NO178337B - Analogous Process for Preparing Therapeutically Active 5-Fluoro-2 [[(4-Cyclopropyl- (methoxy-2-pyridinyl) methyl] sulfinylA-1H-benzimidazole and intermediates - Google Patents
Analogous Process for Preparing Therapeutically Active 5-Fluoro-2 [[(4-Cyclopropyl- (methoxy-2-pyridinyl) methyl] sulfinylA-1H-benzimidazole and intermediates Download PDFInfo
- Publication number
- NO178337B NO178337B NO912415A NO912415A NO178337B NO 178337 B NO178337 B NO 178337B NO 912415 A NO912415 A NO 912415A NO 912415 A NO912415 A NO 912415A NO 178337 B NO178337 B NO 178337B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- methyl
- benzimidazole
- fluoro
- cyclopropylmethoxy
- Prior art date
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- -1 methoxy-2-pyridinyl Chemical group 0.000 title description 7
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- OKHRKOHJIIGRLO-UHFFFAOYSA-N 2-(chloromethyl)-4-(cyclopropylmethoxy)pyridine;hydrochloride Chemical compound Cl.C1=NC(CCl)=CC(OCC2CC2)=C1 OKHRKOHJIIGRLO-UHFFFAOYSA-N 0.000 claims description 4
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- IKRDGNXMWAWVLG-UHFFFAOYSA-N [4-(cyclopropylmethoxy)pyridin-2-yl]methyl acetate Chemical compound C1=NC(COC(=O)C)=CC(OCC2CC2)=C1 IKRDGNXMWAWVLG-UHFFFAOYSA-N 0.000 claims description 4
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Description
Foreliggende oppfinnelse vedrører fremstilling av en ny forbindelse og terapeutisk akseptable salter derav, hvilke inhiberer eksogent eller entogent stimulert mavesyresekresjon og kan derfor benyttes ved forebygging og behandling av peptisk ulcus. Oppfinnelsen angår også nye mellomprodukter for bruk ved fremstilling av den nye farmasøytisk aktive forbindelsen. The present invention relates to the production of a new compound and therapeutically acceptable salts thereof, which inhibit exogenously or entogenously stimulated gastric acid secretion and can therefore be used in the prevention and treatment of peptic ulcer. The invention also relates to new intermediates for use in the preparation of the new pharmaceutically active compound.
Mer generelt kan den fremstilte forbindelsen anvendes for forebygging og behandling av inflammatoriske sykdommer i mave/tarmkanalen, og mavesyrerelaterte sykdommer i pattedyr inkludert mennesket, slik som gastritt, gastrisk ulcus, duodenal ulcus, reflux esofagitt og Zollinger-Ellison-syndrom. Videre kan forbindelsen benyttes for behandling av andre forstyrrelser i mave/tarmkanalen der gastrisk anti-sekretorisk effekt er ønskelig, for eksempel i pasienter med gastrinomer, og i pasienter med akutt blødning i dén øvre delen av mave/tarmkanalen. Den kan også benyttes av pasienter i situasjoner med intensiv pleie, og pre- og postoperativt for å hindre syreaspirasjon og stressulcerasjon. Forbindelsen kan også benyttes for behandling eller profylakse av inflammatoriske tilstander i pattedyr, inkludert mennesket, spesielt de som involverer lysozymale enzymer. Tilstander som spesielt kan nevnes er reaumatoid artritt og podagra. Forbindelsen kan også være nyttig i behandlingen av sykdommer relatert til benmetabolismeforstyrrelser samt behandling av glaukom. More generally, the manufactured compound can be used for the prevention and treatment of inflammatory diseases in the stomach/intestinal tract, and stomach acid-related diseases in mammals including humans, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. Furthermore, the compound can be used for the treatment of other disturbances in the stomach/intestinal tract where a gastric anti-secretory effect is desirable, for example in patients with gastrinomas, and in patients with acute bleeding in the upper part of the stomach/intestinal tract. It can also be used by patients in intensive care situations, and pre- and post-operatively to prevent acid aspiration and stress ulceration. The compound may also be used for the treatment or prophylaxis of inflammatory conditions in mammals, including humans, particularly those involving lysozymal enzymes. Conditions that can be particularly mentioned are rheumatoid arthritis and gout. The compound may also be useful in the treatment of diseases related to bone metabolism disorders as well as the treatment of glaucoma.
Det er et spesielt hovedformål med oppfinnelsen å tilveie-bringe en forbindelse med et høyt biotilgjengelighetsnivå. Denne forbindelsen vil også utvise høye stabilitetsegenskaper It is a particular main object of the invention to provide a compound with a high level of bioavailability. This compound will also exhibit high stability properties
ved nøytral pE-verdi og en høy virkningsgrad med hensyn til inhibering av mavesyresekresjon. Biotilgjengelighet er definert som den fraksjon, eller prosent, av den admini-strerte dose av forbindelse som absorberes uendret i det systemiske blod. Virkningsgraden er i foreliggende sammenheng definert som ED50 verdien. at a neutral pE value and a high degree of effectiveness with regard to inhibition of gastric acid secretion. Bioavailability is defined as the fraction, or percentage, of the administered dose of compound that is absorbed unchanged into the systemic blood. In this context, the effectiveness is defined as the ED50 value.
Tidligere teknikk og oppfinnelsens bakgrunn Prior art and background of the invention
Bezimidazolderivater som er beregnet for inhibering av mavesyresekresjon er beskrevet i en rekke patenter. Blant disse kan nevnes GB 1.500.043, GB 1.525.958, US 4.182.766, US 4.255.431. US 4.599.347, EP 124.495, US 4.555.518, US 4.727.150, US 4.628.098, EP 208.452 og Derwent abstract 87-294449/42. Benzimidalzolderivater som er foreslått for bruk i behandlingen eller forebyggingen av spesielle imflammatoriske sykdommer i mave/tarmkanalen er beskrevet i US 4.539.465. Bezimidazole derivatives intended for inhibition of gastric acid secretion are described in a number of patents. Among these can be mentioned GB 1,500,043, GB 1,525,958, US 4,182,766, US 4,255,431. US 4,599,347, EP 124,495, US 4,555,518, US 4,727,150, US 4,628,098, EP 208,452 and Derwent abstract 87-294449/42. Benzimidazole derivatives which are proposed for use in the treatment or prevention of particular inflammatory diseases of the gastrointestinal tract are described in US 4,539,465.
Foreliggende oppfinnelse Present invention
Forbindelser som er beskrevet i den tidligere tekikk, som angitt ovenfor, er effektive syresekresjonsinhibitorer og er således nyttige som antiulcus-forbindelser. For ytterligere å forbedre brukbarheten av denne type legemidler så har en høyere biotilgjengelighet vært ønsket, men forbindelsene bør fremdeles ha en høy virkningsgrad når det gjelder inhibering av mavesyresekresjon og også en høy kjemisk stabilitet ved nøytral pH. Compounds described in the prior art, as indicated above, are effective acid secretion inhibitors and are thus useful as antiulcer compounds. To further improve the usability of this type of drug, a higher bioavailability has been desired, but the compounds should still have a high degree of effectiveness in terms of inhibition of gastric acid secretion and also a high chemical stability at neutral pH.
