NO311673B1 - Phenyl-oxo-alkyl (4-piperidinyl) benzoate - Google Patents
Phenyl-oxo-alkyl (4-piperidinyl) benzoate Download PDFInfo
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- NO311673B1 NO311673B1 NO19971375A NO971375A NO311673B1 NO 311673 B1 NO311673 B1 NO 311673B1 NO 19971375 A NO19971375 A NO 19971375A NO 971375 A NO971375 A NO 971375A NO 311673 B1 NO311673 B1 NO 311673B1
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- 150000001875 compounds Chemical class 0.000 claims description 103
- -1 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidyl-4-amino-5-chloro-2,3-dihydro-7 -benzofurancarboxylate Chemical compound 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 22
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- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 210000001072 colon Anatomy 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
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- 238000002360 preparation method Methods 0.000 claims description 13
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- 230000004899 motility Effects 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
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- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
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- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Description
Foreliggende oppfinnelse vedrører nye benzoatderivater, farmasøytiske sammensetninger omfattende de nye forbindelser, fremgangsmåter ved fremstilling av forbindelsene og sammensetningene og anvendelse derav som medisin, spesielt for behandling av tilstander som involverer en redusert motilitet i colon. The present invention relates to new benzoate derivatives, pharmaceutical compositions comprising the new compounds, methods for producing the compounds and compositions and their use as medicine, especially for the treatment of conditions involving a reduced motility in the colon.
I vår EP-0.389-037-A, publisert 26. september 1990, er det beskrevet N- (3-hydroksy-4-piperidinyl) (dihydrobenzofuran eller dihydro-2H-benzopyran) karboksamidderivater med gastrointestinal motilitets-stimulerende egenskaper. I vår EP-0.445.852-A, publisert 11. september 1991, er det beskrevet N- (4-piperidinyl) (dihydrobenzofuran eller dihydro-2H-benzo-pyran) karboksamidderivater som også har gastrointestinal motilitets-stimulerende egenskaper. WO 93/03725 (SmithKline Beecham), publisert 4. mars 1993, viser generisk anvendelse som 5HT4-reseptorantagonister av estere med generell formel X-CO-Y-Z, hvori X kan være et substituert fenyl, Y kan være oksygen og Z kan være en substtuert piperidingruppe. W094/- 08995 (SmithKline Beecham), publisert 28. april 1994, beskriver generisk f.eks. substituert 7-benzofuran-karbok-sylater som også har 5HT4-antagonistisk aktivitet. De to siste patentsøknader beskriver anvendelsen av 5HT4-anta-gonistiske forbindelser ved behandling av irritabel-tarm - syndrom (IBS), spesielt diaréaspektene ved IBS. In our EP-0,389-037-A, published September 26, 1990, N-(3-hydroxy-4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxamide derivatives with gastrointestinal motility stimulating properties are described. In our EP-0,445,852-A, published September 11, 1991, N-(4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxamide derivatives are described which also have gastrointestinal motility stimulating properties. WO 93/03725 (SmithKline Beecham), published March 4, 1993, discloses the generic use as 5HT4 receptor antagonists of esters of the general formula X-CO-Y-Z, wherein X may be a substituted phenyl, Y may be oxygen and Z may be a substituted piperidine group. W094/- 08995 (SmithKline Beecham), published April 28, 1994, generically describes e.g. substituted 7-benzofuran-carboxylates which also have 5HT4-antagonistic activity. The last two patent applications describe the use of 5HT4-antagonistic compounds in the treatment of irritable bowel syndrome (IBS), especially the diarrheal aspects of IBS.
Uventet er det blitt funnet at de nye forbindelsene utviser intestinal prokinetisk aktivitet. Følgelig er det i det foreliggende vist forbindelser som er anvendelige ved behandling av tilstander som involverer en redusert motilitet i tarmene, spesielt i colon. Unexpectedly, the new compounds have been found to exhibit intestinal prokinetic activity. Accordingly, disclosed herein are compounds useful in the treatment of conditions involving a reduced motility in the intestines, particularly in the colon.
Den foreliggende oppfinnelse vedører nye benzoatderivater med formel The present invention relates to new benzoate derivatives with formula
W-oksid-formene, farmasøytisk akseptable syreaddisjonssalter og de stereokjemisk isomere former derav, hvori R<1> er halogen eller C^alkylsulfonylamino, The W-oxide forms, pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R<1> is halogen or C 1-4 alkylsulfonylamino,
enten er R<2> hydrogen og R<3> er C^alkyl, C2.6alkenyl eller C2.6alkynyl; eller either R<2> is hydrogen and R<3> is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; or
R<2> og R3 danner sammen et bivalent radikal med formelen: R<2> and R3 together form a bivalent radical with the formula:
hvori ett eller to hydrogenatomer i de bivalente radikaler med formel (a), (b) eller (c) kan erstattes med Ci.galkyl ; Alk er C-^alkandiyl ; R* er hydrogen eller C^alkyloksy; R<5>, R6 og R<7> er uavhengig av hverandre hydrogen, halogen, C^alkyl, C^alkyloksy; eller R5 og R<6> danner sammen et bivalent radikal med formelen in which one or two hydrogen atoms in the bivalent radicals of formula (a), (b) or (c) can be replaced by C 1-6 alkyl; Alk is C 1-6 alkanediyl; R* is hydrogen or C 1-6 alkyloxy; R<5>, R6 and R<7> are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkyloxy; or R5 and R<6> together form a bivalent radical with the formula
R<8> og R<9> er uavhengig av hverandre hydrogen eller C^.g-alkyl; R<8> and R<9> are independently hydrogen or C 1-6 alkyl;
R<10> er hydrogen, C^alkylkarbonyl, C^alkyloksykarbonyl; og m er 1 eller 2. R<10> is hydrogen, C1-4 alkylcarbonyl, C1-4 alkyloxycarbonyl; and m is 1 or 2.
Som anvendt i de ovennevnte definisjoner og i det følgende, er halogen generisk for fluor, klor, brom og jod; C^alkyl definerer rettkjedede og forgrenede mettede hydrokarbonradikaler med 1-6 karbonatomer, såsom metyl, etyl, propyl, butyl, pentyl, heksyl, 1-metyletyl, 2-metylpropyl og lignende; C2.6alkenyl definerer rettkjedede forgrenede hydrokarbonradikaler inneholdende en dobbelbinding og med 2-6 karbonatomer, såsom etenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-metyl-2-butenyl, 3-heksenyl og lignende; C2.6alkynyl definerer rettkjedede og forgrenede hydrokarbonradikaler inneholdende en trippelbin-ding og 2-6 karbonatomer, såsom etynyl, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-heksynyl og lignende; C^-alkandiyl definerer bivalente rettkjedede eller forgrenede hydrokarbonradikaler inneholdende 1-6 karbonatomer, såsom metylen, 1,2-etandiyl, 1,3-propandiyl, 1,4-butandiyl, 1,5-pentandiyl, 1,6-heksandiyl. As used in the above definitions and in the following, halogen is generic for fluorine, chlorine, bromine and iodine; C 1-6 alkyl defines straight-chain and branched saturated hydrocarbon radicals of 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl and the like; C2.6alkenyl defines straight-chain branched hydrocarbon radicals containing a double bond and with 2-6 carbon atoms, such as ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3- hexenyl and the like; C2.6alkynyl defines straight-chain and branched hydrocarbon radicals containing a triple bond and 2-6 carbon atoms, such as ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-hexynyl and the like; C 1 -alkanediyl defines bivalent straight chain or branched hydrocarbon radicals containing 1-6 carbon atoms, such as methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl.
De farmasøytisk akseptable syreaddisjonssalter som nevnt ovenfor er ment å omfatte de terapeutisk aktive ikke-tok-siske syreaddisjonssaltformer som forbindelser med formel (I) evner å danne. Sistnevnte kan hensiktsmessig erholdes ved å behandle baseformen med passende syre. Passende syre omfatter f.eks. uorganiske syrer som hydrohalosyrer, f.eks. salt- eller hydrobromsyre; svovelsyre; salpetersyre; fos-forsyre og lignende syrer; eller organiske syrer såsom eddiksyre, propansyre, hydroksyeddiksyre, melkesyre, pyro-vinsyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumar-syre, eplesyre, vinsyre, sitronsyre, metansulfonsyre, etan-sulfonsyre, benzensul f onsyre, p-toluensul f onsyre, cyklam-syre, salisylsyre, p-aminsalisylsyre, pamoasyre og lignende syrer. Uttrykket addisjonssalt som anvendt ovenfor, omfatter også solvatene som forbindelsene med formel (I) samt salter derav er istand til å danne. Slike solvatene er f.eks. hydrater, alkoholater og lignende. Motsatt kan salt-formen omsettes til den frie baseform ved behandling med alkali. The pharmaceutically acceptable acid addition salts mentioned above are intended to include the therapeutically active non-toxic acid addition salt forms which compounds of formula (I) are capable of forming. The latter can conveniently be obtained by treating the base form with a suitable acid. Suitable acid includes e.g. inorganic acids such as hydrohalo acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and similar acids; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyrotartaric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and similar acids. The term addition salt as used above also includes the solvates which the compounds of formula (I) and salts thereof are capable of forming. Such solvates are e.g. hydrates, alcoholates and the like. Conversely, the salt form can be converted to the free base form by treatment with alkali.
Uttrykket "stereokjemisk isomere former" som anvendt ovenfor, definerer alle mulige isomere former som forbindelsene med formel (I) kan ha. Hvis intet annet er nevnt eller antydet, betyr den kjemiske designering av forbindelsene blandingen av alle mulige stereokjemisk isomere former, hvilke blandinger inneholder alle diastereomere og enantiomere av den grunnleggende molekylstruktur. Mer spesielt kan stereogene sentre ha R- eller S-konfigurasjon; substituen-ter på bivalente cykliske (delvis) mettede radikaler kan ha enten cis- eller trans-konfigurasjonen og C2.6alkenylradi-kaler kan ha E- eller Z-konfigurasjon. Det er åpenbart hen-sikten at stereokjemisk isomere former av forbindelsen med formel (I) skal være omfattet av rammen for foreliggende oppfinnelse. The term "stereochemically isomeric forms" as used above defines all possible isomeric forms that the compounds of formula (I) may have. Unless otherwise stated or implied, the chemical designation of the compounds means the mixture of all possible stereochemically isomeric forms, which mixtures contain all diastereomers and enantiomers of the basic molecular structure. More specifically, stereogenic centers can have R or S configuration; substituents on bivalent cyclic (partially) saturated radicals can have either the cis or trans configuration and C2.6alkenyl radicals can have the E or Z configuration. It is obviously intended that stereochemically isomeric forms of the compound of formula (I) shall be included within the scope of the present invention.
Noen av forbindelsene med formel (I) kan også foreligge i sin tautomere form. Slike former er, selv om de ikke er eksplisitt indikert i formlene ovenfor, tiltenkt å være omfattet innenfor rammen for foreliggende oppfinnelse. For eksempel kan forbindelsene med formel (I) hvori R<5> og R<6 >sammen danner et bivalent radikal med formel (d) hvori R<8>, R<9> eller begge er hydrogen, foreligge i sin tilsvarende tau-tomere form. Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms, even if they are not explicitly indicated in the formulas above, are intended to be included within the scope of the present invention. For example, the compounds of formula (I) in which R<5> and R<6> together form a bivalent radical of formula (d) in which R<8>, R<9> or both are hydrogen can exist in their corresponding tau- tomer form.
N-oksidformene av forbindelsene med formel (I) er ment å omfatte de forbindelser av formel (I) hvori ett eller flere nitrogenatomer er oksidert til det såkalte W-oksid, spesielt de N-oksider hvor piperidin-nitrogener er W-oksidert. The N-oxide forms of the compounds of formula (I) are intended to include those compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called W-oxide, especially those N-oxides where piperidine nitrogens are W-oxidized.
R<1> er passende fluor, klor eller brom, fortrinnsvis er R<1 >klor; R<1> is suitably fluorine, chlorine or bromine, preferably R<1> is chlorine;
R<3> er når den ikke tas sammen med R<2>, passende et C^alkyl, fortrinnsvis metyl; R<3> when not taken together with R<2> is suitably a C 1-4 alkyl, preferably methyl;
når R<2> og R<3> tas sammen, er et bivalent radikal med formelen (b) foretrukket; when R<2> and R<3> are taken together, a bivalent radical of formula (b) is preferred;
Alk er passende 1,2-etandiyl, 1,3-propandiyl eller 1,4-butandiyl, fortrinnsvis 1,3-propandiyl; Alk is suitably 1,2-ethanediyl, 1,3-propanediyl or 1,4-butanediyl, preferably 1,3-propanediyl;
R<4> er passende hydrogen eller metoksy; R<4> is suitably hydrogen or methoxy;
R<5>, R6 og R<7> er passende hydrogen, C^alkyl, C^alkoksy eller klor, fortrinnsvis metyl, metoksy eller hydrogen; eller R<5>, R6 and R<7> are suitably hydrogen, C1-6 alkyl, C1-6 alkoxy or chlorine, preferably methyl, methoxy or hydrogen; or
når R<5> eller R<6> tas sammen er et bivalent radikal med formel (d) eller (e) foretrukket, spesielt et radikal med formelen (d). when R<5> or R<6> are taken together, a bivalent radical of formula (d) or (e) is preferred, especially a radical of formula (d).
Fordelaktige forbindelser med formel (I) er de forbindelser med formel (I) hvori R<1> er klor. Advantageous compounds of formula (I) are those compounds of formula (I) in which R<1> is chlorine.
Ytterligere fordelaktige forbindelser med formel (I) er de forbindelser med formel (I) hvori R<2> og R<3> sammen danner et bivalent radikal med formel (b). Further advantageous compounds of formula (I) are those compounds of formula (I) in which R<2> and R<3> together form a bivalent radical of formula (b).
Mer fordelaktige forbindelser er de forbindelsene hvori Alk er 1,3-propandiyl. More advantageous compounds are those compounds in which Alk is 1,3-propanediyl.
Foretrukne forbindelser er de mer interessante forbindelser hvori R<5>, R6 og R<7> er metoksy. Preferred compounds are the more interesting compounds in which R<5>, R6 and R<7> are methoxy.
Foretrukne forbindelser er også de mer interessante forbindelser hvori R<7> er hydrogen og R<5> og R<6> sammen danner et radikal med formel (d) hvori R<8> og R<9> er hydrogen. Preferred compounds are also the more interesting compounds in which R<7> is hydrogen and R<5> and R<6> together form a radical of formula (d) in which R<8> and R<9> are hydrogen.
Andre foretrukne forbindelser er de mer interessante forbindelser hvori R<5> og R<7> er metyl og R6 er metoksy. Other preferred compounds are the more interesting compounds in which R<5> and R<7> are methyl and R6 is methoxy.
De mest foretrukne forbindelser er: The most preferred compounds are:
cis-3-metoksy-1-[4-okso-4-(3,4,5-trimetoksyfenyl)butyl]-4-piperidyl-4-amino-5-klor-2, 3 -dihydro-7-benzofurankarboksylat; 1- [4-okso-4- (3,4, 5-trimetoksyf enyl) butyl] -4-piperidyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat; 1- [4- (2, 3-dihydro-2-okso-lH-benzimidazol-5-yl) -4-okso-butyl] -4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzo-furan-karboksylat; og 1-[4-(4-metoksy-3,5-dimetylfenyl)-4-oksobutyl]-4-piperidinyl-4-amino-5-klor-2, 3-dihydro-7-benzofurankarboksylat; de stereoisomere former derav og de farmasøytisk akseptable syreaddisjonssalter derav. For å forenkle de strukturelle representasjoner av forbindelsene med formel (I) og visse intermediater derav, vil radikalet med formel heretter bli representert ved symbolet D, og radikalet cis-3-methoxy-1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; 1-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-4-oxo-butyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro- 7-benzofuran carboxylate; and 1-[4-(4-methoxy-3,5-dimethylphenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; the stereoisomeric forms thereof and the pharmaceutically acceptable acid addition salts thereof. To simplify the structural representations of the compounds of formula (I) and certain intermediates thereof, the radical of formula will hereafter be represented by the symbol D, and the radical
vil heretter bli representert ved L. will henceforth be represented by L.
I de følgende fremstillinger kan reaksjonsproduktene iso-leres fra reaksjonsblandingen og, hvis nødvendig, kan de bli ytterligere renset i henhold til metoder som er allment kjent i faget, som f.eks. ekstraksjon, destillasjon, kry-stallisasjon, triturasjon og kromatografi. In the following preparations, the reaction products can be isolated from the reaction mixture and, if necessary, they can be further purified according to methods generally known in the art, such as e.g. extraction, distillation, crystallization, trituration and chromatography.
Forbindelsene med formel (I) kan fremstilles ved N-alkyler-ing av et piperidin med formel (II) med et intermediat med formel (III). The compounds of formula (I) can be prepared by N-alkylation of a piperidine of formula (II) with an intermediate of formula (III).
W<1> i intermediatet med formel (III) er en passende utgående gruppe, såsom halogen, f.eks. klor, brom eller jod, eller en sulfonyloksygruppe, f.eks. metansulfonyloksy, toluensulfonyloksy og lignende utgående grupper. N-alkyleringsreaksjon av (II) med (III) utføres hensiktsmessig i henhold til kjente alkyleringsprosedyrer. W<1> in the intermediate of formula (III) is a suitable leaving group, such as halogen, e.g. chlorine, bromine or iodine, or a sulphonyloxy group, e.g. methanesulfonyloxy, toluenesulfonyloxy and similar leaving groups. N-alkylation reaction of (II) with (III) is conveniently carried out according to known alkylation procedures.
Forbindelsene med formel (I) kan også fremstilles ved forestring av en alkohol med formel (IV) , hvori R<4> og L er som definert ovenfor, med en karboksylsyre med formel (V) hvori R<1>, R2 og R<3> er som definert ovenfor, eller et funksjonelt derivat derav, såsom et acylhalid, et symmetrisk eller blandet anhydrid eller en ester, fortrinnsvis en aktivert ester, i henhold til prosedyrer kjent innen faget. Det kan være fordelaktig å beskytte amingruppen i intermediatet med formel (V) under reaksjonsforløpet, slik at en unngår uønskede bireaksjoner. Den aminbeskyttende gruppe fjernes etter at forestringen er fullført. Passende beskyttende grupper omfatter enkelt fjernbare grupper, såsom C^alkylkarbonyl, C^alkyloksykarbonyl, fenylmetyl og lignende beskyttende grupper. The compounds of formula (I) can also be prepared by esterification of an alcohol of formula (IV), in which R<4> and L are as defined above, with a carboxylic acid of formula (V) in which R<1>, R2 and R< 3> is as defined above, or a functional derivative thereof, such as an acyl halide, a symmetrical or mixed anhydride or an ester, preferably an activated ester, according to procedures known in the art. It can be advantageous to protect the amine group in the intermediate of formula (V) during the course of the reaction, so that unwanted side reactions are avoided. The amine protecting group is removed after the esterification is complete. Suitable protecting groups include easily removable groups such as C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, phenylmethyl and similar protecting groups.
Forbindelser med formel (I) hvori Rs og R<6> sammen danner en radikal med formel (d), idet forbindelsene er representert ved formel (I-d), kan fremstilles ved å omsette et intermediat med formel (VI) med 1,11 -karbonylbis-lff-imidazol eller et funksjonelt derivat derav i henhold til kjente prosedyrer. Compounds of formula (I) in which Rs and R<6> together form a radical of formula (d), the compounds being represented by formula (I-d), can be prepared by reacting an intermediate of formula (VI) with 1.11 - carbonyl bis-lff-imidazole or a functional derivative thereof according to known procedures.
Forbindelser med formel (I) hvor R5 og R<6> sammen danner et radikal med formel (e) og forbindelsene er representert ved formel (I-e), kan fremstilles ved å reagere et intermediat med formel (VI) hvori R<8> og R<9> begge er hydrogen, og intermediatene er representert ved formel (VI)-a), med et intermediat med formel (VII) i henhold til kjente reaksjonspro-sedyrer. Compounds of formula (I) where R5 and R<6> together form a radical of formula (e) and the compounds are represented by formula (I-e), can be prepared by reacting an intermediate of formula (VI) in which R<8> and R<9> are both hydrogen, and the intermediates are represented by formula (VI)-a), with an intermediate of formula (VII) according to known reaction procedures.
Forbindelsene med formel (I) kan også konverteres til hverandre. For eksempel kan forbindelsene med formel (I) hvori R<10> er hydrogen, konverteres til forbindelser med formel (I) , hvori R<10> er C^alkylkarbonyl eller C^alkyl-oksykarbonyl, ved kjente iV-acyleringsreaks joner. The compounds of formula (I) can also be converted into each other. For example, the compounds of formula (I) in which R<10> is hydrogen can be converted to compounds of formula (I), in which R<10> is C 1-4 alkylcarbonyl or C 1-4 alkyl-oxycarbonyl, by known iV-acylation reactions.
Forbindelsene med formel (I) hvori R<3> er C^alkenyl eller C2.6alkenyl, kan omdannes til forbindelser med formel (I) hvori R<3> er det tilsvarende mettede alkylradikal, ved kjente hydrogeneringsteknikker. The compounds of formula (I) in which R<3> is C-1 alkenyl or C2-6 alkenyl can be converted into compounds of formula (I) in which R<3> is the corresponding saturated alkyl radical, by known hydrogenation techniques.
Forbindelsene med formel (I) kan også omdannes til de tilsvarende W-oksidformer i henhold til kjente prosedyrer for konvertering av et trivalent nitrogen til sin W-oksidform. W-oksideringsreaksjonen kan generelt utføres ved å reagere utgangsmaterialet med formel (I) med et passende organisk eller uorganisk peroksid. Passende uorganiske peroksider omfatter f.eks. hydrogenperoksid, alkalimetall- eller jord-alkalimetallperoksider, f.eks. natriumperoksid, kaliumper-oksid; passende organiske peroksider kan omfatte peroksy-syrer såsom perbenzosyre eller halogensubstituert perbenzosyre, f.eks. 3-klorperbenzosyre, peroksoalkanoinsyre, f.eks. peroksoeddiksyre, alkylhydroperoksider, f.eks. tert-butyl-hydroperoksider. Passende løsningsmidler er f.eks. vann, lavere alkanoler, f.eks. etanol, og lignende, hydrokarboner, f.eks. toluen, ketoner, f.eks. 2-butanon, haloge-nerte hydrokarboner, f.eks. diklormetan, og blandinger av slike løsningsmidler. The compounds of formula (I) can also be converted into the corresponding W-oxide forms according to known procedures for converting a trivalent nitrogen into its W-oxide form. The W-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include e.g. hydrogen peroxide, alkali metal or alkaline earth metal peroxides, e.g. sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxyacids such as perbenzoic acid or halogen-substituted perbenzoic acid, e.g. 3-chloroperbenzoic acid, peroxoalkanoic acid, e.g. peroxoacetic acid, alkyl hydroperoxides, e.g. tert-butyl hydroperoxides. Suitable solvents are e.g. water, lower alkanols, e.g. ethanol, and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Intermediatene med formel (II) kan avledes fra et passende substituert piperidin med formel (VIII) med en intermediat syre med formel (V) eller et funksjonelt derivat derav, i henhold til kjente esterdannende prosedyrer, og deretter kan den beskyttende gruppe P fjernes i henhold til kjente prosedyrer. P representerer en enkelt fjernbar beskyttende gruppe, såsom Cl.4alkylkarbonyl, C^alkyloksykarbonyl, fenylmetyl og lignende beskyttende grupper. The intermediates of formula (II) may be derived from a suitably substituted piperidine of formula (VIII) with an intermediate acid of formula (V) or a functional derivative thereof, according to known ester-forming procedures, and then the protecting group P may be removed according to to known procedures. P represents a single removable protecting group, such as C1-4 alkylcarbonyl, C1-4 alkyloxycarbonyl, phenylmethyl and similar protecting groups.
Fremstillingen av intermediatsyrer med formel (V) er beskrevet i EP-0.389.037-A. The preparation of intermediate acids of formula (V) is described in EP-0,389,037-A.
Intermediatene med formel (VI-a) kan fremstilles ved reduksjon av et intermediat med formel (IX) med et egnet reduk-sjonsmiddel, såsom en kombinasjon av platina på aktivert karbon og hydrogen, i et reaksjons-intert løsningsmiddel såsom tetrahydrofuran. The intermediates of formula (VI-a) can be prepared by reduction of an intermediate of formula (IX) with a suitable reducing agent, such as a combination of platinum on activated carbon and hydrogen, in a reaction-inert solvent such as tetrahydrofuran.
Intermediatene med formel (IX) kan fremstilles ved W-alkyl-ering av piperidin med formel (II) med et intermediat med formel (X) hvori W<1> er en passende utgående gruppe, såsom et halogenatom, på en måte som er analog med fremstillingen av forbindelsene med formel (I) fra intermediatene (II) og (III)• The intermediates of formula (IX) can be prepared by W-alkylation of piperidine of formula (II) with an intermediate of formula (X) in which W<1> is a suitable leaving group, such as a halogen atom, in a manner analogous to with the preparation of the compounds of formula (I) from the intermediates (II) and (III)•
Intermediatene med formelen (VIII') hvori P<1> representerer The intermediates of formula (VIII') in which P<1> represents
P som definert ovenfor så vel som hydrogen, kan fremstilles ved reduksjon av et intermediat med formel (XI) i henhold til kjente metoder. Spesielt kan intermediatene med formel (VIII1) hvori R4 er C^alkoksy og intermediatene er representert ved formel (VIII1 -a) , og hvori R4 og hydroksylgrup-pen har cis-konfigurasjon, kan fremstilles ved reduksjon av et intermediat med formel (XI-a) ved anvendelse av et re-duksjonsmiddel såsom et substituert borhydrid, f.eks. litium tris-sec-butylborhydrid, kalium tris-sec-butylborhydrid, substituert aluminiumhydrid, litium-tri-tert-butoksyaluminhydrid og lignende, i et reaksjons-inert løsningsmiddel såsom tetrahydrofuran. Det kan også være fordelaktig å utføre reaksjonen ved en lavere temperatur, fortrinnsvis ved en temperatur under -70°C. Ved anvendelse av stereokjemisk rene reagenser kan reduksjonen utføres på en stereospesifikk måte. P as defined above as well as hydrogen can be prepared by reduction of an intermediate of formula (XI) according to known methods. In particular, the intermediates of formula (VIII1) in which R4 is C 1-4 alkoxy and the intermediates are represented by formula (VIII1 -a), and in which R4 and the hydroxyl group have cis configuration, can be prepared by reduction of an intermediate of formula (XI- a) by using a reducing agent such as a substituted borohydride, e.g. lithium tris-sec-butylborohydride, potassium tris-sec-butylborohydride, substituted aluminum hydride, lithium tri-tert-butoxyaluminum hydride and the like, in a reaction-inert solvent such as tetrahydrofuran. It may also be advantageous to carry out the reaction at a lower temperature, preferably at a temperature below -70°C. By using stereochemically pure reagents, the reduction can be carried out in a stereospecific manner.
Cis og trans diastereomere racemater av forbindelsen med formel (I) eller ethvert av de andre intermediatene kan også adskilles til deres optiske isomere, cis(+), cis-(-), trans( + ) og trans(-) ved anvendelse av kjente metoder. Diastereoisomerene kan skilles ved fysiske separasjonsme-toder, såsom em selektiv krystallisering og kromatografiske teknikker, f.eks. motstrømsdistribusjon, og enantiomere kan separeres fra hverandre ved selektiv krystallisering av deres diastereomere salter med enantiomere rene syrer eller deres enantiomert rene derivater. Cis and trans diastereomeric racemates of the compound of formula (I) or any of the other intermediates can also be separated into their optical isomers, cis(+), cis-(-), trans( + ) and trans(-) using known methods. The diastereoisomers can be separated by physical separation methods, such as selective crystallization and chromatographic techniques, e.g. countercurrent distribution, and enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with enantiomerically pure acids or their enantiomerically pure derivatives.
Forbindelene med formel (I) og intermediatene med formel (II) og (VI), N-oksidformene, de farmasøytisk akseptable salter og stereoisomere former derav innehar fordelaktige intestinal motilitets-stimulerende egenskaper. Spesielt viser de foreliggende forbindelser en vesentlig motilitets-fremmende effekt i tarmen. De sistnevnte egenskaper er vist ved resultatet erholdt i "Marsvin ileum koaksial stimu-lerings "-testen og i "Colon-motilitet i bevisst hund"-testen. Begge testene er beskrevet i det følgende. Noen av forbindelsene viser også aktivitet i "Lidamidintest i hunder". The compounds of formula (I) and the intermediates of formula (II) and (VI), the N-oxide forms, the pharmaceutically acceptable salts and stereoisomeric forms thereof possess beneficial intestinal motility-stimulating properties. In particular, the present compounds show a significant motility-promoting effect in the intestine. The latter properties are shown by the results obtained in the "Guinea pig ileum coaxial stimulation" test and in the "Colon motility in conscious dog" test. Both tests are described below. Some of the compounds also show activity in the "Lidamidine test in dogs".
I lys av deres nyttige intestinal motilitets-fremmende egenskaper kan de foreliggende forebindelsene formuleres i en rekke former i administrasjonsøyemed. In view of their useful intestinal motility promoting properties, the present compounds can be formulated in a variety of forms for purposes of administration.
For å fremstille de farmasøytiske sammensetninger ifølge oppfinnelsen blandes en effektiv mengde av den spesielle forbindelse i base- eller syreaddisjonssaltform som aktiv ingrediens, godt med et farmasøytisk akseptabelt bærerstoff, hvilket bærerstoff kan anta en rekke ulike former, avhengig av formen av det preparat som er ønsket for administrasjon. Det er ønskelig at disse farmasøytiske blandinger fortrinnsvis er i enhetsdoseringsform, egnet for administrasjon oralt, rektalt eller ved prenteral injeksjon. For eksempel, ved fremstilling av sammensetningene i oral doseringsform kan ethvert av de alminnelige farmasøytiske media anvendes, f.eks. vann, glykoler, oljer, alkoholer og lignende for tilfeller av preparasjoner med oral væske, såsom suspensjoner, siruper, eliksirer og løsninger; eller faste bærerstoffer såsom stivelse, sukker, kaolin, smøre-midler, bindemidler, disintegreringsmidler og lignende i tilfelle av pulvere, piller, kapsler og tabletter. På grunn av at de er så enkle å administrere, representerer kapsler og tabletter den mest foretrukne orale doseringsenhetsform, hvori faste farmasøytiske bærestoffer anvendes. For paren-terale sammensetninger vil bærerstoff normalt omfatte ste-rilt vann, i det minste for mesteparten, selv om andre ingredienser kan innbefattes, f.eks. for å lette løselig-heten. F.eks. kan injiserbare løsninger fremstilles hvori bærerstoffet omfatter en saltoppløsning, glukoseoppløsning eller en blanding av salt- og glukoseoppløsning. Injiserbare suspensjoner kan også fremstilles hvori passende flytende bærerstoff, suspenderende midler og lignende kan anvendes. I sammensetningene egnet for perkutan administrasjon omfatter bærerstoffet eventuelt et penetrasjonsfrem-mende middel og/eller et passende fuktemiddel, eventuelt kombinert med egnede additiver av enhver natur i mindre an-deler, hvilke additiver ikke forårsaker en signifikant ska-delig effekt på huden. Additivene kan lette administra-sjonen til huden og/eller være anvendelige ved fremstilling av de ønskede sammensetninger. Disse sammensetninger kan administreres på ulike måter, f.eks. i form av en transder-mal patch, som en "spot-on" og som en salve. Syreaddisjonssalter av (I), (II) eller (VI) er på grunn av sin økede vannløselighet sammenlignet med baseformen bedre egnet ved preparasjon av vandige sammensetninger. Det er spesielt fordelaktig å formulere de ovenfornevnte farmasøytiske sammensetninger i doseringsenhetsform for enkel administrasjon og enhetlig dosering. Doseringsenhetsform som anvendes i beskrivelsen og kravene heri, refererer til fysiske enkeltenheter egnet som enhetsdoseringer, idet hver enhet inneholder en forhåndsbestemt mengde av aktiv ingrediens beregnet til å fremskaffe den ønskede terapeutiske effekt sammen med det påkrevede farmasøytiske bærerstoff. Eksempler på slike doseringsenhetsformer er tabletter (innbe-fattende tabletter med innsnitt eller belagte tabletter), kapsler, piller, pulverpakker, oblater, injiserbare oppløs-ninger eller suspensjoner, teskjemengder, spiseskjemengder og lignende, samt adskilte multipler derav. To prepare the pharmaceutical compositions according to the invention, an effective amount of the particular compound in base or acid addition salt form as active ingredient is mixed well with a pharmaceutically acceptable carrier substance, which carrier substance can assume a number of different forms, depending on the form of the desired preparation for administration. It is desirable that these pharmaceutical mixtures are preferably in unit dosage form, suitable for administration orally, rectally or by preenteral injection. For example, when preparing the compositions in oral dosage form, any of the common pharmaceutical media can be used, e.g. water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, capsules and tablets represent the most preferred oral dosage unit form in which solid pharmaceutical carriers are employed. For parenteral compositions, the carrier will normally comprise sterile water, at least for the most part, although other ingredients may be included, e.g. to facilitate solubility. E.g. injectable solutions can be prepared in which the carrier comprises a salt solution, glucose solution or a mixture of salt and glucose solution. Injectable suspensions can also be prepared in which suitable liquid carriers, suspending agents and the like can be used. In the compositions suitable for percutaneous administration, the carrier substance optionally comprises a penetration-promoting agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in smaller proportions, which additives do not cause a significant harmful effect on the skin. The additives may facilitate administration to the skin and/or be useful in the preparation of the desired compositions. These compositions can be administered in various ways, e.g. in the form of a transder-mal patch, as a "spot-on" and as an ointment. Acid addition salts of (I), (II) or (VI) are, due to their increased water solubility compared to the base form, better suited for the preparation of aqueous compositions. It is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in dosage unit form for easy administration and uniform dosage. Dosage unit form as used in the description and claims herein refers to individual physical units suitable as unit dosages, each unit containing a predetermined amount of active ingredient intended to produce the desired therapeutic effect together with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored tablets or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoon amounts, tablespoon amounts and the like, as well as separate multiples thereof.
I lys av deres evne til å stimulere motiliteten av det intestinale system og spesielt deres evne til å fremme motilitet i kolon, anvendes de foreliggende forbindelser for å normalisere eller forbedre den intestinale transit i individer som lider av symptomer relatert til forstyrret motilitet, f.eks. en redusert peristaltikk av tynn- og tykktarmen alene eller i kombinasjon med forsinket gastrisk tømming. I lys av anvendeligheten til forbindelsene ifølge foreliggende oppfinnelse kan de anvendes for å behandle varmblodige dyr som lider av motilitetsforstyrrelser i det intestinale system, såsom forstoppelse, pseudo-obstruksjon, intestinal atoni, postoperativ intestinal atoni, irritabel-tarm-syndrom (IBS), medikamentindusert forsinket transit og spesielt hindret transit i colon. En effektiv intestinal-stimulerende mengde av en forbindelse med formel (I) , et N-oksid, et farmasøytisk akseptabelt syreaddisjonssalt eller en mulig stereoisomer form kan administreres systemisk til varmblodige dyr. Følgelig tilveiebringes anvendelsen av en forbindelse med formel (I) som medisin, og spesielt anvendelsen av en forbindelse med formel (I) ved fremstilling av et medikament for behandling av tilstander som involverer en redusert motilitet i colon. In view of their ability to stimulate the motility of the intestinal system and especially their ability to promote motility in the colon, the present compounds are used to normalize or improve intestinal transit in individuals suffering from symptoms related to disturbed motility, e.g. . a reduced peristalsis of the small and large intestine alone or in combination with delayed gastric emptying. In view of the applicability of the compounds according to the present invention, they can be used to treat warm-blooded animals suffering from motility disorders in the intestinal system, such as constipation, pseudo-obstruction, intestinal atony, postoperative intestinal atony, irritable bowel syndrome (IBS), drug-induced delayed transit and especially obstructed transit in the colon. An effective intestinal-stimulating amount of a compound of formula (I), an N-oxide, a pharmaceutically acceptable acid addition salt or a possible stereoisomeric form can be administered systemically to warm-blooded animals. Accordingly, there is provided the use of a compound of formula (I) as a medicine, and in particular the use of a compound of formula (I) in the manufacture of a medicament for the treatment of conditions involving a reduced motility in the colon.
Normalt er det forventet at en terapeutisk effektiv mengde vil være i området 0,001 - 10 mg/kg kroppsvekt, fortrinnsvis 0,02 - 5 mg/kg kroppsvekt. En behandlingsmetode kan også innbefatte administrasjon av den aktive ingrediens ved en kur med mellom to og fire inntak pr. dag. Normally, it is expected that a therapeutically effective amount will be in the range of 0.001 - 10 mg/kg body weight, preferably 0.02 - 5 mg/kg body weight. A treatment method can also include administration of the active ingredient in a course of between two and four intakes per day. day.
Eksperimentell del Experimental part
A. Fremstilling av intermediatene A. Preparation of the intermediates
Eksempel 1 Example 1
a) Natriumborhydrid (7,7 g) ble satt dråpevis til en rørt oppløsning av 3-metoksy-l-(fenylmetyl)-4-piperidinon (44,8 g) i etanol (610 ml). Etter fullførelse ble det hele av-kjølt til romtemperatur, og omrøring ble fortsatt i 3 t ved a) Sodium borohydride (7.7 g) was added dropwise to a stirred solution of 3-methoxy-1-(phenylmethyl)-4-piperidinone (44.8 g) in ethanol (610 ml). After completion, the whole was cooled to room temperature, and stirring was continued for 3 h
romtemperatur. Reaksjonsblandingen ble konsentrert til et volum på omtrent 150 ml. Vann (300 ml) ble satt til konsen-tratet, og alle spor av etanol ble fordampet. Etter avkjøl- room temperature. The reaction mixture was concentrated to a volume of approximately 150 mL. Water (300 ml) was added to the concentrate and all traces of ethanol were evaporated. After cooling-
ing ble blandingen ekstrahert med dietyleter. Ekstraktet ble vasket med vann, tørket, filtrert og inndampet. Den oljeaktige rest ble renset ved kolonnekromatografi på kiselgel (eluent: CHC13/CH30H 96/4). De rene fraksjoner ble ing, the mixture was extracted with diethyl ether. The extract was washed with water, dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel (eluent: CHCl3/CH3OH 96/4). The pure fractions were
samlet opp, og eluenten ble dampet av. Resten ble separert ved kolonnekromatografi på kiselgel (eluent: heksan/CHCl3/-(CH3OH/NH3) 50/50/1). Den første fraksjon ble samlet opp og eluenten dampet av, hvilket ga 11,5 g (25,5%) trans-3-mwtoksy-1-(fenylmetyl)-4-piperidinol (intermediat 1). Den andre fraksjon ble samlet opp og eluenten dampet av, hvilket ga 7,7 g (17,1%) cis-3-metoksy-1-(fenylmetyl)-4-piperi-dinol (intermediat 2). collected, and the eluent was evaporated. The residue was separated by column chromatography on silica gel (eluent: hexane/CHCl3/-(CH3OH/NH3) 50/50/1). The first fraction was collected and the eluent evaporated to give 11.5 g (25.5%) of trans-3-mwtoxy-1-(phenylmethyl)-4-piperidinol (intermediate 1). The second fraction was collected and the eluent evaporated to give 7.7 g (17.1%) of cis-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 2).
a') En oppløsning av 3-metoksy-1-(fenylmetyl)-4-piperi-dinon (4,4 g) i tetrahydrofuran ble avkjølt til -75°C. Litium-tris-sec-butylborhydrid ble satt til dråpevis, og reaksjonsblandingen ble rørt i 2 t ved -70°C. Eddiksyre 10% a') A solution of 3-methoxy-1-(phenylmethyl)-4-piperidinone (4.4 g) in tetrahydrofuran was cooled to -75°C. Lithium-tris-sec-butylborohydride was added dropwise, and the reaction mixture was stirred for 2 h at -70°C. Acetic acid 10%
(100 ml) ble satt til dråpevis ved romtemperatur. Det organiske løsningsmiddel ble dampet av. Den vandige rest ble alkalisert med NH4OH og deretter ekstrahert to ganger med diisopropyleter. Det separerte organiske skikt ble vasket med vann, tørket over MgS04, filtrert og løsningsmidlet ble dampet av. Resten ble renset ved kort-kolonnekromatografi på kiselgel (eluent: CH2Cl2/CH3OH 95/5 oppgradering til 98/2), hvilket ga 1,3 g (29,4%) cis-3-metoksy-1-(fenylmetyl) -4-piperidinol (intermediat 2). (100 ml) was added dropwise at room temperature. The organic solvent was evaporated off. The aqueous residue was alkalized with NH 4 OH and then extracted twice with diisopropyl ether. The separated organic layer was washed with water, dried over MgSO 4 , filtered and the solvent was evaporated. The residue was purified by short-column chromatography on silica gel (eluent: CH2Cl2/CH3OH 95/5 upgrading to 98/2), yielding 1.3 g (29.4%) of cis-3-methoxy-1-(phenylmethyl)-4 -piperidinol (intermediate 2).
b) En blanding av 11,5 g av intermediat (2) og 150 ml metanol ble hydrogenert ved normalt trykk og ved romtemperatur med 2 g palladium-på-karbon (trekull)-katalysator (10%). Etter at den beregnede mengde av hydrogen var tatt b) A mixture of 11.5 g of intermediate (2) and 150 ml of methanol was hydrogenated at normal pressure and at room temperature with 2 g of palladium-on-carbon (charcoal) catalyst (10%). After the calculated amount of hydrogen had been taken
opp, ble katalysatoren filtrert av og filtratet dampet inn. Resten ble renset ved kolonnekromatografi på kiselgel (eluent: CHC13/(CH3OH/NH3) 85/15). De rene fraksjoner ble samlet opp og eluenten ble dampet av, hvilket ga 3,6 g (53%) cis-3-metoksy-4-piperidinol i form av en oljeaktig rest (intermediat 3) . up, the catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl 3 /(CH 3 OH/NH 3 ) 85/15). The pure fractions were collected and the eluent was evaporated, giving 3.6 g (53%) of cis-3-methoxy-4-piperidinol as an oily residue (intermediate 3).
c) En oppløsning av bis(1,1'-dimetyletyl)dikarbonat (65,5 g) i CHC13 (100 ml) ble satt dråpevis til en oppløsning av intermediat (3) (34 g) i triklormetan (350 ml) , og reaksj onsbl åndingen ble omrørt i 3 t ved romtemperatur. Reaksj onsblandingen ble vasket med vann og ammoniakk og deretter med vann. Det separerte organiske skikt ble tørket over MgS04, filtrert og løsningsmidlet dampet inn. Resten (9 g) ble renset ved kolonnekromatografi på kiselgel: CH2C12/-(CH3OH/NH3) Sl/ 2, oppgraderende til 95/4). De rene fraksjoner ble samlet opp, og løsningsmidlet dampet inn, hvilket ga 58 g av (+)-1,1-dimetyl cie-4-hydroksy-3-metoksy-l-piperidinkarboksylat (grov rest) (intermediat 4). d) Natriumhydrid (4 g) ble satt til en oppløsning av intermediat (4) (19,4 g) i tetrahydrofuran (400 ml) . Blandingen ble rørt og kokt under tilbakeløp i 3 t (oppløsning I). 1,1<1->karbonylbis-lH-imidazol (13,6 g) ble satt til en suspensjon av 4-amino-5-klor-2,3-dihydro-7-benzofurankar-boksylsyre (18 g) i acetonitril (400 ml), og denne blandingen ble rørt i 2 t ved romtemperatur. Løsningsmidlet ble dampet inn, resten ble oppløst i tetrahydrofuran (400 ml), hvilket ga oppløsning II. Ved romtemperatur ble opp-løsning (II) helt i oppløsning (I) og reaksjonsblandingen ble rørt i 2 t ved romtemperatur. Løsningsmidlet ble dampet inn. Resten ble fordelt mellom CH2C12 og H20. Det organiske skikt ble separert, og det vandige skikt ble ekstrahert to ganger med CH2C12. Det separerte organiske skikt ble tørket over MgS04, filtrert og løsningsmidlet dampet av. Resten ble renset på kort-kolonnekromatografi på kiselgel, elueringsmiddel: CH2Cl2/CH3OH 98/2). De ønskede fraksjoner ble samlet opp og løsningsmidlet dampet av, hvilket ga 32 g ( + ) -cis-1-[(1,1-dimetyletoksy)karbonyl]-3-metoksy-4-piperidinyl-4-amino-5-klor-2, 3 -dihydro-7-benzof urankarboksylat (87%) (intermediat 5). e) En blanding av intermediat (5) (32 g) i tetrahydrofuran (500 ml) og saltsyre (50 ml) ble rørt og oppvarmet under tilbakeløp i 30 min. Reaksj onsblandingen ble avkjølt og alkalisert med NH4OH. Skiktene ble separert. Det vandige skikt ble ekstrahert med tetrahydrofuran. Det separerte organiske skikt ble dampet av. Resten ble renset ved kolonnekromatograf i på kiselgel (elueringsmiddel: CH2C12/-(CH3OH-/NH3) 93/7). De rene fraksjoner ble samlet opp, og løsningsmidlet ble dampet av. Resten ble krystallisert fra acetonitril. Utfellingen ble filtrert av og tørket (vakuum; 80°C), hvilket ga 6,4 g (+)-cis-3-metoksy-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat (26%) c) A solution of bis(1,1'-dimethylethyl)dicarbonate (65.5 g) in CHCl 3 (100 ml) was added dropwise to a solution of intermediate (3) (34 g) in trichloromethane (350 ml), and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was washed with water and ammonia and then with water. The separated organic layer was dried over MgSO 4 , filtered and the solvent evaporated. The residue (9 g) was purified by column chromatography on silica gel: CH 2 Cl 2 /-(CH 3 OH/NH 3 ) Sl/ 2, upgrading to 95/4). The pure fractions were collected and the solvent evaporated to give 58 g of (+)-1,1-dimethyl cy-4-hydroxy-3-methoxy-1-piperidine carboxylate (crude residue) (intermediate 4). d) Sodium hydride (4 g) was added to a solution of intermediate (4) (19.4 g) in tetrahydrofuran (400 ml). The mixture was stirred and refluxed for 3 h (solution I). 1,1<1->carbonylbis-1H-imidazole (13.6 g) was added to a suspension of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (18 g) in acetonitrile ( 400 ml), and this mixture was stirred for 2 h at room temperature. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (400 ml) to give solution II. At room temperature, solution (II) was poured into solution (I) and the reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated. The residue was partitioned between CH 2 Cl 2 and H 2 O. The organic layer was separated and the aqueous layer was extracted twice with CH 2 Cl 2 . The separated organic layer was dried over MgSO 4 , filtered and the solvent evaporated. The residue was purified on short-column chromatography on silica gel, eluent: CH2Cl2/CH3OH 98/2). The desired fractions were collected and the solvent evaporated to give 32 g of (+ )-cis-1-[(1,1-dimethylethoxy)carbonyl]-3-methoxy-4-piperidinyl-4-amino-5-chloro- 2,3-dihydro-7-benzofuran carboxylate (87%) (intermediate 5). e) A mixture of intermediate (5) (32 g) in tetrahydrofuran (500 ml) and hydrochloric acid (50 ml) was stirred and heated under reflux for 30 min. The reaction mixture was cooled and basified with NH 4 OH. The layers were separated. The aqueous layer was extracted with tetrahydrofuran. The separated organic layer was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/-(CH3OH-/NH3) 93/7). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and dried (vacuum; 80°C), yielding 6.4 g of (+)-cis-3-methoxy-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7- benzofuran carboxylate (26%)
(intermediat 6). (intermediate 6).
Eksempel 2 Example 2
a) En blanding av 4-amino-5-klor-2,3-dihydro-7-benzofuran-karboksylsyre (4,3 g) i tionylklorid (100 ml) og CHC13 (200 a) A mixture of 4-amino-5-chloro-2,3-dihydro-7-benzofuran-carboxylic acid (4.3 g) in thionyl chloride (100 ml) and CHCl 3 (200
ml) ble rørt og oppvarmet under tilbakeløp i 2 t. Blandingen ble avkjølt og løsningsmidlet dampet av. Toluen ble satt til, og det ble igjen dampet av, hvilket ga 4,8 g 4-amino-5-klor-2,3-dihydro-7-benzofurankarbonylklorid (100% grov rest) (intermediat 7). ml) was stirred and heated under reflux for 2 h. The mixture was cooled and the solvent evaporated. The toluene was added and it was again evaporated to give 4.8 g of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarbonyl chloride (100% crude residue) (intermediate 7).
b) En løsning av 1,l-dimetyletyl-4-hydroksy-l-piperidin-karboksylat (4,02 g) og N,W-dimetyl-4-pyridinamin (3,7 g) i b) A solution of 1,1-dimethylethyl-4-hydroxy-1-piperidine carboxylate (4.02 g) and N,N-dimethyl-4-pyridinamine (3.7 g) in
diklormetan (200 ml) ble rørt ved romtemperatur. En løsning av intermediat (7) (4,8 g) i CH2C12 (200 ml) ble helt på løsningen. Reaksjonsblandingen ble omrørt i 3 t ved romtemperatur. Blandingen ble vasket med vann, med en 5% NaOH-løsning og igjen med vann. Det organiske skikt ble separert, tørket over MgS04, filtrert og løsningsmidlet dampet av. Resten (7,4 g) ble renset ved kolonnekromatograf i over kiselgel (eluent: CH2C12/(CH30H 98/2). De rene fraksjoner ble samlet opp og løsningsmidlet dampet av, hviket ga 4,7 g 1,1-dimetyletyl 4-[[(4-amino-5-klor-2,3-dihydro-7-benzo-furanyl)karbonyl]oksy]-1-piperidinkarboksylat (59%) (intermediat 8) . c) En blanding av intermediat (8) (7 g) i tetrahydrofuran (20 ml) og saltsyre (20 ml) ble omrørt og kokt under tilba-keløp i 2 t. Reaksj onsblandingen ble avkjølt og alkalisert med NH4OH. Det organiske skikt ble fjernet ved dekantering, og løsningsmidlet ble dampet av. Resten ble renset ved kolonnekromatograf i på kiselgel (eluent: CH2C12/ (CH3OH/NH3) 92/8) . De rene fraksjoner ble samlet opp og løsningsmidlet dampet av. Resten (5,5 g) ble igjen renset ved HPLC (kolon-ne: 200 g Kromasil; 10 um; 100 Å; eluent: (0,5% NH4OAc i vann)/metanol 70/30). De rene fraksjoner ble samlet opp, ekstrahert med NH3/CH2C12. Ekstraktet ble dampet inn. Resten ble krystallisert fra acetonitril. Bunnfallet ble filtrert av og tørket (vakuum; 70°C) , hvilket ga 2,60 g 4-piperidinyl - 4 - amino - 5- klor-2,3 - dihydro - 7 - benzof ur ankarboksyl at (54%) (intermediat 9). dichloromethane (200 mL) was stirred at room temperature. A solution of intermediate (7) (4.8 g) in CH 2 Cl 2 (200 mL) was poured onto the solution. The reaction mixture was stirred for 3 h at room temperature. The mixture was washed with water, with a 5% NaOH solution and again with water. The organic layer was separated, dried over MgSO 4 , filtered and the solvent evaporated. The residue (7.4 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /(CH 3 OH 98/2). The pure fractions were collected and the solvent evaporated to give 4.7 g of 1,1-dimethylethyl 4- [[(4-amino-5-chloro-2,3-dihydro-7-benzo-furanyl)carbonyl]oxy]-1-piperidinecarboxylate (59%) (intermediate 8) . c) A mixture of intermediate (8) ( 7 g) in tetrahydrofuran (20 ml) and hydrochloric acid (20 ml) was stirred and refluxed for 2 h. The reaction mixture was cooled and alkalized with NH 4 OH. The organic layer was removed by decantation, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3) 92/8). The pure fractions were collected and the solvent evaporated. The residue (5.5 g) was again purified by HPLC (column: 200 g Kromasil; 10 µm; 100 Å; eluent: (0.5% NH 4 OAc in water)/methanol 70/30). The pure fractions were collected, extracted with NH 3 /CH 2 Cl 2 . The extract was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and dried (vacuum; 70°C), yielding 2.60 g of 4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (54%) (intermediate 9).
Eksempel 3 Example 3
a) En blanding av cyklopropyl (4-amino-3-nitrofenyl)metanon (80 g), fremstilt som beskrevet i US 3.357.267, og konsentrert HC1 (420 ml) ble omrørt og kokt under tilbakeløp i 30 minutter. Reaksj onsblandingen ble avkjølt og vann ble tilsatt. Utfellingen ble filtrert av, vasket med vann og tør-ket, hvilket ga 80 g (84,5%) 1-(4-amino-3-nitrofenyl)-4-klor-l-butanon; smp. 150°C (intermediat 10) . b) En blanding av intermediat (9) (14,8 g) , intermediat (10), (12,13 g) og W,2/-dietyletanamin (8,3 ml) i N, N- di-metylformamid (150 ml) ble omrørt i 20 timer ved + 70°C. Løsningsmidlet ble avdampet. Resten ble fortynnet med vann, og denne blandingen ble ekstrahert to ganger med CH2C12. Det separerte organiske skikt ble vasket med vann, tørket over MgS04, filtrert og løsningsmidlet dampet av. Resten ble renset ved kolonnekromatografi på kiselgel (eluent: CH2Cl2/CH3OH 90/10) . De ønskede fraksjoner ble samlet opp, og løsningsmidlet ble dampet av. Resten (10 g) ble krystallisert fra diisopropyleter. Bunnfallet ble filtrert av og tørket, hvilket ga 8,3 g (33%) 1-[4-(4-amino-3-nitrofenyl)-4 -oksobutyl] -4 -piperidinyl -4 -amino- 5 -klor-2,3-dihydro- 7 - benzofurankarboksylat (intermediat 11). a) A mixture of cyclopropyl (4-amino-3-nitrophenyl)methanone (80 g), prepared as described in US 3,357,267, and concentrated HCl (420 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and water was added. The precipitate was filtered off, washed with water and dried to give 80 g (84.5%) of 1-(4-amino-3-nitrophenyl)-4-chloro-1-butanone; m.p. 150°C (intermediate 10) . b) A mixture of intermediate (9) (14.8 g), intermediate (10), (12.13 g) and N,2/-diethylethanamine (8.3 ml) in N,N-dimethylformamide (150 ml) was stirred for 20 hours at + 70°C. The solvent was evaporated. The residue was diluted with water and this mixture was extracted twice with CH 2 Cl 2 . The separated organic layer was washed with water, dried over MgSO 4 , filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated. The residue (10 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried to give 8.3 g (33%) of 1-[4-(4-amino-3-nitrophenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2 ,3-dihydro-7-benzofurancarboxylate (intermediate 11).
c) En blanding av intermediat (11) (8,2 g) i tetrahydrofuran (150 ml) ble hydrogenert med platina på aktivert karbon c) A mixture of intermediate (11) (8.2 g) in tetrahydrofuran (150 ml) was hydrogenated with platinum on activated carbon
(5%) (2 g) som katalysator. Etter opptak av H2 (3 ekviva-lenter) ble katalysatoren filtrert av over dikalitt, og filtratet ble dampet inn. Resten ble fortynnet med vann, og denne blandingen ble ekstrahert to ganger med CH2C12. Det separerte organiske skikt ble vasket med vann, tørket over MgS04, filtrert og løsningsmidlet dampet av. Resten (8 g) ble renset ved kolonnekromatografi på kiselgel (eluent: CH2C12/ (CH3OH/NH3) 92/8). De rene fraksjoner ble samlet opp, og løsningsmidlet ble dampet av. Resten (7,5 g) ble krystallisert fra CH3CN. Bunnfallet ble filtrert av og tørket, hvilket ga 5,43 g (70,5%) 1-[4-(3,4-diaminofenyl)-4-okso-butyl] -4-piperidinyl-4-amino-5-klor-2,3-dihhydro-7-benzofurankarboksylat, smp. 173,4°C (intermediat 12). (5%) (2 g) as catalyst. After uptake of H2 (3 equivalents), the catalyst was filtered off over dicalite, and the filtrate was evaporated. The residue was diluted with water and this mixture was extracted twice with CH 2 Cl 2 . The separated organic layer was washed with water, dried over MgSO 4 , filtered and the solvent evaporated. The residue (8 g) was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / (CH 3 OH/NH 3 ) 92/8). The pure fractions were collected and the solvent was evaporated. The residue (7.5 g) was crystallized from CH 3 CN. The precipitate was filtered off and dried to give 5.43 g (70.5%) of 1-[4-(3,4-diaminophenyl)-4-oxo-butyl]-4-piperidinyl-4-amino-5-chloro -2,3-dihydro-7-benzofurancarboxylate, m.p. 173.4°C (intermediate 12).
B. Fremstilling av sluttforbindelser B. Preparation of end connections
Eksempel 4 Example 4
En blanding av intermediat (6) (2,3 g), 4-klor-3,4,5-trimetoksyf enyl) -1-butanon (2 g), natriumkarbonat (2,1 g) og kaliumjodid (katalytisk mengde) i 4-metyl-2-pentanon (150 ml; på forhånd tørket over MgS04) ble rørt og oppvarmet under tilbakeløp over natten. Reaksjonsblandingen ble av-kjølt, vasket med vann, tørket over MgS04, filtrert, og filtratet ble dampet inn. Ressten ble renset ved kollonne-kromatografi over kiselgel (eluent: CH2C12, oppgradert til CH2C12/(CH3OH/NH3) 97/3). De rene fraksjoner ble samlet opp, og løsningsmidlene ble dampet av. Resten ble oppløst i metanol og omsatt til etandionsyresalt med etandionsyre (0,6 g). Blandingen ble kokt, deretter avkjølt, og bunnfallet ble filtrert av og rekrystallisert fra 2-propanol. Bunnfallet ble oppløst i vandig NH40H/CH2C12. Det organiske skikt ble separert, tørket over MgS04, filtrert, og løs-ningsmidlet ble dampet av. Resten ble rørt i kokende diisopropyleter, avkjølt, og det resulterende bunnfall ble filtrert av og tørket (vakuum; 80°C) , hvilket ga 1,10 g av ( + ) - cis-3 -metoksy-1- [4-okso-4- (3,4, 5-trimetoksyf enyl) - butyl]-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat (28%); smp. 132,3°C (forbindelse 1). A mixture of intermediate (6) (2.3 g), 4-chloro-3,4,5-trimethoxyphenyl)-1-butanone (2 g), sodium carbonate (2.1 g) and potassium iodide (catalytic amount) in 4-Methyl-2-pentanone (150 mL; previously dried over MgSO 4 ) was stirred and heated under reflux overnight. The reaction mixture was cooled, washed with water, dried over MgSO 4 , filtered, and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 , upgraded to CH 2 Cl 2 /(CH 3 OH/NH 3 ) 97/3). The pure fractions were collected, and the solvents were evaporated. The residue was dissolved in methanol and converted to ethanedioic acid salt with ethanedioic acid (0.6 g). The mixture was boiled, then cooled, and the precipitate was filtered off and recrystallized from 2-propanol. The precipitate was dissolved in aqueous NH4OH/CH2C12. The organic layer was separated, dried over MgSO 4 , filtered, and the solvent was evaporated. The residue was stirred in boiling diisopropyl ether, cooled, and the resulting precipitate was filtered off and dried (vacuum; 80°C), yielding 1.10 g of (+ )-cis-3-methoxy-1-[4-oxo- 4-(3,4,5-trimethoxyphenyl)-butyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (28%); m.p. 132.3°C (compound 1).
På lignende måte ble også følgende forbindelser fremstilt: 1-[4-okso-4-(3,4,5-trimetoksyfenyl)butyl)-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat-etandiolat (1:1); smp. 177,8°C (forbindelse 2); 1-[4-(4-etylfenyl)-4-oksobutyl]-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat, smp. 121,3°C (forbindelse 3); 1-[4-(3,5-diklorfenyl)-4-oksobutyl]-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat, smp. 122,6°C (forbindelse 4); 1- [4- (3,4-dimetoksyfenyl)-4-oksobutyl]-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat, smp. 156,3°C (forbindelse 5); 1- [4- (4-metoksyfenyl) -4-oksobutyl] -4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat, smp. 136,4°C (forbindelse 6); 1-[4-(4-metoksy-3, 5-dimetylfenyl)-4-oksobutyl]-4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzofurankarboksylat, (E)-2-butendiolat(1:1), smp. 171,2°C (forbindelse 7); In a similar manner, the following compounds were also prepared: 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl)-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7- benzofurancarboxylate-ethanediolate (1:1); m.p. 177.8°C (compound 2); 1-[4-(4-ethylphenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate, m.p. 121.3°C (compound 3); 1-[4-(3,5-dichlorophenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate, m.p. 122.6°C (compound 4); 1-[4-(3,4-dimethoxyphenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate, m.p. 156.3°C (compound 5); 1-[4-(4-methoxyphenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate, m.p. 136.4°C (compound 6); 1-[4-(4-Methoxy-3, 5-dimethylphenyl)-4-oxobutyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate, (E)-2- butenediolate (1:1), m.p. 171.2°C (compound 7);
Eksempel 5 Example 5
4-(4-hydroksy-l-piperidinyl)-1-(3,4,5-trimetoksyfenyl)-butanon (3,3 g) ble satt til en løsning av natriumhydrid (0,4 g) i tetrahydrofuran (100 ml) (løsning I) under en N2-strøm. En blanding av 5-amino-6-klor-3,4-dihydro-2H-l-ben-zopyran-8-karboksylsyre (2,14 g) og 1,1<1->karbonylbis-lH- 4-(4-hydroxy-1-piperidinyl)-1-(3,4,5-trimethoxyphenyl)-butanone (3.3 g) was added to a solution of sodium hydride (0.4 g) in tetrahydrofuran (100 ml) (solution I) under a stream of N2. A mixture of 5-amino-6-chloro-3,4-dihydro-2H-1-benzo-zopyran-8-carboxylic acid (2.14 g) and 1,1<1->carbonylbis-1H-
imidazol (2 g) i acetonitril (100 ml) ble rørt i 2 t ved romtemperatur og løsningsmidlet ble dampet av. Resten ble oppløst i tetrahydrofuran (100 ml) (løsning II) . Ved romtemperatur ble løsning (II) helt på løsning (I) , og reaksj onsblandingen ble rørt i 4 t ved romtemperatur. Løsnings-midlet ble dampet av. Resten ble fortynnet med vann og ekstrahert to ganger med CH2C12. Det separerte organiske skikt ble vasket med vann, tørket over MgS04, filtrert, og løsningsmidlet ble dampet av. Resten ble renset ved kolonnekromatograf i på kiselgel (elueringsmiddel: CH2Cl2/heks-an/CH3OH/NH3) 50/42/3) . De ønskede fraksjoner ble samlet opp og løsningsmidlet ble dampet av. Resten (2,3 g) ble renset ved HPLC på kiselgel (eluent: CH2Cl2/CH3OH 90/10). De rene fraksjoner ble samlet opp, og løsningsmidlet ble dampet av. Resten (1,2 g) ble krystallisert fra diisopropyleter. Bunnfallet ble filtrert av og tørket, hvilket ga 0,93 g 1- [4-okso-4- (3 ,4, 5-trimetyoksyfenyl) -butyl] -4-piperidinyl - 5 -amino- 6 -klor- 3,4 -dihydro-2H-benzopyran- 8 -karboksylat (17%); smp. 112,7°C (forbindelse 8). imidazole (2 g) in acetonitrile (100 ml) was stirred for 2 h at room temperature and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (100 ml) (solution II). At room temperature, solution (II) was poured onto solution (I), and the reaction mixture was stirred for 4 h at room temperature. The solvent was evaporated off. The residue was diluted with water and extracted twice with CH 2 Cl 2 . The separated organic layer was washed with water, dried over MgSO 4 , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/hex-an/CH3OH/NH3) 50/42/3). The desired fractions were collected and the solvent was evaporated. The residue (2.3 g) was purified by HPLC on silica gel (eluent: CH2Cl2/CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried to give 0.93 g of 1-[4-oxo-4-(3,4,5-trimethyloxyphenyl)-butyl]-4-piperidinyl-5-amino-6-chloro-3,4 -dihydro-2H-benzopyran-8-carboxylate (17%); m.p. 112.7°C (compound 8).
På lignende måte ble de følgende forbindelser fremstilt: 1-[4-okso-4-(3,4,5-trimetoksyfenyl)butyl] -4-piperidinyl-4-amino-5-klor-2, 3-dihydro-2, 2-dimetyl-7-benzofurankarboksylat; smp. 154,2°C (forbindelse 9); In a similar manner, the following compounds were prepared: 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-2, 2-dimethyl-7-benzofurancarboxylate; m.p. 154.2°C (compound 9);
1- [4-okso-4- (3,4,4-trimetoksyfenyl)butyl] -4-piperidinyl-4-amino-5-klor-2-metoksybenzoat-monohydrat; smp. 90°C (forbindelse 10) ; 1-[4-oxo-4-(3,4,4-trimethoxyphenyl)butyl]-4-piperidinyl-4-amino-5-chloro-2-methoxybenzoate monohydrate; m.p. 90°C (compound 10);
1-[4-okso-4- (3,4,5-trimetoksyfenyl)butyl]-4-piperidinyl-4-amino-5-klor-2-metyl-7-benzofurankarboksylat; smp. 128,6°C (forbindelse 11). 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl-4-amino-5-chloro-2-methyl-7-benzofurancarboxylate; m.p. 128.6°C (compound 11).
Eksempel 6 Example 6
En blanding av intermediat (12) (2,4 g) og saltsyre (noen få dråper) i vann (50 ml) ble omrørt ved romtemperatur. En løsning av kaliumisocyanat (2,5 g) i vann (50 ml) ble satt til, og den resulterende reaksjonsblanding ble omrørt og oppvarmet under tilbakeløp i 2 timer. Reaksjonsblandingen ble avkjølt, alkalisert med NH4OH, og deretter ekstrahert to ganger med CH2C12. Det separerte organiske skikt ble tørket over MgS04, filtrert, og løsningsmidlet ble dampet av. Resten (2,5 g) ble blandet med 1,1'-karbonylbis-lH-imidazol (0,93 g) i tetrahydrofuran (80 ml). Reaksjonsblandingen ble rørt og oppvarmet under tilbakeløp i 2 timer. Løsningsmidlet ble dampet av. Resten ble fortynnet med vann, og denne blanding ble ekstrahert to ganger med CH2C12. Det separerte organiske skikt ble vasket med vann, tørket over MgS04, filtrert, og løsningsmidlet ble dampet av. Resten ble krystallisert fra 2-propanon/metanol. Bunnfallet ble filtrert av og tørket, hvilket ga 0,53 g l-[4-(2, 3-dihydro-2-okso-lH-benzimidazol-5-yl) -4-oksobutyl] -4-piperidinyl-4-amino-5-klor-2,3-dihydro-7-benzof urankarbok-sylat (21,2%); smp. 272,7°C (forbindelse 12). A mixture of intermediate (12) (2.4 g) and hydrochloric acid (a few drops) in water (50 ml) was stirred at room temperature. A solution of potassium isocyanate (2.5 g) in water (50 ml) was added and the resulting reaction mixture was stirred and heated under reflux for 2 hours. The reaction mixture was cooled, basified with NH 4 OH, and then extracted twice with CH 2 Cl 2 . The separated organic layer was dried over MgSO 4 , filtered, and the solvent was evaporated. The residue (2.5 g) was mixed with 1,1'-carbonylbis-1H-imidazole (0.93 g) in tetrahydrofuran (80 ml). The reaction mixture was stirred and heated under reflux for 2 hours. The solvent was evaporated off. The residue was diluted with water and this mixture was extracted twice with CH 2 Cl 2 . The separated organic layer was washed with water, dried over MgSO 4 , filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone/methanol. The precipitate was filtered off and dried to give 0.53 g of 1-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-4-oxobutyl]-4-piperidinyl-4-amino -5-chloro-2,3-dihydro-7-benzofurancarboxylate (21.2%); m.p. 272.7°C (compound 12).
Eksempel 7 Example 7
En blanding av intermediat (12) (1,8 g), metyl-(a-imin-a-metoksymetyl ) karbamat (0,5 g) og eddiksyre (0,75 ml) i CHC13 (100 ml) ble omrørt og oppvarmet under tilbakeløp i 2 dager. Reaksj onsblandingen ble alkalisert med NH4OH. Det organiske skikt ble separert, og den vandige skikt ble ekstrahert med CH2C12. De kombinerte organiske skikt ble vasket med vann, tørket over MgS04, filtrert, og løsnings-midlet ble dampet av. Resten ble krystallisert to ganger fra metanol. Bunnfallet ble filtrert av og tørket, hvilket ga 0,4 g 1-[4- [2-[(metoksykarbonyl)amino]-lH-benzimidazol-5-yl]-4-oksobutyl]-4-piperidinyl-4-amino-5-klor-2,3-di-hydro-7-benzofurankarboksylat-monohydrat (18,7%); smp. 201,6°C (forbindelse 13). A mixture of intermediate (12) (1.8 g), methyl-(α-imine-α-methoxymethyl) carbamate (0.5 g) and acetic acid (0.75 mL) in CHCl 3 (100 mL) was stirred and heated under reflux for 2 days. The reaction mixture was basified with NH 4 OH. The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were washed with water, dried over MgSO 4 , filtered, and the solvent was evaporated. The residue was crystallized twice from methanol. The precipitate was filtered off and dried to give 0.4 g of 1-[4-[2-[(methoxycarbonyl)amino]-1H-benzimidazol-5-yl]-4-oxobutyl]-4-piperidinyl-4-amino- 5-chloro-2,3-dihydro-7-benzofurancarboxylate monohydrate (18.7%); m.p. 201.6°C (compound 13).
C. Farmakologisk eksempel C. Pharmacological example
Eksempel 8: Marsvin- ileum koaksial stimulering Example 8: Guinea pig ileum coaxial stimulation
Dunkin Hartley marsvin av begge kjønn (kroppsvekt +500 g) ble drept ved dekapitasjon. Ileum ble fjernet og renset med oppvarmet og oksygenert Krebs-Henseleit-løsning. 4,5 cm lange, ikke-terminale, intakte ileum-segmenter fra marsvin ble vertikalt suspendert med en "preload" på 1 g i 100 ml Krebs-Henseleit-løsning (37,5°C), gasset med en blanding av 95% Oj og 5% C02. Transmural eksitasjon ble påført over hele lengden av ileumsegmentet ved hjelp av to platinaelek-troder, idet anoden var tredd gjennom ileums lumen, og med katoden i badeløsningen. Preparasjonen ble eksitert med enkelte rektangulære stimuli [1 ms; 0,1 Hz; submaksimal respons (strøm som gir 80% av maksimal respons)] fra en programmerbar stimulator. Kontraksjoner ble målt isometri-sk. I løpet av stabiliseringsperioden på 3 0 min ble remsene gjentatte ganger strukket til en spenning på 2 g for å oppnå en steady state spenning på 1 g. Før igangsetting av den elektriske stimulering ble det gitt en kumulativ dose responskurve for acetylcholin. Den elektriske stimulering ble startet ved supramaksimal strøm for å bestemme den maksimale amplitude av rykke-responsen. Når disse response-ne var stabile, ble en submaksimal stimulering gitt for å erholde 80% av den maksimale respons inntil rykke-respon-sene var konstant i minst 15 min, hvoretter en enkelt dose av testforbindelsen ble satt til badefluidet. Amplituden på rykke-responsen 5 min etter administrasjon av testforbindelsen sammenlignes med amplituden før administrasjon av testf orbindelsen. Forbindelsene 1, 2, 7 og 13 viste en økt amplitude i rykke-responsen på mer enn 5% ved en konsentrasjon på 3, IO"9 M. Dunkin Hartley guinea pigs of both sexes (body weight +500 g) were killed by decapitation. The ileum was removed and cleaned with warmed and oxygenated Krebs-Henseleit solution. 4.5 cm long, non-terminal, intact guinea pig ileum segments were vertically suspended with a preload of 1 g in 100 ml of Krebs-Henseleit solution (37.5°C), gassed with a mixture of 95% Oj and 5% CO 2 . Transmural excitation was applied over the entire length of the ileum segment by means of two platinum electrodes, the anode being threaded through the lumen of the ileum, and with the cathode in the bath solution. The preparation was excited with single rectangular stimuli [1 ms; 0.1 Hz; submaximal response (current giving 80% of maximal response)] from a programmable stimulator. Contractions were measured isometrically. During the 30 min stabilization period, the strips were repeatedly stretched to a tension of 2 g to achieve a steady state tension of 1 g. Prior to initiating the electrical stimulation, a cumulative dose response curve for acetylcholine was provided. The electrical stimulation was started at supramaximal current to determine the maximal amplitude of the twitch response. When these responses were stable, a submaximal stimulation was given to obtain 80% of the maximal response until the startle responses were constant for at least 15 min, after which a single dose of the test compound was added to the bathing fluid. The amplitude of the startle response 5 min after administration of the test compound is compared with the amplitude before administration of the test compound. Compounds 1, 2, 7 and 13 showed an increased amplitude of the startle response of more than 5% at a concentration of 3.10"9 M.
Ytterligere resultater er gitt i Tabell A. Additional results are given in Table A.
Eksempel 9. Motilitet av colon i bevisst hund Example 9. Motility of the colon in a conscious dog
Beagle-tisper med en vekt på 7-17 kg ble implantert med isometriske kraft-transducere under generell anestesi og aseptiske betingelser. For å studere motilitet i colon ble transducere festet til colon med en avstand på 8, 16, 24 og 32 cm fra den ileo-caecale ventil. Hundene ble gitt en rekonvalesensperiode på minst to uker. Eksperimentene ble startet etter en fasteperiode på + 20 t, hvorunder vann var tilgjengelig ad libitum. Under eksperimentene fikk hundene bevege seg fritt i burene, under anvendelse av et telemetr-isk (trådløst) system. Burene var bygget i et spesielt rom utstyrt med glass som var gjennomskinnelig for lys i én retning, dvs. observatøren kunne se hundene, mens hundene ikke kunne se observatøren. Ved hjelp av dette system var det mulig å observere hundene for adferdsendringer og for å bestemme når de hadde avføring. Informasjon fra transduce-rne ble sendt i digitalisert form til en liten, spesialbygget sender-boks. Denne boksen var plassert i en jakke som hunden hadde på seg. Signalene ble mottatt via en mikrofon over hvert bur og ble sent til et sentralt compu-tersystem. En av parametrene i denne test er hundenes avfø-ring. I løpet av de første tre timene etter administrasjon av testforbindelsene ble hundene observert for å fastslå om avføring fant sted. Forbindelsene 1, 2, 5, 6, 12 og 13 induserte avføring i minst 50% av forsøksdyrene i mengder på 0,31 mg/kg i løpet av de første tre timer. Beagle bitches weighing 7-17 kg were implanted with isometric force transducers under general anesthesia and aseptic conditions. To study motility in the colon, transducers were attached to the colon at a distance of 8, 16, 24 and 32 cm from the ileo-caecal valve. The dogs were given a convalescence period of at least two weeks. The experiments were started after a fasting period of + 20 h, during which water was available ad libitum. During the experiments, the dogs were allowed to move freely in the cages, using a telemetric (wireless) system. The cages were built in a special room equipped with glass that was translucent to light in one direction, ie the observer could see the dogs, while the dogs could not see the observer. Using this system, it was possible to observe the dogs for behavioral changes and to determine when they defecated. Information from the transducers was sent in digitized form to a small, purpose-built transmitter box. This box was placed in a jacket that the dog was wearing. The signals were received via a microphone above each cage and sent to a central computer system. One of the parameters in this test is the dogs' excrement. During the first three hours after administration of the test compounds, the dogs were observed to determine if defecation occurred. Compounds 1, 2, 5, 6, 12 and 13 induced defecation in at least 50% of the test animals at amounts of 0.31 mg/kg during the first three hours.
D. Sammenligningseksempler D. Comparative examples
Forbindelser i EP-A-389 037 og EP-A-445 862 utviser også gastrointestinal prokinetisk aktivitet og ble sammenlignet med forbindelser av den foreliggende oppfinnelse. Compounds in EP-A-389 037 and EP-A-445 862 also exhibit gastrointestinal prokinetic activity and were compared with compounds of the present invention.
Forbindelse 28 i EP-A-389 037, referert til som "forbindelse A" gjennom denne tekst, er representert ved formelen: Compound 28 of EP-A-389 037, referred to as "compound A" throughout this text, is represented by the formula:
Forbindelse 1 i foreliggende søknad er representert ved formelen: Compound 1 in the present application is represented by the formula:
Forbindelse 47 i EP-A-445 862, referert til som "forbindelse B" gjennom denne tekst, er representert ved formelen: Compound 47 of EP-A-445 862, referred to as "compound B" throughout this text, is represented by the formula:
Forbindelse 2 i foreliggende søknad er representert ved formelen: Compound 2 in the present application is represented by the formula:
Således er den eneste strukturelle forskjell mellom tidligere kjente forbindelser A og B, og forbindelsene 1 og 2 av den foreliggende oppfinnelse erstatningen av -NH-gruppen med en -O-gruppe. Thus, the only structural difference between previously known compounds A and B, and compounds 1 and 2 of the present invention is the replacement of the -NH group with an -O group.
Forbindelsene 1 og 2, og forbindelsene A og B ble testet, ved forskjellige tider, i "gastrisk tømming av et kalorifattig flytende måltid forsinket ved administrasjon av lidamidin i bevisste hunder"-testen. Denne test demonstrerer de intestinale motilitets stimulerende egenskaper, spesielt den gastriske tømmingsaktivitet, og ble utført som beskrevet under: " Gastrisk tømming av et kalorifattig flytende måltid forsinket ved administrasjon av lidamidin i bevisste hunder" tester Compounds 1 and 2, and compounds A and B were tested, at different times, in the "gastric emptying of a low-calorie liquid meal delayed by administration of lidamidine in conscious dogs" test. This test demonstrates the intestinal motility stimulating properties, particularly the gastric emptying activity, and was performed as described under: "Gastric emptying of a low-calorie liquid meal delayed by administration of lidamidine in conscious dogs" tests
Hunn beagle-hunder, som veier 7-14 kg ble trenet til å stå stille i Pavlov-rammer. En gastrisk kanyle ble implantert under generell anestesi og aseptiske forhåndsregler. Etter en median laparatomi, ble et snitt gjort gjennom den gastriske vegg i den longitudinale retning mellom de større og mindre kurver, 2 cm over Latarjetnervene. Kanylen ble sikret/festet til den gastriske vegg ved hjelp av en dobbel snurpetråd sutur og brakt ut via et stikksår ved den ven-stre kvadrant av hypokondriet. Hundene ble gitt en rekonvalesensperiode på minst 2 uker. Female beagle dogs, weighing 7-14 kg were trained to stand still in Pavlov frames. A gastric cannula was implanted under general anesthesia and aseptic precautions. After a median laparotomy, an incision was made through the gastric wall in the longitudinal direction between the greater and lesser curves, 2 cm above the Latarjet nerves. The cannula was secured/attached to the gastric wall by means of a double barbed suture and brought out via a puncture wound at the left quadrant of the hypochondrium. The dogs were given a convalescence period of at least 2 weeks.
Eksperimentene ble startet etter en fasteperiode på 24 timer, i denne perioden var vann tilgjengelig ad liJbitum. Ved eksperimentets begynnelse ble kanylen åpnet for å fjerne all magesaft eller matrester. The experiments were started after a fasting period of 24 hours, during which time water was available ad liJbitum. At the beginning of the experiment, the cannula was opened to remove any gastric juice or food residues.
Magen ble renset med 40 til 50 ml lunkent vann. Test forbindelsen ble administrert I.V. (i et volum < 3 ml via vena kefalika) , S.C. (i et volum < 3 ml) eller P.O. (i et volum på 1 ml/kg kroppsvekt, applisert intragastrielt via kanylen med en anordning som fylte lumen av kanylen; etter injeksjon av testforbindelsen ble 5 ml NaCl 0,9% injisert for å korrigere for dødvolumet i injeksjonssystemet). Øyeblik-kelige etter administrasjon av testf orbindelsen eller dens løsningsmiddel ble lidamidin 0,63 mg/kg administrert sub-kutant. 3 0 minutter senere ble kanylen åpnet for å bestemme fluidmengden tilstede i magen, raskt etterfulgt av reintroduksjon av fluidet. Deretter ble testmåltidet administrert via kanylen. Dette testmåltid bestod av 250 ml destillert vann inneholdende glukose (5 g/l) som en markør. Kanylen forble lukket i 30 minutter, hvoretter det gastriske inn-hold ble trukket fra magen for å måle totalvolum (t=30 minutter) . For senere analyse ble 1 ml av mageinnholdet tatt, raskt etterfulgt av reintroduksjon av restvolumet inn i magen. Denne sekvens ble repetert 4 ganger med 3 0 minutters intervaller (t=60, 90, 120 og 150 minutter). The stomach was cleansed with 40 to 50 ml of lukewarm water. The test compound was administered I.V. (in a volume < 3 ml via vena cephalica) , S.C. (in a volume < 3 ml) or P.O. (in a volume of 1 ml/kg body weight, applied intragastrically via the cannula with a device that filled the lumen of the cannula; after injection of the test compound, 5 ml NaCl 0.9% was injected to correct for the dead volume in the injection system). Immediately after administration of the test compound or its solvent, lidamidine 0.63 mg/kg was administered subcutaneously. 30 minutes later, the cannula was opened to determine the amount of fluid present in the stomach, quickly followed by reintroduction of the fluid. Then the test meal was administered via the cannula. This test meal consisted of 250 ml of distilled water containing glucose (5 g/l) as a marker. The cannula remained closed for 30 minutes, after which the gastric contents were withdrawn from the stomach to measure total volume (t=30 minutes). For later analysis, 1 ml of the stomach contents was taken, quickly followed by reintroduction of the residual volume into the stomach. This sequence was repeated 4 times at 30 minute intervals (t=60, 90, 120 and 150 minutes).
Glukosekonsentrasjonene ble målt i 1 ml prøvene av mageinnholdet ble på en Hitachi 717 automatisk analysator ved heksokinasemetoden. Disse data ble anvendt for å bestemme den absolutte mengde av glukose som forble i magen etter hver 3 0 minutters periode, som et mål på restvolumet av måltidet i seg selv, uavhengig av syresekresjon. Glucose concentrations were measured in 1 ml samples of stomach contents on a Hitachi 717 automatic analyzer by the hexokinase method. These data were used to determine the absolute amount of glucose remaining in the stomach after each 30 minute period, as a measure of the residual volume of the meal itself, independent of acid secretion.
Kurver ble tilpasset til målepunktene (glukose versus tid) ved å anvende veiet ikke-lineær regresjonsanalyse. Gastrisk tømming ble kvantifisert som tiden nødvendig for å tømme 70% av måltidet (t70%) . Kontrolltømmetiden ble beregnet som gjennomsnittlig t70% av de siste 5 løsningsmiddeleksperi-menter i den samme hund. Akselerasjon av forsinket gastrisk tømming (At) tidsforskjellen mellom t70%forbindelse og tvoviasningsmiddei• J° mer negativ akselerasjon (At/t), jo bedre akselerere testforbindelsen gastrisk tømming. Curves were fitted to the measurement points (glucose versus time) using weighted non-linear regression analysis. Gastric emptying was quantified as the time required to empty 70% of the meal (t70%). The control emptying time was calculated as the average t70% of the last 5 solvent experiments in the same dog. Acceleration of delayed gastric emptying (At) the time difference between t70%compound and tvoviasningmiddei• J° more negative acceleration (At/t), the better the test compound accelerates gastric emptying.
Forbindelsene 1 og 2, og forbindelsene A og B ble også testet, ved forskjellige tider, i "Fekal pellet propulsjon i marsvin colon descendes"-testen. Denne test måler propulsjonen av fekal pelleter gjennom tykktarmen og demonstrerer de motilitetsøkende effekter på colon, som beskrevet i under: " Fekal pellet propulsjon i marsvin colon descendes" test Compounds 1 and 2, and compounds A and B were also tested, at different times, in the "Fecal pellet propulsion in guinea pig colon descendes" test. This test measures the propulsion of faecal pellets through the large intestine and demonstrates the motility-increasing effects on the colon, as described below: "Faecal pellet propulsion in guinea pig colon descendes" test
Dunkin-Hartley marsvin av begge kjønn (350 g eller mer, ikke fastet) ble avlivet ved cervikal dilokasjon etterfulgt av dekapitasjon. Colon descendes ble kuttet ved ±5 cm fra rektum, kuttet og underbundet i en lengde på ±4 0 cm og frigjort for vedhengende vev. Da det var minst 10 pelleter i colon ble vevet overført til et glassbeger inneholdende 200 ml Krebs-Henseleitsløsning, gasset med en blanding av 95% oksygen og 5% karbondioksid og holdt ved 37°C. Løsningen inneholdt enten rent løsningsmiddel eller testforbindelsen. De utdrevne pelletter ble talt og fjernet fra løsningen hvert 5 minutt under en maksimumsperiode på 60 minutter. Dunkin-Hartley guinea pigs of both sexes (350 g or more, not fasted) were euthanized by cervical dislocation followed by decapitation. The descending colon was cut at ±5 cm from the rectum, cut and ligated for a length of ±40 cm and freed of adherent tissue. When there were at least 10 pellets in the colon, the tissue was transferred to a glass beaker containing 200 ml Krebs-Henseleits solution, gassed with a mixture of 95% oxygen and 5% carbon dioxide and kept at 37°C. The solution contained either pure solvent or the test compound. The expelled pellets were counted and removed from the solution every 5 minutes for a maximum period of 60 minutes.
Det kumulative antall pelletter utdrevet fra colon ved hvert punkt ble uttrykket som prosenten av det totale antall pelletter tilstede i hele colon ved starten av eksperimentet. Tids-responskurver ble laget ved å plotte den kumulative prosent av pelletter utdrevet fra colon versus tid. For akselerasjonen av fekal pellett propulsjon ble prosenten av utdrevne pelletter etter 10 minutter anvendt som et mål på legemiddeleffekt. The cumulative number of pellets expelled from the colon at each point was expressed as a percentage of the total number of pellets present in the entire colon at the start of the experiment. Time-response curves were made by plotting the cumulative percentage of pellets expelled from the colon versus time. For the acceleration of faecal pellet propulsion, the percentage of expelled pellets after 10 minutes was used as a measure of drug effect.
Resultatene fra de "gastrisk tømming av et kalorifattig The results of the "gastric emptying of a low-calorie
flytende måltid forsinket ved administrasjon av lidamidin i bevisste hunder"-tester er vist i tabell 1, og resultatene fra de "Fekal pellet propulsjon i marsvin colon descendes"-tester er rapportert i tabell 2. liquid meal delayed by administration of lidamidine in conscious dogs" tests are shown in Table 1, and the results of the "Faecal pellet propulsion in guinea pig colon descendes" tests are reported in Table 2.
Det er åpenbart fra dataene i tabell 1 at forbindelsene 1 og 2 av den foreliggende oppfinnelse har bedre gastrisk tømmingsaktivitet enn de tidligere kjente forbindelser A og B, hvilket derved støtter de overlegende motilitetsøkende egenskaper til de foreliggende forbindelser. It is obvious from the data in Table 1 that the compounds 1 and 2 of the present invention have better gastric emptying activity than the previously known compounds A and B, thereby supporting the superior motility-increasing properties of the present compounds.
Tabell 2 Table 2
Akselerert fekal pellet propulsjon (%) i marsvin colon ved en konsentrasjon på 310"<6> M, 10"s M, 310"<7> M og IO"<7> M. Accelerated fecal pellet propulsion (%) in guinea pig colon at a concentration of 310"<6> M, 10"s M, 310"<7> M and IO"<7> M.
Som summert i tabell 2 er prosenten av utfrevne fekal pelletter etter 10 minutter høyere for forbindelsene 1 og 2 av den foreliggende oppfinnelse sammenlignet med tidligere kjente forbindelser A og B, hvilket derved dokumenterer de overlegende motilitetsøkende egenskaper til de foreliggende forbindelser. As summarized in table 2, the percentage of exfoliated faecal pellets after 10 minutes is higher for compounds 1 and 2 of the present invention compared to previously known compounds A and B, which thereby documents the superior motility-increasing properties of the present compounds.
Konklusjon Conclusion
Forbindelsene 1 og 2 av den foreliggende søknad har overlegene motitlitetsøkende egenskaper sammenlignet med tidligere kjente forbindelser A og B, som vist ved resultatene fremsatt i tabell 1 og 2. Compounds 1 and 2 of the present application have superior antitrust-increasing properties compared to previously known compounds A and B, as shown by the results presented in Tables 1 and 2.
E. Sammensetningseksempler E. Composition examples
De følgende sammensetninger eksemplifiserer typiske farma-søytiske sammensetninger i doseringsenhetsf orm egnet for systemisk eller topisk administrasjon til varmblodige dyr i henhold til foreliggende oppfinnelse. The following compositions exemplify typical pharmaceutical compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals according to the present invention.
"Aktiv ingrediens" (A.I.) som anvendt i disse eksempler vedrører en forbindelse med formel (I) , en N-oksidform, et farmasøytisk akseptabelt syreaddisjonssalt eller en stereokjemisk isomer form derav. "Active ingredient" (A.I.) as used in these examples refers to a compound of formula (I), an N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
Eksempel 10: Orale løsninger Example 10: Oral solutions
9 g metyl-4-hydroksybenzoat og 1 g propyl-4-hydroksybenzoat løses opp i 4 1 kokende renset vann. 10 g 2,3-dihydroksybu-tandionsyre og deretter 20 g A.I. løses opp i 3 1 av denne løsning. Denne blanding kombineres med den gjenværende del av den førstnevnte løsning, og 12 1 1,2,3-propantriol og 3 1 sorbitol 70% løsning settes til. 40 g natriumsakkarin oppløses i 0,5 1 vann, og 2 ml bringebæres sens og 2 ml 9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate are dissolved in 4 1 of boiling purified water. 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of A.I. dissolve in 3 1 of this solution. This mixture is combined with the remaining part of the first-mentioned solution, and 12 1 of 1,2,3-propanetriol and 3 1 of sorbitol 70% solution are added. Dissolve 40 g of sodium saccharin in 0.5 l of water, and 2 ml of raspberry sens and 2 ml
stikkelsbæressens settes til. Den sistnevnte løsning kombineres med den forrige, vann settes til q.s. til et volum på 20 1, hvilket tilveiebringer en oral løsning omfattende 5 g A. I. pr. teskjefull (5 ml). Den resulterende løsning fylles i passende beholdere. thorn berry essence is added. The latter solution is combined with the former, water is added to q.s. to a volume of 20 1, which provides an oral solution comprising 5 g A. I. per teaspoonful (5 ml). The resulting solution is filled into suitable containers.
Eksempel 11: Kapsler Example 11: Capsules
20 g A.I., 6 g natriumlaurylsulfat, 56 g stivelse, 56 g laktose, 0,8 g kolloidal silikondioksid og 1,2 g magne-siumstearat blandes godt sammen. Den resulterende blanding fylles deretter på 100 egnede hardnede gelatinkapsler, hver inneholdende 20 mg A.I. 20 g of A.I., 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.2 g of magnesium stearate are mixed well together. The resulting mixture is then filled into 100 suitable hardened gelatin capsules, each containing 20 mg of A.I.
Eksempel 12: Filmbelagte tabletter Example 12: Film-coated tablets
Fremstilling av tablettkjerne Production of tablet core
En blanding av 100 g A. I., 570 g laktose og 200 g stivelse blandes godt og fuktes deretter med en løsning av 5 g natriumdodeculsulfat og 10 g polyvinylpyrrolidon i omkring 200 ml vann. Den våte pulverblanding siktes, tørkes og siktes igjen. Deretter settes det til 100 g mikrokry-stallinsk cellulose og 15 g hydrogenert vegetabilsk olje. Det hele blandes godt og komprimeres til tabletter, hvilket gir 10.000 tabletter som hver inneholder 10 mg av den aktive ingrediens. A mixture of 100 g of A.I., 570 g of lactose and 200 g of starch is mixed well and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are then added. The whole is mixed well and compressed into tablets, which gives 10,000 tablets each containing 10 mg of the active ingredient.
Belegg Coating
En løsning av 10 g metylcellulose i 75 ml denaturert etanol ble tilsatt en løsning av 5 g etylcellulose i 150 ml diklor metan. Deretter settes det til 75 ml diklormetan og 2,5 ml 1,2,3-propantriol. 10 g polyetylenglykol smeltes og løses i 75 ml diklormetan. Den sistnevnte løsning settes til den forrige, og deretter settes det til 2,5 g magne-siumoktadekanoat, 5 g polyvinylpyrrolidon og 3 0 ml konsentrert fargesuspensjon, og det hele homogeniseres. Tablettkjernene belegges med blandingen erholdt på denne måte i et belegningsapparat. A solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added to a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are then added. 10 g of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the previous one, and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension are added, and the whole is homogenized. The tablet cores are coated with the mixture obtained in this way in a coating apparatus.
Eksempel 13: Injiserbar løsning Example 13: Injectable solution
1,8 g metyl-4-hydroksybenzoat og 0,2 g propyl-4-hydroksy-benzoat ble oppløst i ca. 0,5 1 kokende vann for injise-ring. Etter avkjøling til omtrent 50°C ble det satt til 4 g melkesyre, 0,05 g propylenglykol og 4 g A.I. under omrø-ring. Løsningen ble avkjølt til romtemperatur og supple-mentert med vann for injeksjon q.s. til 1 1 volum, hvilket gir en løsning med 4 mg/ml av A.I. Løsningen ble sterili-sert ved filtrering (U.S.P. XVII s. 811) og fylt på sterile beholdere. 1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate were dissolved in approx. 0.5 1 boiling water for injection. After cooling to approximately 50°C, 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of A.I. while stirring. The solution was cooled to room temperature and supplemented with water for injection q.s. to 1 1 volume, giving a solution with 4 mg/ml of A.I. The solution was sterilized by filtration (U.S.P. XVII p. 811) and filled into sterile containers.
Eksempel 14: Suppositorier Example 14: Suppositories
3 g A.I. ble opløst i en løsning av 3 g 2,3-dihydroksy-butandionsyre i 25 ml polyetylenglykol 400. 12 g surfaktant og triglycerider q.s. til 3 00 g ble smeltet sammen. Den sistnevnte blanding ble godt blandet med den førstnevnte løsning. Den således erholdte blanding ble helt i former ved en temperatur på 37-38°C for å danne 100 suppositorier som hver inneholder 3 0 mg av den aktive ingrediens. 3g A.I. was dissolved in a solution of 3 g of 2,3-dihydroxybutanedioic acid in 25 ml of polyethylene glycol 400. 12 g of surfactant and triglycerides q.s. until 300 g was fused. The latter mixture was well mixed with the former solution. The mixture thus obtained was poured into molds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg of the active ingredient.
Claims (11)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94202791 | 1994-09-27 | ||
US45477695A | 1995-05-31 | 1995-05-31 | |
PCT/EP1995/003690 WO1996010026A1 (en) | 1994-09-27 | 1995-09-19 | Phenyl-oxo-alkyl-(4-piperidinyl)benzoate derivatives |
Publications (3)
Publication Number | Publication Date |
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NO971375D0 NO971375D0 (en) | 1997-03-24 |
NO971375L NO971375L (en) | 1997-05-05 |
NO311673B1 true NO311673B1 (en) | 2002-01-02 |
Family
ID=26136611
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO19971375A NO311673B1 (en) | 1994-09-27 | 1997-03-24 | Phenyl-oxo-alkyl (4-piperidinyl) benzoate |
Country Status (7)
Country | Link |
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CZ (1) | CZ288942B6 (en) |
HU (1) | HUT77311A (en) |
IL (1) | IL115412A (en) |
MY (1) | MY117105A (en) |
NO (1) | NO311673B1 (en) |
NZ (1) | NZ293604A (en) |
PL (1) | PL182174B1 (en) |
-
1995
- 1995-09-19 CZ CZ1997919A patent/CZ288942B6/en not_active IP Right Cessation
- 1995-09-19 NZ NZ293604A patent/NZ293604A/en not_active IP Right Cessation
- 1995-09-19 HU HU9701818A patent/HUT77311A/en unknown
- 1995-09-19 PL PL95319998A patent/PL182174B1/en not_active IP Right Cessation
- 1995-09-22 IL IL11541295A patent/IL115412A/en not_active IP Right Cessation
- 1995-09-26 MY MYPI95002871A patent/MY117105A/en unknown
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1997
- 1997-03-24 NO NO19971375A patent/NO311673B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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NZ293604A (en) | 1998-07-28 |
NO971375D0 (en) | 1997-03-24 |
HUT77311A (en) | 1998-03-30 |
CZ288942B6 (en) | 2001-10-17 |
MX9702356A (en) | 1997-10-31 |
NO971375L (en) | 1997-05-05 |
PL182174B1 (en) | 2001-11-30 |
CZ91997A3 (en) | 1997-12-17 |
IL115412A0 (en) | 1995-12-31 |
PL319998A1 (en) | 1997-09-01 |
MY117105A (en) | 2004-05-31 |
IL115412A (en) | 2000-02-17 |
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