CH494231A - 2-sulphonamidopyrimidines - Google Patents
2-sulphonamidopyrimidinesInfo
- Publication number
- CH494231A CH494231A CH1690869A CH1690869A CH494231A CH 494231 A CH494231 A CH 494231A CH 1690869 A CH1690869 A CH 1690869A CH 1690869 A CH1690869 A CH 1690869A CH 494231 A CH494231 A CH 494231A
- Authority
- CH
- Switzerland
- Prior art keywords
- prepared
- sulfonamido
- phenoxyacetic acid
- dimethylamide
- sulfon
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- -1 aliphatic mono- Chemical class 0.000 claims abstract description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 29
- IIILLPUTZFBNTB-UHFFFAOYSA-N 2-(4-sulfamoylphenoxy)acetic acid Chemical compound NS(=O)(=O)C1=CC=C(OCC(O)=O)C=C1 IIILLPUTZFBNTB-UHFFFAOYSA-N 0.000 claims description 9
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 claims description 7
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 7
- 229960003424 phenylacetic acid Drugs 0.000 claims description 7
- 239000003279 phenylacetic acid Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 150000003458 sulfonic acid derivatives Chemical class 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract description 7
- 210000004369 blood Anatomy 0.000 abstract description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JCKHSOMIXYGMOX-UHFFFAOYSA-N 5-propoxypyrimidin-2-amine Chemical compound CCCOC1=CN=C(N)N=C1 JCKHSOMIXYGMOX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical class CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
2-Sulphonamido-pyrimidine derivs. of general formula (I): - X = -O or -S or a direct C-C bond; Y = -O or a direct C-C bond; R and R' = H or a lower- or medium-alkyl group, or: R + R' together with N may form a heterocyclic ring; R" = a possible branched, saturated or unsaturated bivalent hydrocarbon residue possibly interrupted by one or more O-atoms; Z = H or a hydroxyl group which may be esterified with a low- or medium aliphatic mono- or dicarboxylic acid or an aromatic or araliphatic carboxylic acid. - The new compounds have blood sugar-lowering properties.
Description
Verfahren zur Herstellung von 2-Sulfonamidopyrimidin-derivaten Die vorliegende Erfindung bezieht sich auf ein Ver fahren zur Herstellung von 2-Sulfonamidopyrimidin-de- rivaten sowie deren Salzen. Die neuen Verbindungen, falls sie eine Hydroxylgruppe enthalten, können auch durch Umsetzung mit niederen oder mittleren aliphati schen Mono- oder Dicarbonsäuren, aromatischen oder araliphatischen Carbonsäuren in die entsprechenden Ester überführt werden.
Die neuen Verbindungen werden durch die folgende Formel dargestellt:
EMI0001.0002
in der X ein Sauerstoff- oder Schwefelatom oder eine di rekte C-C-Bindung, Y ein Sauerstoffatom oder eine di rekte C-C-Bindung, R und R' ein Wasserstoffatom oder einen niederen oder mittleren Alkylrest oder R und R' zusammen mit dem Stickstoffatom einen heterocyclischen Ring bedeuten und R" für einen unverzweigten oder verzweigten, gesättigten oder ungesättigten, gegebenen falls durch ein oder mehrere Sauerstoffatome unterbro chenen 2wertigen Kohlenwasserstoffrest und Z für ein Wasserstoffatom oder eine Hydroxylgruppe steht.
Aus der belgischen Patentschrift Nr. 609 270 ist be kannt, dass u.a. 2-Benzolsulfonamido-5-nieder-alkoxy- äthoxypyrimidine, die im Phenylrest durch niedere Al kyl- oder Alkoxygruppen und/oder Halogen substituiert sein können, blutzuckersenkende Eigenschaften besitzen.
Die erfindungsgemäss erhältlichen Verbindungen wei sen ebenfalls hervorragende blutzuckersenkende Eigen schaften auf. Die Senkung des Blutzuckerspiegels wurde an Kaninchen bestimmt. Nach 24stündiger Nüchternheit wurde der Blutzuckerspiegel der Versuchstiere (Initial konzentration) gemessen und anschliessend die wässrige Lösung des Natriumsalzes der Testsubstanz per os appli ziert.
Die guten blutzuckersenkenden Eigenschaften der neuen Verbindungen werden beispielsmässig durch die folgende Tabelle gezeigt.
EMI0001.0007
Verbindung <SEP> Dosis <SEP> Höhe <SEP> des <SEP> Blutzuckergehaltes
<tb> mg/kg <SEP> % <SEP> der <SEP> Initialkonzentration <SEP> nach
<tb> 2 <SEP> Stunden <SEP> 4 <SEP> Stunden <SEP> 6 <SEP> Stunden
<tb> 4(5-n-Propoxypyrimidinyl-2)-sulfonamido-phenyl- <SEP> 16 <SEP> 90 <SEP> 83 <SEP> 83
<tb> -essigsäure-dimethylamid
<tb> (Natriumsalz) <SEP> 8 <SEP> 94 <SEP> 89 <SEP> 85
<tb> 4(5-Propoxypyrimidinyl-2)-sulfonamido-phenyl- <SEP> 16 <SEP> 79 <SEP> 74 <SEP> 75
<tb> -essigsäure-diäthylamid
<tb> (Natriumsalz) <SEP> 8 <SEP> 83 <SEP> 85 <SEP> 86
<tb> 4(5-n-Propoxypyrimidinyl-2)
-sulfonamido-phenyl- <SEP> 16 <SEP> 79 <SEP> 79 <SEP> 82
<tb> -thio-essigsäure-dimethylamid <SEP> 8 <SEP> 84 <SEP> 81 <SEP> 87 Aus der Tabelle ist ersichtlich, dass die erfindungsge mäss erhältlichen Substanzen selbst in so geringen Men gen wie 8 bzw. 16 mg/kg eine beachtliche Wirkung zei gen.
Zum therapeutischen Gebrauch können die neuen Sulfonamide verabreicht werden als freie Verbindungen, als Salze mit physiologisch vertretbaren anorganischen und/oder organischen Basen, wie z.B. Natrium-, Li thium-, Calcium-, Ammoniumhydroxyd, Aminen wie Methylglukamin, Morpholin, Piperazin, Äthanolamin u.a., oder auch in Form von Mischungen der freien Sulfon- amide mit einem geeigneten Alkalicarbonat bzw. -hy- drogencarbonat.
Die Konfektionierung der Substanzen kann ohne oder mit den in der galenischen Pharmazie üblichen Zusätzen, Trägersubstanzen und Geschmackskorrigenzien erfolgen, und zwar beispielsweise in Pulverform, als Tabletten, Dragees, Kapseln, Pillen, in Form von Suspensionen oder Lösungen. Die Substanzen sollen gewöhnlich in einer Menge von 0,01 bis 0,6 g/kg Körpergewicht verabfolgt werden. Die Sulfonamide sollen normalerweise oral und zu Testzwecken auch intravenös appliziert werden.
Die neuen Verbindungen werden erfindungsgemäss hergestellt, indem man Verbindungen der Formel
EMI0002.0008
worin X, R und R' die oben angegebene Bedeutung ha ben, n die Zahlen 0, 1 oder 2 und Q ein Halogenatom bedeutet, mit Pyrimidinderivaten der Formel
EMI0002.0010
worin Y und R" die oben angegebene Bedeutung haben und D, falls n = 2 ist, dasselbe wie Z oder, falls n = 0 oder 1 ist, ein Wasserstoffatom oder ein Acyloxyrest ist, umsetzt und die danach erhaltenen Produkte, falls n = 0 oder 1 ist, zu den Sulfonsäurederivaten oxydiert und an- schliessend gegebenenfalls die Estergruppe verseift.
Die neuen Verbindungen können mit physiologisch vertretbaren anorganischen und/oder organischen Basen in die entsprechenden Salze überführt werden.
<I>Beispiel l</I> 14 g 2-Amino-5-n-propoxypyrimidin werden in 100 ml Pyridin gelöst. Dann werden 29 g 4-Diäthylaminocarbo- nylmethylenbenzolsulfochlorid zugegeben und das Ge misch wird 2 Stunden bei 50 C gerührt. Anschliessend werden 300 ml Wasser zugegeben und das ausgefällte Produkt wird zur Reinigung in verdünntem Ammoniak gelöst, mit Kohle filtriert und mit Salzsäure wieder aus gefällt. Nach Umkristallisieren aus Äthanol werden so 35 g 4-(5-n-Propoxypyrimidinyl-2)-sulfonamido-phenyles- sigsäurediäthylamid vom Schmelzpunkt 159 C erhalten.
Das 4 - Diäthylaminocarbonylmethylenbenzolsulfo- chlorid ist erhältlich durch Chlorsulfonierung von Essig säurediäthylamid. Entsprechend lassen sich die Aus gangsmaterialien für die in der Übersicht auf den 6 und 7 genannten Verbindungen aus den entsprechenden Essig säure- bzw. Thioessigsäurederivaten durch Chlorsulfo- nierung gewinnen.
Ausserdem können nach dem erfindungsgemässen Verfahren hergestellt werden: Allgemeine Formel:
EMI0002.0027
EMI0002.0028
<I>Beispiel 2</I> 1 kg 4-(5-n-Propoxypyrimidinyl-2)-sulfonamido-phe- nylessigsäuredimethylamid, 50 g Polyvinylpyrrolidon, 50 g Kartoffelstärke und 5 g Magnesiumstearat werden homogen gemischt und zu Tabletten mit Bruchrille von 551 mg gepresst.
Die Tabletten enthalten 500 mg Wirkstoff. <I>Beispiel 3</I> 1 kg. 4-(5-n-Propoxypyrimidinyl-2)-sulfonamido-phe- nylessigsäurediäthylamid werden auf einer Strahlmühle zu Partikelchen von maximal 4 .t, Grösse vermahlen. Nach Zumischen, zwecks besserer Fliesseigenschaft, von 1% kolloidaler Kieselsäure (AEROSIL ) wird in Hartgelati nekapseln (Grösse 1) gefüllt, dass in jeder Kapsel 100 mg Wirkstoff enthalten sind.
<I>Beispiel 4</I> 1 kg leicht wasserlösliches Natriumsalz von 4-(5-n- -Propoxypyrimidinyl - 2)-sulfonamido-phenoxyessigsäure- diäthylamid wird mit 450 ml Äthylalkohol verknetet, gra nuliert und über ein Wirbelstromtrockner bis zur Alko holfreiheit geschickt. Dem Granulat mischt man 150 g Maisstärke, 26 g Talkum und 4 g Magnesiumstearat hin zu. Dann wird in stabförmige Tabletten (5,5 X 17,5 X 6,5 mm) gepresst. Gewicht der Tabletten 590 mg (500 mg Wirkstoff). Die Stabtabletten werden mit einer Lösung von 30g Polyglykol 6000 in 70 ml Aceton in einem Dragierkessel überzogen und getrocknet.
<I>Beispiel 5</I> Zur Herstellung von Injektionslösungen zur intra venösen Applikation des Natriumsalzes (Beispiel 4) wer den 1 kg Salz in 19,339 Liter Ampullenwasser, welches 1 g äthylendiamintetraessigsaures Natrium enthält, ge löst. Deo = 1,017, pH-Wert: 8,5 bis 8,7.
Nach Filtration über Seitz Filterschicht EKS 1I wird in Ampullen von 20 ml abgefüllt und 20 Minuten bei 120 C sterilisiert.
<I>Beispiel 6</I> 1 kg 4-(5-Methoxypyrimidinyl-2)-sulfonamido-phen- oxyessigsäurediäthylamid wird mit 450 g pressfähigem Calciumcarbonat, 45 g Maisstärke und 5 g Magnesium- stearat gemischt und zu Tabletten, wie üblich von 150 mg Gewicht entsprechend 100 mg Wirkstoff, verpresst. <I>Beispiel 7</I> 4 kg 4-(5-Hydroxyäthoxypyrimidinyl-2)-sulfonamido- phenoxyessigsäurediäthylamid werden auf einer Strahl mühle bis auf Teilchengrösse von ca. 6 1, vermahlen. An= schliessend wird jeweils eine Menge von 400 mg in Hart gelatinekapseln (Grösse 0) abgefüllt.
Process for the preparation of 2-sulfonamidopyrimidine derivatives The present invention relates to a process for the preparation of 2-sulfonamidopyrimidine derivatives and their salts. The new compounds, if they contain a hydroxyl group, can also be converted into the corresponding esters by reaction with lower or medium aliphatic mono- or dicarboxylic acids, aromatic or araliphatic carboxylic acids.
The new compounds are represented by the following formula:
EMI0001.0002
in which X is an oxygen or sulfur atom or a direct CC bond, Y is an oxygen atom or a direct CC bond, R and R 'is a hydrogen atom or a lower or middle alkyl radical or R and R' together with the nitrogen atom is a heterocyclic Ring and R "is a straight or branched, saturated or unsaturated, if necessary by one or more oxygen atoms interrupted divalent hydrocarbon radical and Z is a hydrogen atom or a hydroxyl group.
From Belgian patent specification No. 609 270 it is known that i.a. 2-Benzolsulfonamido-5-lower-alkoxy- äthoxypyrimidines, which can be substituted in the phenyl radical by lower alkyl or alkoxy groups and / or halogen, have blood sugar-lowering properties.
The compounds obtainable according to the invention also have excellent blood sugar-lowering properties. The decrease in blood sugar levels was determined in rabbits. After fasting for 24 hours, the blood sugar level of the test animals (initial concentration) was measured and then the aqueous solution of the sodium salt of the test substance was administered orally.
The good blood sugar-lowering properties of the new compounds are shown by way of example by the following table.
EMI0001.0007
Connection <SEP> dose <SEP> level <SEP> of the <SEP> blood sugar content
<tb> mg / kg <SEP>% <SEP> according to the <SEP> initial concentration <SEP>
<tb> 2 <SEP> hours <SEP> 4 <SEP> hours <SEP> 6 <SEP> hours
<tb> 4 (5-n-propoxypyrimidinyl-2) -sulfonamido-phenyl- <SEP> 16 <SEP> 90 <SEP> 83 <SEP> 83
<tb> -acetic acid dimethylamide
<tb> (sodium salt) <SEP> 8 <SEP> 94 <SEP> 89 <SEP> 85
<tb> 4 (5-propoxypyrimidinyl-2) -sulfonamido-phenyl- <SEP> 16 <SEP> 79 <SEP> 74 <SEP> 75
<tb> -acetic acid diethylamide
<tb> (sodium salt) <SEP> 8 <SEP> 83 <SEP> 85 <SEP> 86
<tb> 4 (5-n-propoxypyrimidinyl-2)
-sulfonamido-phenyl- <SEP> 16 <SEP> 79 <SEP> 79 <SEP> 82
<tb> -thio-acetic acid-dimethylamide <SEP> 8 <SEP> 84 <SEP> 81 <SEP> 87 The table shows that the substances available according to the invention even in as small amounts as 8 or 16 mg / kg show a remarkable effect.
For therapeutic use, the new sulfonamides can be administered as free compounds, as salts with physiologically acceptable inorganic and / or organic bases, e.g. Sodium, lithium, calcium, ammonium hydroxide, amines such as methylglucamine, morpholine, piperazine, ethanolamine, etc., or in the form of mixtures of the free sulfonamides with a suitable alkali metal carbonate or hydrogen carbonate.
The compounding of the substances can take place with or without the additives, carrier substances and flavor corrections customary in galenic pharmacy, for example in powder form, as tablets, dragees, capsules, pills, in the form of suspensions or solutions. The substances should usually be administered in an amount of 0.01 to 0.6 g / kg body weight. The sulfonamides should normally be administered orally and, for test purposes, also intravenously.
The new compounds are prepared according to the invention by adding compounds of the formula
EMI0002.0008
in which X, R and R 'have the meaning given above, n is the numbers 0, 1 or 2 and Q is a halogen atom, with pyrimidine derivatives of the formula
EMI0002.0010
in which Y and R ″ have the meaning given above and D, if n = 2, is the same as Z or, if n = 0 or 1, is a hydrogen atom or an acyloxy radical, and the products obtained thereafter if n = 0 or 1, is oxidized to the sulfonic acid derivatives and then optionally saponified the ester group.
The new compounds can be converted into the corresponding salts with physiologically acceptable inorganic and / or organic bases.
<I> Example 1 </I> 14 g of 2-amino-5-n-propoxypyrimidine are dissolved in 100 ml of pyridine. Then 29 g of 4-diethylaminocarbonylmethylene benzene sulfochloride are added and the mixture is stirred at 50 ° C. for 2 hours. 300 ml of water are then added and the precipitated product is dissolved in dilute ammonia for purification, filtered with charcoal and precipitated out again with hydrochloric acid. After recrystallization from ethanol, 35 g of 4- (5-n-propoxypyrimidinyl-2) -sulfonamido-phenylacetic acid diethylamide with a melting point of 159 ° C. are obtained.
The 4-diethylaminocarbonylmethylene benzene sulfochloride can be obtained by chlorosulfonation of acetic acid diethylamide. Accordingly, the starting materials for the compounds mentioned in the overview on FIGS. 6 and 7 can be obtained from the corresponding acetic acid or thioacetic acid derivatives by chlorosulfonation.
In addition, the process according to the invention can be used to produce: General formula:
EMI0002.0027
EMI0002.0028
<I> Example 2 </I> 1 kg of 4- (5-n-propoxypyrimidinyl-2) -sulphonamido-phenylacetic acid dimethylamide, 50 g of polyvinylpyrrolidone, 50 g of potato starch and 5 g of magnesium stearate are mixed homogeneously and form tablets with a score of 551 mg pressed.
The tablets contain 500 mg of active ingredient. <I> Example 3 </I> 1 kg. 4- (5-n-Propoxypyrimidinyl-2) -sulfonamido-phenylacetic acid diethylamide are ground in a jet mill to give particles of a maximum size of 4 tons. After adding 1% colloidal silica (AEROSIL) to improve the flow properties, hard gelatin capsules (size 1) are filled so that each capsule contains 100 mg of active ingredient.
<I> Example 4 </I> 1 kg of the readily water-soluble sodium salt of 4- (5-n- propoxypyrimidinyl - 2) -sulfonamido-phenoxyacetic acid diethylamide is kneaded with 450 ml of ethyl alcohol, granulated and through a vortex dryer until alcohol is free cleverly. 150 g of corn starch, 26 g of talc and 4 g of magnesium stearate are mixed with the granules. Then it is pressed into rod-shaped tablets (5.5 X 17.5 X 6.5 mm). Weight of the tablets 590 mg (500 mg active ingredient). The stick tablets are coated with a solution of 30 g of polyglycol 6000 in 70 ml of acetone in a coating pan and dried.
<I> Example 5 </I> To prepare injection solutions for intravenous administration of the sodium salt (Example 4), 1 kg of salt is dissolved in 19.339 liters of ampoule water containing 1 g of sodium ethylenediaminetetraacetate. Deodorant = 1.017, pH value: 8.5 to 8.7.
After filtration through Seitz EKS 1I filter sheet, ampoules of 20 ml are filled and sterilized at 120 ° C. for 20 minutes.
<I> Example 6 </I> 1 kg 4- (5-methoxypyrimidinyl-2) -sulfonamido-phenoxyacetic acid diethylamide is mixed with 450 g compressible calcium carbonate, 45 g corn starch and 5 g magnesium stearate and made into tablets, as usual 150 mg weight corresponding to 100 mg active ingredient, pressed. <I> Example 7 </I> 4 kg of 4- (5-hydroxyethoxypyrimidinyl-2) sulfonamidophenoxyacetic acid diethylamide are ground in a jet mill to a particle size of about 6 liters. A quantity of 400 mg is then filled into hard gelatine capsules (size 0).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1690869A CH494231A (en) | 1967-04-27 | 1967-04-27 | 2-sulphonamidopyrimidines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1690869A CH494231A (en) | 1967-04-27 | 1967-04-27 | 2-sulphonamidopyrimidines |
| CH599167A CH494230A (en) | 1966-04-27 | 1967-04-27 | 2-sulphonamidopyrimidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH494231A true CH494231A (en) | 1970-07-31 |
Family
ID=4302607
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1690969A CH494232A (en) | 1967-04-27 | 1967-04-27 | 2-sulphonamidopyrimidines |
| CH1690869A CH494231A (en) | 1967-04-27 | 1967-04-27 | 2-sulphonamidopyrimidines |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1690969A CH494232A (en) | 1967-04-27 | 1967-04-27 | 2-sulphonamidopyrimidines |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH494232A (en) |
-
1967
- 1967-04-27 CH CH1690969A patent/CH494232A/en not_active IP Right Cessation
- 1967-04-27 CH CH1690869A patent/CH494231A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH494232A (en) | 1970-07-31 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |