DK159966B - Analogy process for preparing oxygen-containing diaryl compounds - Google Patents
Analogy process for preparing oxygen-containing diaryl compounds Download PDFInfo
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- DK159966B DK159966B DK31580A DK31580A DK159966B DK 159966 B DK159966 B DK 159966B DK 31580 A DK31580 A DK 31580A DK 31580 A DK31580 A DK 31580A DK 159966 B DK159966 B DK 159966B
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- compounds
- alk
- diaryl compounds
- preparing oxygen
- containing diaryl
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
DK 159966 BDK 159966 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte oxygenholdige diaryl-forbindelser. Disse forbindelser er terapeutisk anvendelige.The present invention relates to an analogous process for the preparation of novel oxygen-containing diaryl compounds. These compounds are therapeutically useful.
55
De omhandlede forbindelser har den i kravets indledning anførte almene formel I og er især anvendelige ved behandling af kredsløbsforstyrrelser, såsom cardiovasculære sygdomme. Fremgangsmåden ifølge opfindelsen er ejendomme-10 lig ved det i kravets kendetegnende del anførte.The compounds of the present invention have the general formula I set forth in the preamble of the claim and are particularly useful in the treatment of circulatory disorders such as cardiovascular diseases. The process according to the invention is characterized by the characterizing part of the claim.
Det i formel I anvendte symbol "Alk" betegner CH^CH^ eller ch(ch3)ch2.The symbol "Alk" used in formula I represents CH 2 CH 2 or ch (ch 3) ch 2.
15 Fra CH patentskrift nr. 470 332 kendes forbindelser, der er beslægtede med de ifølge opfindelsen fremstillede forbindelser. De fra CH patentskriftet kendte forbindelser har imidlertid kun hypocholesterolæmisk virkning, hvorimod forbindelserne fremstillet ifølge opfindelsen har så-20 vel hypocholesterolæmisk som hypolipidæmisk virkning, hvortil kommer en antiaggregerende virkning.15 from CH patent specification 470 332 are known compounds which are related to the compounds of the invention. However, the compounds known from the CH patent have only hypocholesterolemic effect, whereas the compounds of the invention have both hypocholesterolemic as well as hypolipidemic effect, to which is added an anti-aggregating effect.
De omhandlede forbindelser med formel i fremstilles ifølge opfindelsen ved, at man omsætter p-(p-chlorphenyoxy)-25 phenol med formlenThe present compounds of formula I are prepared according to the invention by reacting p- (p-chlorophenyoxy) -25 phenol of the formula
Cl-<^~^-0-/~\oH (II) 30 N ' \=L/ med er halogenderivat med formlenCl - <^ ~ ^ -0- / ~ \ oH (II) 30 N '\ = L / with is halogen derivative of the formula
Hal-Alk-OH (III) hvori Alk har den ovenfor angivne betydning og Hal betegner et halogenatom, fortrinsvis brom eller chlor.Hal-Alk-OH (III) wherein Alk has the meaning given above and Hal represents a halogen atom, preferably bromine or chlorine.
3535
DK 159966 BDK 159966 B
22
De omhandlede oxygenholdige diarylforbindelser er anvendelige i terapien ved behandling af kredsløbsforstyrrelser, især cardiovasculære sygdomme. Forbindelserne er også anvendelige som hypolipidæmiske og hypocholesterolæmi-5 ske midler, ligesom de virker som antiaggregeringsmidler for blodplader.The present oxygen-containing diaryl compounds are useful in the therapy of the treatment of circulatory disorders, especially cardiovascular diseases. The compounds are also useful as hypolipidemic and hypocholesterolemic agents, as well as act as platelet anti-aggregating agents.
De omhandlede forbindelser kan formuleres til terapeutiske midler i kombination med en fysiologisk acceptabel 10 excipiens.The present compounds can be formulated as therapeutic agents in combination with a physiologically acceptable excipient.
Fysiske data for de omhandlede forbindelser fremgår af nedenstående tabel I.Physical data for the compounds in question are shown in Table I.
2020
Kode nr. Alk. SmeltepunktCode No. Alk. Melting point
CRL 40293 CH^CH^ 78°CCRL 40293 CH2 CH2 78 ° C
CRL 40300 CHtCH|)CH2 <50°CCRL 40300 CHtCH |) CH2 <50 ° C
2525
Opfindelsen illustreres nærmere ved det nedenstående eksempel .The invention is further illustrated by the following example.
EKSEMPELEXAMPLE
30 2-[4-(4-chlorphenoxy)-phenoxy]ethanol 35 32- [4- (4-chlorophenoxy) phenoxy] ethanol 3
DK 1H9966 BDK 1H9966 B
C1~^ -0 —^\^y~°~ch2-ch2-oh 5C1 ~ ^ -0 - ^ \ ^ y ~ ° ~ ch2-ch2-oh 5
Kode nr. CRL 40 293.Code No. CRL 40 293.
6,6 g (0,082 mol) 2-chlorethanol udhældes i løbet af 5 10 minutter i en varm opløsning af 15 g (0,068 mol) p-(p-chlorphenoxy)phenol og 2,75 g (0,068 mol) natriumhydroxidpastiller i 40 ml vandfri ethanol. Man opvarmer under tilbagesvaling i 4 timer, hvorpå mineralsaltene fjernes ved filtrering, og ethanolen afdampes under reduceret 15 tryk. Efter at reaktionsmediet er optaget i diethylether, udvaskes den således opnåede organiske fase med 2N natriumhydroxid og vand og tørres, hvorpå opløsningsmidlet af-dampes, og man opnår 11 g pastaagtige krystaller.6.6 g (0.082 mole) of 2-chloroethanol is poured over 5 minutes into a warm solution of 15 g (0.068 mole) of p- (p-chlorophenoxy) phenol and 2.75 g (0.068 mole) of sodium hydroxide pastes in 40 ml. anhydrous ethanol. It is heated under reflux for 4 hours, then the mineral salts are removed by filtration and the ethanol is evaporated under reduced pressure. After the reaction medium is taken up in diethyl ether, the organic phase thus obtained is washed with 2N sodium hydroxide and water and dried, then the solvent is evaporated off and 11 g of paste-like crystals are obtained.
20 10,5 g af disse krystaller renses ved krystallisation fra diisopropylether, hvorved man opnår 6,7 g skinnende hvide flager.10.5 g of these crystals are purified by crystallization from diisopropyl ether to obtain 6.7 g of shiny white flakes.
Smp. (Køfler) =78°C. Udbytte = 39%.Mp. (Cooktops) = 78 ° C. Yield = 39%.
25 Farmakologiske undersøgelser25 Pharmacological studies
Nedenfor er anført resultaterne af farmakologiske undersøgelser, som er foretaget med henblik på bestemmelse af på den ene side de hypolipidæmiske og hypocholesterolæmi-30 ske egenskaber og på den anden side de antiaggregerende egenskaber af de omhandlede forbindelser.Listed below are the results of pharmacological studies conducted to determine, on the one hand, the hypolipidemic and hypocholesterolemic properties and, on the other, the anti-aggregating properties of the compounds of the invention.
De hypolipidæmiske og hypocholesterolæmiske virkninger er undersøgt på Wistar-rotter.The hypolipidemic and hypocholesterolemic effects have been studied in Wistar rats.
Den antiaggregerende virkning er undersøgt ved studier af de parametre, der karakteriserer aggregeringskurven for 35The anti-aggregation effect has been investigated by studying the parameters that characterize the aggregation curve of 35
DK 159966BDK 159966B
4 blodplader induceret af: (a) Collagen: inhibering af aggregeringen (som svarer til den procentvise transmission), latenstiden og hastig- 5 heden, og (b) ADP: inhibering af aggregeringen (dvs. den procentvise transmission).4 platelets induced by: (a) Collagen: inhibition of the aggregation (corresponding to the percentage transmission), latency and velocity, and (b) ADP: inhibition of the aggregation (i.e., the percentage transmission).
