NL8100067A - USE OF 2- (P-CHLOROPHENYL) -3- (AMINOCARBONYLMETHYL) IMIDAZO-1,2-APYRIDINE IN THE FIGHT AGAINST GASTRODUODENAL ULCUS, GASTRODUODENITIS AND IATROGENIC GASTRITIS. - Google Patents
USE OF 2- (P-CHLOROPHENYL) -3- (AMINOCARBONYLMETHYL) IMIDAZO-1,2-APYRIDINE IN THE FIGHT AGAINST GASTRODUODENAL ULCUS, GASTRODUODENITIS AND IATROGENIC GASTRITIS. Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Description
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VO 1338VO 1338
Toepassing van 2-(p-chloorfenyl)-3-(aminocarbonylmethyl)imidazo-£1.2-a_/pyridine bij de bestrijding van gastroduodenaal ulcus, gastroduodenitis en iatrogene gastritis.Use of 2- (p-chlorophenyl) -3- (aminocarbonylmethyl) imidazo-1,2-a / pyridine in the control of gastroduodenal ulcer, gastroduodenitis and iatrogenic gastritis.
De uitvinding heeft betrekking op de toepassing van 2-(p-chloorfenyl)-3-Caminocarbonylmethyl)imidazq£· 1.2-a_7~pyridine van de formule 1 van het formuleblad, of de zouten daarvan met organische of anorganische zuren bij het bestrijden van gastroduodenaal 5 ulcus, gastroduodenitis en iatrogene gastritis.The invention relates to the use of 2- (p-chlorophenyl) -3-caminocarbonylmethyl) imidazq-1,2-a-7-pyridine of the formula 1 of the formula sheet, or its salts with organic or inorganic acids in combating gas product duodenal Ulcer, gastroduodenitis and iatrogenic gastritis.
De verbinding van de formule 1 behoort tot een grote groep van imidazo^ 1.2-a_7pyridinen waarvan de ontsteking werende werking bekend is, vgl. J. Med. Chem., Band 12 C1969], blz.122 en Brits octrooischrift No.1.076.089.The compound of the formula I belongs to a large group of imidazo-1,2-a-7-pyridines whose anti-inflammatory action is known, cf. J. Med. Chem., Band 12 C1969], p. 122 and British Patent No. 1,076,089.
10 Volgens de uitvinding werd nu vastgesteld, dat de verbinding van de formule 1 als enige verbinding uit deze groep een verrassende anti-ulcuswerking in het gastrointestinale gebied uitoefent.According to the invention it has now been established that the compound of the formula I as the only compound from this group exerts a surprising anti-ulcer activity in the gastrointestinal region.
Deze werking is van aanzienlijk therapeutisch belang en werd tot dusver nog niet waargenomen.This action is of considerable therapeutic importance and has not yet been observed.
15 Onderwerp van de uitvinding zijn geneesmiddelen met anti- ulcuswerking, die uit 2-(p-chloorfenyl)-3-[aminocarbonylmethyl]imi-dazo^"1.2-a_7pyridine van de formule 1 of uit een zout van deze verbinding met zuren bestaan, of deze verbinding of de zouten daarvan als actieve stof bevatten. De verbinding met de formule 1 wordt 20 hierna met het codenummer S.809 aangeduid.The subject of the invention are anti-ulcer drugs which consist of 2- (p-chlorophenyl) -3- [aminocarbonylmethyl] imidazo-1,2-a-7-pyridine of the formula 1 or of a salt of this compound with acids, whether it contains this compound or its salts as active substance The compound of the formula 1 is hereinafter referred to as code number S.809.
De uitvinding heeft ook.betrekking op de toepassing van S.809 resp. de zouten daarvan, voor de therapie van gastroduodenaal ulcus, gastroduodenitis en iatrogene gastritis. Onder toepassing worden alle handelingen bij de bereiding, zuivering, confectione-25 ring tot toe te dienen geneesmiddelen en/of vullen in voor afleve ring geschikte houders verstaan.The invention also relates to the use of S.809 resp. its salts, for the treatment of gastroduodenal ulcer, gastroduodenitis and iatrogenic gastritis. By use is meant all operations in the preparation, purification, preparation of medicaments to be administered and / or filling in containers suitable for delivery.
