chloride was added to the reaction
mix~ure, fvllo~cd by stirring Eor 2 hours ~It loaoc. l'he
reaction mixture was then worked up in ~he same manner as
described in Example 1 and the resulting crystals were
recrystallized from petroleum ether to obtain 22.3 g of
7-chloro-2-(3-N,N-dimethylaminopropyl)-4-ethoxycarbonyl-
1(2~1)-isoquinolone having a melting point of 60C as color-
less needles.
Elementary ~nalysis:
17 21 lN2O3 336.~22:
C, 60.62; ~1, 6.28; N, 8.32 (~)
Found: C, 60.55; Il, 6.32; N, 8.21 (~)
- 20 -
7~
- 21 -
Then, 7-chloro-2-(3-N,N-dimethylaminopropyl)-4-
e~hoxycarbonyl-1(2~l)-isoquinolone was reactccl with maleic
acid in the same manner as described in Example 2 and the
resulting crystals were recrystallized from a mixture of
ethanol and petroleum ether to obtain 7-chloro-2-(3-N,N-
dimethylaminopropyl)-4-ethoxycarbonyl-l(~H)-isoquinolone
maleate-l/2 hydra-tc hav:ing a melting point of 146.5C as
colorlcss needles.
Elementary ~nalysis:
Ci7~121ClN23 c4~ 04-1/2~l2o = 461.904
C, 54.61; H, 5.67; N, 6.06 ~)
Found: C, 54.78; ~-1, 5.53; N, 5.95 ~%)
Example 4
Z5 g of 7-chIoro-4-ethoxycarbonyl-1(2}l)-isoquinolone
was dissolved in 100 ml of dimethylformamide while warming,
and 27 g of anhydrous potassium carbonate was added to the
solution, followed by stirring for 2 hours at 110C. Then,
14 g of 3-chloropropanol was added thereto and~the stirring
was continued for 5 hours at 110C. The solvent was
distilled off and the residue was dissolved in dichloro-
methane. The solution was washed with water, dried and
the solvent was distilled off. The resulting crystals
were recrystallized from a mixture of ethanol and petroleum
ether to obtain 20.1 g of 7-chloro-4-ethoxycarbonyl-2-
(3-hydroxypropyl)-1-(21-l~-isoquinolone having a melting
- 21 -
~3763
- 22 -
point of 193C as colorless prisms.
Elementary Analysis:
Calcd for C15l16ClN4 309.752:
C, 58.16; H~ 5.21; N, 4.52 (%)
Founcl: C, 58.29; }I, 5.26; N, 4.53
Then, 20.1 g of 7~chloro-4 ~ ethoxycarbonyl-2-(3-
hydroxy~ropyl)-1(2ll)-isoquinolone was dissolved in 50 ml
of ethanol, and 100 ml of an ethanolic solution of 5.5 g
of potassium hydroxide was added to the resulting solution,
followed by thorvughly stirring. The resultin~ solution
was then poured into ice-water and the mixture was filtered.
The filtrate was rendered neutral with dilute acetic acid
and the precipitated crystals were filtered and washed
with water. Recrystallization from a mixture of ethanol
and petroleum etller gave 16.4 g o~ 4-carboxy-7-chloro-2-
~3-hydroxypropyl)-lt2~l)-isoquinolone having a melting point
of 193C as colorless prisms.
Elementary ~nalysis:
Calcd for C13lll2ClNO4 = 281.69~: -
20C, 55.43, Il, 4.29; N, 4.97 ~)
Found: C, 55.40; ~I, 4.38; N, 4.86 ~%)
Then, 16.4 g of 4-carboxy-7-chloro-2-(3-hydroxy-
propyl)-1(21~)-isoquinolone was suspended in 100 ml of
benzene, and 25 g of thionyl chloride was added to the
25 - suspension. The resul~ing mixture was heated at reflux
- 23 -
for 3 hours and the solvent was distillcd off. The
residue was dissolved in dichloromethane and the solution
was washed with water and dried. The solvent was distilled
off and the rcsulting crystals were recrystallized from
a mixturc of ethyl acetatc and petroleum ether to obtain
15.6 g of 7-chloro-4-clllorocarbollyl-2-(3-cllloropropyl)-
1(2ll)-iso(luinolollc h.l.Villg a mclting point of 125C as
color]ess prisms.
Elemcntary ~nalysis:
Calcd for C13ll10(13No2 3
C, 49.01; ~1, 3.16; N, 4.40 (~)
Found: C, 49.20; Il, 3.10; N, 4.26 ~%)
Tllcn, a mixturc of 3.2 g of 7^chloro-4-chlorocarbonyl-
2-(3-chloropropyl)-1(2ll)-isoquillolonc, 100 ml of a 20~
solution of dimcthylaminc in acctollc and 2.5 g of anhydrous
t.lSSiUI1l carl~ollate was he.ltc~d at ~0C in an autoclave
for 6 hours. 'I'hc solvcnt was clistillccl off and the residue
was dissolvc(l in dichloroll)ctll.lnc. Ihc solution was washed
Witll w.ltel, dricd arld thc solvcnt was distilled off. The
resultillg crystals were recrystallized from a mixture of
ethanol and pctrolcum ether to obtain 2.5 g of 7-chloro-
2-(3-N,N-dimetllylaminopropyl)-4-N,N-dimct}lylcarbamoyl-1(2H)-
isoquinolone having a melting point of 145C as colorless
prisms.
- 23 -
763
- 2~ -
Elementary Analysis:
Calcd for C17~l22ClN32
C, 60.80; ~I, 6.60; N, 12.51 (%)
Found: C, 60;92; I-l, 6.63; N, 12.41 (%)
Example 5
A mixturc of 21.6 g of 4-ethoxycarbonyl-1~2~l)-
isoquinolone, 25 g of anhydrous potassium carbonate and
100 ml of dimethyl~orlllalnide ~as heated at lOODC for 2 llours.
Then, 14 ml of 3-chloropropallol was adcled thereto and
the mixture was heated at 110C for 4 hours. The solvent
was distilled o-f-f and the residue was extracted with
dichloromethane. The extract was washed with water, dried
and thc solvent was distilled off. 120 ml oE an ethanolic
solution of 5.5 g of ~otassium hydroxide was added to the
residue, and the mixture was warmed. AEter cooling~ the
reaction mixture was poured into ice-water and then filtered.
The filtrate was rendered neutral with dilute acetic acid,
and the precipitated crystals were filtered and recrystal-
lized from a mixturc of ethanol and petroleum ether to
obtain 12.5 g of 4-carboxy-2-(3-hydroxypropyl)-1(2~
isoquinolone having a melting point of 205C as coloTless
prisms.
Elementary Analysis:
Calcd for C13~l13N4 = 247-253
C, 63.15; ~19 5.30; N, 5.66 (%)
Found: C, 63.23; ~-I, 5.3G; N, 5.54 (%)
- 24 -
,'P~l7~3
- 25
Thcn, 12.5 g of 4-carboxy-2-t3-hydroxypropyl)-
1~2H)-isoquinolone was added to a mixture of 50 ml of
carbon tetrachlor;de and 25 ml of thionyl chloride, and
the Tesulting mixture was heated at reflux for 2 hours.