10 Virkningen er undersøgt på blod fra Wistar-hanrotter, idet de anvendte aggregeringsmidler var eddikesur collagen fortyndet til 1/10 samt 1 tiM ADP. I nedenstående tabel II er anført resultaterne med hensyn til den antiaggrege-rende virkning og de hypolipidæmiske og hypocholesterolæ-15 miske virkninger af de omhandlede forbindelser: 20 25 30 35The effect was investigated on blood from male Wistar rats, the aggregates used being acetic acid collagen diluted to 1/10 and 1 µM ADP. Table II gives the results of the anti-aggregating and hypolipidemic and hypocholesterolemic effects of the compounds of the present invention: 20 25 30 35
DK 159966 BDK 159966 B
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DK 159966 BDK 159966 B
66
Man har foretaget andre farmakologiske forsøg med forbindelsen fra eksemplet (CRL 40293):Other pharmacological tests have been carried out with the compound of Example (CRL 40293):
Toxicitet 5 På hunmus er LD^-q per os 2 050 mg/kg, mens LDq per os hos hanrotter er over 600 mg/kg.Toxicity 5 In female mice, LD 2 -q per os is 2,050 mg / kg, while LDq per os in male rats is above 600 mg / kg.
Man har iøvrigt bemærket, at CRL 40 293 er et stof, der 10 tolereres godt. Hos unge rotter ( grupper på 3 dyr), der fik indgivet 1 g/kg produkt gennem en mavesonde, konstaterer man, efter at de er aflivet 8 timer efter indgivelsen, ingen sårdannelse eller inflammation på maven og duodenum .It has also been noted that CRL 40 293 is a well tolerated substance. In young rats (groups of 3 animals) given 1 g / kg of product through an abdominal probe, after being sacrificed 8 hours after administration, no ulceration or inflammation of the stomach and duodenum is found.
1515
Cardiovasculær virkningCardiovascular action
Tre anæstetiserede hunde anvendtes til denne undersøgelse. Produktet blev indgivet intraduodenalt i en gummisus-20 pension.Three anesthetized dogs were used for this study. The product was administered intraduodenally in a rubber suspension.
To hunde med lukket thorax og spontan respiration fik indgivet CRL 40 293 i doser på 100 mg/kg og derpå 200 mg/kg, idet denne anden dosis blev indgivet 1 1/2 - 2 25 timer efter den første. Ingen af de målte parametre modificeredes i de to observationstimer (arterietryk, hjertefrekvens, det intraventrikulære tryk i højre hjertekammer, dp/dt, den afgivne mængde til de vertebrale og femu-rale arterier samt respirationen).Two dogs with closed thorax and spontaneous respiration were given CRL 40 293 at doses of 100 mg / kg and then 200 mg / kg, this second dose being administered 1 1/2 - 2 25 hours after the first. Neither of the measured parameters was modified in the two observation hours (arterial pressure, heart rate, intraventricular pressure in the right ventricle, dp / dt, the amount delivered to the vertebral and femoral arteries, and the respiration).
3030
En hund med åben thorax fik indgivet 100 mg/kg og derpå en time senere 200 mg/kg CRL 40 293. Ingen af de· målte parametre modificeredes i løbet af de to observationstimer (arterietryk, hjertefrekvens, intraventrikulært tryk i 35 højre hjertekammer, dp/dt, afgiven mængde til aorta, arbejdet af højre hjertekammer samt den afgivne mængde til coronararterien).An open thoracic dog was administered 100 mg / kg and then one hour later 200 mg / kg CRL 40 293. Neither of the measured parameters were modified during the two observation hours (arterial pressure, heart rate, intraventricular pressure in 35 right heart chambers, dp / dt, amount delivered to the aorta, work done by the right heart chamber and the amount delivered to the coronary artery).
DK 159966BDK 159966B
7 På disse dyr modificeredes virkningerne af injektioner af noradrenalin, acetylcholin, tyramin, DMPP, histamin og serotonin ikke, og det samme gælder okklusionsvirkninger- * ne på carotiderne og stimulationen på den centrale ende 5 og den perifere ende af nervus vagus.7 In these animals, the effects of injections of noradrenaline, acetylcholine, tyramine, DMPP, histamine and serotonin were not modified, as were the occlusion effects on the carotids and stimulation on the central end 5 and the peripheral end of the vagus nerve.
Produktet har en god hypolipidæmisk og hypocholesterolæ-misk virkning som anført i tabel II ved en oral dosis på 50 ml/kg. Endvidere er formindskelsen af de totale lipi-10 der og cholesterol 20% efter 3-4 dages behandling med en daglig peroral dosis på 10 mg/kg.The product has a good hypolipidemic and hypocholesterolemic effect as listed in Table II at an oral dose of 50 ml / kg. Furthermore, the reduction of total lipids and cholesterol is 20% after 3-4 days of treatment with a daily oral dose of 10 mg / kg.
Man har ved kliniske forsøg kunnet verificere de farmakologiske undersøgelser. Således gav CRL 40 293 indgivet i 15 form af kapsler med 400 mg aktiv ingrediens, indgivet daglig i mængder på 2 gange 2 kapsler, gode resultater ved behandling af kredsløbsforstyrrelser, især lipidiske forstyrrelser.Pharmacological studies have been verified in clinical trials. Thus, CRL 40,293 administered in 15 form capsules with 400 mg of active ingredient, administered daily in 2x 2 capsules, gave good results in the treatment of circulatory disorders, especially lipidic disorders.
20 25 30 3520 25 30 35
Claims (1)
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4238774 | 1974-09-30 | ||
| GB4238774A GB1519147A (en) | 1974-09-30 | 1974-09-30 | Sulphur and oxygen-containing diaryl compounds |
| GB158775 | 1975-01-14 | ||
| GB158775 | 1975-01-14 | ||
| FR7502307A FR2258846A1 (en) | 1974-01-25 | 1975-01-24 | Bis((N-hydroxy alkyl)-amino alkyl thio)alkane and derivs - as agents preventing blood platelet aggregation |
| FR7502307 | 1975-01-24 | ||
| DK437075 | 1975-09-29 | ||
| DK437075A DK146336C (en) | 1974-09-30 | 1975-09-29 | ANALOGY PROCEDURE FOR THE PREPARATION OF ACID ADDITION SALTS OF SULFUL DIARYL COMPOUNDS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK31580A DK31580A (en) | 1980-01-25 |
| DK159966B true DK159966B (en) | 1991-01-07 |
| DK159966C DK159966C (en) | 1991-05-27 |
Family
ID=27439711
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK31580A DK159966C (en) | 1974-09-30 | 1980-01-25 | ANALOGY PROCEDURE FOR THE PREPARATION OF OXYGEN-CONTAINED DIARYL COMPOUNDS |
| DK31780A DK31780A (en) | 1974-09-30 | 1980-01-25 | METHOD OF ANALOGUE FOR THE PREPARATION OF OXYGEN-CONTAINED DIARYL COMPOUNDS AND ACID ADDITION SALTS |
| DK31680A DK152206C (en) | 1974-09-30 | 1980-01-25 | METHOD OF ANALOGUE FOR THE PREPARATION OF SULFUR AND / OR OXYGEN-DIARYL COMPOUNDS OR ACID ADDITION SALTS |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK31780A DK31780A (en) | 1974-09-30 | 1980-01-25 | METHOD OF ANALOGUE FOR THE PREPARATION OF OXYGEN-CONTAINED DIARYL COMPOUNDS AND ACID ADDITION SALTS |
| DK31680A DK152206C (en) | 1974-09-30 | 1980-01-25 | METHOD OF ANALOGUE FOR THE PREPARATION OF SULFUR AND / OR OXYGEN-DIARYL COMPOUNDS OR ACID ADDITION SALTS |
Country Status (1)
| Country | Link |
|---|---|
| DK (3) | DK159966C (en) |
-
1980
- 1980-01-25 DK DK31580A patent/DK159966C/en not_active IP Right Cessation
- 1980-01-25 DK DK31780A patent/DK31780A/en not_active Application Discontinuation
- 1980-01-25 DK DK31680A patent/DK152206C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK31680A (en) | 1980-01-25 |
| DK159966C (en) | 1991-05-27 |
| DK31780A (en) | 1980-01-25 |
| DK152206B (en) | 1988-02-08 |
| DK152206C (en) | 1988-07-11 |
| DK31580A (en) | 1980-01-25 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |