NO151362B - Analogifremgangsmaate til fremstilling av terapeutisk aktive urinstoffderivater - Google Patents
Analogifremgangsmaate til fremstilling av terapeutisk aktive urinstoffderivater Download PDFInfo
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- NO151362B NO151362B NO801965A NO801965A NO151362B NO 151362 B NO151362 B NO 151362B NO 801965 A NO801965 A NO 801965A NO 801965 A NO801965 A NO 801965A NO 151362 B NO151362 B NO 151362B
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- phenyl
- trifluoromethyl
- chloro
- general formula
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- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000002485 urinary effect Effects 0.000 title 1
- -1 3-chloro-4-trifluoromethyl-phenyl Chemical group 0.000 claims description 30
- 150000003672 ureas Chemical class 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 3
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical class OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000013543 active substance Substances 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000004006 olive oil Substances 0.000 description 5
- 235000008390 olive oil Nutrition 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 201000005577 familial hyperlipidemia Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- HCWZJEXQULSHSD-UHFFFAOYSA-N 2-chloro-4-isocyanato-1-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(N=C=O)C=C1Cl HCWZJEXQULSHSD-UHFFFAOYSA-N 0.000 description 1
- VKTTYIXIDXWHKW-UHFFFAOYSA-N 2-chloro-5-(trifluoromethyl)aniline Chemical compound NC1=CC(C(F)(F)F)=CC=C1Cl VKTTYIXIDXWHKW-UHFFFAOYSA-N 0.000 description 1
- KZAMRRANXJVDCD-UHFFFAOYSA-N 3-chloro-4-(trifluoromethyl)aniline Chemical compound NC1=CC=C(C(F)(F)F)C(Cl)=C1 KZAMRRANXJVDCD-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000021149 fatty food Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
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- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
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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
- C07D295/12—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 singly or doubly bound nitrogen atoms
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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
- C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Description
Oppfinnelsen vedrører analogifremgangsmåten til fremstilling av terapeutisk aktive urinstoffderivater.
Noen urinstoffderivater er allerede kjent (sml. DOS 1.443. 560, US-patent 3.335.142, 3.856.952 og 3.903.130). Disse kjente urinstoffderivater er det likeledes omtalt noen bio-logiske virkninger. De kan f. eks. anvendes som herbizider, bakterizider, fungizider og fortilsetningsstoffer. Deres virkning på fettstoffskiftet, spesielt deres lipidabsorbsjonshemmende virkning er tidligere ikke kjent.
Oppfinnelsen vedrører følgelig analogifremgangsmåte til fremstilling av terapeutisk aktive urinstoffderivater med den generelle formel
hvori
(I) når R betyr 3-klor-4-trifluormetyl-fenyl, betyr
R 4 en rest fra gruppen 4-fluor-fenyl, 3-klor-4-trifluormetyl-fenyl, 3-cyanofenyl, 3-trifluormetyl-fenyl og 3-trifluormetoksy-fenyl,
(II) nar R 3 betyr 3-trifluormetyl-fenyl, betyr R4 en rest fra gruppen 3-klor-4-trifluormetylmerkapto-fenyl, 3-trifluor-metylmerkapto-fenyl og 4-klor-3-trifluormetyl-fenyl, eller (III) når R3 betyr 3-trifluormetoksy-fenyl, betyr R4 en rest
fra gruppen 3-trifluormetylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4-tri
fluormetoksy-fenyl, eller (IV) når R3 betyr 3-cyanofenyl, betyr R4 en rest fra gruppen 3- trifluor-metylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4- trifluormetoksy-fenyl.
Overraskende viser urinstoffderivatene med den generelle formel I en sterk lipidabsorbsjonshemmende virkning. Men kjennskap til teknikkens stand kunne det ikke ventes at forbindelser av denne stoffklasse kunne anvendes som lipidab-sorbs jonshemmende virksomme stoffer. Deres allerede kjente anvendelse som fortilsetningsstoffer i dyrehold og deres bakterizide virkning lot vente at etter deres applikasjon legemet forsterket opptar næringsmidler, hvilket fører til den i dyrehold ønskede vektsøkning. Lipidabsorbsjonshemme-virkningen av den herav resulterende mulighet til å anvende urinstoffderivater som tilleggsstoff ved næringsmidler, resp. ved applikasjon av tilsvarende legemiddelformuleringer å hemme.^lipidabsorbsjonen fra næringsmidler er overvinnelse av en fra teknikkens stand resulterende fordom.
Anvendelsen av urinstoffderivatene ved behandling av hyperlipemi muliggjør behandling også av slike pasienter som over-for allerede kjente lipidabsorbsjonshemmere viser uforenlig-het eller tilvenning. Den førstegangs anvendelse av urin-stof f derivatene som virksomme stoffer ved behandling av hyperlipemi er således en berikelse av farmasien.
Urinstoffderivatene med den generelle formel I fremstilles på i og for seg kjent måte, idet
a) et amin med den generelle formel II
hvori
R 4har ovennevnte betydning, omsettes med en forbindelse med den generelle formel III
hvori
R^ har den angitte betydning,
i et inert organisk oppløsningsmiddel ved temperaturer mellom 20°C og 120°C eller
b) et amin med den generelle formel II
hvori
R 4 har ovennevnte betydning, omsettes med klormaursyrefenylester med formel IV
ved temperaturer mellom 0 og 25°C og de derved dannede fenylkarbamidsyreestere med den generelle formel V omsettes direkte eller etter isolering med et amin med den generelle formel VI
2 3
hvori R og R har ovennevnte betydning, i et inert organisk oppløsningsmiddel ved temperaturer mellom 20°C og 200°C.
Ved de ovennevnte fremgangsmåtevarianter a) og b), kan aminene med den generelle formel (II) resp. den generelle formel (VI) hver gang anvendes alternativt når betydningen av R resp. av R 3 er gitt på • forhå•nd i den eventuelle reaksjonsdeltager.
Fremstillingen av de nye forbindelsene fra de med den generelle formel (I) definerte stoffklasse foregår likeledes etter i og for seg kjente metoder, ifølge de ovennevnte fremgangsmåtevarianter a) til b), idet de som utgangsstoffer anvendte iso-cyanatderivater, aminer og fenylkarbamidsyreestere med de generelle formler (III), (IV) og (VI) er kjent eller kan fremstilles etter kjente metoder (sml. R. Wagner et al., Synthetic Organic Chem. Wiley, New York, (1953), side 640, 645, 653).
Urinstoffderivatene ifølge formel (I) viser en fordelaktig hemming av lipidabsorbsjonen hos mennesker og dyr. Ved opp-tak av fettholdig næring fører de til en mindre elementær hyperlipami, ved samtidig hemming av cholesterolabsorbsjon, således at de spesielt kan anvendes til behandling av fett-stoff skiftef or styrrelser som f. eks. hyperlipoproteinami, atherosklerose eller adipositas.
Påvisningen av den fordelaktige virkning lar seg vise på følgende forsøksanordning på rotter: For frembingelse av en elementær hyperlipemi får en gruppe rotter 2,5 ml/kg olivenolje pr. os administrert (kontrollgruppe) . En tilsvarende gruppe av andre rotter får samtidig med olivenolje-applikasjonen det virksomme stoff som sus-pensjon i tragangslim administrert med sluksonde. En ytter-ligere kontrollgruppe av rotter får bare applisert tragant-slim.
2 timer etter applikasjon av olivenolje bestemmes konsen-trasjonen av serumtriglycerider i alle tre rottegrupper
(Metode: J. Ziegenhorst, Klin. Chem. 21, (1975) 1627). To timer etter fettapplikasjonen viser de bare med olivenolje behandlede rotter (gruppe 1) i forhold til rottene uten fett-applikas jon (gruppe 3) en tydelig økning av serumtriglycerider. Med denne økning, som er satt lik 100 %, sammenlignet den forminskede serumtriglyceridøkning av de med virkomt stoff og olivenolje behandlede dyr (gruppe). Det ble funnet,, at allerede mindre doseringer av urinstoffderivater ifølge formel (I) be-virker en signifikant senkning av serumtriglyceridene. Ved siden av den sterke lipidabsorbsjonshemmende virkning viser forbindelsene også en utpreget god tålbarhet.
Farmasøytiske tilberedninger, kan ved siden av ikke-toksiske inerte farmasøytiske egnede bærestoffer inneholde en eller flere forbindelser av ovennevnte formel eller bestå av en eller flere forbindelser av ovennevnte formler, samt frem-gangsmåter til fremstilling av disse tilberedninger.
De virksomme stoffer eller de farmasøytiske tilberedninger
kan appliseres oralt, parenteralt, fortrinnsvis oralt.
Generelt har det såvel i human- som også i veterinær-medisinen vist seg som fordelaktig å applisere det eller de virksomme stoffer i mengder fra ca. 1,0 til ca. 500, fortrinnsvis 5 til 100 mg/kg legemsvekt pr. 24 timer, fordelt på 1 til 6 administreringer, niemlig før og/eller under og/ eller etter måltidet. En enkeltinngivning inneholder det eller de virksomme stoffer, fortrinnsvis i mengder fra ca. 1 til ca. 100 mg/kg legemsvekt. Det kan imidlertid være nødvendig å avvike fra de nevnte doseringer, nemlig avhengig-het av type og legemsvekt av objektet som skal behandles, sykdommens type og tyngde, typen av tilberedning og applikasjon av legemidlet, samt tidsrommet, resp. intervallet innen hvilket administreringen foregår. Således kan det i noen tilfelle være tilstrekkelig å komme ut med mindre enn ovennevnte mengde virksomt stoff, mens i andre tilfelle ovennevnte virksomme stoffmengde må overskrides. Fastleggelse av den hver gang nødvendige optimale dosering og applikasjons-type av det virksomme stoff kan lett foregå av enhver fagmann på grunn av hans fagkunnskaper.
Eksempel 1 (Variant a)
0,05 mol 2-klor-5-trifluormetylanilin oppløses i 30 ml tetrahydrofuran og utrøres med en oppløsning av 0,05 mol 3-klor-4-trifluormetylfenylisocyanat i 30 ml tetrahydrofuran. Reaksjonsblandingen oppvarmes til 50°C, idet det faller ut N-2-klor-5-trifluormetylfenyl-N'-3-klor-4-trifluormetylfenyl-urinstoff.
Sm.p. 210-212°C, utbytte: 82 % av det teoretiske.
Eksempel 2 (variant b)
En oppløsning av 0,5 mol p-fluoranilin i 300 ml diklor-benzen og 70 ml (0,5 mol) trietylamin blandes med 0,5 mol klormaursyrefenylester under avkjøling (0-10°C). Reaksjonsblandingen hensettes deretter 24 timer ved værelsestempera-tur. Man frasuger dannet trietylamin-hydroklorid og blander filtratet med 0,5 mol 3-klor-4-trifluormetylanilin. Reak-sjonsoppløsningen oppvarmes 6 timer ved 180°C, oppløs-ningsmidlet fjernes under vakuum og residuet kokes ut i 250 ml eter og frasuges igjen. Man får N-4-fluorfenyl-N'-3-klor-4-trifluormetyl-fenylurinstoff av sm.p. 212 til 212°C. Utbytte: 67 % av det teoretiske.
Claims (1)
- Analogifremgangsmåte til fremstilling av terapeutisk aktive urinstoffderivater med den generelle formel hvori (I) når R_ betyr 3-klor-4-trifluormetyl-fenyl, betyr R4 en rest fra gruppen 4-fluor-fenyl, 3-klor-4-trifluormetyl-fenyl, 3-cyanofenyl, 3-trifluormetyl-fenyl og 3-trifluormetoksy-fenyl, (II) når R^ betyr 3-trifluormetyl-fenyl, betyr R4 en rest fra gruppen 3-klor-4-trifluormetylmerkapto-fenyl, 3-trifluor-metylmerkapto-fenyl og 4-klor-3-trifluor-i metyl-fenyl, eller (III) når R3 betyr 3-trifluormetoksy-fenyl, betyr R^ en rest fra gruppen 3-trifluormetylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4-tri-) fluormetoksy-fenyl, eller (IV) når R3 betyr 3-cyanofenyl, betyr R4 en rest fra gruppen 3-trifluor-metylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4-trifluormetoksy-fenyl,karakterisert ved at a) et amin med den generelle formel II hvori R^ har den ovennevnte betydning, omsettes med en forbindelse med den generelle formel III hvori 3 R har ovennevnte betydning, i et inert organisk oppløsningsmiddel ved temperaturer mellom20°C og 120°C, eller b). et amin med den generelle formel IIhvoriR<4> har den ovennevnte betydning,omsettes med klormaursyrefenylester med formel IVved temperaturer mellom 0°C og 25°C og de derved dannede fenylkarbamidsyreestere med den generelle formel Vomsettes direkte eller etter isolering med et amin med den generelle formel VIhvoriR 3 har ovennevnte betydning, i et inert organisk oppløsnings-middel ved temperaturer mellom 20°C og 200°C.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19792928485 DE2928485A1 (de) | 1979-07-14 | 1979-07-14 | Verwendung von harnstoffderivaten als arzneimittel bei der behandlung von fettstoffwechselstoerungen |
Publications (3)
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NO801965L NO801965L (no) | 1981-01-15 |
NO151362B true NO151362B (no) | 1984-12-17 |
NO151362C NO151362C (no) | 1985-03-27 |
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Application Number | Title | Priority Date | Filing Date |
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NO801965A NO151362C (no) | 1979-07-14 | 1980-06-30 | Analogifremgangsmaate til fremstilling av terapeutisk aktive urinstoffderivater. |
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US (1) | US4405644A (no) |
EP (1) | EP0022958A1 (no) |
JP (1) | JPS5616411A (no) |
AU (1) | AU544252B2 (no) |
DE (1) | DE2928485A1 (no) |
DK (1) | DK302480A (no) |
ES (1) | ES493327A0 (no) |
IL (1) | IL60555A0 (no) |
NO (1) | NO151362C (no) |
ZA (1) | ZA804180B (no) |
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-
1979
- 1979-07-14 DE DE19792928485 patent/DE2928485A1/de not_active Withdrawn
-
1980
- 1980-06-30 NO NO801965A patent/NO151362C/no unknown
- 1980-07-02 EP EP80103765A patent/EP0022958A1/de not_active Withdrawn
- 1980-07-08 AU AU60194/80A patent/AU544252B2/en not_active Expired - Fee Related
- 1980-07-11 ZA ZA00804180A patent/ZA804180B/xx unknown
- 1980-07-11 ES ES493327A patent/ES493327A0/es active Granted
- 1980-07-11 IL IL60555A patent/IL60555A0/xx unknown
- 1980-07-11 JP JP9410880A patent/JPS5616411A/ja active Pending
- 1980-07-11 DK DK302480A patent/DK302480A/da not_active Application Discontinuation
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1981
- 1981-12-17 US US06/331,712 patent/US4405644A/en not_active Expired - Fee Related
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DK302480A (da) | 1981-01-15 |
AU6019480A (en) | 1981-01-15 |
NO151362C (no) | 1985-03-27 |
US4405644A (en) | 1983-09-20 |
NO801965L (no) | 1981-01-15 |
ES8105292A1 (es) | 1981-05-16 |
ES493327A0 (es) | 1981-05-16 |
JPS5616411A (en) | 1981-02-17 |
IL60555A0 (en) | 1980-09-16 |
ZA804180B (en) | 1981-07-29 |
EP0022958A1 (de) | 1981-01-28 |
DE2928485A1 (de) | 1981-01-29 |
AU544252B2 (en) | 1985-05-23 |
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