'I'he solvcnt was distilled oEf and the residue was dissolved
in dichloromethanc. The solution was washecl witll water,
dried and tlle solvent was distilled off. The resulting
crystals were recrystalliæed -from a mixture of ethyl acetate
and petroleum ether to obtain 12.8 g of 4-chlorocarbonyl-
102-~3-chloropropyl)-1~2~-1)-isoquinolone having a melting
point of 101C as colorless prisms.
Elementary Analysis:
Calcd for Cl~HllC12N2
C, 5~.95; Il, 3.~0; N, 4.93 (~)
15Found: C, 5~.83; Il, 3.92; N, 4.86 (%)
Then, 12.8 g of ~-chlorocarbonyl-2-(3-chloropropyl)-
1-(21-l)-isoquinolone was dissolved in 150 ml of chloroform,
and a mixture of 6.6 g of n-butylamine and 20 n~l of triethyl-
amine was added thereto while stirring. ~fter 5 hours,
the reaction mixture was washed with water and dried.
The solvent was distilled off and the resulting crystals
were recrystalli~ed from a mixture of ethyl acetate and
petroleum ether to obtain 10 g of 4-N-n-butylcarbamoyl-2
(3-chloropropyl)-1(2~1)-isoquinolone having a melting point
of 1~9C as colorless prisms.
7ç~3
- 26 -
Elementary Analysis:
Calcd for C17~121ClN22
C, 63.65; 1-1, 6.60; N, 8.73 (%)
Found: C, 63.79; ~-1, 6.53; N, 8.70 (%)
Then, 10 g of 4-N-n-butylcarbamoyl-2-(3-chloroprGpyl)-
1(2l-1)-iso~luinolonc, 9.5 g of anhydro-ls potassiwn carbonate
and 200 ml of a 20% solution of dimcthylamine in acetaone
were placed in an autoclave, and the mi.xture was heated
a-t 90C for 5 hours. Therea-fte~, -the reaction mixture was
filtered and the solvent was distilled off from the filtrate.
The resulting oily substance was reacted with oxalic acid
in the same manner as described in Example 1 for the
preparation of tartaric acid salt. The resulting crystals
were recrystallizcd from a mixtur~ of methanol and diethyl
ether to obtain 7.5 g of 4-1~-n-butylcarbamoyl-2-(3-N,N-
dimethylaminopropyl)-1(21-1)-iso~uinolone oxalate ha~ing a
melting point of 211C (with dccomposition) as colorless
prisms.
Elementary Analysis:
Calcd for C19~127N302 C2~124
C, 60.13; 1-1, 6.97; N, 10.02 (%)
Found: C, 60.29; H, 6.90; N, 10.08 ~)
The following compounds were prepared in the same
manner as desribed in the foregoing Examples 1 to 5.
- 26 -
37~3
- 27 -
Examr)le 6
2-(2-N,N-Dimethylaminoet]lyl3-4-phenyl-lt2H)-
isocuinolone. Recrystallized from a mixture of diethyl
ether and petroleum ether. Colorless prisms having a
melting point of 89C.
Elcmcntary Analysis:
lc ror C191120N2 292.384:
C, 78.05; 1-1, 6.89; N, 9.58 ~)
Found: C, 78.09; ~1, 6.79; N, 9.63 (%)
2-(2-N,N-Dimethylaminoe~hyl)-4-phenyl-1~21-1)-
isoquinolone hydrochloride. Recrystallized from a mixt~re
.
of ethanol and petroleum ether. Colorless needles having
a melting point of 258.5C.
Elementary Analysis:
Calcd for C19}12oN2~ -lCl = 328.845:
C, 69.40; 1-1, 6.44; N, 8.52 (%)
Found: C, 69.49; H, 6.46, N, 8.53 (%)
Example 7
2-(3-N,N Diethylaminopropyl)-4-phenyl-1(21-1~-
isoquinolone. Recrystallized from petroleum ether.
Colorless leaflets having a melting point of 41C.
Elementary Analysis:
Calcd for C221126N2 334-465
C, 79.01; 1-1, 7.84; N, 8.38 ~%)
Found: C, 78.95; H, 7.91; N, 8.25 ~%)
- 27 -
i .?, j~716; 3
- 28 -
2-(3-N,N-Diethylaminopropyl)-4-phenyl-1(2~
isoquinolone maleate. Recrystallized from a mixture of
ethanol and diethyl etller. Colorl~ss prisms having
melting point of 140C.
Elementary Analysis:
Calcd for C221l26N20 C4l-l~0~ 150.539:
(:, 69.31; ~I, 6.71; N, 6.22 ~%)
Found: C, 69.42; ~I, 6.73; N, 6.09 ~%)
2-~3-N,N-Diethylaminopropyl)-4-phenyl-1(2}l)-
isoquinolone hydrobromicle. Recrystallized from a mixture
oE mcthanol and petroleum ethcr. Colorlcss prisms havin~
a melting point of 1'16.5C.
Elementary Analysis:
Calcd for C22ll26N20 I r 15.
15C, 63.62; ~I, 6.55; N, 6.74 ~%)
Found: C, 63.75; I-l, 6.46; N, 6.69 (%)
Example 8
4-Phenyl-2-(3-pyrrolidinopropyl)-1(21-1)-isoquinolone.
Recrystallized from diethyl ether and petroleum ether.
Colorless prisms having a melting point oE 115C.
Elementary Analysis:
Calcd for C22ll24N20 = 332-449:
C, 79.48; ~1, 7.28; N, 8.43 (%)
Found: C, 79.59; ~I, 7.33; N, 8.40 (%)
- 28-
- 29 -
4-Phenyl-2-(3-pyrrolidinopropyl)-1(211~-isoquinolone
hydrobromide. Recrystallized ~rom a mixture o-f methanol
and pctroleum ether. Colorless needles having a melting
point of 277C.
Elementary /~nalysis:
Calcd for C221124N2O
C, 63.93; Il, 6.10; N, 6.78 ~%)
Found: C, 63.85; Il, 6.:1G; N, 6.70 (~)
Exalllple 9
2-(3-~lorpholinopropyl)-4-phenyl-1(21i)-isoquinolone.
Recrystallized from a mixture of diethyl ether and petroleum
ether. Colorless prisms having a melt;ng point of 101C.
Elementary Analysis:
Calcd for C22ll24N22
C, 75.83; H, 6.94; N, 8.04 (%)
Found: C, 75.95; H, 6.99; N, 7.95 (%)
2- (3-~orpholinopropyl)-4-p}lenyl-1(21-l)-isoquinolone
maleate. Recrystallized from a m;xture of et~anol and
diethyl ether. Colorlcss leclflets haVill~ a melting point
of 192C.
Elementary Analysis:
Calcd for C22H24N22 C41144
C, 67.23; H, 6.08; N, 6.03 (%)
Found: C, 67.41; Il, 6.15; N, 5.90 (%)
- 29 -
763
- 30 -
2-(3-Morpholinopropyl)-4-phenyl-1(21l)-isoquinolonc
hydrobromide. Recrystallized Erom a mixture of methanol
and petroleum cther. Colorless n~cdles having a melting
point higher than 290C.
Elementary Analysis:
Calcd for CZ2ll24N22 IIB
C, 61.54; ~I, 5.87; N, 6.52 ~%)
Found: C, 61.63; Il, 5.89; N, 6.44 (%)
x~ le 10
2-~3-~4-Methylpiperclzin-l-yl)yropyl~-4-pllenyl-1(2
isoquinolone. Recrystallized from a mixture of diethyl
ether and petroleum ether. Colorless prisms having a
melting point of 116C.
