DK146336B - ANALOGY PROCEDURE FOR THE PREPARATION OF ACID ADDITION SALTS OF SULFUL DIARYL COMPOUNDS - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF ACID ADDITION SALTS OF SULFUL DIARYL COMPOUNDS Download PDF

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DK146336B
DK146336B DK437075A DK437075A DK146336B DK 146336 B DK146336 B DK 146336B DK 437075 A DK437075 A DK 437075A DK 437075 A DK437075 A DK 437075A DK 146336 B DK146336 B DK 146336B
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preparation
addition salts
sulful
acid addition
compounds
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Victor Lafon
Louis Lafon
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Lafon Labor
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    • 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
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Description

i 146336in 146336

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte syreadditionssalte af svovlholdige diarylforbindelser, hvilke salte har den almene formel 2 01—\ / 3°n \ ' (?Η2>ιο β u>The present invention relates to an analogous process for the preparation of novel acid addition salts of sulfur-containing diaryl compounds, which salts have the general formula 20 (3).

\=/ S(CH2)2NH2(CH2)20H\ = / S (CH 2) 2 NH 2 (CH 2) 20 H

hvori n er 0, 1 eller 2, og Alk er CHiCH^) eller C(CH3)2.wherein n is 0, 1 or 2 and Alk is CH 2 CH 2) or C (CH 3) 2.

Disse syreadditionssalte har en nyttig hypolipidæmisk virkning.These acid addition salts have a useful hypolipidemic effect.

Fra tysk offentliggørelsesskrift nr. 2 355 115 kendes beslægtede diarylforbindelser med nyttig hypolipidæmisk virkning.From German Publication No. 2,355,115, related diaryl compounds having useful hypolipidemic effect are known.

Denne nyttige virkning er imidlertid ikke så udpræget som virkningen af forbindelserne fremstillet ifølge opfindelsen.However, this useful effect is not as pronounced as the effect of the compounds of the invention.

Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man omsætter en svovlholdig diarylcarboxylsyre med den almene formelThe process of the invention is characterized by reacting a sulfur-containing diaryl carboxylic acid of the general formula

Cl_ / V so„ / V 0-Alk-C00H (II) \=/ \=/ hvori n og Alk har de ovenfor angivne betydninger, med forbindelsen 6,17-dithia-3,20-diaza-l,22-docosandiol, som har formlen HO(CH2)2NH(CH2)2S-(CH2)λ0-S(CH2)2NH(CH2)20H (III) 2 148336Wherein N and Alk have the above meanings, with the compound 6,17-dithia-3,20-diaza-1,22-docosanediol having the formula HO (CH2) 2NH (CH2) 2S- (CH2) λ0-S (CH2) 2NH (CH2) 20H (III) 2

En opløsning af den udvalgte forbindelse med formel II i varm ethanol udhældes i en varm opløsning af den halve molære mængde af forbindelsen med formel III i ethanol. Efter omrøring eller henstand afdampes opløsningsmidlet til opnåelse af saltet med formel I.A solution of the selected compound of formula II in hot ethanol is poured into a hot solution of the half molar amount of the compound of formula III in ethanol. After stirring or standing, the solvent is evaporated to give the salt of formula I.

Fremstillingen af forbindelsen (III) er beskrevet i FR patentskrift nr. 2258846.The preparation of the compound (III) is described in FR Patent No. 2258846.

De omhandlede forbindelser kan formuleres til terapeutiske midler i kombination med en fysiologisk acceptabel excipiens.The present compounds can be formulated as therapeutic agents in combination with a physiologically acceptable excipient.

Fremgangsmåden ifølge opfindelsen illustreres nærmere ved de følgende eksempler.The process of the invention is further illustrated by the following examples.

EKSEMPEL_1EKSEMPEL_1

Di-p-(g-chlorphenylthio)-phenoxy-isobutyratet af 6,17-dithia-5»20-diaza-1^22-docosandiol CCH2)10£S-(CB2)2-»H2-(CB2)2-0H]2, 2CU-^^-S-^^-0-C-C00 Kode nr. CRL 40.240.The di-β- (g-chlorophenylthio) -phenoxy-isobutyrate of 6,17-dithia-5 »20-diaza-1 ^ 22-docosanediol CCH2) 10 0H] 2, 2CU - ^^ - S - ^^ - 0-C-C00 Code No. CRL 40.240.

I en vann opløsning af 3,8 g (0,01 mol) 6,17-dithia-3,20-diaza- 1,22-docosandiol i 25 ml vandfri ethanol udhældes en varm opløsning af 6,45 g (0,02 mol) p-(p-chlorphenylthio)-phenoxy-isosmørsyre i 25 ml vandfri ethanol. Man omrører i 2 timer ved omgivelsestemperaturen, hvorpå man afdamper opløsningsmidlet under reduceret tryk. Efter at have udvasket remanensen med acetonitril opnår man 8,4 g af et svagt beigefarvet pulver, der er uopløseligt i vand, men opløseligt i alkohol.In a water solution of 3.8 g (0.01 mole) of 6,17-dithia-3,20-diaza-1,22-docosanediol in 25 ml of anhydrous ethanol, pour a hot solution of 6.45 g (0.02 mole) of p- (p-chlorophenylthio) -phenoxy-isobutyric acid in 25 ml of anhydrous ethanol. The mixture is stirred for 2 hours at ambient temperature, after which the solvent is evaporated under reduced pressure. After washing out the residue with acetonitrile, 8.4 g of a slightly beige powder is obtained, which is insoluble in water but soluble in alcohol.

Smp. (Kofler) = 75 °C.Mp. (Koffler) = 75 ° C.

Udbytte = 82 %.Yield = 82%.

3 146336 EKSEMPEL_2_EXAMPLE_2_

Pi—p-(p-chlorphen.ylsulf onyl)-phenoxy-isobutyratet af 6,17-dithia- 5,20-diaza-1,22-docosandiol ® . _ /=\ /-\ Γ3 ΘThe pi-p- (p-chlorophenylsulfonyl) phenoxy-isobutyrate of 6,17-dithia-5,20-diaza-1,22-docosanediol ®. _ / = \ / - \ Γ3 Θ

(CH2) s~cCH?>2-KH2-(cn2)2-0H/2 , 2G1-^ jj- SO^ ^-O-C-COO(CH2) s ~ cCH?> 2-KH2- (cn2) 2-0H / 2, 2G1- ^ jj- SO ^^ -O-C-COO

Kode nr. CR1 40.241.Code No. CR1 40,241.

I en varm opløsning af 5,54 g (0,0095 mol) 6,17-dithia-5,20-diaza- 1,22-docosandiol i 25 ml vandfrit ethanol udhældes en varm opløsning af 6,6 g (0,0186 mol) p-.(p-chlorphenylsulfonyl)-phenoxy-iso-smørsyre i 25 ml vandfri ethanol. Man omrører i 2 timer ved omgivelsestemperaturen, hvorpå man afdamper opløsningsmidlet under reduceret tryk. Efter udvaskning med acetonitril opnår man 9,9 g af et svagt rosa pulver, der er uopløseligt i vand, men opløseligt i varm alkohol.In a hot solution of 5.54 g (0.0095 mol) of 6,17-dithia-5,20-diaza-1,22-docosanediol in 25 ml of anhydrous ethanol, pour a hot solution of 6.6 g (0.0186 mole) p - (p-chlorophenylsulfonyl) -phenoxy-iso-butyric acid in 25 ml of anhydrous ethanol. The mixture is stirred for 2 hours at ambient temperature, after which the solvent is evaporated under reduced pressure. After washing out with acetonitrile, 9.9 g of a pale pink powder is obtained, which is insoluble in water but soluble in hot alcohol.

Smp. (Kofler) = 157° 0.Mp. (Koffler) = 157 ° 0.