De verbinding S.809 heeft bij onderzoekingen ter vaststelling van de acute toxiciteit, die aan verschillende dierspecies werden uitgevoerd, een tamelijk hoge verdraagzaamheid getoond, zo- 8 1 00 06 7 * · - 2 - als uit tabel A blijkt. B.v. bedraagt de OL^-waarde bij orale toediening bij de muis 6000 mg/kg en b'ij de rat meer dan 6000 mg per kg. Bij toxiciteitsonderzoekingen van lange duur met dagelijkse doseringen van 50, 100 en 300 mg/kg p.o. bleek bij ratten van 5 de Sprague-Dawley-stam C200 dieren] bij meer dan 6 maanden durende proefduur een optimale verdraagzaamheid, zonder dat afwijkingen van de belangrijkste organische functies konden worden waargenomen.Compound S.809 has shown fairly high tolerability in acute toxicity studies conducted on various animal species, as shown in Table A. E.g. the OL value for oral administration in the mouse is 6000 mg / kg and in the rat more than 6000 mg per kg. Long-term toxicity studies with daily doses of 50, 100 and 300 mg / kg po showed optimal tolerability in rats of 5 Sprague-Dawley strain C200 animals] over 6 months of testing, without deviations from major organic functions could be observed.
Bij Beagle-honden (18 dieren] gaf een orale toediening van 25 mg/kg bij een proefduur van meer dan 6 maanden een optimale veria draagzaamheid.In Beagle dogs (18 animals), oral administration of 25 mg / kg over 6 months of trial gave optimal tolerability.
De specifieke farmacodynamische activiteit van de verbinding volgens de uitvinding manifesteert zich in een beschermende werking (bij gemiddelde doses van 50 - 100 mg/kg zowel oraal alsook endoperitoneaal] tegen de vorming van experimentele maagzweren, 15 onafhankelijk van het feit of deze door geneesmiddelen (indometa- cine, fenylbutazon, acetylsalicylzuur en dergelijke] zijn veroorzaakt of van nerveuze of gemengde oorsprong zijn, b.v. stress-ulcus, ulcus door pylorusligatuur en ulcos door duodenumcompressie. In het verdere worden de resultaten van twee proeven vermeld. Bij 20 de eerste proef betreft het ulcerogene doses van met indometacine behandelde ratten (tabel B), terwijl bij de tweede proef ratten . aan stress worden blootgesteld doordat ze bij lage temperaturen werden gekalmeerd (tabel C].The specific pharmacodynamic activity of the compound according to the invention manifests itself in a protective action (at average doses of 50-100 mg / kg both orally and endoperitoneally) against the formation of experimental gastric ulcers, regardless of whether they are by drugs (indometa - cine, phenylbutazone, acetylsalicylic acid and the like] have been caused or are of nervous or mixed origin, eg stress ulcer, ulcer by pyloric ligature and ulcer by duodenum compression. ulcerogenic doses of indomethacin-treated rats (Table B), while in the second trial, rats are exposed to stress by being calmed at low temperatures (Table C].
Een geprononceerde beschermende werking blijkt voor de ver-25 binding S.809 ook tegen door polymyxine B veroorzaakte hemorrhagi- sche maagzweren en tegen door indometacine veroorzaakte intestinale zweren.A pronounced protective effect also appears for the compound S.809 against hemorrhagic gastric ulcers caused by polymyxin B and against intestinal ulcers caused by indomethacin.
Bij andere proeven aan de rat kon worden aangetoond dat S.809 een geprononceerde antagonistische activiteit tegen door een 30 pylorusligatuur veroorzaakte maagsaphypersecretie uitoefent (vgl.In other rat experiments it could be shown that S.809 exerts a pronounced antagonistic activity against gastric saphyper secretion induced by a pylorus ligature (cf.
tabel 0].table 0].
Het produkt volgens de uitvinding dat hij in vitro proeven een algemene antispastische activiteit vertoont en dat generlei anticholinergische werking heeft, werkt een verlaging van het mu-35 coproteïnegehalte van maagcurettages, dat bij verschillende expe- 8 1 0 0 06 7 - 1 · • \ - 3 - rimenteel opgewekte maagkwalen optreedt, tegen (vgl. tabel E).The product according to the invention, which shows in vitro tests a general antispastic activity and which has no anticholinergic effect, has a reduction in the mu-35 coprotein content of gastric curettages, which at different expirations. - 3 - rimentally induced stomach ailments occur, against (see Table E).
Hieruit kan worden geconcludeerd dat de beschermende werking van de verbinding volgens de uitvinding op de maag als gevolg van een op de maagwand uitgeoefende mucopojetische werking is.It can be concluded from this that the protective effect of the compound according to the invention on the stomach is due to a mucopoietic action exerted on the stomach wall.
5 Bij de voor het aantonen van de anti-ulcuswerking toegepas te doses blijkt bij de verschillende proeven Csterfte door procaine in verbinding met natriumwaterstofsulfiet bij de muis, lokale blaasjes door chloroform bij de rat en bij konijnen, door.bradyki-nine bij. de' muis en dergelijke) een significante vasale antidiffu-10 sorische en antipermeabiliserende werking.The doses used to demonstrate the anti-ulcer activity show C-mortality by procaine in connection with sodium hydrogen sulfite in the mouse, local vesicles by chloroform in the rat and in rabbits, by bradkykinin in the various experiments. the mouse and the like) a significant vasal anti-diffusion and anti-permeabilizing action.
De ontsteking werende, analgetische en anti-pyretische werking van deze verbinding, die in de genoemde literatuur is beschreven treedt bij aanzienlijk hogere doses op. Bij deze hogere doses C200 mg/kg en meer) blijkt bij de rat een duidelijke vertraging 15 van de gastrolntestinale doorgang.The anti-inflammatory, analgesic and anti-pyretic activity of this compound, described in the aforementioned literature, occurs at considerably higher doses. At these higher doses (C200 mg / kg and above), there is a marked delay in gastrointestinal passage in the rat.
Bij.mensen vertoont S.809 een zeer goede verdraagzaamheid.In humans, S.809 shows very good tolerance.
Bij orale toediening van driemaal daags 200 - 400 mg in een tijd van 3-4 weken vindt een uitgesproken herstellende werking bij g astroduodenaal ulcus plaats. Bij patiënten, die tegenover secun-20 daire werkingen op de maag van ontsteking werende geneesmiddelen bijzonder gevoelig zijn oefent het produkt volgens de uitvinding een geprononceerde beschermende werking op de slijmhuidgrens uit.Oral administration of 200-400 mg three times a day over a period of 3-4 weeks has a pronounced restorative effect on astroduodenal ulcer. In patients who are particularly sensitive to secondary anti-inflammatory drugs on the stomach, the product according to the invention exerts a pronounced protective effect on the mucous membrane border.
Zoals reeds vermeld vertoont S.809 de volgende therapeuti-- sche indicaties; gastroduodenaal ulcus, gastroduodenitis en iatro- 25. gene gastritis.As already mentioned, S.809 shows the following therapeutic indications; gastroduodenal ulcer, gastroduodenitis and iatrogenic gastritis.
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De anti-ulcuswerking van 2-(p-chloorfenyl)-3~(aminocarbanyl-methyl)imidazq£*1.2-a_7pyridine werd bij Klinische proeven met succes bevestigd. Aan 20 patiënten met ulcereuse en peri-ulcereuse toestand in de maag en duodenum Cdiagnose volgens endoscopische 5 controle) werden 4 weken lang 800 - 1000 mg_S.809 dagelijks in de vorm van 200 mg capsules toegediend. Ook de beoordeling na beëindi-. ging van de therapie geschiedde door middel van endoscopische controle. Oe resultaten zijn vermeld in tabel F.The anti-ulcer activity of 2- (p-chlorophenyl) -3- (aminocarbanyl-methyl) -imidazq-1,2-α-pyridine was successfully confirmed in Clinical trials. Twenty patients with ulcerative and peri-ulcerous conditions in the stomach and duodenum (diagnosis by endoscopic control) were administered 800-1000 mg_S.809 daily in the form of 200 mg capsules for 4 weeks. Also the assessment after termination. Therapy was accomplished by endoscopic monitoring. The results are shown in Table F.
In de eerste kolom zijn de initialen, in de tweede kolom de 10 leeftijd en in de derde kolom het geslacht van de patiënten aange geven. u betekent ulcus en b.d. bulbus duodeni.In the first column the initials, in the second column the age and in the third column the sex of the patients. u means ulcer and the like bulbus duodeni.
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De verbinding S.809 kan rechtstreeks als zodanig worden toegediend. Bij voorkeur wordt zij in de vorm van zouten met organische zuren, zoals citroenzuur, maleïnezuur, appelzuur, wijnsteenzuur, malonzuur en dergelijke, of met anorganische zuren, zoals 5 zoutzuur, broomwaterstofzuur, fosforzuur, zwavelzuur en dergelijke, toegediend. Enkele van deze zouten zijn bekend; vgl. J. Med. Chem. Band 12 C1969], blz.122.The compound S.809 can be administered directly as such. Preferably it is administered in the form of salts with organic acids such as citric acid, maleic acid, malic acid, tartaric acid, malonic acid and the like, or with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like. Some of these salts are known; cf. J. Med. Chem. Band 12 C1969], p. 122.
De navolgende voorbeelden illustreren de bereiding van nieuwe zouten.The following examples illustrate the preparation of new salts.
IQ Voorbeeld IIQ Example I
2- Cp-chloorfenyl)-3-Caminocarbonylmethyl} -imidazo£" 1.2-a__7pyridine-citraat.2- Cp-chlorophenyl) -3-caminocarbonylmethyl} -imidazo [1,2-a] pyridine citrate.
4,2 g CQ,02 mol} citroenzuur werden in de warmte in een meng-3 3 sel uit 150 cm ethanol en 50 cm methanol opgelost. De heldere op-15 lossing werd met 5,7 g CO,02 mol] 2-Cp-chloorfenyl)-3-Caminocarbo- nylmethyl]-imidazq£'1.2-a__7pyridine in de vorm van de vrije base Cbereid volgens de reeds genoemde literatuurplaatsen) gemengd en onder verwarmen in oplossing gebracht.4.2 g CQ, 02 mol} citric acid were dissolved in a mixture of 150 cm ethanol and 50 cm methanol in the heat. The clear solution was prepared in the form of the free references C with 5.7 g of CO, 02 mol] 2-Cp-chlorophenyl) -3-Caminocarbonylmethyl] -imidazq. 1,2-a-7-pyridine in the form of the free base C ) mixed and dissolved under heating.
Na afkoeling tot kamertemperatuur werd de oplossing met 3 20 350 cm diëthylether gemengd. Het neergeslagen ruwe zout werd ge- 1 8 1 0 0 06 7 filtreerd op het filter met ether gewassen en uit 50 cm absolute methanol geherkristalliseerd. Men verkrijgt 5 g zuiver zout met een smeltpunt van 169 - 170°C Cniet gecorrigeerd}.After cooling to room temperature, the solution was mixed with 350 ml of diethyl ether. The crude salt precipitated was washed with ether on the filter, filtered and recrystallized from 50 cm absolute methanol. 5 g of pure salt, m.p. 169-170 [deg.] C., not corrected, are obtained.
C21H20C1N3°8 t477-ae) 25 berekend! C 52,78, H 4,22, Cl 7,42, N 8,79%! gevonden: C 52,67, H 4,25, Cl 7,31, N 8,58%.C21H20C1N3 ° 8 t477-ae) 25 calculated! C 52.78, H 4.22, Cl 7.42, N 8.79%! found: C 52.67, H 4.25, Cl 7.31, N 8.58%.
Voorbeeld IIExample II
2-Cp-chloorfenyl}-3-Caminocarbonylmethyl)-imidazo^ 2.1-a_ƒ pyridine-hydrobromide.2-Cp-chlorophenyl} -3-caminocarbonylmethyl) -imidazo-2,1-alpha pyridine hydrobromide.
30 Een mengsel uit 3,0 g (0,01 mol} 2-Cp-chloorfenyll-3-Camino- - carbonylmethyl}-imidazq/’1.2-a_7pyridine in de vorm van de vrije base Cbereid volgens de eerder genoemde literatuurplaatsen} in 95%¾ ethanol werd onder roeren verwarmd tot de verbinding volkomen in oplossing ging.A mixture of 3.0 g (0.01 mol} 2-Cp-chlorophenyl-3-Camino-carbonylmethyl} -imidazq / 1,2-a-7-pyridine in the form of the free base C prepared according to the above-mentioned references} in 95 % Ethanol was heated with stirring until the compound dissolved completely.
3 35 De oplossing werd met 3,0 cm 47%'s broomwaterstofzuur ge- y * - 12 - msngd. Hst bij afkoelen van de oplossing uitgekristalliseerde zout 3 werd afgefiltreerd, met diëthylether gewassen en uit 150 cm absolute ethanol geherkristalliseerd. Men verkreeg een analyse-zuiver produkt met Smp. 236 - 23fl°C (niet gecorrigeerd).The solution was mixed with 3.0 cm 47% hydrobromic acid. Hst crystallized salt 3 on cooling of the solution was filtered off, washed with diethyl ether and recrystallized from 150 ml of absolute ethanol. An analysis pure product was obtained with Mp. 236 - 23fl ° C (uncorrected).
5 C15H13BrCl!\l30 £366,65) berekend: C. 49,14, H 3,57,. N 11,46%,· gevonden: C 49,30, H 3,44, N 11,26%.5C15H13BrCl (l30 £ 366.65) calculated: C. 49.14, H 3.57. N 11.46%. Found: C 49.30, H 3.44, N 11.26%.
S.809 kan b.v. in de vorm van capsules, tabletten of dragees worden toegediend.S.809 can e.g. administered in the form of capsules, tablets or dragees.
10 Thans volgen enkele voorbeelden betreffende de samenstelling van farmaceutische preparaten: 1) Gelatinecapsules 2-Cp-chloorfenyl)'-3-Caminocarbonylmethyl)-imidazo-^"1.2-a_7pyridine-citraat 330 mg 15 polyvinylpyrrolidon 10 mg talcum 5 mg magnesiumstearaat 5 mg 2) Tabletten 2-Cp-chloorfenyl)-3-(aminocarbonylmethyl)-imidazo-20 £ 1.2~aJ7pyridine-citraat 330 mg lactose, maïszetmeel·, Gummi arabicum, talcium, magnesiumstearaat q.s. tot 450 mg 3) Dragees 2-Cp-chloorfenyl)-3-Caminocarbonylmethyl)-imidazo-25 ^”1.2-a^pyridine-hydrabromide - 250 mg zetmeel, Gummi arabicum, magnesiumstearaat, talcum,Some examples regarding the composition of pharmaceutical preparations are now given: 1) Gelatin capsules 2-Cp-chlorophenyl) -3-Caminocarbonylmethyl) -imidazo-1,2-a-7-pyridine citrate 330 mg 15 polyvinylpyrrolidone 10 mg talcum 5 mg magnesium stearate 5 mg 2 Tablets 2-Cp-chlorophenyl) -3- (aminocarbonylmethyl) -imidazo-20 lb 1.2 ~ a7pyridine citrate 330 mg lactose, corn starch, Gummi arabicum, talcium, magnesium stearate qs to 450 mg 3) Dragees 2-Cp-chlorophenyl) -3-Caminocarbonylmethyl) -imidazo-25-1,2-a-pyridine hydrabromide - 250 mg starch, Gummi arabicum, magnesium stearate, talcum,
TiOj, CaC03, kaolien, suiker, kleurstof q.s. tot . 500 mg 8 1 00 06 7TiOj, CaCO3, kaolin, sugar, dye q.s. until . 500 mg 8 1 00 06 7
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2118880 | 1980-04-04 | ||
| IT21188/80A IT1141271B (en) | 1980-04-04 | 1980-04-04 | PHARMACEUTICAL COMPOSITIONS WITH ANTI-ULTER ACTIVITY |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8100067A true NL8100067A (en) | 1981-11-02 |
Family
ID=11178097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8100067A NL8100067A (en) | 1980-04-04 | 1981-01-08 | USE OF 2- (P-CHLOROPHENYL) -3- (AMINOCARBONYLMETHYL) IMIDAZO-1,2-APYRIDINE IN THE FIGHT AGAINST GASTRODUODENAL ULCUS, GASTRODUODENITIS AND IATROGENIC GASTRITIS. |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5812256B2 (en) |
| BE (1) | BE886757A (en) |
| DE (1) | DE3046510A1 (en) |
| IT (1) | IT1141271B (en) |
| LU (1) | LU82990A1 (en) |
| NL (1) | NL8100067A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0822194A4 (en) * | 1995-04-21 | 1998-04-29 | Shinnippon Pharmaceutical Inc | FUSED IMIDAZO 1,2-a]PYRIDINES |
-
1980
- 1980-04-04 IT IT21188/80A patent/IT1141271B/en active
- 1980-12-10 DE DE19803046510 patent/DE3046510A1/en not_active Ceased
- 1980-12-10 LU LU82990A patent/LU82990A1/en unknown
- 1980-12-19 BE BE2/58912A patent/BE886757A/en not_active IP Right Cessation
- 1980-12-19 JP JP55181188A patent/JPS5812256B2/en not_active Expired
-
1981
- 1981-01-08 NL NL8100067A patent/NL8100067A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| LU82990A1 (en) | 1981-03-26 |
| JPS5812256B2 (en) | 1983-03-07 |
| BE886757A (en) | 1981-04-16 |
| IT8021188A0 (en) | 1980-04-04 |
| IT1141271B (en) | 1986-10-01 |
| DE3046510A1 (en) | 1981-10-08 |
| JPS56140919A (en) | 1981-11-04 |
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