Elementary Analys;s:
lS Calcd for C23ll27N3O
C, 76.42; ~I, 7.53; N, 11.62 ~)
Found: C, 76.49; fl, 7.50; N, 11.63 (%)
Example 1l
2-~3-{4-(2-llydroxyethyl)piperazin-1-yl~propyl]-
4-phenyl-1~2l-l)-isoquinolone. Recrystallized from a mixture
of ethyl acetate and petroleum ether. Colorless prisms
having a melting point of 131C.
Elementary Analysis:
CalCd for C24fl29N32
C, 73.63; }1, 7.47; N, 10.73 ~%)
r:ound: C, 73.56; ~I, 7.49; N, 10.72 ~%)
- 30 -
~3~ 3
2-[3-~4-~Z-I-Iydroxyethyl)piperazin-l-yl}propyl]-
4-phenyl-1~21l)-isoquinolone dimalcate. Rccrystallized
from ethanol. Colorless prisms having a melting point
of 192C.
Elementary Analysis:
Calcd for C24ll29N3o2 (C4ll44)2
C, 61.63; ~l, 5.98; N, 6.74 (%)
Found: C, 61.83; l-l, 6.02; N, 6.63 (%)
Example 12
2-t3-N-Iso~ropylaminopropy])-4-phenyl-1(2~
iso~uinolone hydrobromide. Rccrystallized from a mixture
of ethanol and petroleum ethcr. Colorless necdles having
a melting ~oint of 139C.
~lementary ~nalysis:
lS Calcd for C211l24N2 ~IBr
C, 62.85; i-l, 6.28; N, 6.98 (~)
Found: C, 62.89; H, 6.35; N, 6.96 (%)
Example 13
2-(2-N,N-Dimethylaminopropyl)-4-phenyl-l(211)-
isoquinolone. Recrystallized from a mixture of ethanol
and n-hexane. Colorl~ss flakes having a melting point
of 107C.
Elementary Analysis:
Calcd for C20~122N2O
C, 78.40; H, 7.24; N, 9.14 (%)
Found: C, 78.51; ~1, 7.30; N, 9.00 (%)
- 31 -
- 32 -
2-(2-N,N-Dimethylaminopropyl)-4-phellyl-1(2~
isoquinolone maleate. Recrystallized ~rom a mixture of
ethanol and diethyl ether. Colorless needles having a
mclting point of 139C.
Elementary ~nalysis:
C~lcd for C2oll22N20 C411404 =422-485
C, 68.23; Il, 6.20; N, 6.63 (%~
Found: C, 68.35; Il, 6.26;;N, 6.69 ~)
Exam le 14
2-(3-N,N-I)imethylamillo-2-mct}~ylpropyl)-4-phenyl-
1~2}-l)-isoquinolone malcate. Recrystallized from a mixture
of methanol and cliethyl ether. Colorless prisms having
a melting point of 174C.
Elementary Analysis:
Calcd for c21~l24N20 C4~l44
C, 68.79; I-l, 6.47; N, 6.42 (%)
Found: C, 68.74; ~1, 6.56; N, 6.29 ~)
Example 15
2-~3-N,N-Dimethylaminopropyl)-7-methoxy-4-~p-
methoxyphenyl)-1~21-1)-isoquinolone. Recrystallized from
a mixture of diethyl ether and petroleum ethcr. Colorless
needles having a melting pOillt oE 74C.
Elementary l~nalysis:
or C221126N23 366.464:
C, 72.11; Il, 7.15; N, 7.64 (%)
Fountl: C, 72.25; Il, 7.15; N, 7.54 ~%)
- 32
37~`~
2-~3-N,N-~imethylaminopropyl)-7-mcthoxy-4-(p-
methoxyphenyl)-1(211)-isoquinolone maleate. Recrystallized
from a mixture of ethanol and diethyl ether. Colorless
prisms having a melting point of 146C.
Elementary Analysis:
Calc~l for C221126N23 C~ 4
C, 64.72; Il, 6.27; N, 5.81 (%)
Found: C, 64.86; ~1, 6.15; N, 5.90 (%)
Examr~le 16
4-Cyano-2-(2-N,N-diethylaminoethylj-1~2H)-isoquino-
lone. Recrystallized from ligroin. Colorless prisms
having a melting point of 90C.
Elementary Analysis:
Calc(l for C16~119~l3 = 269.349:
C, 71.35; Il, 7.11; N, 15.60 (%)
Found: C, 71.29; Il, 7.16; N, 15.52 (%)
4-Cyano-2-(2-N,N-diethylaminoethyl~-1(2~1)-iso-
quinololle maleate. Rec~ystallized from a mixture of
ethanol and diethyl ether. Colorless needles having a
meltin~ point of 145C
Elcmentary Analysis:
Calcd for C16~119N30 C4114~)4
C, 62.33; ~-1, 6.02; N~ 10.90 (%)
Found: C, 62.20; ~1, 5.89; N, 10.85 (%)
- 33 -
r.~ 7~3
- 34 -
Exam~le 17
4-Cy~no-2-~3-N,N-dime-thylaminopropyl-1(21~
isoquinolone monohydrate. Recrys~allized from pctroleum
ethcr. Colorless needlcs having a melting point o-E 60C.
Elementary Analysis:
Calcd Eor C1SII17N30-~l2O 7
C, 65.91; }1, 7.01; N, 15.37 (%)
Found: C, 65.84; H, 6.85; N, 15.35 (%)
4-Cyano-2-~3-N,N-dime-thylaminopropyl)-1(2}1)-
iso~uinolone tartrate hemihydrate. Recrystallized froma mixture of methanol and petroleum ether. Colorless
prisms having a melting point of 178C.
Elementary Analysis:
Calcd or Clsl-ll7N30-C4ll66 1/ 2
C, 55.07; I-l, 5.83; N, 10.14 (%)
POUJId: C, 55.16; ~I, 5.66; N, 9.~7 (%)
EXamP1e 18
4-Cyano-2-(3-N,N-dimethylaminopropyl)-7-methoxy-
1(2ll)-isoquinolone. Recrystallized from ligroin.
Colorless ~risms having a melting point of 116C.
Elementary Analysis:
Calcd for C16H19N32
C, 67.35; ~I, 6.71; N, 14.73 (%)
Found: C, 67.43; ~1, 6.75; N, 14.60 (%)
- 34 -
37
- 35 -
4-Cyano-2-(3-N,N-dimetllylaminopropyl)-7-methoxy-
lt2~l)-isoquinolone maleate. Recrystallized from a mixture
of ethanol and diethyl ether. Colorless prisms having a
melting point of 174~C.
Elementary Analysis:
Calcd for Cl6}llgN32 C4H404
C, 59.84; 1-l, 5.78; N, 10.47 ~%)
Found: C, 59.73; Il, 5.76; N, 10.55 ~%)
Example l9
2-~3-N,N-dimethylaminopropyl)-4-ethoxycarbonyl-
1(2H)-isoquinolone tartrate hemihydrate. Recrystallized
from a mixture of ethanol and diethyl ether. Colorless
needles having a melting point of 184C ~ith decomposi-
tion).
Elementary Analysis:
Calcd for Cl7ll22N23 C4ll66 / 2
C; 54.42; Il, 6.31; N, 6.04 ~%)
Found: C, 54.60; ~I, 6.25; N, 6.23 ~%)
Example 20
2-~3-N,N-Dimethylaminopropyl)-4-ethoxycarbonyl-
7-mcthoxy-1(21-l)-isoquinolone. Recrystallized frcm petroleum
ether. Colorless needles having a melting point of 50C.
Elementary Analysis:
Calcd for Clg~l24N24 332.403:
C, 65.04; Il, 7.28; N, 8.43 ~%)
Found: C, 65.10; ~I, 7.22; N, 8.43 (%)
- ~5 -
.37~i3
- 36 -
2-~3-N,N-dimethylaminopropyl~-4-ethoxycarbonyl-7-
methoxy-1(2~1)-isoquinolone maleate hemihydrate.
Recrystallizcd from a mi~ture of ethanol and diethyl ether.
Colorless leaflets having a melting point of 121C.
Elementary Analysis:
Calccl for cl8~-l24N2O~ c4ll4O4 1/ 2
C, 57.76; I-l, 6.39; N, 6.12 (%)
Found: C, 57.73; Il, 6.21; N, 6.19 ~%)
Example 21
7-Chloro-4-(p-chlorop}lenyl)-2-(3-N,N-dimethylamino-
propyl)-1(2H~-iso~uillolone. Recrystallized from ligroin.
Colorless prisms having a melting point of 100C
Elcmentary Analysis:
Calcd -for C20}l20C12N2 = 375-301
t', 64.01; ~I, 5.37; N, 7.46 (%)
Found: C, 64.20; I-l, 5.31; N, 7.47 (%)
7-Chloro-4-(p-chlorophenyl)-2-~3-N,N-dimethylamino-
propyl)-1~2}1)-isoquinolone tartrate. Recrystallized from
a mixture of ethanol and diethyl ether. Colorless crystalline
powder having a melting point of 192C.
Elementary Analysis:
Calcd for C20~-l20C12N2 C4~166
C, 54.87; }-I, 4.99; N, 5.33 (%)
Found: C, 54.97; }I, 4.96; N, 5.46 (%)
- 36 -
7 ~ 3
Example 22
7-Chloro-2-(3-N,N-dimethylaminopropyl) 4-N,N-
dimethylcarbamoyl-1~21l)-isoquinolone oxalate. Recrystal-
lized from a mixture of ethanol and diethyl ether.
Colorless needlcs having a melting pOillt of 223C.
Elementary ~nalysis:
Calcd for C17ll22ClN32 C21124
C, 53.59; Il, 5.68; N, 9.87 ~%)
Found: C, 53.46; ~1, 5.62; N, 9.88 (%)
Example 23
7-Chloro-4-(4-methylpiperazin-1-yl-carbonyl)-2-
t 3-(4-methylpiperazin-1-yl~propyl}-1(21-1)-isoquinolone.
Recrystallized from a mixture of diethyl ether and petro-
leum ether. Colorless prisms ha~ing a melting point o~
128C.
Elcmentary Analysls:
Calcd or C23~132ClN5O2 = 445.997:
C, 61.94; }1, 7.23; N, 15.70 (%~
Found: C, 62.06; Il, 7.36; N~ 15.61 ~0)
7-Chloro-4-(4-methylpiperazin-1-yl-carbonyl)-2-
~3-(4-methylpiperazin-1-yl)propyl}-1(2~1)-isoquinolone
tri-maleate. Recrystallized from a mixture of methanol
and diethyl ether. Colorless crystalline powder having
a melting point of 146C.
- 37 -
i43~i3
- 38 -
Elementary Analysis:
Calcd for C23~l32ClN52 3C4~l4O4
C, 52.93; Il, 5.58; N, 8.82 ~%)
Found: C, 52.86; H, 5.66; N, 8.70 ~%)
Example 24
7-Chloro-4-morpholinocarbonyl-2-~3-morpholino-
propyl)-1(2l-1)-isoquinolone. Recrystallized -from a mixture
of ethyl acetate and petroleum ether~ Colorless prisms
having a melting point o-f 178C.
Elementary Analysis:
Calcd for C21l-126ClN3O4 = 419.912:
C, 60.07; 1-1, 6.24; N, lû.01 (%)
Found: C, 60.16; }I, 6.22; N, 9.83 (%)
7-Chloro-4-morpholinocarbonyl-2-(3-morpllolino-
propyl)-1(21-l)-isotluinolone malea-te. Recrystallized from
a mixture of ethanol and diethyl ether. Colorless
needlcs having a melting pOillt of 178C.
Elementary Analysis:
Calcd for C21ll26ClN34 C4~144
20C, 56.02; Il, 5.64; N, 7.84 (%)
Found: C, 56.16; ~I, 5.70; N, 7.88 ~%)
Example 25
4-Carbamoyl-2- ~3-N,N-dimethylaminopropyl)-1(2l-l)-
isoquinolone monohydrate. Recrystallized from a mixture
of ethanol and petroleum ether. Colorless crystalline
powder having a meltin~ point o-f 159C (Wit]l decomposition).
- 38 -
7~3
- 39 -
Elementary Analysis:
Calcd for C15~ 9N32 ~l2
C, 61.84; ~I, 7.27; N, 14.42 (%)
Found: C, 61.79; ~I, 7,30; N, 14.55 (%)
4-Carbamoyl-2-~3-N,N-dime-thylaminopropyl)-1~2ll~-
isoquinolone oxalatc. Recrystallized from a mixturc of
ethanol and pctrolcum cthcr. Colorlcss crystalline powder
having a melting point of 156C.
Elementary Analysis:
; 10 calcd for C15lll9N302 C2}l24
C, 56.19; H, 5.83; N, 11.56 ~%)
Found: C, 56.32; }I, 5.72; N, 11.46 (%)
Example 26
2-~3-N,N-Diethylaminopropyl)-4-N,N-diethylcarbamoyl-
1(2~1)-isoquinolone oxalate. Recrystallized from a mixture
of metllanol and diethyl ether. Colorless prisms haYing
a melting point of 168C.
Elementary Analysis:
Calcd for C21~l31N3~2 C2~l24
C, 61.73; ~-I, 7.43; N, 9.39 (%)
Found: C, 61.65; 1-1, 7.49; N, 9.30 (%)
Example 27
4-n-Butoxycalbonyl-2-(3-N,N-dimethylaminopropyl)-
1(211)-isoquinolone maleate. Recrystallized from a mix-ture
of ethanol and diethyl ether. Colorless prisms having a
- 3'~ -
-
- ~o -
melting point of 142~C.
Elementary Analysis:
calcd for clgll26N2O3 C4~1404
C~ 61.87; Il, 6.77; N, 6.27 t~)
5Found: C, 61.99; }1, 6.76; N, 6.24 ~%)
Exa~ le 28
2-(2-N,N-Diethylaminoethyl)-4-phenyl-1(211)-iso-
quinolone maleate. RecIystallized from a mixture oF
ethanol and dietllyl ether. Colorless needles having
10a melting point of 197.5C.