Udbytte =98 EKSEMPEL-3Yield = 98 EXAMPLE-3

Di-(-)-2-[ p-(p-chl or phenyl sulf onyl)-phenoxy] -propionatet af 6^,17-MjMa^^O-diaza-l^gg-dicosandiol ® _ r\ JT\ i"3 0The di - (-) - 2- [p- (p-chloro or phenyl sulfonyl) phenoxy] propionate of the 6β, 17-MjMaaO-diaza-1β-g-dicosanediol® _ r \ JT \ i "3 0

(CH2)lc/S'(CH2)2"NH2“(CH2)2"0-i » 2C1*\ / S02\ Vo-CH-COO(CH2) lc / S '(CH2) 2 "NH2" (CH2) 2 "0-i» 2C1 * \ / SO2 \ Vo-CH-COO

Kode nr. CR1 40.249.Code No. CR1 40,249.

I en varm opløsning af 2,84 g (0,0075 mol) 6,17-dithia-5,20-diaza- 4 1-46336 1,22-docosandiol i 20 ml vandfri ethanol udhaeldes en varm opløsning af 5,10 g (0,0150 mol) (-)-2-[p-(p-chlorphenylsulfo-nyl)-phenoxy]-propionsyre i 20 ml vandfri ethanol. Efter henstand i 15 minutter afdamper man opløsningsmidlet under reduceret tryk, og den krystallinske remanens udvaskes derpå med acetonitril, hvorved man opnår 7,8 g af et hvidt pulver, der er uopløseligt i vand og alkohol.In a hot solution of 2.84 g (0.0075 mol) of 6,17-dithia-5,20-diaza-4 1-46336 1,22-docosanediol in 20 ml of anhydrous ethanol, a hot solution of 5.10 g was poured out. (0.0150 mol) (-) - 2- [p- (p-chlorophenylsulfonyl) phenoxy] propionic acid in 20 ml of anhydrous ethanol. After standing for 15 minutes, the solvent was evaporated under reduced pressure and the crystalline residue was then washed with acetonitrile to give 7.8 g of a white powder which is insoluble in water and alcohol.

Smp.: (Kofler) = 149-150 °C Udbytte = 98,3 %.Mp: (Copper) = 149-150 ° C Yield = 98.3%.

EKSEMPEL_4 dithia-3,20-diaza-l,22-docosandiol CCK2)10 L s-(CH2)2-liH2-(cH2)2-0H' ]2, 2C1--^"^-SO-^ ^—O-j-COO®EXAMPLE_4 dithia-3,20-diaza-1,2,22-docosanediol CCK2) 10 L s- (CH2) 2-LiH2- (cH2) 2-OH '] 2,2C1 - -COO®

Kode nr. CR1 40.242.Code No. CR1 40.242.

I en varm opløsning af 3,8 g (0,01 mol) 6,17-dithia-3,20-diaza- 1,22-docosandiol i 25 ml ethanol udhældes en varm opløsning af 6,77 g (0,02 mol) 4-{4-chlorphenylsulfinyl)-phenoxyisosmørsyre i 25 ml ethanol. Man omrører i 30 minutter ved omgivelsestemperaturen, hvorpå opløsningsmidlet afdampes under reduceret tryk. Efter at have optaget remanensen i diisopropylether opnås 10,4 g af et hvidt vanduopløseligt pulver, der er opløseligt i alkohol.In a hot solution of 3.8 g (0.01 mole) of 6,17-dithia-3,20-diaza-1,22-docosanediol in 25 ml of ethanol, pour a hot solution of 6.77 g (0.02 mole) ) 4- (4-Chlorophenylsulfinyl) phenoxyisobutyric acid in 25 ml of ethanol. The mixture is stirred for 30 minutes at ambient temperature and the solvent is evaporated under reduced pressure. After taking up the residue in diisopropyl ether, 10.4 g of a white water-insoluble powder is soluble in alcohol.

Smp.: (Kofler); Cirka 85 °C Udbytte: = 98,5 % 146336 5 EKSEMPEL_5Mp .: (Kofler); Yield: = 98.5% 146336 EXAMPLE_5

Di(g-chlorphenylthio) -phenoxy-isoljutyratet af 6,17-clithia-3,20-diaza-1?22-docosandiol © ' /=\ /=\ f‘3 © (CH2\oCS~'CH2>2~KV(CH2>2"OHV2' C1—^ //~S~\The di (g-chlorophenylthio) phenoxy isolate tyrate of 6,17-clithia-3,20-diaza-1,22-docosanediol © '/ = \ / = \ f'3 © (CH2 \ oCS ~' CH2> 2 ~ KV (CH2> 2 "OHV2 'C1- ^ // ~ S ~ \

Kode nr. CRL -40.247.Code No. CRL -40.247.

