CA1072108A - Pyrrolidones and process for their manufacture - Google Patents
Pyrrolidones and process for their manufactureInfo
- Publication number
- CA1072108A CA1072108A CA267,691A CA267691A CA1072108A CA 1072108 A CA1072108 A CA 1072108A CA 267691 A CA267691 A CA 267691A CA 1072108 A CA1072108 A CA 1072108A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- pyrrolidone
- compound
- metal
- defined above
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Abstract of tho Disclosure:
This invention is directed to pyrrolidones prepared by a multistep process and useful as spasmogcnic and spasmoly-tic agents, for example with a bronchidilatatory and antihyper-tensive activity, and which are able to inhibit the secretion of gastric juice and have abortive effects. The compounds of the invention have the formula I
wherein Rl represents a straight-chained or branched alkyl group of 1 to 7 carbon atoms, which may be substituted by alkoxy of 1 to 3 carbon atoms;
R2 represents lower alkyl;
R3 represents lower alkyl, lower alkenyl, lower alkinyl or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms; and n represents the integers two, three or four.
This invention is directed to pyrrolidones prepared by a multistep process and useful as spasmogcnic and spasmoly-tic agents, for example with a bronchidilatatory and antihyper-tensive activity, and which are able to inhibit the secretion of gastric juice and have abortive effects. The compounds of the invention have the formula I
wherein Rl represents a straight-chained or branched alkyl group of 1 to 7 carbon atoms, which may be substituted by alkoxy of 1 to 3 carbon atoms;
R2 represents lower alkyl;
R3 represents lower alkyl, lower alkenyl, lower alkinyl or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms; and n represents the integers two, three or four.
Description
iO';'Z108 The present invention i5 directed to pyrrolidones of the formula I
-CH -cH=cH-(cH2)n-cooR
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
-CH -cH=cH-(cH2)n-cooR
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;
,'. -'' .
~, ' . . ' ' ' .
:-iOqZ1~8 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
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 '``' :
, .' 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.
~ , ''' ' .
~' :
~ ~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-~.
- ' ~, . .
: :
:, : ' ` 10'~ 08 ~ . , 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.
, .,~
, _ g _ .~
' ~
, , . .
, ' , .
, ,, ' , ~ . , .
- ' ` ~O'~Z108 , 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
.. . .
.. , '. '' .... . _ _ . _ , ' ' - ' - ' ` .
,, . , , `
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 - -.
- - , . . - v -- . ' .
., ' '' ,~'.' ',." '' . --- , ' -- -- , ' ' .
. ' ' ' ' , - - - .
- . ' . . - . ' ' , , - .
. " ''" ' "''' " '' '. '.
, , . . - . -'' ' , " '" '' "' ' " ' " ' ' .. . . ---' . ' ' :' '.'' ' ' ::" . ' '- .
- 12 - :
. . -' :- , - ` ~
.
.
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;
,'. -'' .
~, ' . . ' ' ' .
:-iOqZ1~8 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
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 '``' :
, .' 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.
~ , ''' ' .
~' :
~ ~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-~.
- ' ~, . .
: :
:, : ' ` 10'~ 08 ~ . , 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.
, .,~
, _ g _ .~
' ~
, , . .
, ' , .
, ,, ' , ~ . , .
- ' ` ~O'~Z108 , 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
.. . .
.. , '. '' .... . _ _ . _ , ' ' - ' - ' ` .
,, . , , `
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 - -.
- - , . . - v -- . ' .
., ' '' ,~'.' ',." '' . --- , ' -- -- , ' ' .
. ' ' ' ' , - - - .
- . ' . . - . ' ' , , - .
. " ''" ' "''' " '' '. '.
, , . . - . -'' ' , " '" '' "' ' " ' " ' ' .. . . ---' . ' ' :' '.'' ' ' ::" . ' '- .
- 12 - :
. . -' :- , - ` ~
.
.
