DK152125B - Analogifremgangsmaade til fremstilling af 1-(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dion - Google Patents

Analogifremgangsmaade til fremstilling af 1-(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dion Download PDF

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Publication number
DK152125B
DK152125B DK487476AA DK487476A DK152125B DK 152125 B DK152125 B DK 152125B DK 487476A A DK487476A A DK 487476AA DK 487476 A DK487476 A DK 487476A DK 152125 B DK152125 B DK 152125B
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Prior art keywords
nitrophenyl
dimethylimidazolidine
trifluoromethyl
trifluormethyl
dion
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DK487476AA
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DK487476A (da
DK152125C (da
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Jacques Perronnet
Pierre Girault
Claude Bonne
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Roussel Uclaf
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Electromechanical Clocks (AREA)

Description

DK 152125 B
- i -
Opfindelsen angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse l-(31-trifluor-methyl-4'-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dion med den i kravets indledning angivne formel I.
5 Denne forbindelse har interessante farmakologiske egenskaber. Man har navnlig konstateret, at den inhibe-rer virkningerne af androgener på de perifere receptorer uden at øve nogen indflydelse på hypofysens normale funktion .
10 De forsøg, som er anført i den eksperimentelle del nedenfor, illustrerer denne antiandrogene virkning på rotter.
Som følge af sin antiandrogene virkning og sin uskadelighed over for hypofysens funktion kan forbindelsen med 15 formlen I anvendes i terapien, dels hos børn og unge uden risiko for vækststandsning, dels hos voksne uden risiko for visse effekter i retning af kemisk kastrering.
1—(31-trifluormethyl-4'-nitrophenyl)-4,4-dimethylimi-dazolidin-2,5-dion finder navnlig anvendelse som medikament 20 til behandling af adenomer og neoplasi i prostata, hirsu-tisme, acne, seborrhagi og for kraftig hårvækst.
Forbindelsen kan ligeledes finde anvendelse på det veterinære område.
Den kan anvendes ad parenteral, oral, perlingual el-25 ler rektal vej eller i topisk applikation.
Fremgangsmåden til fremstilling af den hidtil ukendte forbindelse med den almene formel I er ejendommelig ved det i kravets kendetegnende del anførte.
Den tertiære base, i hvis nærværelse man udfører kon-30 densationen af 2-amino-2-cyanpropan med 3-trifluormethyl- 4-nitrophenylisocyanat, kan navnlig være pyridin, methyl-ethylpyridin eller triethylamin.
Denne kondensation udføres med fordel i et organisk opløsningsmiddel såsom tetrahydrofuran, ether eller iso-3 5 propylether.
- 2 -
DK 152125B
Den syre, i hvis nærværelse man udfører hydrolysen af 1—(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethyl-5-iminoimidazolidin-2-on, kan navnlig være saltsyre eller svovlsyre.
5 Nedenstående eksempel illustrerer fremgangsmåden ifølge opfindelsen.
Eksempel
Fremstilling af l-(31-trifluormethyl-4'-nitrophenyl)- 4.4- dimethylimidazolidin-2,5-dion 10 Trin A: 1-(3'-trifluormethyl-4 *-nitrophenyl)-4,4-dimethyl- 5-iminoimidazolidin-2-on I 500 ml tetrahydrofuran indfører man 49,6 g 3-tri-fluormethyl-4-nitrophenylisocyanat, 1 ml triethylamin samt hurtigt 18 g 2-amino-2-cyanpropan, og man omrører i 72 ti-15 mer ved 20°C, inddamper til tørhed ved destillation under formindsket tryk, chromatograferer resten på silicagel under eluering med en blanding af methylenchlorid og acetone i forholdet 8:2 og får 27 g l-(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethyl-5-iminoimidazolidin-2-on med 20 smp. 168°C.
Analyse: ^12H11F3N4^3 beregnet: C% 45,57 H% 3,50 N% 17,71 fundet: 45,6 3,6 17,5 I.R. spektrum (chloroform): 25 -1
