DK156395B - ANALOGY PROCEDURE FOR PREPARING A (3-PYRROLIDINOPROPYL) -KETONE DERIVATIVE - Google Patents
ANALOGY PROCEDURE FOR PREPARING A (3-PYRROLIDINOPROPYL) -KETONE DERIVATIVE Download PDFInfo
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- DK156395B DK156395B DK419178AA DK419178A DK156395B DK 156395 B DK156395 B DK 156395B DK 419178A A DK419178A A DK 419178AA DK 419178 A DK419178 A DK 419178A DK 156395 B DK156395 B DK 156395B
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A61P9/08—Vasodilators for multiple indications
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Description
DK 156395 BDK 156395 B
Der> forel iggende opfindelse angâr en analogif remgangsmâde til fremstilling af hidtil ukendte derivater af phloroglucin eller deres syreadditionssalte eller kvaternære amrooni umsalte.The present invention relates to an analogous process for the preparation of novel derivatives of phloroglucine or their acid addition salts or quaternary ammonia salts.
5 Det er kendt, at chlorhydrat af (2,4,6-trimethoxyphenyl)-(3-pyrrolidinopropyl)-keton, soin har været beskrevet i britisk patent nr. 1.325.192, og som har kodenummeret LL 1656, er et perifert vasodi1atorisk middel, som for tiden findes i handel-en under betegnelsen Fonzylane (international fællesbetegnel-10 se: Buflomedil chlorhydrat), og hvis farmakologiske egenskaber er genstand for en artikel: Debray m.fl., Thérapie (1975), 30, side 259-266.It is known that chlorohydrate of (2,4,6-trimethoxyphenyl) - (3-pyrrolidinopropyl) ketone, soin has been disclosed in British Patent No. 1,325,192 and which has the code number LL 1656, is a peripheral vasodilator agent currently available in the trade under the name Fonzylane (International Common Designation-10: Buflomedil Chlorohydrate) and whose pharmacological properties are the subject of an article: Debray et al., Thérapie (1975), 30, p. 259- 266th
Det har nu overraskende vist sig, at forbindelserne fremstil-15 let ifelge opfindelsen (som har en struktur, der ligner struk-turen af LL 1656), er mindre toksiske og har en mere langvarig virkning end LL 1656, medens deres nærmeste homologe ud fra et struktursynspunkt (især CRL 40.633 og CRL 40.634, der er un-dersogt i det folgende), mangler vasodi1atorisk virkning.It has now surprisingly been found that the compounds of the invention (which have a structure similar to the structure of LL 1656) are less toxic and have a longer lasting effect than LL 1656, while their closest homologue from a structural point of view (especially CRL 40.633 and CRL 40.634, which is examined below), lacks vasodilatory effect.
2020
De hidtil ukendte forbindelser fremstillet ifelge opfindelsen er : (hydroxyphenyl)-(3-pyrrolidinopropyl)-ketoner med formlen: 25The novel compounds of the invention are: (hydroxyphenyl) - (3-pyrrolidinopropyl) ketones of the formula:
OROR
R0 *^(3-C0-CH2-CH2-CH2-K^] ( I )R0 * (3-CO-CH2-CH2-CH2-K3) (I)
30 0H30H
hvor de to R'er er ens og er H eller CH3, eller deres syreadditionssalte eller kvaternære ammoniumssalte.wherein the two R's are the same and are H or CH 3, or their acid addition salts or quaternary ammonium salts.
35 Syreaddi tionssal tene kan fâs pâ i og for sig kendt màde, f.eks. ved reaktion af den frie base med en uorganisk eller organisk syre. Blandt de syrer, som kan anvendes til dette formâl, kan især nævnes saltsyre, brombrintesyre, jodbrinte-35 Acid addition salts can be obtained in a manner known per se, e.g. by reaction of the free base with an inorganic or organic acid. Among the acids which can be used for this purpose are especially hydrochloric, hydrobromic,
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2 syre, svovlsyre, phosphorsyre, myresyre, oxalsyre, æblesyre, fumarsyre, maleinsyre, citronsyre, ascorbinsyre, benzosyre, glutaminsyre, aspartinsyre, methansulfonsyre, paratoluosulfon-syre. Blandt de mulige kvaternære ammoniumsalte kan nævnes de 5 salte, der fâs ud fra den frie base og JCH3 og CICH3. De fore" trukne salte fremsti11 et ifolge opfindelsen er ch 1orhydrater-ne, tartraterne og citraterne.2 acid, sulfuric acid, phosphoric acid, formic acid, oxalic acid, malic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, benzoic acid, glutamic acid, aspartic acid, methanesulfonic acid, paratoluosulfonic acid. Among the possible quaternary ammonium salts are the 5 salts obtained from the free base and JCH3 and CICH3. The preferred salts prepared according to the invention are the carbohydrates, tartrates and citrates.
Forbindelserne af formlen I fremstilles ved fremgangsmàden 10 ifolge opfindelsen ved, at man lader en forbindelse med form-1 enThe compounds of formula I are prepared by the process 10 of the invention by leaving a compound of formula I
/OR/ OR
„ ”-Q"-Q
OHOH
hvor de 2 R'er er ens og er H eller CH3, reagere med 4-pyrro-1 idino-butyronitri1 med formlenwherein the 2 R's are the same and are H or CH 3 react with 4-pyrro-1 idino-butyronitrile of the formula
20 NC - CH2 - CH2 - CH2 - N20 NC - CH2 - CH2 - CH2 - N
i et vandfrit oplosningsmiddel i nærværelse af ZnCl2 eller AlC13, hvorpâ man eventuelt lader den sâledes fremkomne for-25 bindelse reagere med en uorganisk eller organisk syre til dan-nelse af det tilsvarende syreacfcfitionssalt eller med en kva-terniserende forbindelse som ICH3 eller C1CH3 til dannelse af det tilsvarende kvaternære ammoniumsalt.in an anhydrous solvent in the presence of ZnCl2 or AlC13, optionally reacting the thus obtained compound with an inorganic or organic acid to form the corresponding acid addition salt or with a quaternizing compound such as ICH3 or C1CH3 to form of the corresponding quaternary ammonium salt.
30 Reaktionen forlober efter skemaet:The reaction proceeds according to the scheme:
OR OROR OR
RO—jfAt HC-(CH^rH -ί·Κ0-RO-jfAt HC- (CH ^ rH -ί · Κ0-
OH .OHOH .OH
hvor R har den ovennævnte betydning, idet reaktionen eventuelt fuldendes med isolerings- og rensningsoperationer.wherein R has the above meaning, the reaction being optionally completed with isolation and purification operations.
33
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Forbindelserne af formlen I og deres salte, især chlorhydra-terne, citraterne og tartraterne er perifere vasodi1atoriske midler og anvendes terapeutisk til behandling af artérielle kredslobsinsufficienser i lemmerne og især til behandling af 5 Raynaud's syndrom og liggesâr.The compounds of formula I and their salts, in particular the chlorohydrates, citrates and tartrates, are peripheral vasodilatory agents and are used therapeutically for the treatment of arterial circulatory insufficiency in the limbs and in particular for the treatment of Raynaud's syndrome and ulcer.
Fremgangsmàden ifolge opfindelsen er nærmere anskueliggjort af de folgende eksempler 1-2, medens eksemplerne 3-5 illustrerer fremsti11ingen af sammenligningsforbindelserne, der anvendes i 10 de farmakologiske prover.The process of the invention is further illustrated by the following Examples 1-2, while Examples 3-5 illustrate the preparation of the comparative compounds used in the pharmacological samples.
I tabel 1 er sammenstillet produkterne, fremstillet ifolge opfindelsen (eksemplel 1 og 2), deres homologe (sammenlignings-eksempler 3 til 5) og et ref erenceprodukt, der allerede er 15 kendt i terapien (LL 1656).Table 1 lists the products prepared according to the invention (Examples 1 and 2), their homologs (Comparative Examples 3 to 5), and a reference product already known in the therapy (LL 1656).
Eksempel 1Example 1
Chlorydrat af (2,4,6-trihydroxypheny1)-(3-pyrrolidinopropy1)-20 keton.Chloride of (2,4,6-trihydroxyphenyl) - (3-pyrrolidinopropyl) -20 ketone.
OHOH
’ hci'Hci
26 0H26 0H
Kodenummer CRL 40.598 I 500 ml vandfri diethylether torret pâ CaCl2 oploses 38,30 g (0,304 mol) vandfri phloroglucin og 41,95 g (0,304 mol) 4-pyr-30 roiidinobutyronitri1. Man tilsætter 7,28 g zinkchlorid og la-der HCl gas boble igennem reaktionsmediet indtil mætning. Man lader henstâ en nat og tilsætter vand til reaktionsmediet.Code number CRL 40.598 In 500 ml of anhydrous diethyl ether dried on CaCl2 dissolve 38.30 g (0.304 mole) of anhydrous phloroglucine and 41.95 g (0.304 mole) of 4-pyrrolidinobutyronitrile. 7.28 g of zinc chloride are added and HCl gas is bubbled through the reaction medium until saturation. One is left to stand for one night and water is added to the reaction medium.
Man fâr en vandig fase og en etherfase. Man vasker etherfasen 35 med vand og samler derefter den vandige fase og vaskevandet og opvarmer den fremkomne blanding til tiIbagesvaling i en time. Man afkoler, neutraliserer med natriumbicarbonat og filtrerer basen. Man oploser basen i en minimal mængde dime-You get an aqueous phase and an ether phase. The ether phase 35 is washed with water and then the aqueous phase and the wash water are collected and the resulting mixture is heated to reflux for one hour. It is cooled, neutralized with sodium bicarbonate and filtered off the base. The base is dissolved in a minimal amount of dime.
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4 thylformamid i varmen og syrner med 45 ml 7 N éthanol isk chlorbrinte. Man afdamper dimethylformamiddet i vakuum uden at gà til t0rhed og tilsætter ether for at lette udfældningen af det onskede chlorhydrat. Ved omkrystal1isation af blandingen af 5 lige rumfang methanol og acetone fàs 15 g (udbytte 16%) chlorhydrat af (2,4,6-trihydroxyphenyl)-(3-pyrroiidinopropy1)- keton.4 thylformamide in the heat and acidify with 45 ml of 7 N ethanol is hydrogen chloride. The dimethylformamide is evaporated in vacuo without going to dryness and ether is added to facilitate the precipitation of the desired chlorohydrate. By recrystallizing the mixture of 5 equal volumes of methanol and acetone, 15 g (yield 16%) of chlorohydrate of (2,4,6-trihydroxyphenyl) - (3-pyrrolidinopropyl) ketone are obtained.
Smeltepunkt 260 °C.Melting point 260 ° C.
1010
Analyse: % N mèlt =4,52% % N teoretisk = 4,64%.Analysis:% N measured = 4.52%% N theoretical = 4.64%.
Renheden af CRL 40598 kontrolleres ved tyndtlagskromatografi 15 (eluant: CH3OH-CH3COCH3-NH4OH (50:50:2) v/v, plade: Silicagel (MERCK F 254) fremka1delse : U.V. plus Draggendorf).The purity of CRL 40598 is checked by thin layer chromatography (eluent: CH3OH-CH3COCH3-NH4OH (50: 50: 2) v / v, plate: Silica gel (MERCK F 254) preparation: U.V. plus Draggendorf).