Det har blitt erkjent at testede 2-[(2-pyridinylmetyl)-sulfinyl]-lE-benzimidazoler viser en sterk variasjon i biotilgjengelighet samt i virkningsgrad og stabilitet, og det er vanskelig å identifisere forbindelser som er i besittelse av alle de tre fordelaktige egenskapene. Det er ingen veiledning i den tidligere teknikk med hensyn til hvordan man kan oppnå forbindelser med denne kombinasjon av egenskaper. It has been recognized that tested 2-[(2-pyridinylmethyl)-sulfinyl]-1E-benzimidazoles show a wide variation in bioavailability as well as in potency and stability, and it is difficult to identify compounds that possess all three advantageous properties . There is no guidance in the prior art as to how to achieve compounds with this combination of properties.
Det har blitt funnet at den ifølge oppfinnelsen fremstilt forbindelse viser ytterst høy biotilgjengelighet og fremdeles er forbindelsen meget effektiv som inhibitor for mavesyresekresjon og viser en høy kjemisk stabilitet i oppløsning ved en nøytral pH-verdi. Den nye forbindelsen kan derfor benyttes i de ovenfor angitte indikasjoner i pattedyr, inkludert mennesket. It has been found that the compound produced according to the invention shows extremely high bioavailability and the compound is still very effective as an inhibitor of gastric acid secretion and shows a high chemical stability in solution at a neutral pH value. The new compound can therefore be used in the above indications in mammals, including humans.
Den nye forbindelsen som er 5-fluor-2-[[(4-cyklopropylmetoksy-2-pyridinyl)metyl]sulfinyl]-lH-benzimidazol (forbindelse I) og farmasøytisk akseptable salter derav fremstilles ifølge foreliggende oppfinnelse ved at 5-fluor-2-[ [ ( 4-cyklopropylmetoksy-2-pyridinyl )metyl]tio] -lH-benz-imidazol oksyderes, hvoretter en således oppnådd forbindelse I, om ønsket, omdannes til et farmasøytisk akspetabelt salt. The new compound which is 5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (compound I) and pharmaceutically acceptable salts thereof are prepared according to the present invention by 5-fluoro-2 -[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]thio]-1H-benz-imidazole is oxidized, after which a thus obtained compound I is, if desired, converted into a pharmaceutically acceptable salt.
Oksydasjonen kan utføres ved bruk av et oksydasjonsmiddel slik som salpetersyre, hydrogenperoksyd, (eventuelt i nærvær av vanadiumforbindelser), persyrer, perestere, ozon, dinitrogentetraoksyd, iodosobenzen, N-halogensuksinimid, 1-klorbenzotriazol, t-butylhypokloritt, diazabicyklo-[2,2,2]-oktan-bromkompleks, natriummetaperiodat, selendioksyd, mangandioksyd, kromsyre, seriumammoniumnitrat, brom, klor og sulfurylklorid. Oksydasjonen finner vanligvis sted i et oppløsningsmiddel, slik som halogenerte hydrokarboner, alkoholer, etere, ketoner. The oxidation can be carried out using an oxidizing agent such as nitric acid, hydrogen peroxide, (possibly in the presence of vanadium compounds), peracids, peresters, ozone, dinitrogen tetraoxide, iodosobenzene, N-halogensuccinimide, 1-chlorobenzotriazole, t-butyl hypochlorite, diazabicyclo-[2,2 ,2]-octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulfuryl chloride. The oxidation usually takes place in a solvent, such as halogenated hydrocarbons, alcohols, ethers, ketones.
Oksydasjonen kan også utføres enzymatisk ved bruk av et oksyderende enzym eller mikrobiotisk ved bruk av en egnet mikroorganisme. The oxidation can also be carried out enzymatically using an oxidizing enzyme or microbiotically using a suitable microorganism.
Avhengig av prosessbetingelsene og utgangsmaterialene så oppnås forbindelse I enten i nøytral form eller i saltform. Både den nøytrale forbindelsen og saltene derav er omfattet av oppfinnelsen. Således kan basiske, nøytrale eller blandede salter oppnås samt hemi-, mono-, sesqui- eller polyhydrater. Depending on the process conditions and the starting materials, compound I is obtained either in neutral form or in salt form. Both the neutral compound and its salts are covered by the invention. Thus basic, neutral or mixed salts can be obtained as well as hemi-, mono-, sesqui- or polyhydrates.
Alkaliske salter av forbindelse I oppfinnelsen er eksempli-fisert ved dens salter med Li<+>, Na<+>, K<+>, MG2 +, Ca2 + og N<+>(R)4, hvor R er (1-4 C)alkyl. Spesielt foretrukne er Na<+>, Ca2 + og Mg2 + saltene. Spesielt foretrukne er Na<+> og Mg2 + saltene. Slike salter kan fremstilles ved omsetning av forbindelsen med en base som kan frigjøre det ønskede kationet. Alkaline salts of the compound of the invention are exemplified by its salts with Li<+>, Na<+>, K<+>, MG2+, Ca2+ and N<+>(R)4, where R is (1- 4 C) alkyl. Particularly preferred are the Na<+>, Ca2 + and Mg2 + salts. Particularly preferred are the Na<+> and Mg2 + salts. Such salts can be prepared by reacting the compound with a base which can release the desired cation.
Eksempler på baser som kan frigjøre slike kationer og eksempler på reaksjonsbetingelser er angitt i det nedenstående . a) salter hvor kationet er Li<+>, Na<+> eller K<+> fremstilles ved behandling av forbindelse I med LiOH, NaOH eller KOH i et vandig eller ikke-vandig medium eller med LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 eller KNR2, hvor R er en alkylgruppe inneholdene 1-4 karbonatomer, i et ikke-vandig medium. Examples of bases that can release such cations and examples of reaction conditions are given below. a) salts where the cation is Li<+>, Na<+> or K<+> are prepared by treating compound I with LiOH, NaOH or KOH in an aqueous or non-aqueous medium or with LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 or KNR2, where R is an alkyl group containing 1-4 carbon atoms, in a non-aqueous medium.
b) salter hvor kationet er Mg2 + eller Ca2 + fremstilles ved behandling av forbindelse I med Mg(OR)2, Ca(0R)2 eller b) salts where the cation is Mg2 + or Ca2 + are prepared by treating compound I with Mg(OR)2, Ca(OR)2 or
CaH2, hvor R er en alkylgruppe inneholdene 1-4 karbonatomer, i et ikke-vandig oppløsningsmiddel slik som en alkohol (bare for alkoholatene), for eksempel ROH, eller i en eter slik som tetrahydrofuran. CaH2, where R is an alkyl group containing 1-4 carbon atoms, in a non-aqueous solvent such as an alcohol (only for the alcoholates), for example ROH, or in an ether such as tetrahydrofuran.
Ifølge foreliggende oppfinnelse er det også tilveiebragt nye mellomprodukter som er kjennetegnet ved at de utgjøres av 4-cyklopropylmetoksy-2-metylpyridin-l-oksyd, 2-acetoksymetyl-4-cyklopropylmetoksypyridin, 4-cyklopropylmetoksy-2-hydroksymetylpyridin, 4-cyklopropylmetoksy-2-klormetylpyridinhydro-klorid, 5-fluor-2-[[(4-cyklopropylmetoksy-2-pyridinyl)-metyl]tio]-lH-benzimidazol. According to the present invention, new intermediates are also provided which are characterized by the fact that they consist of 4-cyclopropylmethoxy-2-methylpyridine-1-oxide, 2-acetoxymethyl-4-cyclopropylmethoxypyridine, 4-cyclopropylmethoxy-2-hydroxymethylpyridine, 4-cyclopropylmethoxy-2 -chloromethylpyridine hydrochloride, 5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)-methyl]thio]-1H-benzimidazole.