Elementary Analysis:
Calcd for C21~124N2'C411404
C, 68.79; ~I, 6.47; N, 6.42 ~%)
Found: C, 68.93; Il, 6.55; N, 6.39 ~%)
15~,xample 29
4-Phenyl-2-(2-pyrrolidinoethyl)-1~2f-1)-isoquinolone.
Recrystallized from a mixture of ethyl acetate and petroleum
ether. Colorless prisms having a melting point of 131.5C.
Elementary Analysis:
Calcd for C211122N2O 318.422:
` C, 79.21; Il, 6.96; N, 8.80 (%)
Found: C, 79.16; ~I, 7.04; N, 8.69 ~)
4-Phenyl-2- (2-pyrroliclinoethyl)-1(2ll)-iso~uinolone
maleate. Recrystallized from a mixture of ethanol and
dietilyl ether. (,olorless nc,~edles having a melting point
- ~0 -
-
.q~7~
of 176.5C.
~lementary Analysis:
Calcd for C2~ 22N2 C4ll~4 43 -
C, 69.11; ~I, 6.03; N, 6.45 (%)
~ound: C, 69.29; H, 5.91; N, 6.55 (%)
Ex.lm~le 30
2-(2-l~,N-Llicthylaminol)ropyl)-4-~henyl-1(21l)-
isoquinolone. Recryst~llized from a mixture o-f diethyl
ethel and petroleum ether. Colorless prisms having a
melting point of 92C.
Elementary Analysis:
Calcd -for C 1I N 0 = 334.465:
C, 79.01; }I, 7.84; N, 8.38 (%)
Found: C, 79.00; Il, 7.69; N, 8.45 (~)
lS 2-(2-N,N-Diethylaminopropyl~-4-phenyl-1(2H~-
isoquinolone hydrochloride. Recrystallized from a
mixture of methanol and diethyl ether. Colorless needles
having a melting point of 203C.
Elementary ~nalysis:
Calcd for C221l26N2 IICl
C, 71.24; Il, 7.34; N, 7.55 (%)
Found: C, 71.32t ~I, 7.31; N, 7.38 ~%)
2-(2-N,N-Diethylaminopropyl)-4-phenyl-1(2~
isoquinolone maleate. Recrystallized from a mixture of
methanol and diethyl ether. Colorless prigms having a
- ~1 -
7Ç;3
- 42 -
melting point oE 142C.
Elementary Analysis:
Calcd for C22ll26N2 C411404
C, 69.31; ~1, 6.71; N, 6.22 (%)
5Found: C, 69.51; 11, 6.78; N, 6.25 (%)
Example 31
2-[2-~4-metllylpiperazin-1-yl)ethyl]-4-phenyl-
1~2~1)-isoquinolone. Recrystallized from a mixture of
ethyl acetate and petroleum ether. Colorless prisms
10having a melting point of 103.5C.
Elementary l~\nalysis:
Calcd for C22~125N3 = 347-464
C, 76.05; ~1, 7.25; N, 12.09 (%)
Found: C, 75.92; 11, 7.31; N, 11.95 ~)
2-[2-~4-methylpiperazin-1-yl)ethyl] -4-phenyl-
1(2}1)-isoquinolonc dimaleate. Recrystalli~ed from a
mixture of dimethylfoImamide and methanol. ~hite
crystalline powder having a melting point of 207C
(with decomposition).
Elemelltary Analysis:
Calcd for C22}125N3 2C411404
C, 62.17; }19 5.74; N, 7.25 ~%)
Found C, 62.30; H, 5.65; N, 7.10 (%)
Example 32
4-Phenyl-2- ~2-pyrrolidinopropyl)-1(2~1)-isoquinolone.
- 42 -
7~3
- ~3 -
Recrystallized -from a mixture of di~thyl ether and petro-
leum etllcr. Colorless prisms having a melting point of 84C.
Elementary Analysis:
Calcd for C22ll24N2 3
C, 79.48; Il, 7.28; N, 8.43 (%~
Found: C, 79.44; H, 7.25; N, 8.41 (%)
4-Phenyl-2-(2-pyrrolidinopropyl)-1(2~l)-isoquinolone
hydrochloride. Recrystallized from a mixture of ethanol
and diethyl ether. Colorless needles having a melting
point of 237C (-~ith decomposition).
Elementary Analysis:
Calcd for C22H24N2 IICl
C, 71.63; ~I, 6.83; N, 7.59 (%)
Found: C, 71.56; H, 6.90; N, 7.66 (%)
Bxample 33
4-Phenyl-2-~2-pipcrizinopropyl)-1~2EI)-isoquinolone
hydrochloride. Recrystallized from a mixture of ethanol
and diethyl ether. l~hite crystalline powder having a
melting point of 250C ~with decomposition).
Elementary Analysis:
Calcd for C23ll26N2 ~lCl = 382-937
C, 72.14, ~I, 7.11; N, 7.32 (%)
Found: C, 72.26; H, 7.13; N, 7.20 (%)
Example 34
2-~2-(4-Me~hylpiperazin-l-yl)propyl}-4-phenyl-
1~2H)-isoquinolone dimaleate. Recr-ystallized from a
- 43 -
i376~
- 44 -
mixture of dimethylormamide and ethallol. White crystal-
linc powder having a melting point of 189.5C.
; Elementary Analysis:
Calcd for C231127N3 2C411404
C, 62.72; Il, 5.94; N, 7.08 ~%)
Found: C, 62.93; ~1, 5.81; N, 7~15 (~)
Example 35
7-Cllloro-4-(p-chlorophenyl)-2-~2-N,N-diethylamino-
ethyl)-1(2~1)-isoquinolone. Recrystallized from petroleum
ether. Colorless prisms ha~ring a melting point of 90C.
Elementary Analysis:
Calcd Eor C21~122C12N2
C, 64.79; Il, 5.70; N, 7~20 (%)
E:oun~: C, 64.71; 1-!, 5.73; N, 7.1~ (%)
7-Chloro-4-(p-chlorophenyl)-2-~2-N,N-diethylamino-
ethyl)-1(2H)-iso~llinolone maleate. Recrystallized from
a mixture of ethanol and diethyl ether. Colorless prisms
having a melting point of 134C.
Elementary Analysis:
Calcd for C21~122C12N2-C4~144
C, 59.41; Il, S.l9; N, 5.54 (%)
Found: C, 59.27; ~1, 5.25; N, 5.63 ~%)
Examplc 36
7-Chloro-4-~p-chlorophenyl)-2-(2-N,N-diethylamino-
propyl)-l~l)-isoquinolone. Recrystallized from petroleum
- 44 -
- ~5 -
ether. Colorless pr;sms having a melting point o~` 107C.
Elementary Analysis:
Calcd for C22~-l2~C12N2 = 403-355
C, 65.51; Il, 6.00; N, 6.95 ~%)
Found: C, 65.68; H, 6.11; N, 6.87 (%)
7-Chloro-4-(p-chlorophenyl)-2- (2-N,N-diethylamino-
propyl)-1(211)-isoquinolone hydrochloride. Recrystallized
from aqueous ethanol. Colorless prisms having a meltin~
point of 195C.
Elementary Analysis:
Calcd for C22~124C12N2 HCl = 439-~16
C, 60.08; ~1, 5.73; Nt 6.37 (%)
Found: C, 60.18; }1, 5.62; N, 6.49 (%)
7-Chloro-4-(p-chlorophenyl)-2-(2-N,N-diet:hylamino-
propyl)-1(2~l~-isoquinolonc maleate. Recrystallized from
a mixture of ethanol and diethyl ether. I\~hite crystalline
powder having a melting point of 112C.
Elementary Analysis:
Calcd for C22~124C12N2 C4~144
20C, 60.12; H, 5.43; N, 5.39 (~)
Found: C, 60.06; }19 5.55; N, 5.26 (~)
Example 37
2-~2-N,N-Diethylaminoethyl)-7-methoxy-4-~p-methoxy-
phenyl)-1(211)-isoquinolone malea~e. Recrystallized from
a mixture of methanol and diethyl ether. Colorless prisms
having a melting point of 161C.
- 45 -
93
- ~6 -
E~lementary Analysis:
Calcd for C23~128N23 C41~404
C, 65.31; H, 6.50; N, 5.64 (%)
Found: C~ 65.48; H, 6.48; N, 5.53 (%)
Example 38
2- (2-N,N-Diethylaminoethyl)-4-e~hoxycarbonyl-7-
methoxy-1~2~1)-isoquinolone. Recrystallized from petro-
leum ether. Colorless prisms having a melting point of
47C
Elementary Analysis:
Calcd Eor C191126N24 = 346 43Q
C, 65.88; Il, 7.56; N, 8.09 (%)
Found: C, 65.81; ~I, 7.62; N, 8.06 ~%)
2-(2-N,N-Diethylaminoethyl)-4-ethoxycarbonyl-7-
methoxy-1~2}1)-isoquinolone maleate. Recrystallized from
a mixture of eth~nol and diethyl ether. Colorless needles
having a melting point o~ 135C.
Elementary Analysis:
Calcd for cl9~l26N2o4 C4~1404
20C, 59.73; ~1, 6.54; N, 6.06 (%)
Found: C, 59.90; H, 6.50; N, 6.14 (%)
Example 39
2-(2-N,N-Diethylaminopropyl)-7-methoxy-4-(I)-methoxy-
phenyl)-1(2H)-isoquinolone hydrocllloridc. Recrystallized
from a mixture of ethanol and diethyl ether. Colorless
- l~6 -
7~3
- 47 -
prisms having a melting point of 244C.
Elementary Analysis:
Calcd for C24~l30N23
C, 66.89; ~I, 7.25; N, 6.50 ~%)
Found: C, 66.76; Il, 7.28; N, 6.48 ~%)
Example 40
2-(2-N,N-Diethylaminopropyl)-4-etlloxycarbonyl-7-
methoxy-1~2H)-isoquinolone. Recrystallized from petroleum
ether. Colorless prisms having a melting point of 100C.
Elementary Analysis:
Calcd for C20H28N20~ 360.457
C, 66.64; H, 7.83; N, 7.77 ~%)
Found: C, 66.78; 1-l, 7.70; N, 7.65 (~)
Example 41
2-(2-N,N-Diethylamino-l-methylethyl)-4-phenyl-
1(2~l)-isoquinolone. Recrystallized from a mixture of
diethyl ether and petroleum ether. Colorless prisms having
a melting point o-f 95C.
Elementary ~nalysis:
Calcd for C22~l26N20 334.4
C, 79.01; H, 7.84; N, 8.38 (%)
Found: C, 79.10; H, 7.90; N, 8.25 ~%)
2-~2-N,N-Diethylamino-l-methylethyl)-4-phenyl-
1(2H)-isoquinolone hydrochloride. Recrystallized from
a mixture of ethanol and diethyl ether. Colorless prism~
- ~7 -
7~'3
- 48 -
having a melting point of 198C (~ith decomposition).
Elementary Analysis:
Calccl for C22I-I26N20 I-ICl = 370.926:
C, 71.24; ~I, 7.34; N> 7.55 ~%)
Found: C, 71.16; II~ 7.45; N9 7.60 (%)
Example 42
4-Cyano-2-(2-N,N-diethylaminopropyl)-1(21-I)-iso-
quinolone. Recrystallized from a mixture of diethyl ether
and petroleum ether. Colorless prisms having a melting
point of 93C.
Elementary Analysis:
Calcd for C17II21N30 283.376:
C, 72.06; II, 7.47; N, 14.83 (%~
Found: C, 71.91; Il, 7.55; N, 14.79 (%)
4-Cyano-2-~2-N,N-dietllylaminopropyl)-1(2~I)-iso-
quinolone maleate. Recrystallized from a mixture o~
methanol and diethyl ether. Colorless prisms havillg a
melting point of 148C.
Elementary Analysis:
Calcd for cl7I-I21N30 C4~1404
C, 63.15; H, 6.31; N, 10.52 1%~
Found: C, 63.31; I-I, 6.22; N, 10.4
Example 43
4-Cyano-2-~2-N~N-dimethylaminopropyl)-1(2H)-iso
quinolone. Recrystallized from a mixtuTe oE e~hyl acetate
- ~8 -
i3~3
~9
and ~etroleum etller. Col.orless prisms having a melting
point of 141C.
Elementary Analysis:
Calcd ~or ~15H17N30 255.322:
C, 70.56; Il, 6.71; N, 16.46 {%)
Found: C, 70.44; Il, 6.71; N, 16.59 (%)
4-Cyano-2-(2-N,N-dimethylaminopropyl~-1(2l-l)-
isoquinolone maleate. Recrystallizecl fro~n a mixture of
methanol and diethyl ether. White crystalline powder
having a melting point of 177C.
Elementary Analysis:
Calcd for C15lll7N30 C4~l40~ = 371.396:
C, 61.~5; Il, 5.70; ~, 11.31 ~%)
~ound: C, 61.61; Il, 5.78; N, 11.33 ~%)
The pharmacological activities, acu~e toxicity
and pharmaceutical ~reparations o typical ~xamples of
the comyounds of this invention having the formula tI~ are
illustrated below, in comparison with the typical known
compounds.
EXAMPLE 44
2-(2-N,N-Diethylaminopropyl)-4-phenyl-7-methoxy
1(2H)-isoquinolone malea-te. Recrystallized from a mixture
of ethyl acetate and diethyl ether. Colorless needles having
a melting poin-t of 9BC.
Elementary Analysis:
Calcd for c23H2gN22 C4H4 4
~9
7~3
1 C, 67.48; H, 6.71; N, 5.83 (%)
Found: C, 67~31; H, 6.66; N, 5.88 (%)
EXAMPLE 45
4-(p-Methoxyphenyl)-2-(2-N,N-diethylaminoethyl)-
1(2H)~isoquinolone hydrochloride hemihydrate. Recrys-tall-
ized from a mixture of ethanol and diethyl ether. White
needles having a melting point of 193 C.
Elementary Analysis:
Calc~ for C22H26N22 HCl 1/2 H2O
C, 66.74; H, 7.13; N, 7.07 (~)
Found: C, 66.74; H, 6.91; N, 7.18 ~%)
EXAMPLE 46
4-(p-Chlorophenyl)-2-(2-N,N-diethylaminoethyl)-
1(2H)-isoquinolone hydrochloride hemihydrate. Recrystall-
ized from a mixture of methanol and diethyl ether. White
crystalline powder having a melting point of 194 C.