Eksempel 2 20 Chlorhydrat af (2,4-dimethoxy-6-hydroxypheny1)-(3-pyrroiidinopropy 1 )-keton.Example 2 Chlorohydrate of (2,4-dimethoxy-6-hydroxyphenyl) - (3-pyrrolidinopropyl 1) ketone.
CCH,CCH,
AA
25 E3C0-A m-C0-CCH2)3-hQ , HClE3 CO-A m-CO-CCH2) 3-hQ, HCl
OHOH
Kodenummer CRL 40.635 30 I en 2 liter 3-halset kolbe oploses 69 g (0,5 mol) 4-pyrroli-dinobutyronitri1 i 0,5 liter chlorbenzen. Man tilsætter langsomt 67 g (0,5 mol) Ald.3 og derefter 77 g (0,5 mol) 3,5-dimethoxyphenol. Man leder derefter en strom af HCl ind i re-35 aktionsmediet (der holdes pà 25 til 30°C) i 2 timer (en varig-hed derer nodvendig for at mætte reaktionsmediet), og derefter lader man henstâ ved omgivelsernes temperatur (15-20°C) en nat. Man tilsætter langsomt 0,5 liter vand (for at hydrolyse- 5Code number CRL 40.635 30 In a 2 liter 3 neck flask, 69 g (0.5 mole) of 4-pyrrolidinobutyronitrile is dissolved in 0.5 liter of chlorobenzene. 67 g (0.5 mole) of Ald.3 and then 77 g (0.5 mole) of 3,5-dimethoxyphenol are slowly added. A stream of HCl is then fed into the reaction medium (maintained at 25 to 30 ° C) for 2 hours (a duration necessary to saturate the reaction medium), and then allowed to stand at ambient temperature (15 ° C). 20 ° C) and one night. 0.5 liters of water are slowly added (to hydrolyze 5)
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re ketiminen, som er dannet) og dekanterer den vandige fase, som opsamles. Den vandige fase opvarmes til tiIbagesvaling i 1 time. Man afkoler, og der dannes et bundfald P, soin fraskilles ved filtrering (bundfaldet P, som hovedsagelig udgores af den 5 isomere 2,6-dimethoxy-4-hydroxyphenylforbindelse, isoleres som vist i sammenligningseksempel 5). Filtratet ekstraheres med chloroform, og kloroformoplosningen inddampes til torhed under reduceret tryk. Man oploser inddampningsremanensen i en minimal mængde vand og danner den frie base med natr iumcarbonat.re the ketimine formed) and decant the aqueous phase which is collected. The aqueous phase is heated to reflux for 1 hour. Charcoal is formed and a precipitate P is formed, which is separated by filtration (the precipitate P, which is mainly constituted by the 5 isomeric 2,6-dimethoxy-4-hydroxyphenyl compound, is isolated as shown in Comparative Example 5). The filtrate is extracted with chloroform and the chloroform solution is evaporated to dryness under reduced pressure. The evaporation residue is dissolved in a minimal amount of water and the free base is formed with sodium carbonate.
10 Man frafiltrerer uoploseligt stof og ekstraherer basen med chloroform. Den nye chloroformop1osning inddampes til torhed under reduceret tryk. Den sâledes fremkomne olie optages i isopropanol, og man gennembobler HCl indtil pH 2. Det onskede chlorhydrat krysta11iserer. Ved filtrering fâs 25 g (udbytte 15 15¾) chlorhydrat af ( 2,4-dimethoxy-6-hydroxypheny1)-(3-pyrro- lidinopropyl)-keton.10 Insoluble matter is filtered off and the base is extracted with chloroform. The new chloroform solution is evaporated to dryness under reduced pressure. The oil thus obtained is taken up in isopropanol and the HCl is bubbled up to pH 2. The desired chlorohydrate is crystallized. By filtration, 25 g (yield 15¾) of chlorohydrate of (2,4-dimethoxy-6-hydroxyphenyl) - (3-pyrrolidinopropyl) ketone are obtained.
Smeltepunkt 170°C.Melting point 170 ° C.
20 Analyse: % Cl" mâlt = 10,68% % Cl” teoretisk = 10,74%Analysis:% CI "measured = 10.68%% CI" theoretical = 10.74%
Eksempel 3 (sammen1igning) 25 Chlorydrat af (2,4,6-trihydroxypheny1)-(3-diethylaminopropy1)-keton.Example 3 (Comparison) Chlorinated of (2,4,6-trihydroxyphenyl) - (3-diethylaminopropyl) ketone.
Kodenummer CRL 40.624 30 Ud fra 12,6 g phloroglucin (0,10 mol), 14,0 g 4-diethylamino-butyronitril (0,10 mol), 2,4 g ZnCl2 og 125 ml diethylether fâs, (idet der gâs frem som i eksempel 1), 8 g (udbytte 27%) chlorhydrat af (2,4,6-trihydroxytphenyl)-(3-diethylaminopro-pyl)-keton.Code number CRL 40.624 30 From 12.6 g of phloroglucine (0.10 mole), 14.0 g of 4-diethylamino-butyronitrile (0.10 mole), 2.4 g of ZnCl 2 and 125 ml of diethyl ether were obtained ( as in Example 1), 8 g (yield 27%) of chlorohydrate of (2,4,6-trihydroxytophenyl) - (3-diethylaminopropyl) ketone.
3535
Smeltepunkt 260°C,Melting point 260 ° C,
Analyse: % Cl mâlt = 11,46%Analysis:% Cl = 11.46%
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66
Bemærkni ng; CRL 40.624 er ikke synderlig oplaselig i vand og fysiologisk sérum ved omgivelsernes temperatur. Ved 60 °C er dets oplose-5 lighed i fysiologisk sérum (vand indeholdende 4 til 9 gram NaCl pr. liter mindre end 6 g pr. liter. Tartratet og citra-tet er ikke mere oplcselige end chlorhydratet.Notice; CRL 40.624 is not particularly soluble in water and physiologically specific at ambient temperature. At 60 ° C, its solubility in physiological semen (water containing 4 to 9 grams of NaCl per liter is less than 6 g per liter. The tartrate and citrate are no more soluble than the chlorohydrate.
Eksempel 4 {sammen1igning) 10Example 4 {Comparison) 10
Chlorhydrat af (2,6-dihydroxy-4-methoxypheny1)-(3-pyrrolidino~ propy1)-keton eller chlorhydrat af (2,4-dihydroxy-6-methoxy-phenyl)-(3-pyrrolidinopropyl)-keton.Chlorohydrate of (2,6-dihydroxy-4-methoxyphenyl) - (3-pyrrolidino-propyl) -ketone or chlorohydrate of (2,4-dihydroxy-6-methoxy-phenyl) - (3-pyrrolidinopropyl) -ketone.
15 Kodenummer CRL 40.633 I en 2 liter trehalset kolbe oploses 69 g (0,5 mol) 4-pyrroli-dino-butyronitri1 i 1 liter diethy1ether, og man tilsætter 13,6 g (0,1 mol) ZnCl2 og derefter 70 g (0,5 mol) 1,3-dihy-20 droxy-5-methoxybenzen. Man leder derefter en strem af HCl igennem reaktionsmediet, der holdes ved 25 til 30 °C i 2¾ ti-me, og lader derefter henstà natten over. Man inddamper til torhed under reduceret tryk og optager inddampningsremanensen i 1 liter vand, opvarmer til ti1bagesva1ing i 1 tîme og afko-25 1er sà. Produktet krystalliserer, og man isolerer ved filtrer-ing og derefter omkrystal1isation af en blanding af methanol og vand (3:1) v/v. Der fâs 69 g (udbytte 44%) CRL 40.633.In a 2 liter three-neck flask, 69 g (0.5 mole) of 4-pyrrolidino-butyronitrile are dissolved in 1 liter of diethyl ether and 13.6 g (0.1 mole) of ZnCl 0.5 mole) of 1,3-dihydroxy-5-methoxybenzene. A stream of HCl is then passed through the reaction medium, maintained at 25 to 30 ° C for 2¾ hours, and then allowed to stand overnight. It is evaporated to dryness under reduced pressure and the evaporation residue is taken up in 1 liter of water, heated to reflux for 1 hour and then cooled down. The product crystallizes and is isolated by filtration and then recrystallization from a mixture of methanol and water (3: 1) v / v. 69 g (yield 44%) of CRL 40.633 are obtained.
Smeltepunkt 270°C.Melting point 270 ° C.
3030
Analyse: % Cl mâlt = 11,35% % Cl" teoretisk = 11,22%Analysis:% CI measured = 11.35%% CI "theoretical = 11.22%
Bemærkni nger: 35 1. Pâ grund af mangel pâ perifer vasodi1atorisk virkning af CRL 40.633 er bestemmelsen af den n0jagtige stilling af metho-xygruppen ikke udfart. Det er i ovrigt muligt, at begge de to isomere er til stede i det isolerede produkt.Notes: 35 1. Due to lack of peripheral vasodilatory effect of CRL 40.633, determination of the exact position of the methoxy group is not made. It is also possible that both of the isomers are present in the isolated product.
77
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2. CRL 40.633 er ikke meget oploseligt i vand og fysiologisk sérum ved omgivelsernes temperatur. Ved 60 °C er den maksimale oploselighed i fysiologisk sérum (vand indeholdende 4 til 9 gram NaCl pr. liter) 10 gram pr. liter. Tartratet og citratet 5 er ikke mere oploselige end chlorhydratet.2. CRL 40.633 is not very soluble in water and physiologically specific at ambient temperature. At 60 ° C, the maximum solubility in physiological serum (water containing 4 to 9 grams of NaCl per liter) is 10 grams per liter. liter. The tartrate and citrate 5 are no more soluble than the chlorohydrate.
Eksempel 5 (sammenligning)Example 5 (Comparison)
Chlorhydrat af (2,6-dimethoxy-4-hydroxyphenyl)-(3-pyrrolidino-10 propyl)-keton.Chlorohydrate of (2,6-dimethoxy-4-hydroxyphenyl) - (3-pyrrolidinopropyl) ketone.
Kodetal CRL 40.634Code Number CRL 40.634
Bundfaldet P, fremkommet i eksempel 2, omkrystalliseres af en 15 blanding af lige rumfangsdele acetone og éthanol og giver 49,5 gram (udbytte 30%) chlorhydrat af (2,6-dimethoxy-4-hydroxyphe-nyl)-(3-pyrrolidinopropyl)-keton.The precipitate P, obtained in Example 2, is recrystallized from a mixture of equal volumes of acetone and ethanol to give 49.5 grams (yield 30%) of chlorohydrate of (2,6-dimethoxy-4-hydroxyphenyl) - (3-pyrrolidinopropyl) ) ketone.
Smeltepunkt 177 °C.Melting point 177 ° C.
2020
Analyse: % Cl" mâlt = 10,72% % Cl" teoretisk = 10,74%.Analysis:% Cl "measured = 10.72%% Cl" theoretical = 10.74%.
Bemarkn i ng: 25Marketing: 25
Stillingen af 4-hydroxygruppen i CRL 40.634 og af 6-hydroxy-gruppen i CRL 40.635 (produkt fra eksempel 2) bestemmes ved analyse.The position of the 4-hydroxy group in CRL 40.634 and of the 6-hydroxy group in CRL 40.635 (product of Example 2) is determined by analysis.
30 I det folgende er resumeret resultaterne af prover, som er ud-fort med produkterne fra eksempel 1 (CRL 40.598) og 2 (CRL 40.635), produkterne fra sammenligningseksemplerne 3 (CRL 40.624), 4 (CRL 40.633) og 5 (CRL 40.634) og et referencepro-dukt, der er kendt som perifert vasodilatorisk middel (LL 35 1656).The following is summarized the results of samples taken with the products of Examples 1 (CRL 40,598) and 2 (CRL 40,635), the products of Comparative Examples 3 (CRL 40,624), 4 (CRL 40,633) and 5 (CRL 40,634). ) and a reference product known as peripheral vasodilatory agent (LL 35 1656).
1· Akut toxicitet.1 · Acute toxicity.
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88
Ad oral vej pâ hanmus (de undersogte produkter administreres i vandig oplosning) er DL-50 vmrdierne f0lgende: CRL 40.598: DL-50 = 1400 ± 112 mg/kg 5 CRL 40.635: DL-50 = 800 ± 76 mg/kg LL 1656 : DL-50 = 280 ± 25 mg/kg 2. Vasodilatorisk virkning.By oral route in male mice (the products studied are administered in aqueous solution), the DL-50 values are as follows: CRL 40.598: DL-50 = 1400 ± 112 mg / kg 5 CRL 40.635: DL-50 = 800 ± 76 mg / kg LL 1656 : DL-50 = 280 ± 25 mg / kg 2. Vasodilatory effect.
10 Den vasodi1atoriska virkning undersoges pà hanhund anæstetis-eret med nembutal (6 dyr pr. dosis og pr. produkt). Produk-terne, der skal sammenlignés, administreres i oplosning i fy-siologisk sérum i et rumfang pâ 6 ml pr. dyr ad intravenos vej (perfusion af 1 ml pr. minut) (6 ti1 9 ml pr. dyr ved per-15 fusion af 1,5 til 2 ml pr. minut for CRL 40.624 pâ grund af dets ringe oploselighed) og i et rumfang pâ 10 ml pr. dyr ad intraduodenal vej (oplosningerne af CRL 40.633 opbevares pâ vandbad). I forhold til kontrollen (samme dyr der kun modtager fysiologisk sérum) mâles 3 paramétré: mi ddelarterietrykket 20 (udtrykt i mm Hg) hjertefrekvensen (udtrykt i slag pr. minut) og 1ârarteriegennemstromningen (udtrykt i ml pr. minut). Va-riationerne i disse paramétré, udtrykt i procent i forhold til kontrollen, er anfort i tabel II (intravenos administration) og III_.( i ntraduodenal administration).The vasodilatory effect was examined on male dogs anesthetized with nembutal (6 animals per dose and per product). The products to be compared are administered in solution in physiological semen at a volume of 6 ml per ml. by intravenous route (perfusion of 1 ml per minute) (6 to 9 ml per animal at a per-fusion of 1.5 to 2 ml per minute for CRL 40,624 due to its poor solubility) and in a volume of 10 ml per animals by intraduodenal route (the solutions of CRL 40.633 are stored in a water bath). In relation to the control (the same animal receiving only physiological semen), 3 parameters are measured: at the arterial pressure 20 (expressed in mm Hg) heart rate (expressed in beats per minute) and the arterial flow (expressed in ml per minute). The variations in these parameters, expressed as a percentage of control, are listed in Tables II (intravenous administration) and III (in intraduodenal administration).
2525
Den perifere vasodilation er her karakteriseret ved en for-ogelse af lârarteriegennemstromningen, og de to andre paramétré (mfdde-larterietryk og hjertefrekvens) er anfort for at il-lustrere produkternes optræden i organismen. Ifolge de fore-30 liggende undersogelsesbetingelser siger man, at et produkt er et perifert vasodilatorisk middel, hvis lârarteriegennem-stromningen foreges med mindst 30% ved intravenes administration og ved intraduodenal administration.The peripheral vasodilation is characterized here by an increase in femoral artery flow, and the other two parameters (medial arterial pressure and heart rate) are used to illustrate the appearance of the products in the organism. According to the present examination conditions, a product is said to be a peripheral vasodilatory agent if the femoral artery flow is at least 30% by intravenous administration and intraduodenal administration.
35 Ad intravenos vej (se tabel II) iagttager man pâ anæstetiseret hund, at CRL 40.598 og CRL 40.635 foroger middelarterietrykket lidt, at de er praktisk taget uden virkning pâ hjertefrekvensen, og at de foroger 1ârarteriegennemstromningen meget mere 935 By intravenous route (see Table II), on anesthetized dogs, CRL 40.598 and CRL 40.635 are observed to slightly increase the mean arterial pressure, to be virtually unaffected by heart rate, and to increase 1 year artery flow much more.
DK 156395 BDK 156395 B
end LL 1656. Man konstaterer blandt andet, at vasodi!ationen fremkaldt af CRL 40.598 og CRL 40.635 varer ca. 10 minu.tter for aile de undersogte doser, og denne er længere end af LL 1656. Tabel II viser i ©vrigt, at produkterne fra sammenlig-5 ningseksemplerne (CRL 40.624, CRL 40.633 og CRL 40.634) générait ikke har nogen vasodi1atorisk virkning, og at denne vi rk-ning, hvis den viser s i g (i en dosis pâ 3 mg pr. kg for CRL 40.634 og i en dosis pâ 6 mg pr. kg for CRL 40.624) er flygtig ©lier af kort varighed.than LL 1656. Among other things, it is found that the vasodilatation induced by CRL 40,598 and CRL 40,635 lasts approx. 10 minutes for all the doses examined and this is longer than that of LL 1656. Table II shows that the products of Comparative Examples (CRL 40.624, CRL 40.633 and CRL 40.634) have no vasodilatory effect, and that this finding, if shown (at a dose of 3 mg per kg for CRL 40,634 and at a dose of 6 mg per kg for CRL 40,624) is of short duration volatility.
1010
Ad intraduodenal vej pâ anæstetiseret hund blev LL 1656 admi-nistreret i doser svarende til henholdsvis 1/40, 1/20 og 1/10 af DL-50 for mus ad oral vej, og CRL 40.598 og CRL 40.634 blev administreret i forholdsvis svagere doser svarende til 1/70 af 15 DL-50 for forstnævnte og 1/44 af DL-50 for sidstnævnte. Man konstaterer, at efter intraduodenal administration er varighe-den af den perifere vasodi1atoriske virkning af CRL 40.598 og CRL 40.635 længere end af LL 1656, idet kinetikken af den vasodi 1atoriske virkning er folgende: 20By intraduodenal route on anesthetized dog, LL 1656 was administered at doses corresponding to 1/40, 1/20 and 1/10 of DL-50, respectively, for mice by oral route, and CRL 40,598 and CRL 40,634 were administered at relatively weaker doses. corresponding to 1/70 of 15 DL-50 for the former and 1/44 of DL-50 for the latter. It is found that after intraduodenal administration, the duration of the peripheral vasodilatory effect of CRL 40,598 and CRL 40,635 is longer than that of LL 1656, the kinetics of the vasodilatory effect being as follows:
For LL 1656 viser virkningen sig 5 minutter efter admi nistra-tionen, og denne virkning nâr sit maksimum pâ 15 minutter, og den maksimale varighed er 60 til 90 minutter.For LL 1656, the effect appears 5 minutes after administration and this effect reaches its maximum of 15 minutes and the maximum duration is 60 to 90 minutes.
25 For CRL 40.598 fremkommer den vasodilatoriske virkning langs-ommere, idet den viser sig ca. 30 minutter efter injektionen, og denne virkning nâr sit maksimum 2 til 4 timer efter injektionen, og dens maksimale varighed er 5 timer.25 For CRL 40.598, the vasodilatory effect appears more slowly, showing 30 minutes after injection and this effect reaches its maximum 2 to 4 hours after injection and its maximum duration is 5 hours.
30 For CRL 40.635 begynder den vasodilatoriske virkning 20 minutter efter injektionen, nâr sit maksimum pâ 30 til 60 minutter og varer mere end 2 timer.30 For CRL 40,635, the vasodilatory effect begins 20 minutes after injection, reaching its maximum of 30 to 60 minutes and lasting more than 2 hours.
Resultaterne i tabel III viser, at ad intraduodenal vej er CRLThe results in Table III show that the intraduodenal route is CRL
35 40.598, CRL 40.635 og LL 1656 aktive, medens de ©vrige pro- dukter (CRL 40.624, CRL 40.633 og CRL 40.634) mangler vasodi-latorisk virkning, for variationen i 1ârarteriegennemstrom-ningen, som de fremkalder, er meget svag. I ©vrigt iagttager 1035 40,598, CRL 40,635 and LL 1656 are active, while the other products (CRL 40,624, CRL 40,633 and CRL 40,634) lack vasodilatory effect, because the variation in arterial flow that they induce is very weak. I © observes 10
DK 156395 BDK 156395 B
man, at CRL 40.598 og CRL 40.635 ikke fremkalder nogen ændring i hudfarven (ore, tunge, trædepuder) selv ved den kraftigste vasodilation.CRL 40.598 and CRL 40.635 do not induce any change in skin color (ears, tongue, pads) even with the strongest vasodilation.
5 Sammenfattende viser de sammenlignende resultater at: (a) Produkterne fremstillet if0lge opfindelsen er perifere vasodi 1 atoriske midler, der er ligesâ intéressante terapeutisk som referenceproduktet, LL 1656, og de adskiller sig fra dette 10 ved en svagere toksicitet og en péri fer vasodilatorisk virk-ning af længere varighed, og (b) forbindelserne fremstillet ifolge sammenligni ngseksem-plerne, som med hensyn til struktur ligger meget nær ved for- 15 bindelserne fremstillet ifolge opfindelsen, mangler perifer vasodilatorisk virkning.In summary, the comparative results show that: (a) The products prepared according to the invention are peripheral vasodi 1 atoric agents which are equally as therapeutic as the reference product, LL 1656, and they differ from this 10 by a weaker toxicity and a peripheral vasodilatory effect. longer duration, and (b) the compounds prepared according to the comparative examples which are very close to the compounds prepared according to the invention in terms of structure lack peripheral vasodilatory effect.
3. Antiaqqregerende virkning.3. Antioxidant effect.
20 Man har ogsà konstateret, at forbindelserne fremstillet ifolge opfindelsen har en gavnlig antiaggregerende virkning pô blod-pladerne. Sâledes ændrer CRL 40.598 blodpladeaggregeringen ifolge ADP proven (adenosin diphosphat) i en dosis pâ 50 mg pr. kg pr. dag i fire dage hos rotte (middelhæmning 44%).It has also been found that the compounds prepared according to the invention have a beneficial anti-aggregating effect on the platelets. Thus, CRL 40,598 changes platelet aggregation according to ADP (adenosine diphosphate) samples at a dose of 50 mg per day. kg per day for four days in the rat (mean inhibition 44%).
25 4. Kliniske prever.25 4. Clinical Trials.
Kliniske prever foretaget med forbindelserne fremstillet ifolge opfindelsen har givet gode resultater hos menneske ved 30 medicinske behandlinger, hvor man seger en vasodilation af blodkarrene. CRL 40.598 administreret i form af tabletter el-ler gelatinose piller (hver indeholdende 100 mg til 200 mg CRL 40.598) i en mængde af 2 til 3 tabletter eller piller pr. dag har sâledes muliggjort effektiv behandling af Raynaud's syg-35 dom, og administreret ad intravenos vej (injicerbar ampul indeholdende 50 mg til 100 mg CRL 40.598) i en mængde af 2 til 3 injektioner pr. dag har muliggjort en cérébral vasodilatorisk behandling.Clinical tests performed with the compounds of the invention have produced good results in humans in 30 medical treatments, where a vasodilation of the blood vessels is said. CRL 40,598 administered in the form of tablets or gelatinosis pills (each containing 100 mg to 200 mg CRL 40,598) in an amount of 2 to 3 tablets or pills per day. day has thus enabled effective treatment of Raynaud's disease and administered by intravenous route (injectable ampoule containing 50 mg to 100 mg CRL 40,598) in an amount of 2 to 3 injections per day. day has enabled a cérébral vasodilatory treatment.
11 DK 156395 B11 DK 156395 B
TABEL ITABLE I
A-C0-(CH2)3-B, HClA-CO- (CH2) 3-B, HCl
Produkt Kode nr. A B FProduct Code No. A B F
— — 0H — —- - 0H - -
Eksempel 1 CRL 40598 pyrrolidino 260°CExample 1 CRL 40598 pyrrolidino 260 ° C
m .m.
. 0CH3. 0CH3
Eksempel 2 CRL 40655 H^CO-^y- pyrrolidino 170°CExample 2 CRL 40655 H₂CO₂-pyrrolidino 170 ° C
W _W _
Eksempel 3 CRL 40624 βΕ N(C£H5)2 260°CExample 3 CRL 40624 βΕ N (C £H H) 2 260 ° C
( s amme nli gning ) HO(sighing) HO
(b) ^""^OH(b) ^ "" OH
OHOH
Eksempel 4 CRL 40633 H^CO-^y- pyrrolidino 270°CExample 4 CRL 40633 H 2 CO- γ-pyrrolidino 270 ° C
(sammenligning) eller 3h (b) (c) HO^)(comparison) or 3h (b) (c) HO
OHOH
*qqH^* Qqh ^
Eksempel 5 CRL 40634 H0~C^" r pyrrolidino 177°CExample 5 CRL 40634 H0 ~ C4 pyrrolidino 177 ° C
(sammenligning) 3 (b) (d)______ _PCH3(comparison) 3 (b) (d) ______ _PCH3
FONZYLANE LL 1656 H3ca^V- pyrrolidino 192°CFONZYLANE LL 1656 H3ca ^ V- pyrrolidino 192 ° C
(reference) OCH-^ (a)(reference) AND- (a)
Noter: (a) Produktet er aktivt som perifert vasodilatorisk middel (b) Produktet er inaktivt som perifert vasodilatorisk middel, (c) Produktet, hvis struktur ikke er blevet bestemt, kunne være en blanding af de to isomere, (d) Isomer af produktet fra eksempel 2,Notes: (a) The product is active as a peripheral vasodilatory agent (b) The product is inactive as a peripheral vasodilatory agent, (c) The product whose structure has not been determined could be a mixture of the two isomers, (d) Isomer of the product from Example 2,
12 DK 156395 B12 DK 156395 B
TABEL IITABLE II
Variation i paramétré efter intraven0s administra= til anæstetiseret hund. .Variation in parameters according to intraven0s administration = to anesthetized dog. .
Produkt Dosis _Variationer i %_ mg/kg arterie= lârarterie= hjerte^ tryk gennemstromning frekvens CRL 40598 1,5 +9 +56 (a) +3 CRL 40635 1,5 +3 +38 (a) +2 CRL 40624 1,5 -5 +3 -5 CRL 40633 1,5 0 +5 +1 CRL 40634 1,5 +2 +10 0 LL 1656 1,5 0 +33 (¾) +5 CRL 40598 3 +10 +63 (a) 0 CRL 40635 3 .+5 +40 (a) +1 CRL 40624 3 -7 +1 -6 CRL 40633 3 +1 +8 -2Product Dose _ Variations in% _ mg / kg artery = thigh artery = heart ^ pressure flow rate CRL 40598 1.5 +9 +56 (a) +3 CRL 40635 1.5 +3 +38 (a) +2 CRL 40624 1, 5 -5 +3 -5 CRL 40633 1.5 0 +5 +1 CRL 40634 1.5 +2 +10 0 LL 1656 1.5 0 +33 (¾) +5 CRL 40598 3 +10 +63 (a) 0 CRL 40635 3. + 5 +40 (a) +1 CRL 40624 3 -7 +1 -6 CRL 40633 3 +1 +8 -2
CRL 40634 3 -1 +30 (c) OCRL 40634 3 -1 +30 (c) 0
LL 1656 3 -2 +36 (b) +6 CRL 40598 6 +4 +63 (a) +3 CRL 40635 6 +2 +44 (a) +1 CRL 40624 6 -10 ' +26 (d) -8 CRL 40633 6 +2 +7 +1 CRL 40634 6 +1 +7 +2 LL 1656 6 -2 +39 (b) 0LL 1656 3 -2 +36 (b) +6 CRL 40598 6 +4 +63 (a) +3 CRL 40635 6 +2 +44 (a) +1 CRL 40624 6 -10 '+26 (d) -8 CRL 40633 6 +2 +7 +1 CRL 40634 6 +1 +7 +2 LL 1656 6 -2 +39 (b) 0
Noter: (a) Varighed af virkning: 10 minutter (b) Varighed af virkning: 5 minutter (c) Varighed af virkning: 3 minutter (d) Varighed af virkning: 1 minutNotes: (a) Duration of effect: 10 minutes (b) Duration of action: 5 minutes (c) Duration of action: 3 minutes (d) Duration of effect: 1 minute
13 DK 156395 B13 DK 156395 B
TABEL IIITABLE III
Variation i paramétré efter intraduodenal administration til anæstetiseret iiund.Variation in parameters after intraduodenal administration to anesthetized iiund.
Produkt Dosis Variationer i %JProduct Dose Variations in% J
mg/kg artêrie= lârarterie= hjerte= tryk gennemstromning frekvens LL 1656 7 +2 +44 +7 LL 1656 14 -3,5 +73 +4,5 LL 1656 28 -4,5 +100 +6 CRL 40598 20 -2 +60 -8 CRL 40624 2Q 0+2 +1 CRL 40633 20 +1 +3 +2 CRL 40634 20 -1 +5 -1 CRL 40635 20 -2 +60 -8mg / kg artery = thigh artery = heart = pressure flow rate LL 1656 7 +2 +44 +7 LL 1656 14 -3.5 +73 + 4.5 LL 1656 28 -4.5 +100 +6 CRL 40598 20 -2 +60 -8 CRL 40624 2Q 0 + 2 +1 CRL 40633 20 +1 +3 +2 CRL 40634 20 -1 +5 -1 CRL 40635 20 -2 +60 -8
Claims (2)
Applications Claiming Priority (2)
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GB3998277 | 1977-09-26 | ||
GB3998277 | 1977-09-26 |
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DK419178A DK419178A (en) | 1979-03-27 |
DK156395B true DK156395B (en) | 1989-08-14 |
DK156395C DK156395C (en) | 1990-01-08 |
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DK419178A DK156395C (en) | 1977-09-26 | 1978-09-21 | ANALOGY PROCEDURE FOR PREPARING A (3-PYRROLIDINOPROPYL) -KETONE DERIVATIVE |
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JP (1) | JPS5495562A (en) |
AU (1) | AU523963B2 (en) |
BE (1) | BE870717A (en) |
CA (1) | CA1126738A (en) |
CH (1) | CH633774A5 (en) |
DE (1) | DE2858813C2 (en) |
DK (1) | DK156395C (en) |
ES (1) | ES473689A1 (en) |
FR (1) | FR2404003A1 (en) |
IE (1) | IE47367B1 (en) |
IT (1) | IT1108172B (en) |
LU (1) | LU80277A1 (en) |
NL (1) | NL190720C (en) |
SE (1) | SE436277B (en) |
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US4273776A (en) | 1980-01-30 | 1981-06-16 | E. R. Squibb & Sons, Inc. | Antibacterial and antifungal derivatives of 3-(1H-imidazol-1-yl)-2-propen-1-ones |
FR2504136A1 (en) * | 1981-04-15 | 1982-10-22 | Lafon Labor | (2,6-DIMETHOXY-4-HYDROXYPHENYL) - (3-PIPERIDINOPROPYL) -CETONE AND ITS ADDITION SALTS, THERAPEUTIC USE AND PREPARATION METHOD |
KR930010702B1 (en) * | 1985-04-11 | 1993-11-08 | 닛뽕 가야꾸 가부시기가이샤 | New derivatives of an aminoketone |
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FR2092133B1 (en) * | 1970-05-06 | 1974-03-22 | Orsymonde | |
FR2134218A1 (en) * | 1971-04-27 | 1972-12-08 | Penciolelli Madeleine | Phloroglucinol aminoketones - vasodilators and antispasmodics |
-
1978
- 1978-09-14 FR FR7826464A patent/FR2404003A1/en active Granted
- 1978-09-18 IE IE1883/78A patent/IE47367B1/en not_active IP Right Cessation
- 1978-09-21 SE SE7809916A patent/SE436277B/en not_active IP Right Cessation
- 1978-09-21 DK DK419178A patent/DK156395C/en not_active IP Right Cessation
- 1978-09-25 BE BE2057301A patent/BE870717A/en not_active IP Right Cessation
- 1978-09-25 IT IT69202/78A patent/IT1108172B/en active
- 1978-09-25 CH CH997678A patent/CH633774A5/en not_active IP Right Cessation
- 1978-09-25 DE DE2858813A patent/DE2858813C2/de not_active Expired - Fee Related
- 1978-09-25 LU LU80277A patent/LU80277A1/en unknown
- 1978-09-26 AU AU40195/78A patent/AU523963B2/en not_active Expired
- 1978-09-26 ES ES473689A patent/ES473689A1/en not_active Expired
- 1978-09-26 JP JP11756078A patent/JPS5495562A/en active Pending
- 1978-09-26 CA CA312,144A patent/CA1126738A/en not_active Expired
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Also Published As
Publication number | Publication date |
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FR2404003B1 (en) | 1981-07-31 |
NL7809754A (en) | 1979-03-28 |
IT7869202A0 (en) | 1978-09-25 |
SE7809916L (en) | 1979-03-27 |
IE781883L (en) | 1979-03-26 |
BE870717A (en) | 1979-03-26 |
DE2858813C2 (en) | 1993-07-01 |
ES473689A1 (en) | 1979-05-01 |
NL190720C (en) | 1994-07-18 |
IE47367B1 (en) | 1984-03-07 |
JPS5495562A (en) | 1979-07-28 |
AU523963B2 (en) | 1982-08-26 |
IT1108172B (en) | 1985-12-02 |
SE436277B (en) | 1984-11-26 |
AU4019578A (en) | 1980-04-03 |
NL190720B (en) | 1994-02-16 |
DK156395C (en) | 1990-01-08 |
FR2404003A1 (en) | 1979-04-20 |
LU80277A1 (en) | 1979-06-01 |
DK419178A (en) | 1979-03-27 |
CA1126738A (en) | 1982-06-29 |
CH633774A5 (en) | 1982-12-31 |
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