"Utgangsmaterialene som er beskrevet i mellomprodukteksemplene kan oppnås ifølge i og for seg kjente fremgangsmåter. "The starting materials described in the intermediate product examples can be obtained according to methods known per se.
For klinisk bruk blir forbindelse I formulert til farma-søytiske preparater for oral, rektal, parenteral eller andre administråsjonsmåter. Den farmasøytiske formuleringen inneholder forbindelse I normalt i kombinasjon med en farmasøytisk akseptabel bærer. Bæreren kan være i form av et fast, halvfast eller flytende fortynningsmiddel, eller en kapsel. Mengden av aktiv forbindelse er vanligvis mellom 0,1 og 90 vekt-# av preparatet, mellom 0,2 og 20 vekt-# i preparater for parenteral bruk og mellom 1 og 50 vekt-# i preparater for oral administrasjon. For clinical use, compound I is formulated into pharmaceutical preparations for oral, rectal, parenteral or other routes of administration. The pharmaceutical formulation normally contains compound I in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. The amount of active compound is usually between 0.1 and 90 wt-# of the preparation, between 0.2 and 20 wt-# in preparations for parenteral use and between 1 and 50 wt-# in preparations for oral administration.
Ved fremstillingen av farmasøytiske formuleringer inneholdene forbindelse I i form av doseringsenheter for oral administrasjon kan den valgte forbindelsen blandes med en fast, pulverformig bærer slik som laktose, sakkarose, sorbitol, mannitol, stivelse, amylopektin, cellulosederivater, gelatin eller en annen egnet bærer, stabiliserende stoffer slik som alkaliske forbindelser for eksempel karbonater, hydroksyder og oksyder av natrium, kalium, kalsium, magnesium og lignende samt med smøremidler slik som magnesiumstearat, kalsium-stearat, natriumstearylfumarat og polyetylenglykolvokser. Blandingen blir deretter bearbeidet til granuler eller presset til tabletter. Granuler og tabletter kan belegges med et enterisk belegg som beskytter den aktive forbindelsen overfor syrekatalysert nedbrytning så lenge som doserings-formen befinner seg i maven. Det enteriske belegget velges blant farmasøytisk akseptable materialer for enterisk belegging, for eksempel bivoks, skjellakk eller anioniske filmdannende polymerer slik som celluloseacetatphtalat, hydroksypropylmetylcellulosephtalat, delvis metylforestrede metakrylsyrepolymerer og lignende, om foretrukket i kombinasjon med en egnet mykner. Forskjellige farvestoffer kan tilsettes til belegget for å skjelne mellom tabletter eller granuler med forskjellige aktive forbindelser eller med forskjellige mengder av tilstedeværende aktiv forbindelse. In the preparation of pharmaceutical formulations containing compound I in the form of dosage units for oral administration, the selected compound can be mixed with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or another suitable carrier, stabilizing substances such as alkaline compounds for example carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. The mixture is then processed into granules or pressed into tablets. Granules and tablets can be coated with an enteric coating that protects the active compound against acid-catalyzed degradation as long as the dosage form is in the stomach. The enteric coating is selected from pharmaceutically acceptable materials for enteric coating, for example beeswax, shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, partially methylesterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. Different dyes can be added to the coating to distinguish between tablets or granules with different active compounds or with different amounts of active compound present.
Myke gelatinkapsler kan fremstilles med kapsler inneholdene en blanding av den aktive forbindelse I vegetabilsk olje, fett, eller en annen egnet bærer for myke gelatinkapsler. Myke gelatinkapsler kan også forsynes med enterisk belegg som beskrevet ovenfor. Harde gelatinkapsler kan inneholde granuler eller enterisk belagte granuler av den aktive forbindelsen. Harde gelatinkapsler kan også inneholde den aktive forbindelsen i kombinasjon med en fast, pulverformig bærer slik som laktose, sakkarose, sorbitol, mannitol, potetstivelse, amylopektin, cellulosederivater eller gelatin. De harde gelatinkapslene kan forsynes med enteriske belegg som beskrevet ovenfor. Soft gelatin capsules can be prepared with capsules containing a mixture of the active compound in vegetable oil, fat, or another suitable carrier for soft gelatin capsules. Soft gelatin capsules can also be supplied with an enteric coating as described above. Hard gelatin capsules may contain granules or enteric-coated granules of the active compound. Hard gelatin capsules may also contain the active compound in combination with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. The hard gelatin capsules can be provided with enteric coatings as described above.
Doseringsenheter for rektal administrasjon kan fremstilles i form av suppositorier som inneholder den aktive substans blandet med en nøytral fettbasis, eller de kan fremstilles i form av en rektal gelatinkapsel som inneholder den aktive substansen i en blanding med en vegetabilsk olje, paraffin-olje eller annen egnet bærer for rektale gelatinkapsler, eller de kan fremstilles i form av et ferdiglaget mikro-klyster, eller de kan fremstilles i form av en tørr mikro-klysterformulering som er beregnet for rekonstitusjon i et egnet oppløsningsmiddel like for administrasjon. Dosage units for rectal administration can be prepared in the form of suppositories containing the active substance mixed with a neutral fatty base, or they can be prepared in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable carrier for rectal gelatin capsules, or they may be prepared in the form of a ready-made micro-enema, or they may be prepared in the form of a dry micro-enema formulation intended for reconstitution in a suitable solvent immediately before administration.
Flytende preparat for oral administrasjon kan fremstilles i form av siruper eller suspensjoner, for eksempel oppløsninger eller suspensjoner inneholdene 0,2-20 vekt-$ av den aktive bestanddel og resten bestående av sukker eller sukker-alkoholer og en blanding av etanol, vann, glyserol, propylen-glykol og/eller polyetylenglykol. Slike flytende preparater kan om ønsket inneholde fargemidler, aromamidler, sakkarin og karboksymetylcellulose eller andre fortykningsmidler. Flytende preparapter for oral administrasjon kan også fremstilles i form av et tørt pulver beregnet for rekon-stitusj on med et egnet oppløsningsmiddel før bruk. Liquid preparation for oral administration can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing 0.2-20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol , propylene glycol and/or polyethylene glycol. Such liquid preparations can, if desired, contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickeners. Liquid preparations for oral administration can also be prepared in the form of a dry powder intended for reconstitution with a suitable solvent before use.
Oppløsninger for parenteral administrasjon kan fremstilles som en oppløsning av forbindelse I i et farmasøytisk akseptabelt oppløsningsmiddel, fortrinnsvis i en konsentrasjon på 0,1-10 vekt-#. Disse oppløsningene kan også inneholde stabiliseringsmidler og/eller buffermidler og kan fremstilles i forskjellige enhetsdoseampuller eller -flasker. Opp-løsninger for parenteral administrasjon kan også fremstilles som et tørt preparat beregnet for rekonstitusjon med et egnet oppløsningsmiddel like før bruk. Solutions for parenteral administration may be prepared as a solution of compound I in a pharmaceutically acceptable solvent, preferably at a concentration of 0.1-10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be produced in different unit dose ampoules or bottles. Solutions for parenteral administration can also be prepared as a dry preparation intended for reconstitution with a suitable solvent just before use.