Claims (4)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a pyrrolidone of the formula I
wherein R1 represents a straight-chained or branched, alkyl group of 1 to 7 carbon atoms which may be substituted by alkoxy of 1 to 3 carbon atoms;
R represents lower alkyl;
R3 represents lower alkyl, lower alkenyl, lower alkinyl or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, and n represents the integers two, three or four, and free acids thereof and the physiologically acceptable metal and amine salts thereof, in which a) a pyrrolidone of the formula XXVIII
XXVIII
wherein R1, R2 and n are as defined above is reacted with a metal-organic compound prepared from R3-X, in which X is a halogen atom and R3 is as defined above and wherein the metal is selected from the first and second main groups of the Periodic Table, to give a compound of the formula I and the compound may be converted into the free acid or a physiologically acceptable metal or amine salt thereof, or b1) the pyrrolidone of the formula X
X
wherein R1 is as defined above is reacted with a metal-organic compound prepared from R3-X, wherein X is a halogen atom and R3 is as defined above aAd wherein the metal is selected from the first and second main groups of the Periodic Table, to give a compound of the formula XXIX
XXIX
b2) the alcohol group in the pyrrolidone of the formula XXIX
is protected by a protective group in a manner known in the art such as by reaction with an enol ether in the presence of an acid catalyst thus forming a compound of the formula XXX
XXX
wherein R1 and R3 are as defined above, b3) the pyrrolidone of the formula XXX is reacted in the presence of a base with a carboxylic acid derivative of the formula XII
Y - CH2 - CH = CH - (CH2)n - COOR2 XII
wherein R2, Y and n are as defined above to give a compound of the formula XXXI
XXXI
b4) the alcohol protective group R4 in a compound of the formula XXXI is protected by a protective group in a manner known in the art such as by reaction with an enol ether in the presence of an acid catalyst, thus forming a compound of the formula I, and the latter may be converted into the free acid or a physiologically acceptable metal or amine salt thereof, or, b4') the pyrrolidone of the formula XXIX is reacted in the pre-sence of a base with a carboxylic acid derivative of the formula XII to give a compound of the formula I, and the latter may be converted into the free acid or the physiologi-cally acceptable metal or amine salt thereof.
wherein R1 represents a straight-chained or branched, alkyl group of 1 to 7 carbon atoms which may be substituted by alkoxy of 1 to 3 carbon atoms;
R represents lower alkyl;
R3 represents lower alkyl, lower alkenyl, lower alkinyl or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, and n represents the integers two, three or four, and free acids thereof and the physiologically acceptable metal and amine salts thereof, in which a) a pyrrolidone of the formula XXVIII
XXVIII
wherein R1, R2 and n are as defined above is reacted with a metal-organic compound prepared from R3-X, in which X is a halogen atom and R3 is as defined above and wherein the metal is selected from the first and second main groups of the Periodic Table, to give a compound of the formula I and the compound may be converted into the free acid or a physiologically acceptable metal or amine salt thereof, or b1) the pyrrolidone of the formula X
X
wherein R1 is as defined above is reacted with a metal-organic compound prepared from R3-X, wherein X is a halogen atom and R3 is as defined above aAd wherein the metal is selected from the first and second main groups of the Periodic Table, to give a compound of the formula XXIX
XXIX
b2) the alcohol group in the pyrrolidone of the formula XXIX
is protected by a protective group in a manner known in the art such as by reaction with an enol ether in the presence of an acid catalyst thus forming a compound of the formula XXX
XXX
wherein R1 and R3 are as defined above, b3) the pyrrolidone of the formula XXX is reacted in the presence of a base with a carboxylic acid derivative of the formula XII
Y - CH2 - CH = CH - (CH2)n - COOR2 XII
wherein R2, Y and n are as defined above to give a compound of the formula XXXI
XXXI
b4) the alcohol protective group R4 in a compound of the formula XXXI is protected by a protective group in a manner known in the art such as by reaction with an enol ether in the presence of an acid catalyst, thus forming a compound of the formula I, and the latter may be converted into the free acid or a physiologically acceptable metal or amine salt thereof, or, b4') the pyrrolidone of the formula XXIX is reacted in the pre-sence of a base with a carboxylic acid derivative of the formula XII to give a compound of the formula I, and the latter may be converted into the free acid or the physiologi-cally acceptable metal or amine salt thereof.
2. A pyrrolidone of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in claim for the preparation of 1-(6-methoxycarbonyl-(z)-2-hexene-1-yl)-5-(3-hydroxy-3-methyl-(E)-l-octene-l-yl)-pyrrolidone-2 in which 1-(6-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-(E)-l-octene-l-yl) in solution is reacted with methyl-magnesium iodide and the resultant product is subsequently isolated.
