Note: Descriptions are shown in the official language in which they were submitted.
iO';'Z108
The present invention i5 directed to pyrrolidones of
the formula I
O 2
-CH -cH=cH-(cH2)n-cooR
R3
CH=CH-C ~Rl
OH
wherein R represents a straight-chained or branched, alkyl group
having 1 to 7 carbon atoms, which may be substituted by alkoxy of
1 to 3 carbon atoms;
R represents lower alkyl;
n represents the integer two, three or four; and
R3 represents lGwer alkyl, lower alkenyl, lower alkinyl or an
araliphatic hydrocarbon radical having 3 to 7 carbon atoms.
The present invention is also directed to the
preparation of these compounds by
a) reacting the pyrrolidone of the formula XXVIII
0~ CH CH CH (CH ) COOR2
; ~ 2 n
CH=CH-C-R XXVIII
O
wherein Rl, R2 and n are as defined above, with a metal-organic
compound prepared from R3-X, wherein X is a halogen atom and
R3 is as defined above, to give compounds of the formula I,
and converting the same optionally into the free acid or the
physiologically acceptable metal or amine salts thereof, or
bl) reacting the pyrrolidone of the formual X
- 2
- ~ '
;
lO'~ZlV8
1 CH=CH-C-R
wherein R is as defined above with a metal-organic compound
: prepared from R -X wherein X is a halogen atom and R3 is as
~' C;
,'. -'' .
~, ' . . ' ' ' .
:-
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defined above, to give a compound of the formula XXIX
0 ~ ~H
~ ",R3 XXIX
C~ Rl
5 b2) protecting in the pyrrolidone of the formula XIX the
alcohol group by a group R4 which can be easily re ved under
acid conditions, thus forming a compound of the formula XXX
r
~ Rl XXX
10R40 R3
wherein Rl and R3 are as defined-above,
b3) deprotonizing the pyrrolidone of the formula XXX with a
base at the nitrogen atom and reacting the anion thus formed
with a carboxylic acid derivative of the formula XII
: 15 CH2 CH CH - (CH2)n - COOR2 XII
., wherein R2, Y and n are as defined above to yield a compound
of the formula XXXI
- CH2 - CH = CH ~ (CH2)n - COOR2
~ ~ Rl XXXI
CH CH 4CI ~ R3
b4) splitting off the alcohol protective group R4 in a compound
of the formula XXXI, thus forming a compound of the formula I
and converting the latter optionally into the ~ree acid of the
physiologically acceptable metal or amine salt thereof, or
. b4') deprotonizing the pyrrolidone of the formula XXIX without
: 27 introducing a protective group at the hydroxyl function at the
,.~,
. -- 4 --
.
~O~Z108
nitrogen atom and reacting the anion formed with a carboxylic
acid derivative of the formula XII to give a compound of the
formula I, and converting the latter optionally into the free
acid or the physiologically acceptable metal or amine salt thereof.
Particularly preferred are the following substituents
for
Rl a straight-chained or branched alkyl group of 1 to 7 carbon
atoms, a straight-chained or branched alkenyl group of 3
to 5 carbon atoms, or a cycloalkyl group of 5 to 7 carbon
~ atoms, which may be substituted by
a) a straight-chained or branched alkoxy, alkylthio,
alkenyloxy or alkènylthio group of 1 to 3 carbon atoms,
b) a phenoxy group which may carry one or two methyl,
trifluoromethyl or methoxy groups, chlorine or fluorine
atoms, or optionally chlorinated or fluorinated phenoxy
groups,
.~ c) a thienyloxy or benzyloxy group which may carry in its
~ nucleus one or two methyl, trifluoromethyl or methoxy
groups, chlorine or fluorine atoms,
d) a trifluoromethyl group,
e) a cycloalkyl group of 5 to 7 carbon atoms,
f~ a phenyl or thienyl group which may carry one or two
methyl, trifluoromethyl or methoxy group or chlorine
or fluorine atoms;
for R2 a straight-chained alkyl group of 1 to 6 carbon atoms,
a branched alkyl group of 3 to 5 carbon atoms, a
straight-chained alkenyl group of 2 to 4 carbon atoms,
28 the cyclopentyl and cyclohexyl group, and the benzyl
'``'
- 5 -
:
,
.'
0'~108
group, and
for n preferably the integer 3.
Among the meanings for R3, preference is given to
the following:
Straight-chained or branched alkyl groups having
from l to 4 carbon atoms, especially the methyl, ethyl, propyl
and isopropyl groups, furthermore, alkenyl and alkinyl groups
having from 2 to 4 carbon atoms, especially the vinyl, propenyl,
allyl and ethinyl groups, and finally the benzyl group.
$he metal-organic compounds used for the process of
the invention according to a) as well-as b) are derived from
metals of the first and second main group of the Periodic Table
of the Elements. There are mentioned in particular lithium-
or magnesium-organic compounds (Grignard compounds), which are
prepared according to one of the usual methods, for example,
from a compound R3-X, in which R3 is as defined in formula I
and X is a halogen atom, for example, chLorine, bromine or
iodine and the corresponding metal, such as lithium or magnesium.
The compounds of the formula XXVIII may be prepared
according to the method described in applicant's co-pending
application, Canadian serial number 255,666, filed July 25, 1976.
Further, the compounds of the formula X may also be prepared
according to the method described in said Canadian application.
Further reaction of the pyrrolidones of the formula
XXVIII or formula X there are mentioned those solvents which
are inert under the reaction conditions, for example, hydro-
carbons are preferably ethers, such as diethyl ether, tetra-
hydrofuran or 1,2-dimethoxyethane. In this process, tempera-
., .
-~ - 6 -
,
,' ' . .
-- :lO'YZ108
tures in the range of from -60C to ~30C, preferably from
-30C to 0C, may be applied. It is of no importance whether
the substrate is added to the metal-organic compound or vice
versa.
However, the metal-organic compound is preferably
added to the substrate, in order to prevent side reactions
which might occur. For the working-up, the reaction product
is mixed with water, diluted mineral acid or a solution of
ammonium salts, such as ammonium chloride in water, and is
- 10 then isolated in a usual manner. If the synthesis method
- b) is chosen, the reaction of X to XXIX is carried out while
using a-metal-organic compound, in which process the conditions
- already mentioned for process a) are applied.
The steps b2) to b4) and b4'), respectively are
carried through under the same conditions as described in
applicant's aforementioned Canadian application serial number
255,666 for steps a6) to a8).,
The compounds of the invention are distinguished by
an activity which is spasmogenic on one hand and bronchodi-
latatory on the other hand, furthermore, they have antihyper-
- tensive properties, they are able to inhibit the secretion
of gastric juice and have abortive effects. They may therefore
be used as drugs.
The pharmacological properties were tested on the
following.
-- 7
~ , ''' ' .
~' :
~ ~nimals and/or organs: iO'~108
Spasmogenic effect: isolated rat stomach,
isolated guinea-pig uterus
Bronchodilatatory effect: guinea-pig
Antihypertensive effect: dog
Secretion of gastric juice: rat
Abortive effect: hamster.
The compounds of formula I of the invention may be employed
as free acids, in the form of the physiologically acceptable in-
organic or organic salts thereof or as esters of aliphatic, cyclo-
aliphatic or araliphatic alcohols.
As inorganic salts, there may be used, for example, alkali
metal salts, alkaline earth metal salts or ammonium salts; for
a formation of salts with organic bases, there are used bases
derived from primary, secondary and tertiary amines which may
contain further hydrophilic groups; for example salts with
methyl, triethyl, benzyl, phenylethyl, allyl amine or also with
piperidine, pyrrolidine, morpholine or with ethanol amine, tri-
ethanol amine, tris-(hydroxymethyl) methylamine; as esters, there
are preferably used esters of lower aliphatic alcohols, such as
methyl, ethyl, propyl, butyl or hexyl ester, and benzyl ester.
The acids and salts or esters may be administered in the
form of the aqueous solutions and suspensions thereof or also in
a solution or suspension in pharmacologically acceptable or-
ganic solvents, such as mono- or polyhydric alcohols, for ex-
ample ethanol, ethylene glycol or glycerol; oils, for example
sunflower oil or castor oil; ethers, for example diethylene
glycol dimethyl ether, or polyethers, for example polyethylene
glycol, or even in the presence of other pharmacologically ac-
~.
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ceptable polymer carriers, for example polyvinyl pyrrolidone.
Pharmaceutical compositions are the usual galenic infusion
or injection solutions as well as tablets, and locally
administerable compositions, such as creams, emulsions, suppo-
sitories and especially sprays.
The new compounds may further be used in combination with
other active ingredients. Among other appropriate substances,
for example compounds influencing the fertility and hormones,
such as LH-RH, FSH, estradiol or LH, the following compounds
may be especially mentioned:
Diuretics, for example Furosemide, antihyperglycemics, for
example glycodiazin, tolbutamide, glibenclamide, phenformin,
buformin, metformin, or circulatory agents in the broadest
sense of the term, for example cardiovascular-dilatatory agents,
such as chromonar or prenylamine, antihypertensive agents, such
as reserpin ~ -methyl-dopa or clonidines, or anti-arrhythmics,
antihyperlipidemic agents or geriatrics, and other compositions
acting on the metabolism, psychopharmaceuticals, for example
chlorodiazepoxide, diazepam or heprobamate, as well as vitamins,
or other prostaglandins or prostaglandin-like compounds and
prostaglandin antagonists.
The dosage unit is in the range of from about 5 ~g to 5 mg,
the daily dosage unit is from about 10 ~g to 20 mg.
The following Examples illustrate the invention.
,
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,
E X A_M P L E l :
1- (6-Methoxycarbonyl- ~Z? -2-hexene-1-Yl)-5-(3-hYdroxY-3-methyl-
(E)-1-octene-1-yl)-p~yrrolidone-2
A solution of 10 ~oles of 1-(6-methoxycarbonyl-(Z)-2-hexene-
1-yl`-~5-(3-oxo-(E)-1-octene-1-yi) in 70 ml of ether was cooled
to -15 C under an argon atmosphere. Subseguently, 8 ml of a
1.5 molar solution (12 millimoles) of methyl-magnesium iodide in
ether was added dropwise, while stirring, the mixture was con-
tinued to be stirred for 30 minutes and was heated to room tem-
perature. Afterwards about 1.5 ml of a saturated ammonium chlo-
ride solution was added at 0 C, in which process a colorless
.
precipitate was formed. After about 10 minutes, anhydrous mag-
nesium sulfate was added, the product was suction-filtered, con-
centrated and chromatographed on silica gel (eluent: tolueneJ
acetic ester/methanol 5:4:0.3).
NMR: d~ = 3.7 ppm (s) COOCH3
- S = 5.~ - 5.7 ppm (m) CH-CH 2 prot.
.
= 1.35 ppm (s) C-CH3
IR: ; 1680 cm 1 ~ C=O
1730 cm 1 ~ C=O
E X A M P L E 2:
1-(6-Methox~carbonyl-(Z)-2-hexene-1-yl)-5-(3-hydroxy-3 ethin~l-
(E)-1-octene-1-Yl)-Pyrrolidone-2
was prepared according to the method describ~d in Example l from
-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-(E)-1-octene-1-
yl? and lithium ethinyl.
Chromatography: toluene/acetic ester~methanol 5:g:0.1
NMR: ~ = 3.6 ppm (s) COOCH3 - -
~ = 2.7 ppm (s) CeCH
.
,
. . .
:- ...... ...
,. ,. : ~
,:
~ ~ ' ' ~ ' ' . `
- :
~ Z1~8 ..
=.5.4 ~ 5.6 p~m (~l CH~-CH
IR: ~730 cm ~ ~ C=O
. . 1680 cm ~ ~ C=O
E X A M P L E 3: . .
i- ~ carbonyl-(Z~-2-h.exene-~-yl ? -5-(3-hydroxy-3-~rop-2-
en-yl-(E)-1-octelle-1-yl)-pyrrolidotle-2
. - was prepared according to the method described ~n Example l from
.. . . .
. 1-(6-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-(E)-1-octene-
- . , - . .
: - 1-yl)-pyrrolidone-2 and allyl-magnesium bromide.
Chromato~raphy: toluene/acetic ester/methanol 5:4:0.1
- NMR: S = 3.7 ppm (s) COOCH3
.. . = 5.2 -.5.7 ppm (m) CH=CH and CH=CE12. (5 prot.)
IR: 1735 cm ~ ~- C=O
. ~685 cm 1 ~ C=O
- E X A M P L E 4.
. :
1-(6-Methoxycal-bonyl-(Z)-~-hexene-1-yl?-5-(3-hydrox~-3-!nethxl-
5-ethox~-4~4-dimethyl-(E)-1-pentene-1-yl~-pyrrolidone-2
was prepared according to the method described in Example l from
-~ 1-(6-methoxycarbonyl-~Z)-2-hexene-1-yl).-5-(3-oxo-5-ethoxy-9,4-
dimethyl-(E)-1-pentene-1-yl)-pyrrolidone-2 and methyl-magnesiu~
iodide. - .
~; . Chromatography: toluene/acetic ester/methanol 5:4:0.3
. NMR: ~ = O.95 ppm C(CH3)2 6 prot.
. ~ = 1.4 ppm C-CH3
~'. S = 3.65 ppm COOCH3
. IR: 1685 cm 1 ~ C=O . ~ ~~
: 1735 cm ~ . ~ C=O
.. . .
.. , '. ''
- 11 -
.... . _ _ . _ ,
' ' - ' - ' ` .
,, . ,
, `
107'~08
. .
E X A M P L E 5 : -
.
1-~6-MethoxYcarbonYl-(2)-2-hexene-1-Yl)-5-(3-hYdroxy-3-phen
methYl-(E)-1-decene-1-yl)-PYrrolidone-2
was prepared according to the method described in Example l from
1-(6-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-~E)-1-decene-
1-yl)-pyrrolidone 2 and benzyl-magnesium chloride.
Chromatography: toluene/acetic ester/methanol 5:4:0.1
NMR: . ~ - 3.7 ppm COOCH3
= 5.4 - 5.6 ppm CH=CH
.
IR: 1730cm- 1 ~ C=O - -
. -16~0 cm 1 ~ C=O - -
.
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