I en varm opløsning af 2,84 g (0,0075 mol) 6,17-dithia-3,20-diaza- 1,22-docosandiol i 20 ml vandfri ethanol udhældes en varm opløsning af 4,62 g (0,015 mol) (-)-2-[4-chlorphenylthio]-phenoxypro-pionsyre i 20 ml vandfri ethanol. Efter henstand i 15 minutter afdamper man opløsningsmidlet under reduceret tryk. Remanensen omkrystalliseres fra acetonitril under dannelse af 7,2 g af et hvidt vanduopløseligt pulver, der er opløseligt i alkohol.In a hot solution of 2.84 g (0.0075 mol) of 6,17-dithia-3,20-diaza-1,22-docosanediol in 20 ml of anhydrous ethanol, pour a hot solution of 4.62 g (0.015 mol) (-) - 2- [4-Chlorophenylthio] -phenoxypropionic acid in 20 ml of anhydrous ethanol. After standing for 15 minutes, the solvent is evaporated under reduced pressure. The residue is recrystallized from acetonitrile to give 7.2 g of a white water-insoluble powder soluble in alcohol.

Smp. (Kofler) = Cirka 70 °C Udbytte = 96,5 %.Mp. (Copper) = About 70 ° C Yield = 96.5%.

Biologiske undersøgelserBiological studies

Forbindelserne fremstillet ifølge opfindelsen har en u-ventet nyttig hypolipidæmisk virkning i sammenligning med de nært beslægtede diarylforbindelser, der kendes fra det ovennævnte tyske offentliggørelseskrift nr. 2 355 115.The compounds of the invention have an unexpectedly useful hypolipidemic effect in comparison with the closely related diaryl compounds known from the above-mentioned German Publication No. 2,355,115.

Denne overraskende virkningforbedring i forhold til den kendte teknik er eftervist ved nedenstående sammenligningsforsøg imellem forbindelser fremstillet ifølge opfindelsen og forbindelser kendt fra det nævnte tyske offentliggørelsesskrift. Der er foretaget sammenligner af lipid-varia-tion og cholesterol-variation imellem forbindelserne fremstillet ifølge eksemplerne 1-5 og fem nært beslægtede kendte forbindelser.This surprising effect improvement over the prior art is demonstrated by the following comparative experiments between compounds of the invention and compounds known from the aforementioned German publication specification. Comparisons of lipid variation and cholesterol variation have been made between the compounds of Examples 1-5 and five closely related known compounds.

Forbindelserne, der skulle afprøves, blev indgivet til schweiziske rotter, der hver vejede 200 g (10 rotter pr. gruppe), ved 146336 6 oral intubation i en gummi arabicum-suspension (3%) 16 og 24 timer efter iværksættelse af faste. Kontroldyrene modtog kun bærestoffet» der blev udtaget blodprøver fra retro orbital sinus, og disse blodprøver blev anbragt i tørre glas og centrifugeret 24 timer efter den første intubation. Den totale mængde serum-cholesterol blev doseret colorimetrisk ifølge metoden beskrevet af Watson, D. Clin. Chim. Acta 5, side 637-643 (1960), og den totale mængde serum-lipider blev bestemt med sulfophosphorvanillin ifølge Chabrol et al., Presse Med.The compounds to be tested were administered to Swiss rats, each weighing 200 g (10 rats per group), by oral intubation in a gum arabic suspension (3%) at 16 and 24 hours after initiation of fasting. The control animals received only the carrier 'blood samples taken from the retro orbital sinus and these blood samples were placed in dry glass and centrifuged 24 hours after the first intubation. The total amount of serum cholesterol was dosed colorimetrically according to the method described by Watson, D. Clin. Chim. Acta 5, pages 637-643 (1960), and the total amount of serum lipids was determined with sulfophosphorus vanillin according to Chabrol et al., Press Med.

Vol. 45, side 1713-1714 (1937).Vol. 45, pp. 1713-1714 (1937).

De opnåede resultater fremgår af den efterfølgende tabel.The results obtained are shown in the following table.

Doseringen er 100 mg/kg. Lipid- og cholesterol-variationerne er angivet i procent beregnet på kontroldyrene.The dosage is 100 mg / kg. The lipid and cholesterol variations are expressed as a percentage based on the control animals.

TABELTABLE

Forbindelse Dosis Lipid Cholesterol _variation_variationCompound Dose Lipid Cholesterol _variation_variation

Eksempel 1 100 -30 -25Example 1 100 -30 -25

Sml. A 100 -21 -25ECR. A 100 -21 -25

Eksempel 2 100 -33 -27Example 2 100 -33 -27

Sml. B 100 -12 -12ECR. B 100 -12 -12

Eksempel 3 100 -32 -28Example 3 100 -32 -28

Sml. C 100 -7 -10ECR. C 100 -7 -10

Eksempel 4 100 -31 -25Example 4 100 -31 -25

Sml. D 100 -20 -23ECR. D 100 -20 -23

Eksempel 5 100 -30 -27Example 5 100 -30 -27

Sml. E. 100 -8 -8ECR. E. 100 -8 -8

Sammenligningsforbindelser: A: 4-(4-chlorphenylthio)-phenoxyisosmørsyre.Comparative Compounds: A: 4- (4-Chlorophenylthio) phenoxyisobutyric acid.

B: 4-(4-chlorphenylsulfonyl)-phenoxyisosmørsyre.B: 4- (4-Chlorophenylsulfonyl) phenoxyisobutyric acid.

C: (—)—2—[4—(4-chlorphenylsulfonyl)-phenoxy]-propionsyre.C: (-) - 2- [4- (4-chlorophenylsulfonyl) phenoxy] propionic acid.

D: 4-(4-chlorphenylsulfonyl)-phenoxyisosmørsyre.D: 4- (4-chlorophenylsulfonyl) phenoxyisobutyric acid.

E: (-)-2- [4-chlorphenylthio)-phenoxy]-propionsyre.E: (-) - 2- [4-Chlorophenylthio) phenoxy] propionic acid.

Saltene fremstillet ifølge opfindelsen er mere aktive som lipidre-ducerende midler end de tilsvarende syrer.The salts prepared according to the invention are more active as lipid-reducing agents than the corresponding acids.

DK437075A 1974-09-30 1975-09-29 ANALOGY PROCEDURE FOR THE PREPARATION OF ACID ADDITION SALTS OF SULFUL DIARYL COMPOUNDS DK146336C (en)

Priority Applications (3)

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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
DK31580A DK159966C (en) 1974-09-30 1980-01-25 ANALOGY PROCEDURE FOR THE PREPARATION OF OXYGEN-CONTAINED DIARYL COMPOUNDS

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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

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DE1935344U (en) 1965-11-09 1966-03-24 Karosserie Migoe Chr H Mittelg DOUBLE WALL FOR VEHICLE BODIES, ESPECIALLY FOR REFRIGERATION AND THERMAL CARRIAGE OD. THE EQUAL, WHERE THE SPACE BETWEEN TWO WALLS IS FILLED WITH INSULATING MATERIAL.
DE1668896C3 (en) 1968-01-11 1974-08-29 Farbwerke Hoechst Ag, Vormals Meister Lucius & Bruening, 6000 Frankfurt Phenoxyalkanecarboxylic acids, their salts and esters, and processes for the preparation of these compounds
CH511786A (en) * 1968-01-11 1971-08-31 Hoechst Ag Process for the preparation of phenoxyalkanecarboxylic acids, their salts and esters
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IE42609B1 (en) 1980-09-10
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NL7511452A (en) 1976-04-01
DE2560602C2 (en) 1986-08-28
DK437075A (en) 1976-03-31
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NL176776B (en) 1985-01-02
CA1064504A (en) 1979-10-16

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