4. 1-(6-Methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-hydroxy-3-methyl-(E)-l-octene-l-yl)-pyrrolidone-2, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752556326 DE2556326A1 (en) | 1975-12-13 | 1975-12-13 | NEW PYRROLIDONES AND THE PROCESS FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1072108A true CA1072108A (en) | 1980-02-19 |
Family
ID=5964379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA267,691A Expired CA1072108A (en) | 1975-12-13 | 1976-12-13 | Pyrrolidones and process for their manufacture |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5273865A (en) |
| AU (1) | AU2047376A (en) |
| BE (1) | BE849346R (en) |
| CA (1) | CA1072108A (en) |
| DE (1) | DE2556326A1 (en) |
| DK (1) | DK554776A (en) |
| FR (1) | FR2334352A2 (en) |
| GB (1) | GB1569982A (en) |
| IL (1) | IL51090A0 (en) |
| LU (1) | LU76367A1 (en) |
| NL (1) | NL7613643A (en) |
| SE (1) | SE7613948L (en) |
| ZA (1) | ZA767379B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4772601A (en) * | 1988-01-25 | 1988-09-20 | Hoechst-Roussel Pharmaceuticals, Inc. | 5-Substituted 1-(4-(1-pyrrolidinyl)-2-butynyl)-2-pyrrolidinones, pharmaceutical compositions and use |
| DK1408961T3 (en) | 2001-07-16 | 2007-11-05 | Hoffmann La Roche | 2 pyrrolidone derivatives as prostanoid agonists |
| KR20040015364A (en) | 2001-07-16 | 2004-02-18 | 에프. 호프만-라 로슈 아게 | Prostaglandin analogues as ep4 receptor agonists |
| IL159996A0 (en) | 2001-07-23 | 2004-06-20 | Ono Pharmaceutical Co | Remedies for diseases with bone mass loss having ep4 agonist as the active ingredient |
| WO2003074483A1 (en) | 2002-03-05 | 2003-09-12 | Ono Pharmaceutical Co., Ltd. | 8-azaprostaglandin derivative compounds and drugs containing the compounds as the active ingredient |
| CN1735597A (en) | 2003-01-10 | 2006-02-15 | 霍夫曼-拉罗奇有限公司 | 2-piperidone derivatives as prostaglandin agonists |
| US7179820B2 (en) | 2003-06-06 | 2007-02-20 | Allergan, Inc. | Piperidinyl prostaglandin E analogs |
-
1975
- 1975-12-13 DE DE19752556326 patent/DE2556326A1/en active Pending
-
1976
- 1976-12-08 NL NL7613643A patent/NL7613643A/en not_active Application Discontinuation
- 1976-12-10 AU AU20473/76A patent/AU2047376A/en not_active Expired
- 1976-12-10 DK DK554776A patent/DK554776A/en unknown
- 1976-12-10 ZA ZA767379A patent/ZA767379B/en unknown
- 1976-12-10 LU LU76367A patent/LU76367A1/xx unknown
- 1976-12-10 IL IL51090A patent/IL51090A0/en unknown
- 1976-12-10 SE SE7613948A patent/SE7613948L/en unknown
- 1976-12-13 CA CA267,691A patent/CA1072108A/en not_active Expired
- 1976-12-13 BE BE173206A patent/BE849346R/en active
- 1976-12-13 FR FR7637469A patent/FR2334352A2/en active Granted
- 1976-12-13 JP JP51148823A patent/JPS5273865A/en active Pending
- 1976-12-13 GB GB51912/76A patent/GB1569982A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2334352A2 (en) | 1977-07-08 |
| IL51090A0 (en) | 1977-02-28 |
| LU76367A1 (en) | 1977-06-28 |
| SE7613948L (en) | 1977-06-14 |
| FR2334352B2 (en) | 1978-12-08 |
| DK554776A (en) | 1977-06-14 |
| DE2556326A1 (en) | 1977-06-23 |
| ZA767379B (en) | 1977-11-30 |
| GB1569982A (en) | 1980-06-25 |
| JPS5273865A (en) | 1977-06-21 |
| AU2047376A (en) | 1978-06-15 |
| BE849346R (en) | 1977-06-13 |
| NL7613643A (en) | 1977-06-15 |
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