Den typiske daglige dose av den aktive substans vil avhenge av forskjellige faktorer slik som for eksempel hver pasients individuelle krav, adminsitrasjonsmåten og sykdommen. Generelt vil orale og parenterale doseringer være i området 5-500 mg pr dag av aktiv substans. The typical daily dose of the active substance will depend on various factors such as, for example, the individual requirements of each patient, the method of administration and the disease. In general, oral and parenteral dosages will be in the range of 5-500 mg per day of active substance.
Oppfinnelsen illustreres ved følgende eksempler. The invention is illustrated by the following examples.
EKSEMPEL 1 EXAMPLE 1
Fremstilling av 5-fluor-2-[[(4-cyklopropylmetoksy-2-pyri-dinyl)metyl]sulfinyl]-lE-benzimidazol Preparation of 5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinyl]-1E-benzimidazole
5-fluor-2-[[(4-cyklopropylmetoksy-2-pyridinyl)metyl]sulf inyl-lE-benzimidazol (1,25 g, 0036 mol) ble oppløst i CH2C12 (40 ml) NaEC03 (0,6 g, 0,0072 mol) oppløst i H20 (20 ml) ble tilsatt og blandingen ble avkjølt til + 2°C. m-clorperbenzo-syre 84, % (0,73 g, 0,0036 mol) oppløst i CE2C12 (5 ml) ble tilsatt under omrøring. Omrøring ble fortsatt ved romtemperatur i 15 min. De to fasene ble separert og NaOH (0,29 g, 0,0072 mol) oppløst i E20 (25 ml) ble tilsatt til den organiske fasen. Blandingen ble omrørt, fasene ble separert og H20-fasen ble behandlet med noritt og filtrert. Metyl-fomeat (0,45 ml, 0,0073 mol) oppløst i E20 (5 ml) ble tilsatt dråpevis under omrøring. Etter ekstraksjon med CE2C12 og tørking med Na2S04 ble oppløsningsmidlet inndampet. På denne måten ble tittelforbindelsen oppnådd (0,93 g, 69 %). NMR-data for sluttproduktet er angitt i det nedenstående. 5-Fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinyl-1E-benzimidazole (1.25 g, 0036 mol) was dissolved in CH 2 Cl 2 (40 mL) NaECO 3 (0.6 g, 0 .0072 mol) dissolved in H 2 O (20 mL) was added and the mixture was cooled to + 2°C. m-Chloroperbenzoic acid 84.% (0.73 g, 0.0036 mol) dissolved in CE 2 Cl 2 (5 mL) was added with stirring. Stirring was continued at room temperature for 15 min. The two phases were separated and NaOH (0.29 g, 0.0072 mol) dissolved in E 2 O (25 mL) was added to the organic phase. The mixture was stirred, the phases were separated and the H 2 O phase was treated with norite and filtered. Methyl fomate (0.45 mL, 0.0073 mol) dissolved in E 2 O (5 mL) was added dropwise with stirring. After extraction with CE 2 Cl 2 and drying with Na 2 SO 4 , the solvent was evaporated. In this way the title compound was obtained (0.93 g, 69%). NMR data for the final product is given below.
EKSEMPEL 2 EXAMPLE 2
Fremstilling av 5-fluor-2-[[(4-cyklopropylmetoksy-2-pyri-dinyl)metyl]sulfinyl]-lE-benzimidazol, natriumsalt. Preparation of 5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinyl]-1E-benzimidazole, sodium salt.
5-fluor-2-[[ (4-cyklopropylmetoksy-2-pyridinyl )metyl] sulf i-nyl]-lE-benzimidazol (5 g; 14,5 mmol) oppløst i diklormetan (100 ml) og natriumhydroksyd (0,56 g; 14 mmol) oppløst i vann (100 ml), ble overført til en skilletrakt. Blandingen ble 5-Fluoro-2-[[ (4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinyl]-1E-benzimidazole (5 g; 14.5 mmol) dissolved in dichloromethane (100 mL) and sodium hydroxide (0.56 g; 14 mmol) dissolved in water (100 ml), was transferred to a separatory funnel. The mixture was
rystet til likevekt hvorved oppløsningsmiddelfasene ble separert. Vannoppløsningen ble vasket med diklormetan (2 x 25 ml) og deretter frysetørket. Resten ble omkrystallisert fra diklormetan/dietyleter. Utbytte: 3,7 g (71 <f>) av tittelforbindelsen. NMR data er gitt i det nedenstående. shaken to equilibrium whereby the solvent phases were separated. The aqueous solution was washed with dichloromethane (2 x 25 mL) and then freeze-dried. The residue was recrystallized from dichloromethane/diethyl ether. Yield: 3.7 g (71 <f>) of the title compound. NMR data are given below.
Fremstilling av syntetiske mellomprodukter Production of synthetic intermediates
Eksempel I 1 Example I 1
Fremstilling av 4- cvklopropvlmetoksv- 2- metylpvridin- l- oksdvd Preparation of 4-cyclopropylmethoxysv-2-methylpyridin-1-oxodvd
Til natriumhydrid (55 £ rent) (4,4 g 0,1 mol) (vasket med petroleumeter), ble cyklopropylmetanol (50 ml) tilsatt. Deretter ble en oppløsning av 2-metyl-4-nitropyridin-N-oksyd (6,5 g, 0,042 mol) i cyklopropylmetanol (30 ml) tilsatt i løpet av ca 1 time. Den mørke brune blandingen ble oppvarmet til 90°C og omrørt ved 90°C i 1 time. Deretter ble cyklo-propylmetanolen avdestillert under redusert trykk og metylenklorid (100 ml) ble tilsatt til resten. Blandingen ble omrørt i ca 30 min, deretter filtrert og konentrert, hvilket ga 9,5 g råmateriale. To sodium hydride (55 lb pure) (4.4 g 0.1 mol) (washed with petroleum ether), cyclopropyl methanol (50 mL) was added. Then a solution of 2-methyl-4-nitropyridine-N-oxide (6.5 g, 0.042 mol) in cyclopropyl methanol (30 ml) was added over about 1 hour. The dark brown mixture was heated to 90°C and stirred at 90°C for 1 hour. Then the cyclopropyl methanol was distilled off under reduced pressure and methylene chloride (100 ml) was added to the residue. The mixture was stirred for about 30 min, then filtered and concentrated, yielding 9.5 g of crude material.
Råmaterialet ble renset ved flash-kromatografi på silisium-dioksyd med metylenklorid-metanol (90-10) som eluerings-middel, hvilket ga 4,0 g (53 #) ren tittelforbindelse. NMR-data er angitt nedenfor. The crude material was purified by flash chromatography on silica eluting with methylene chloride-methanol (90-10) to give 4.0 g (53#) of pure title compound. NMR data are given below.
Eksempel I 2 Example I 2
Fremstilling av 2- acetoksymetyl- 4- cyklopropylmetoksypyridin Preparation of 2-acetoxymethyl-4-cyclopropylmethoxypyridine
4-cyklopropylmetoksy-2-metylpyridin-l-oksyd (3,8 g 0,021 mol) ble oppløst i eddiksyreanhydrid (10 ml) og ble tilsatt dråpevis til eddiksyreanhydrid (20 ml) (oppvarmet til 90°C). Etter tilsetningen ble temperaturen hevet til 110°C og blandingen ble omrørt ved 110°C i 1 time og deretter ble oppløsningsmidlet avdestillert og råproduktet ble benyttet uten rensing. NMR-data er angitt nedenfor. 4-Cyclopropylmethoxy-2-methylpyridine-1-oxide (3.8 g 0.021 mol) was dissolved in acetic anhydride (10 ml) and was added dropwise to acetic anhydride (20 ml) (heated to 90°C). After the addition, the temperature was raised to 110°C and the mixture was stirred at 110°C for 1 hour and then the solvent was distilled off and the crude product was used without purification. NMR data are given below.
Eksempel I 3 Example I 3
Fremstilling av 4- cyklopropylmetoksy- 2- hydroksymetylpyridin Preparation of 4-cyclopropylmethoxy-2-hydroxymethylpyridine
Til 2-acetoksymetyl-4-cyklopropylmetoksypyridin-råmateriale ble NaOH (100 ml 2 M) tilsatt og blandingen ble tilbakeløps-kokt i 2 timer. Blandingen ble ekstrahert med metylenklorid og fasene ble separert. Det organiske laget ble tørket med Na2S04, filtrert og oppløsningsmidlet inndampet, hvilket ga 2,7 g uren tittelforbindelse. NMR-data er angitt nedenfor. Råproduktet ble benyttet uten ytterligere rensing. To 2-acetoxymethyl-4-cyclopropylmethoxypyridine raw material, NaOH (100 ml 2 M) was added and the mixture was refluxed for 2 hours. The mixture was extracted with methylene chloride and the phases were separated. The organic layer was dried with Na 2 SO 4 , filtered and the solvent evaporated to give 2.7 g of crude title compound. NMR data are given below. The crude product was used without further purification.
Eksempel I 4 Example I 4
Fremstilling av 4-cyklopropylmetoksy-2-klormetylpyridin-hydroklorid Preparation of 4-cyclopropylmethoxy-2-chloromethylpyridine hydrochloride
4-cyklopropylmetoksy-2-hydroksymetylpyridin (93 % ren) (0,9 g 0,0046 mol) ble oppløst i metylenklorid (10 ml) og avkjølt til 0°C. S0C12 (0,5 ml, 0,0069 mol) i metylenklorid (5 ml) 4-Cyclopropylmethoxy-2-hydroxymethylpyridine (93% pure) (0.9 g 0.0046 mol) was dissolved in methylene chloride (10 mL) and cooled to 0°C. SOCl2 (0.5 mL, 0.0069 mol) in methylene chloride (5 mL)
ble tilsatt dråpevis ved 0°C og reaksjonsblandingen ble omrørt i 15 min ved romtemperatur. Isopropanol (0,5 ml) ble tilsatt og blandingen ble inndampet hvilket ga det ønskede produkt (0,68 g, 78 <&). NMR-data er angitt nedenfor. was added dropwise at 0°C and the reaction mixture was stirred for 15 min at room temperature. Isopropanol (0.5 ml) was added and the mixture was evaporated to give the desired product (0.68 g, 78 <&). NMR data are given below.
Eksempel I 5 Example I 5
Fremstilling av 5-fluor-2-[[(4-cyklopropylmetoksy-2-pyridi-nyl)metyl )tio]-lE-benzimidazol benyttet som utgangsmateriale Til 5-fluor-2-merkapto-lH-benzimidazol (0,88 g, 0,0051 mol) i metanol (25 ml) ble det tilsatt NaOE (0,2 g, 0,0051 mol) oppløst i H2O (1 ml) og 4-cyklopropylmetoksy-2-klormetyl-pyridinhydroklorid (0,91 g, 0,0046 mol) oppløst i metanol (10 ml), i den angitte rekkefølge. Blandingen ble oppvarmet til koking og NaOH (0,2 g, 0,005 mol) oppløst i H20 (1 ml) ble tilsatt og blandingen ble tilbakeløpskokt i 1 time. Etter inndamping av metanol så ble CH2CI2 (75 ml) og H2O (50 ml) tilsatt og pH-verdien justert til 10. Blandingen ble sterkt omrørt, fasene ble separert, den organiske fasen ble tørket over Na2SC>4 og inndampet hvilket ga det ønskede produkt (1,25 g, 72 #). NMR-data for produktet er angitt nedenfor. Preparation of 5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl)thio]-1H-benzimidazole used as starting material To 5-fluoro-2-mercapto-1H-benzimidazole (0.88 g, 0.0051 mol) in methanol (25 mL) was added NaOE (0.2 g, 0.0051 mol) dissolved in H2O (1 mL) and 4-cyclopropylmethoxy-2-chloromethyl-pyridine hydrochloride (0.91 g, 0 .0046 mol) dissolved in methanol (10 mL), in the order indicated. The mixture was heated to boiling and NaOH (0.2 g, 0.005 mol) dissolved in H 2 O (1 mL) was added and the mixture was refluxed for 1 hour. After evaporation of methanol, CH2CI2 (75 ml) and H2O (50 ml) were added and the pH adjusted to 10. The mixture was stirred vigorously, the phases were separated, the organic phase was dried over Na2SC>4 and evaporated to give the desired product (1.25g, 72#). NMR data for the product is given below.
Den beste utnyttelsen av oppfinnelsen som i øyeblikket er kjent er anvendelse av natriumsaltet av forbindelse I, det vil si forbindelsen som er beskrevet i eksempel 2. The best utilization of the invention currently known is the use of the sodium salt of compound I, i.e. the compound described in example 2.
Farmasøytiske preparater inneholdene forbindelse I som aktiv bestanddel er illustrert i de følgende formuleringer. Pharmaceutical preparations containing compound I as active ingredient are illustrated in the following formulations.
Sirup Syrup
En sirup inneholdene 1 % (vekt pr volum) av aktiv substans ble fremstilt fra følgende bestanddeler: A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
Sukker og sakkarin ble oppløst i 60 g varmt vann. Etter avkjøling ble den aktive forbindelsen tilsatt til sukker-oppløsningen og glyserol og en oppløsning av aromamidler oppløst i etanol ble tilsatt. Blandingen ble fortynnet med vann til et sluttvolum på 100 ml. Sugar and saccharin were dissolved in 60 g of warm water. After cooling, the active compound was added to the sugar solution and glycerol and a solution of flavoring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.
Enterisk belagte tabletter Enteric coated tablets
En enterisk belagt tablett inneholdene 5 0 mg aktiv forbindelse ble fremstilt fra følgende bestanddeler: An enteric-coated tablet containing 50 mg of active compound was prepared from the following ingredients:
I Forbindelsen ifølge eksempel 1, pulver, ble blandet med laktose og granulert med en vannoppløsning av metyl-cellulose og natriumkarbonat. Den våte massen ble presset gjennom en sikt og granulatet tørket i en ovn. Etter I The compound according to example 1, powder, was mixed with lactose and granulated with an aqueous solution of methyl cellulose and sodium carbonate. The wet mass was pressed through a sieve and the granules dried in an oven. After
tørking ble granulatet blandet med polyvinylpyrrolidon og magnesiumstearat. Den tørre blandingen ble presset til drying, the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was pressed
tablettkjerner (10 000 tabletter), idet hver tablett inneholdt 50 mg aktiv substans, i en tableteringsmaskin ved bruk av stanser av en diameter på 7 mm. tablet cores (10,000 tablets), each tablet containing 50 mg of active substance, in a tableting machine using punches of a diameter of 7 mm.
II En oppløsning av celluloseacetatphtalat og cetylalkohol i isopropanol/metylenklorid ble sprøytet på tablettene I i et Accela Cota® Manesty-beleggningsutstyr. En sluttlig II A solution of cellulose acetate phthalate and cetyl alcohol in isopropanol/methylene chloride was sprayed onto the tablets I in an Accela Cota® Manesty coating equipment. A final one
tablettvekt på 110 mg ble oppnådd. tablet weight of 110 mg was obtained.
Oppløsning for intravenøs administrasjon Solution for intravenous administration
En parenteral formulering for intravenøs bruk inneholdene 4 mg aktiv forbindelse pr ml ble fremstilt fra følgende bestanddeler: A parenteral formulation for intravenous use containing 4 mg of active compound per ml was prepared from the following ingredients:
Den aktive forbindelsen ble oppløst i vann til et sluttvolum på 1000 ml. Oppløsningen ble filtrert gjennom et 0,22 jjm filter og umiddelbart fordelt i 10 ml sterile ampuller. Ampullene ble forseglet. The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a 0.22 µm filter and immediately dispensed into 10 ml sterile vials. The ampoules were sealed.
Kapsler Capsules
Kapsler inneholdene 30 mg aktiv forbindelse ble fremstilt fra følgende bestanddeler: Capsules containing 30 mg of active compound were prepared from the following ingredients:
Den aktive forbindelsen ble blandet med de tørre bestand-delene og granulert med en oppløsning av dinatriumhydrogen-fosfat. Den våte massen ble presset gjennom en ekstruder og sferonisert og tørket i en virvelsjikttørker. The active compound was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate. The wet mass was pressed through an extruder and spheronized and dried in a fluid bed dryer.
500 g av de ovenfor oppnådde pellets ble først belagt med en oppløsning av hydroksypropylmetylcellulose, 30 g, i vann, 750 g, ved bruk av en virvelsj ikt-beleggningsanordning. Etter tørking ble pelletene belagt med et annet belegg som angitt nedenfor: 500 g of the pellets obtained above were first coated with a solution of hydroxypropylmethylcellulose, 30 g, in water, 750 g, using a fluid bed coater. After drying, the pellets were coated with another coating as indicated below:
Beleggningsoppløsning: Coating resolution:
De sluttlige belagte pelletene ble fylt i kapsler. The final coated pellets were filled into capsules.
Suppositorier Suppositories
Suppositorier ble fremstilt fra følgende bestanddeler ved bruk av en sveisemetode. Hvert suppositorium inneholdt 40 mg aktiv forbindelse. Suppositories were prepared from the following ingredients using a welding method. Each suppository contained 40 mg of active compound.
Den aktive forbindelsen ble blandet homogent med Witepsol H-15 ved en temperatur på 41°C. Den smeltede massen ble volumfylt i på forhånd fremstilte suppositoriumpakninger til en nettovekt på 1,84 g. Etter avkjøling ble pakningene varmeforseglet. Hvert suppositorium inneholdt 40 mg aktiv forbindelse. The active compound was mixed homogeneously with Witepsol H-15 at a temperature of 41°C. The molten mass was volume filled into pre-made suppository packs to a net weight of 1.84 g. After cooling, the packs were heat sealed. Each suppository contained 40 mg of active compound.
Biologiske effekter Biological effects
Biotilgjengelighet Bioavailability
Valg av arter for testing. Selection of species for testing.
Resultatene fra tester på to forskjellige dyrearter, rotte og hund, varierer med hensyn til målt nivå av biotilgjengelighet for den samme forbindelsen. Det antas at rotten er den mer relevante art for testing av biotilgjengelighet. Dette er basert på den antagelse at levermetabolisme har den mest dominerende virkning på biotilgjengelighet, og at det levermetaboliske mønster i mennesket for denne type av forbindelser er temmelig lik det til hannrotten (mer enn for hunnrotten og hunden). Testresultater for biotilgjengelighet i hannrotten vil dessuten ha tilbøyelighet til å gi en bredere "spredning" sammenlignet med testresultatene i hunn, og således vil hannrottemodellen gi klarere forskjeller i biotilgjengelighet mellom forskjellige forbindelser. Sagt på en annen måte så kan biotilgjengeligheten slik den er testet i hannrotten forventes å gi en bedre vurdering av de relative forskjeller i mennesket mellom forskjellige testforbindelser sammenlignet med testresultatene oppnådd ved bruk av de samme forbindelsene i hund. The results of tests on two different animal species, rat and dog, differ with respect to the measured level of bioavailability for the same compound. It is believed that the rat is the more relevant species for bioavailability testing. This is based on the assumption that hepatic metabolism has the most dominant effect on bioavailability, and that the hepatic metabolic pattern in humans for this type of compound is quite similar to that of the male rat (more so than for the female rat and dog). Test results for bioavailability in the male rat will also tend to give a wider "spread" compared to the test results in the female, and thus the male rat model will give clearer differences in bioavailability between different compounds. Put another way, the bioavailability as tested in the male rat can be expected to give a better assessment of the relative differences in humans between different test compounds compared to the test results obtained using the same compounds in dogs.
Bestemmelse av biotilgjengelighet. Determination of bioavailability.
Biotilgjengelighet bestemmes ved å beregne kvotienten mellom arealet under plasmakonsentrasjonskurven (AUC) etter intraduodenal (id) administrasjon og intravenøs (iv) administrasjon fra rotte eller hund. Lave, terapeutisk relevante doser ble benyttet. Denne metoden er vitenskapelig anerkjent som effektiv for bestemmelse av biotilgjengelighet (se for eksempel: M. Rowland og T. N. Tozer, Clinical Pharmacokinetics, 2. utg., Lea & Febiger, London 1989, side 42). Dataene fra både rotte og hund er angitt i tabell 3. Bioavailability is determined by calculating the quotient between the area under the plasma concentration curve (AUC) after intraduodenal (id) administration and intravenous (iv) administration from rats or dogs. Low, therapeutically relevant doses were used. This method is scientifically recognized as effective for determining bioavailability (see for example: M. Rowland and T.N. Tozer, Clinical Pharmacokinetics, 2nd ed., Lea & Febiger, London 1989, page 42). The data from both rat and dog are given in Table 3.
Grov screeningmodell. Rough screening model.
Siden biotilgjengelighetsmodellen som er beskrevet ovenfor er tids- og arbeidskrevende og nødvendiggjør et stort antall plasmanalyser, så har også en grov screeningmodell, basert på relative virkningsgrader for inhibering av syresekresjon, blitt benyttet (se for eksempel: A. Goth, Medical Pharma-cology, 7. utg., C. V. Mosby Company, Saint Louis 1974, side 19). Forholdet (betegnet "biotilgjengelighet" i tabell 3) mellom ED50 ved intravenøs administrasjon og ED50 ved intraduodenal administrasjon ble således beregnet. Disse data er også angitt i tabell 3. Since the bioavailability model described above is time- and labor-consuming and necessitates a large number of plasma analyses, a rough screening model, based on relative degrees of effectiveness for inhibiting acid secretion, has also been used (see for example: A. Goth, Medical Pharmacology, 7th ed., C. V. Mosby Company, Saint Louis 1974, page 19). The ratio (designated "bioavailability" in Table 3) between the ED50 by intravenous administration and the ED50 by intraduodenal administration was thus calculated. These data are also shown in table 3.
Virkningsgrad Efficiency
Virkningsgraden for inhibering av syresekresjon har blitt målt i hannrotte og hund, både intravenøst og intraduodenalt. Når det gjelder relevansen av de animalske forsøksdata for virkningsgrad til en gitt forbindelse i mennesket for forbindelser av type I, så antas det at virkningsgrad i mennesket vil tilsvare et nivå et eller annet sted mellom det som måles i hannrotte og det som måles i hund. Data for virkningsgrad fra de to dyreartene er angitt i tabell 3. The degree of effectiveness for inhibition of acid secretion has been measured in male rats and dogs, both intravenously and intraduodenally. When it comes to the relevance of the animal test data for efficacy of a given compound in humans for compounds of type I, it is assumed that efficacy in humans will correspond to a level somewhere between that measured in male rats and that measured in dogs. Data for efficiency from the two animal species are shown in table 3.
Biologiske forsøk Biological experiments
Inhibering av mavesyresekresjon i bevisst hannrotte. Inhibition of gastric acid secretion in the conscious male rat.
Hannrotter av Sprague-Dawley-stammen ble benyttet. De ble utstyrt med kanylerør i maven (lumen) og den øvre delen av duodenum, for oppsamling av gastriske sekresjoner og administrasjon av testsubstanser, respektivt. Det ble gitt adgang til en fjorten dagers rekonvalesensperiode etter inngrep før testing begynte. Male rats of the Sprague-Dawley strain were used. They were equipped with cannula tubes in the stomach (lumen) and the upper part of the duodenum, for collection of gastric secretions and administration of test substances, respectively. A fourteen-day post-operative convalescence period was allowed before testing began.
Før sekretoriske tester ble dyrene holdt borte fra mat, men ikke vann, i 20 timer. Maven ble gjentatte ganger vasket gjennom mavekanylen og 6 ml Ringer-glykose ble gitt s.c. Syresekresjon ble stimulert med en infusjon i løpet av 3,5 timer (1,2 ml/time, s.c.) av pentagastrin og carbachol (20 og 110 nmol/kg time, respektivt), og i løpet av denne tiden ble gastriske sekresjoner oppsamlet i 30 minutters fraksjoner. Testsubstanser eller bærer ble gitt iv eller id ved 90 min etter starten av stimuleringen, i et volum på 1 ml/kg. Mavesaftprøver ble titrert til pH 7,0 med NaOH, 0,1 mol/l, og syreproduksjon beregnet som produktet av titreringsmiddel-volum og konsentrasjon. Ytterligere beregninger ble basert på gruppe-middelresponser fra 4-5 rotter. Syreproduksjonen i løpet av periodene etter administrasjon av testsubstanser eller bærer ble uttrykt som fraksjonsresponser, idet syreproduksjonen i 30 min perioden forut for administrasjon ble satt til 1,0. Prosentvis inhibering ble beregnet fra fraksjonsresponsene som ble utløst av testforbindelse og bærer. ED50 verdier ble oppnådd fra grafisk interpolasjon på log dose-responskurver, eller bestemt fra enkeltdoseforsøk ved å anta en lignende helling for alle dose-responskurver. Et anslag over biotilgjengeligheten ble oppnådd ved beregning av forholdet ED5Q iv/EDsg id. De rapporterte resultatene er basert på mavesyresekresjon i løpet av den andre timen etter legemiddel/bærer-administråsjon.. Before secretory tests, the animals were deprived of food, but not water, for 20 hours. The stomach was repeatedly washed through the gastric cannula and 6 ml of Ringer's glucose was given s.c. Acid secretion was stimulated by an infusion over 3.5 h (1.2 ml/h, s.c.) of pentagastrin and carbachol (20 and 110 nmol/kg h, respectively), during which gastric secretions were collected in 30 minute fractions. Test substances or vehicle were given iv or id at 90 min after the start of the stimulation, in a volume of 1 ml/kg. Gastric juice samples were titrated to pH 7.0 with NaOH, 0.1 mol/l, and acid production calculated as the product of titrant volume and concentration. Further calculations were based on group mean responses from 4-5 rats. The acid production during the periods after administration of test substances or carrier was expressed as fractional responses, with the acid production in the 30 min period preceding administration being set to 1.0. Percent inhibition was calculated from the fractional responses elicited by test compound and vehicle. ED50 values were obtained from graphical interpolation of log dose-response curves, or determined from single-dose experiments by assuming a similar slope for all dose-response curves. An estimate of the bioavailability was obtained by calculating the ratio ED5Q iv/EDsg id. The reported results are based on gastric acid secretion during the second hour after drug/vehicle administration.
Biotilgjengelighet i hannrotte. Bioavailability in the male rat.
Voksne hannrotter av Sprague-Dawley-stammen ble benyttet. En dag før forsøkene ble alle rottene forsynt med kanyle på den venstre halspulsåren under bedøvelse. Rottene som ble benyttet for de intravenøse forsøkene ble også utstyrt med kanyle i halsvenen. (Ref. V. Popovic og P. Popovic, J. Appl. Physiol. 1960; 15, 727-728). Rottene som ble benyttet for de intraduodenale forsøkene ble også utstyrt med kanyle i den øvre delen av duodenum. Kanylene ble lagt utvendig ved halsgropen. Rottene ble oppbevart individuelt etter inngrep og ble holdt borte fra mat, men ikke vann, før administrasjon av testsubstansene. Den samme dosen (4 pmol/kg) ble gitt iv og id som en bolus i ca 1 minutt (2 ml/kg). Adult male rats of the Sprague-Dawley strain were used. One day before the experiments, all rats were cannulated on the left carotid artery under anesthesia. The rats used for the intravenous experiments were also provided with a cannula in the jugular vein. (Ref. V. Popovic and P. Popovic, J. Appl. Physiol. 1960; 15, 727-728). The rats used for the intraduodenal experiments were also provided with a cannula in the upper part of the duodenum. The needles were placed externally at the pit of the neck. The rats were kept individually after intervention and were kept away from food, but not water, before administration of the test substances. The same dose (4 pmol/kg) was given iv and id as a bolus for about 1 minute (2 ml/kg).
Blodprøver (0,1-0,4 g) ble trukket gjentatte ganger fra halspulsåren ved intervaller på opp til 4 timer etter gitt dose. Prøvene ble frosset så snart som mulig inntil analyse av testforbindelsen. Blood samples (0.1-0.4 g) were drawn repeatedly from the carotid artery at intervals of up to 4 hours after the given dose. The samples were frozen as soon as possible until analysis of the test compound.
Arealet under kurven for blodkonsentrasjon mot tid, AUC, ble bestemt ved hjelp av den lineære trapesregelen og ekstrapolert til uendelig ved å dividere den sist bestemte blodkonsentrasjonen med elimineringshastighetskonstanten i den avsluttende fasen. Den systemiske biotilgjengelighet (F %) etter intraduodenal administrasjon ble beregnet som The area under the blood concentration versus time curve, AUC, was determined using the linear trapezoidal rule and extrapolated to infinity by dividing the last determined blood concentration by the terminal phase elimination rate constant. The systemic bioavailability (F%) after intraduodenal administration was calculated as
Inhibering av mavesyresekresjon og biotilgjengelighet i bevisst hund. Inhibition of gastric acid secretion and bioavailability in the conscious dog.
Harrier-hunder av begge kjønn ble benyttet. De ble utstyrt med et duodenalrør for administrasjon av testforbindelser eller bærer og et ventrikulært kanylerør for oppsamling av gastriske sekresjoner. Harrier dogs of both sexes were used. They were fitted with a duodenal tube for administration of test compounds or vehicle and a ventricular cannula for collection of gastric secretions.
Før sekresjonstestene ble dyrene fastet i ca 18 timer, men ble gitt fri adgang til vann. Mavesyresekresjon ble stimulert ved en 4 timers infusjon av histamindihydroklorid (12 ml/time) ved en dose som ga ca 80 % av den individuelle maksimale sekretoriske respons, og mavesyre oppsamlet i etter hverandre følgende 30 minutters fraksjoner. Testsubstans eller bærer ble gitt id eller iv 1 time etter starten av histamininfusjonen, i et volum på 0,5 ml/kg kroppsvekt. Surheten til mavesaftprøvene ble bestemt ved titrering til pE 7,0 og syreproduksjonen ble beregnet. Syreproduksjonen i oppsamlingsperiodene etter administrasjon av testsubstans eller bærer ble uttrykt som fraksjonsresponser, idet syreproduksjonen i fraksjonen forut for administrasjon ble satt til 1,0. Before the secretion tests, the animals were fasted for about 18 hours, but were given free access to water. Gastric acid secretion was stimulated by a 4 hour infusion of histamine dihydrochloride (12 ml/hour) at a dose giving approximately 80% of the individual maximum secretory response, and gastric acid collected in successive 30 minute fractions. Test substance or vehicle was given id or iv 1 hour after the start of the histamine infusion, in a volume of 0.5 ml/kg body weight. The acidity of the gastric juice samples was determined by titration to pE 7.0 and the acid production was calculated. The acid production in the collection periods after administration of the test substance or carrier was expressed as fraction responses, the acid production in the fraction prior to administration being set to 1.0.
Prosentvis inhibering ble beregnet fra fraksjonsresponser utløst av testforbindelse og bærer. ED5Q verdier ble oppnådd ved grafisk interpolasjon på log dose-responskurver eller bestemt fra enkeltdoseforsøk under antakelse av den samme helling på dose-responskurven for alle testforbindelser. Alle rapporterte resultater er basert på syreproduksjon 2 timer etter dosering. Percent inhibition was calculated from fractional responses elicited by test compound and vehicle. ED5Q values were obtained by graphical interpolation on log dose-response curves or determined from single-dose experiments assuming the same slope of the dose-response curve for all test compounds. All reported results are based on acid production 2 hours after dosing.
Blodprøver for analyse av konsentrasjon av testforbindelse i plasma ble tatt ved intervaller på opp til 3 timer etter dosering. Plasma ble separert og frosset innen 30 minutter etter oppsamling. AUC (areal under kurven for plasmakonsen-trasjon - tid), ekstrapolert til uendelig tid, ble beregnet ved hjelp av den lineære trapesregelen. Den systemiske biotilgjengelighet (F %) etter id administrasjon ble beregnet som 100 x (AUCid/AUCiv). Blood samples for analysis of test compound concentration in plasma were taken at intervals of up to 3 hours after dosing. Plasma was separated and frozen within 30 minutes of collection. AUC (area under the plasma concentration-time curve), extrapolated to infinite time, was calculated using the linear trapezoidal rule. The systemic bioavailability (F%) after id administration was calculated as 100 x (AUCid/AUCiv).
Kjemisk stabilitet Chemical stability
Den kjemiske stabiliteten til forskjellige forbindelser fremstilt ifølge oppfinnelsen ble fulgt kinetisk ved lav konsentrasjon ved 37"C i vandig bufferoppløsning ved forskjellige pH-verdier. Resultatene i tabell 3 viser halveringstiden (t Vi) ved pE 7, det vil si tidsperioden etter hvilken halve mengden av de opprinnelige forbindelsene forblir uendret. The chemical stability of various compounds prepared according to the invention was followed kinetically at low concentration at 37"C in aqueous buffer solution at different pH values. The results in table 3 show the half-life (t Vi) at pE 7, that is, the time period after which half the amount of the original compounds remains unchanged.
Resultater av biologiske og stabilitetstester Results of biological and stability tests
Tabell 3 gir en sammenfatning av de testdata som er til-gjengelige for forbindelse I og en strukturelt nær beslektet forbindelse som generisk er beskrevet i den tidligere teknikk, betegnet Ref. i tabell 3, nemlig 5-fluor-2-[[(4-isopropoksy-2-pyridinyl )metyl] sulf inyl] -lH-benzimidazol beskrevet i US 4.727.150. Som det fremgår fra tabell 3 har forbindelse I en høy biotilgjengelighet (F = 82 % i rotte), høy virkningsgrad (EDsgiv =1,2 pmol/kg, EDsgid =2,2 pmol/kg i rotte) og høy kjemisk stabilietet (t Yz = 23 timer). Ved å betrakte den mest fremtredene egenskap for forbindelse I, biotilgjengeligheten, har dessuten forbindelse I en mye høyere verdi (82 % mot 31 %) sammenlignet med den til Ref.-forbindelsen, og er også bedre når det gjelder de andre egenskapene (EDsgiv = 1,8 pmol/kg, EDsgid = 4,0 jjmol/kg og t Yi = 14 timer for Ref.-forbindelsen). Table 3 provides a summary of the test data available for compound I and a structurally closely related compound generically described in the prior art, designated Ref. in Table 3, namely 5-fluoro-2-[[(4-isopropoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole described in US 4,727,150. As can be seen from table 3, compound I has a high bioavailability (F = 82% in the rat), high efficiency (EDsgiv =1.2 pmol/kg, EDsgid =2.2 pmol/kg in the rat) and high chemical stability (t Yz = 23 hours). Moreover, considering the most prominent property of compound I, the bioavailability, compound I has a much higher value (82% vs. 31%) compared to that of the Ref. compound, and is also better in terms of the other properties (EDsgiv = 1.8 pmol/kg, EDsgid = 4.0 jjmol/kg and t Yi = 14 hours for the Ref. compound).
Claims (6)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE19888804628A SE8804628D0 (en) | 1988-12-22 | 1988-12-22 | NEW COMPOUNDS |
| SE19888804629A SE8804629D0 (en) | 1988-12-22 | 1988-12-22 | NEW THERAPEUTICALLY ACTIVE COMPOUNDS |
| PCT/SE1989/000740 WO1990006925A1 (en) | 1988-12-22 | 1989-12-20 | New therapeutically active compound and a process for its preparation |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO912415D0 NO912415D0 (en) | 1991-06-20 |
| NO912415L NO912415L (en) | 1991-08-06 |
| NO178337B true NO178337B (en) | 1995-11-27 |
| NO178337C NO178337C (en) | 1996-03-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO912415A NO178337C (en) | 1988-12-22 | 1991-06-20 | Analogous Process for Preparing Therapeutically Active 5-Fluoro-2 [[(4-Cyclopropyl- (methoxy-2-pyridinyl) methyl] sulfinylA-1H-benzimidazole and intermediates |
Country Status (1)
| Country | Link |
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| NO (1) | NO178337C (en) |
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1991
- 1991-06-20 NO NO912415A patent/NO178337C/en unknown
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| Publication number | Publication date |
|---|---|
| NO912415D0 (en) | 1991-06-20 |
| NO912415L (en) | 1991-08-06 |
| NO178337C (en) | 1996-03-06 |
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