Absorption ved 3442 cm , som er karakteristisk for NH, absorption ved 1755 cm som er karakteristisk for C=0, absorption ved 1673 cm som er karakteristisk for C=N, absorptioner ved 1615 og 1595 cm *", som er karakteristiske for den aromatiske ring, og absorptioner ved 1542, 30 -1 1492 og 1355 cm , som er karakteristiske for NC^-Trin B: 1—(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethyl- imidazolidin-2,5-dion I en blanding af 35 ml 22°Bé vandig saltsyre og 35 ml vand indfører man 10 g l-(3'-trifluormethyl-4'-nitrophenyl)-35 4.4- dimethyl-5-iminoimidazolidin-2-on, opvarmer suspensionen til tilbagesvaling i 1 time, afkøler til 20°C, hælder i vand, isolerer den dannede udfældning ved frasugning,
DK 152125B
- 3 - vasker den, tørrer den og får 9,5 g l-(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dion med smp. 14 9 ° C.
En prøve med mikroanalytisk renhed fås ved krystalli-5 sation af ethanol. Smp. 149°C.
Analyse: ^12^10^3^3^4 beregnet: C% 45,43 H% 3,17 F% 17,96 N% 13,24 fundet: 45,5 3,4 17,9 12,9 I.R. spektrum (chloroform):
Absorption ved 3438 cm som er karakteristisk for NH, absorptioner ved 1792 og 1734 cm \ som er karakteristiske for C=0, absorptioner ved 1613, 1597 og 1501 cm *", som er karakteristiske for den aromatiske ring, og absorptioner ved 1545, 1358 og 1349 cm *", som er karakteristiske for NC^·
Farmakologisk undersøgelse af l-(31-trifluormethyl-41-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dion (forbindelse A)
Forsøgene udføres på rotter af stammen Sprague-Dawley, 20 som er kastreret ad skrotal vej under anæstesi med ether.
Produkterne indgives i opløsning i sesamolie indeholdende 5% benzylalkohol i et rumfang på 0,1 ml.
A) Antiandrogen virkning på rotter
Grupper på 5 kastrerede hanrotter på 75 + 5g modtager 25 dagligt i 7 dage samtidige indgifter ad subkutan ve] af testosteronpropionat (50 pg pr. rotte pr. dag) og af det produkt, som skal undersøges (1 mg pr. rotte pr. dag).
Dyrene aflives 24 timer efter den sidste indgift.
Prostata og sædblærerne fjernes og fikseres i 24 timer i 3Q
en isotonisk saltopløsning tilsat 10% formaldehydopløsning, hvorpå de dissekeres og vejes. Inhiberingen af vægtforøgelsen af genitalorganerne hidført af androgenet muliggør vurderingen af den antiandrogene aktivitet af det undersøgte produkt.
Kontrolgrupperne undergår ikke nogen behandling, og andre grupper modtager kun testosteronpropionat eller det produkt, som skal undersøges.
35 - 4 -
DK 152125B
Variationerne i vægtene af prostata eller af sædblærerne homogeniseres ved logaritmisk transformation ifølge Bartlett (J. Roy. Stat. Soc., 1937, Suppl. 4, 137), og homogeniteten verificeres ved Bartlett's kontrol 5 (Biometrics, 1947, _3' 39). Resultaterne analyseres ved faktoranalyse.
De i tabellerne anførte værdier repræsenterer gennemsnittene ledsaget af den typiske fejl.
Der fås følgende resultater: Sædblærer Ventral prostata Grupper_ vægt i mg vægt i mg
Kontrol 11,5+0,9 16,8+1,0
Testosteronpropionat 79,6+8,1 90,3+7,0
Forbindelse A 12,3+0,8 15,0+1,3 15 Testosteronpropionat + forbindelse A 17,2 +2,9* 45,0 + 4,3* * Faktoranalyse p .£0,01.
1—(31-trifluormethyl-4'-nitrophenyl)-4,4-dimethylimi-dazolidin-2,5-dion fremkalder en inhibering af vægtforøgel-2Q sen af sædblærerne på 92% og af prostata på 61%. Dette produkt udviser altså en god antiandrogen virkning over for testosteronpropionat.
B) Radioaktivitetsprøve, vedrørende inhibering af prostatainkorporering efter injektion af en 25 spordosis af -H-testosteron på rotte
Grupper på 3 kastrerede hanrotter på 70 +10 g, der er kastreret 24 timer i forvejen, modtager i subkutan injektion 5 mg af det produkt, som skal undersøges. 16 timer senere modtager dyrene i intramuskulær injektion 10 pCi/ 2Q 100 g e(- H-testosteron (26 Ci/mmol i alkoholisk opløsning. Dyrene aflives 1 time efter injektionen af det tritiumhol-dige hormon. Den ventrale prostata fjernes, skylles i en isotonisk natriumchloridopløsning, vejes og solubiliseres derefter ved alkalisk behandling.
25 Radioaktiviteten af prøverne måles efter tilsætning af 15 ml scintillerende væske.
- 5 -
DK 152125B
De opnåede resultater udtrykkes i % inhibering af inkorporeringen af testosteron:
Inkorporering
Grupper_ d. p. m/mq* % inhibering 5 Kontrol 114+4
Forbindelse A 35+8 68% * d. p. m/mg = desintegration pr. minut pr. mg frisk prostatavæv.
1-(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimetfeyl-10 imidazolidin-2,5-dion formindsker altså inkorporeringen af det tritiumholdige hormon i prostata.
15

Claims (1)

  1. DK 152125B - 6 - Analogifremgangsmåde til fremstilling af l-(3'-tri-fluormethyl-4'-nitrophenyl)-4,4-dimethylimidazolidin- 2,5-dion med formlen I 0 Γτρ>» °2N']^ I Xc“3 10 *3C kendetegnet ved, at man i nærværelse af en tertiær base omsætter 2-amino-2-cyanpropan med 3-trifluor-methyl-4-nitrophenylisocyanat til opnåelse af l-(3'-tri-15 fluormethyl-41-nitrophenyl)-4,4-dimethyl-5-iminoimidazo-lidin-2-on, som man hydrolyserer i surt miljø til opnåelse af forbindelsen med formlen I. 20
DK487476A 1975-10-29 1976-10-28 Analogifremgangsmaade til fremstilling af 1-(3'-trifluormethyl-4'-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dion DK152125C (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7533084A FR2329276A1 (fr) 1975-10-29 1975-10-29 Nouvelles imidazolidines substituees, procede de preparation, application comme medicament et compositions les renfermant
FR7533084 1975-10-29

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DK487476A DK487476A (da) 1977-04-30
DK152125B true DK152125B (da) 1988-02-01
DK152125C DK152125C (da) 1988-06-20

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US (1) US4097578A (da)
JP (1) JPS6011701B2 (da)
AU (1) AU500542B2 (da)
BE (1) BE847742A (da)
BG (1) BG60533B2 (da)
CA (1) CA1086751A (da)
CH (1) CH599164A5 (da)
DE (1) DE2649925C2 (da)
DK (1) DK152125C (da)
ES (1) ES452746A1 (da)
FR (1) FR2329276A1 (da)
GB (1) GB1518444A (da)
GE (1) GEP19970948B (da)
IE (1) IE43875B1 (da)
LU (2) LU76085A1 (da)
NL (2) NL187102C (da)
SE (1) SE430502B (da)
SU (1) SU596165A3 (da)

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US4097578A (en) 1978-06-27
FR2329276B1 (da) 1979-09-14
GEP19970948B (en) 1997-04-18
IE43875L (en) 1977-04-29
NL187102C (nl) 1991-06-03
GB1518444A (en) 1978-07-19
DK487476A (da) 1977-04-30
NL7611576A (nl) 1977-05-03
IE43875B1 (en) 1981-06-17
BE847742A (fr) 1977-04-28
SU596165A3 (ru) 1978-02-28
AU500542B2 (en) 1979-05-24
JPS5257176A (en) 1977-05-11
DE2649925A1 (de) 1977-05-12
LU76085A1 (da) 1977-05-31
DK152125C (da) 1988-06-20
NL930079I2 (nl) 1993-10-01
NL930079I1 (nl) 1993-09-16
FR2329276A1 (fr) 1977-05-27
AU1909576A (en) 1978-05-04
DE2649925C2 (de) 1986-08-28
CH599164A5 (da) 1978-05-12
SE7610859L (sv) 1977-04-30
JPS6011701B2 (ja) 1985-03-27
BG60533B2 (bg) 1995-07-28
LU88282I2 (fr) 1994-05-04
ES452746A1 (es) 1977-10-01
SE430502B (sv) 1983-11-21
NL187102B (nl) 1991-01-02
CA1086751A (fr) 1980-09-30

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