Elementary Analysis:
C21H23ClN2O HCl^l/2 H2O = 400 3~3:
C, 63.00; H, 6.29i N, 7.00 (%)
Found: C, 62.97; H, 6.17; N, 7.30 (%)
Test Compounds
Compound A: 2-(3-N,N-dimethylaminopropyl)-4-
phenyl-1(2H)-isoquinolone tartarate (prepared in Example 1)
Compound B: 2-(2-N,N-dimethylaminoethyl)-4-
phenyl 1(2II)-isoquinolone hydrochloride (prepared in
Example 6)
-49a-
- so -
Compound C: 4-cyano-2-(3-N,N-dim~thylaminopropyl)-
1(2H)- isoquinololle tartra-te l/2 hydrate
(prepared in Example 17)
Com~oun~ D: 2-(2-N,N-dimetllyl~minol)ropyl)-4-phenyl-
l(211)-isoquinolone malea~e (prepared in
Example l3)
Anal~esic ~ctivity
~ccording to the acetic acid stretching méthod
describe~ by Koster et al [Fed. Pro., l~, 412 ~l959~],
Compoun~ A was administered orally to ddy male mice
(body weight, 20 to 25 g) fasted overnight before test.
One hour aftcr administration of Compound A, a 0.6% aqueous
acetic acid solution was a~ministered intraperitoneally
at a dose o~ 0. 35 ml per mouse and the stretching of the
mice was obscrvcd l0 minutes after the administration of
the acetic acid soiution ~or a ~eriod o~ l0 minutes, alld
the percent inhibition was calculated.
The results obta;ned are shown in T~ble l below.
These results clearly indicate that Compound A inhibited
the pain reaction induced by ~cetic acid injection, at
the dose of 50 and l00 mg/Xg of Compound ~ depending on
the dose lcvel.
- 50 -
63
- 51 -
Table 1
Analgesic ~ctivity
~ose Number of Number of Percent
Compound ~mg/kg) ~nimals Stretching Inhibition
Control 8 36.5~6.5
- Compound A 25 8 33.8+~.2
Compound A 50 8 16.9+4.8 53.7
Compound A 100 8 10.0~2.8** 72.6
* p<0.05
** p<O. 01
Anti-~eserpine Activity (Anti-Depression Activity)
.
Reserpine was administered subcutaneously to ddy
male mice (body weight, 25 to 30 g) at a dose of 2 mg/kg
and, after fasting for 18 hours, reserpine was ~gain
a~ministerccl su~cutaneously at a dose of 2 mg/kg. Five
hours after the second administration o reserpine, the
mice which indicated a constant decrease in body temperature
were selected and administered orally with the test compound
(Compound C), followed by measuring the rectal temperature
of the mice at one hour intervals.
The results obtained are shown in Figure l(a) and
Figure l(b). These results indicate that Compound C
increases at a dose of 50 and 100 mg/kg significantly the
rectal temperature which has been decreased by the pre-
treatment with reserpine.
- 51 -
5`~J~3
1 In this experi.men~, Im.ipramine (lO,ll-dlhydro-N,N-di-
methyl-511-dibenz[b,f]azepine-5-propanamine) ana Ami~riptyline
~3-~lO,ll-dihydro-5H-dibenzo[a,dJ-cyclohyp-ten-5-ylidene)-N,N-di-
methyl-l-propanamine) were used as typical examples of known
compounds for comparison and the results obtained with these com-
pounds are also shown in Figure l(a).
-5.la-
i 37~3
An-ti-histamine and Anti-chlorinergic Activities
-
The ileum of guinea pig (body weight, 300 to 400 g)
was extracted and suspended in a Magnus tube containing
Tyrode's solution (saturated with oxygen) at 31C and the
inhibitory activity of the test compounds on the contraction
indued by administration of histamine or acetylcholine
was determined. The trea~ment with the test compounds
was conducted 30 seconds before inducing the contraction.
The results obtained are shown in Figure 2(a) and
Figure 2(b) for Compound ~, Figure 3(a) and Figure 3(b)
for Compound B and Figure 4~a) and Figure 4(b) for Compound C.
As is apparent from these figures, Compounds A, B and C
shift the histamine-induced contraction curve determined
in gui~ea pig ileum to the rigllt direction on th~ igures
in parallel. This indicates that Compounds ~, B and C
possess a specific anti-histamine activity. Also9
Compounds ~ and B were found to have a non-specific anti-
cholinergic activity.
Gastric Secretion Inhibitory Activity
The pylorus of Wister male rats (body weight, 180
to 200 g) fasted for 24 hours was ligated under ether
anesthesia and, immediately thereafter, the test compound
was administered into the duodenum. Four hours after the
administration, the stomach was extrac~ed and gastric juice
was collected and centrifuged at 3,000 r,p.m. for 15 minutes~
- 52 -
~ . ~h ~ 7 ~ 3
The volume of gastric juice, tlle p~l value and the degree o
acid secretion were then determined with respect to the
supernatant.
The results obtained are shown in Table 2 below.
As is apparent from the results, Compounds A and C reduce
the volume of gastric juice and the acid secretion and
increase the p}l value.
3 - ~
- 5'1 -
O ~_ ~ * k *
~ ~ O
O O I~ Ln L
~) ~)
~i ~ + I+ I
O U
C~; oo ~ t~ Lr)
r-t d o u
~-1
O O O O
r-l +l +~ ~+l ,.
~d ~1 ~o oo
t` o oo
:~
~1
, ,~ ~
U ~ It k
~ t~ ~ O
O r O O O O
H ~1
E~ ~- +l +l ~-
~ ~ ~-t t'l Ll~ O
~ ~ li ~ ", "~ oo ~
n ~ ~' ~ o ~ o
~d O
E-~ ~
~ h ar o o ca -
U ~' ~ r~/ r-1 0 0
~d *
o~ c o ~
~:
~ o
o ~ p~ ~ o
E3 ~ h
O O O O ~
U U C~ C~ ¢
- 54 -
7~i3
Anti-ulcer Activity
i) Stress Ulcer
The test compound was administered orally to l~ister
male ra~s (body ~eig}lt, 200 to 230 g} and then the rats weTe
ticd up with a steel wire and dipped in water at 23C in
a tank to the level of the xiphis-ternum ofrats .
After allowing the rats to stand for 7 hours in water, the
rats were sacrificed and the stomach was extracted. lO ml
of a 1% formalin solution was injected into the stomach
cavity and the stomach was dipped in a 1% formalin solution
for 15 minutes to semi-harden the stomach. The stomach
was excised along the greater curvature thereof ancl the
ulcer generated in the portion of corpus ventriculi was
observcd. The results obtaitled are shown in Table 3 below.
As ls apparent from the results, Compound A inhibits the
ulcer generation caused by water-dipping restriction stress
at the dose of 25, 50 and 100 mg~ with dependency upon
the dose.
7~`3
- 56 -
Table 3
Anti-ulcer Activi~y ~Stress~
Dose Number Ulcerous - Percent
Compound (mg/kg) of Rats Index (mm) Inhibition (%)
Control 6 75.8
Compound A25 6 58.0 23.5
- Compound A50 6 48.2 36.4
Compound A100 ~ 25.3 66.0
Sulpiride*100 6 71.0
Atropine 5 6 5.3 93.0
*Sulpiride = 5-(aminosul~onyl~-N-~(l-ethyl-2-Pyrrolidinyl)methy:
2-methoxy-benzamide.
ii) Indomethacin Ulcer
~ suspension of indomethacin in 0.25% CMC was admini~ter~
subcutaneously at a dose of 20 mg/kg to Wister male rats
(body weightl 125 - 150 g) fasted for 24 hours. The test
Compound was administered ora~ly 30 minutes before the
administration of indomethacin. Seven hours after the
administration of indomethancin, the rats were sacrificed
by dislocation of neck, and the stomach was extracted.
7.5 ml of 1% formalin solution was injected into the stomach
cavity, and the stomach was hardened. The linear-type ulcer
generated in the mucous membrane of the stomach was then
observed,
The results obtained are shown in Table 4. As is
apparent from the results, Compounds B and D inhibit the
indomethacin--~nduced ulcer at a dose oE 50 mg/kg.
- 56 -
.h5 37~i 3
- 57 -
_ ble 4
Anti-ulcer Activity (Indomethacin)
Dose Number Ulcer~us Percent
Compound ~mg/kg) of Rats Index(mm) Inhibi~ion (~
Control 8 15.4
Compound B 50 8 6.0 61.0
Compound D 50 8 4.1 73.0
--, Scralphate* 300 8 2.9 81.1
*Scralphate = basic aluminum sucrose sulfate.
Acute Toxicity
The test compound was administered to ddy male mice
(body weight, 20 to 25 g) asted o~ernight before admini-
stration. ~fter administration, general conditions of
mice were observed for 7 days and 50% lethal dose LD50
tmg/kg) was determined. The results ob~ined are shown
in Table 5 below.
Table 5
Acute Toxicity
Compound LI)50 (mg/kg)
Compound ~ 662
Compound B 195
Compound C 699
Compound ~ 505
- 57
~ ?~ 3
- 58 -
Pre~aration Examples
1. Granules
Compound A 200 mg
Lactose 500 mg
Corn Starch 280 mg
Hydroxypropylcellulosc20 mg
l,000 mg per pack
The granule preparation was prepared in a conventional
manner using the a~ove formulation.
2. Tablets
Compound ~ 100 mg
Lactose 85 mg
Crystalline Cellulose50 mg
Hydroxypropylcellulose30 mg
Talc 4 mg
Magnesium Stearate 1 mg
270 mg per tablet
The tablet preparation was prepared in a conventional
manner using the above ormulation.
3. Capsules
Compound C 200 mg
Lactose 100 mg
Crystalline Cellulose18 mg
- 58 -
s. i,7~ 3
- 59 -
Magnesium Stearate 2 mg
400 mg per capsule
The tablct preparation w~s prepared i.n a convention~l
m~nner using the above formulation.
59
As dcscribcd l-cforc, somc of the starting materials
having tlle formula (II~ arc novel compounds. The prepara-
tions of typical cxam~les of the novel starting materials
are described in thc ~ollowing Reference Examples.
S l~ccrence Example 1
20 g of cthyl l)-chloropllenyl acet;l~e, 10 g of
sodium ethoxiclc an~l 15 ~ of cthyl Eormatc were a~ded in
that order to 200 ~1 o dicthyl cthcr and the mixture was
stirred for 16 hours at room temperature. Thereafter,
water in an cqual amount to the reaction mixture was added
to the rcaction mixture and, after thoroughly shaking~
the a~ueous layer was separatecl. The a~ueous layer was
rcndercd ncutral with 2N hydrochloric acid and the liberated
oily substance wa~ cxtracte~ with dichloromcthane. The
extract was washed wi~h'water and the solvent was dis~illect
off to o~tain 14.2 g of ethyl p-chlorophenyl-(~-formyl)-
acctate havillg a mclting point oE 50C.
Then, 14.2 g of ethyl p-chlorophenyl-t~-formyl~-
acetate and 6.5 g of ure~hane were added .to 50 ml of toluene
containing 0.3 ml of concentrated suluric acid~ and the
mixture was heatcd at reflux while distilling out water
which was formed during the reaction un~il no furtller water
was distilled out. Thereafter, the solvent was distilled
off, and ~hc residuc was ex~racted with di~thyl ether
while hot. The solvcnt was distilled oE-E from the extract
- 60 -
to obtain 13.7 g o cthyl p-chlorophenyl-t~-etlloxycarbonyl-
amino1ne~hylene)acetate having a melting point of 72C.
Then, 13.7 g of cthyl p-chlorophenyl-(~-ethoxy-
carbonylaminomethylcnc)acctate was added to 50 ml of
S ~iphenyl cthcr and thc mixturc was heatc~ at reflux for
3 hours. ~ftcr cooling, henzcne and pctrolcum ether were
added to the reaction mixture, an~ the precipitated crystals
were filtcrcd and recrystallized from a mixture of dimethyl-
formamidc and cthanol to obt~in 7 g of 7-chloro-4-etlloxy-
carbonyl-1~2ll)-isoquinolotlc ha~ing a melting point of 2~3C
as colorless T~risms.
Elementary Analysis:
C~lcd for C12ll10ClN3 = 251-671
C, 57.27; Il, 4.01; N, 5.57 (%)
Found: C, 57.36; Il, 4.05; N, 5.53 (%)
Reference Exa~le 2
l`he procedure described in Reference Example l was
rcpeatecl but using ethyl p-methoxyphenylacetate as a starting
materiaI instead of the ethyl p- chloro phenylacetate, and
the resulting crystals were recrystallized from a mixture
of dimethylEormamide and ethanol to obtain 4-etlloxycarbonyl-
7-methoxy-1(2H)-isoquinolone having a melting point of
191C as colorless prisms. Yield, 64~.
Elementary ~nalysis:
for C13ll13N4 247.253:
- 61 -
h ~ 3
C~ 63.15; Il, 5.30; N, 5.66 (%)
Founcl: C~ 63.27; Il, 5.2~; N, 5.72 (~3
Reference Example 3
The procedure described in Reference Example 1 was
repeat~d but using p-mct}loxyphenylacetonitrile as a startin~
material instead of the ethyl p- chloxo phenylacetate, and
the resulting crystals were recrystaIlized from a mixture
of dimethylformamide and ethanol to obtain 4-cyano-7-
methoxy-1~2H)-isoquinolone having a melting point of 264C.
Yield, 58~.
Elementary Analysis: -
Calcd for C~ 8N22
C, 66.00; ll, 4.03; N~ 13~99 (%)
Found: C, 66.16; ll, 4.20; N, 13.88 (%)
_ f rence Example 4
- A mixture of 19 g of 4-carboxy-1(2~1)-isoquinolone,
10 ml of concentrated sulfuric acid and 1 liter of n-butanol
was hea~ed at reflux for 20 hours. The solvent was distilled
off and petroleum ether was added to the residue, followed
by allowing the mixture to stand. The solidified substance
was separatcd by filtration and recrystalli~ed from a
mixture of n-butanol and petroleum ether to obtain 17 g of
4-n-butoxycarbonyl-l(2ll)-isoquinolone as colorless ne~dles
having a melting point of 170C.
- 62 -
~i3~3
Elementary An~llysis:
Calcd :i~or Cl~ 5N03 2~5. 281:
C, 68.56; Il, 6.16; N, 5.71 (~i)
Found: C, 68.62; Il, 6.11; N, 5.58 ~%)
- 63 -
