NO862241L - NEW PARA-SUBSTITUTED 3-PHENOXY-1-PIPERIDINE CARBONYLAMINOALKYLAMINO-PROPANOL-2 COMPOUNDS WITH BETA-RECEPTOR BLOCKING PROPERTIES AND PROCEDURES FOR THEIR PREPARATION. - Google Patents
NEW PARA-SUBSTITUTED 3-PHENOXY-1-PIPERIDINE CARBONYLAMINOALKYLAMINO-PROPANOL-2 COMPOUNDS WITH BETA-RECEPTOR BLOCKING PROPERTIES AND PROCEDURES FOR THEIR PREPARATION.Info
- Publication number
- NO862241L NO862241L NO862241A NO862241A NO862241L NO 862241 L NO862241 L NO 862241L NO 862241 A NO862241 A NO 862241A NO 862241 A NO862241 A NO 862241A NO 862241 L NO862241 L NO 862241L
- Authority
- NO
- Norway
- Prior art keywords
- group
- formula
- compound
- hydroxy
- integer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
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- 108010079452 beta Adrenergic Receptors Proteins 0.000 title abstract description 4
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 9
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- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Nye forbindelser med den generelle formel:. hvor R^" er hydrogen, hvilke forbindelser har. en særlig høy og selektiv affinitet for beta -. reseptorer. Forbindelser med formel I hvor R1. er en acylgruppe kan gi forbindelser med formel. (I) hvor R er H ved biotransformasjon.I formel (I) er Ar en aromatisk eller heteroaromatisk gruppe, definert ved formelen:hvor m er et helt tall 0 eller 1, n er et helt tall 1-3, forutsatt at n er et helt tall 2-3 når 2 3 3 m er 1, og R er en gruppe -O-R , -O-ICH^) O-R , en pyrazolgruppe eller en gruppe -NH^NHRJ i hvilke grupper q er et helt tall 2-3, og R en rett ellerorgrenet alkylgruppe med 1-8 karbonatomer eller en cykloalkylalkylgruppe med 4-8 karbonatomer, og X er N eller C-R, hvor R er H, CN eller OCH. I acylgruppen. er p et helt tall 0 eller 1, og R er en alifatisk, cykloalifatisk eller aromatisk gruppe, idet hver nevnte gruppe eventuelt er substituert eller avbrutt av heteroatomer.Det er også beskrevet fremgangsmåter for fremstilling av slike forbindelser, farmasøytiske preparater derav og behandlingsmetoder som benytter slike.New compounds with the general formula :. wherein R 1 is hydrogen, which compounds have a particularly high and selective affinity for beta receptors. Compounds of formula I wherein R 1 is an acyl group may give compounds of formula. formula (I) Ar is an aromatic or heteroaromatic group, defined by the formula: where m is an integer 0 or 1, n is an integer 1-3, provided that n is an integer 2-3 when 2 3 3 m is 1 and R is a group -OR, -O-ICH 2) OR, a pyrazole group or a group -NH 2 NHR 2 in which groups q is an integer 2-3, and R is a straight or unbranched alkyl group having 1-8 carbon atoms or a cycloalkylalkyl group having 4-8 carbon atoms, and X is N or CR, where R is H, CN or OCH. each said group is optionally substituted or interrupted by heteroatoms. There are also described processes for the preparation of such compounds, pharmaceutical compositions thereof and treatment methods that use such.
Description
Foreliggende oppfinnelse vedrører nye p-reseptorblokkerende forbindelser og fremgangsmåte for deres fremstilling. De nye forbindelsene er beregnet for bruk i behandlingen av hypertensjon, ischemisk hjerte-sykdom, glaukom og andre mulige indikasjoner hvor p<->adrenoseptor-blokkere har en nytteeffekt. The present invention relates to new β-receptor blocking compounds and methods for their production. The new compounds are intended for use in the treatment of hypertension, ischemic heart disease, glaucoma and other possible indications where p<->adrenoceptor blockers have a beneficial effect.
Siden tidlig i 1960-årene har det blitt utviklet et meget stort antall p-reseptorblokkerende forbindelser. Disse forbindelsene er ofte gruppert i to forbindelseskategorier, en hvor en grad av selektiv aktivitet på<p>j-reseptorer vises, og en hvor aktiviteten er vesentlig ikke-selektiv mellom P-reseptorer. I begge kategorier finnes forbindelser som har en mer eller mindre uttalt intrinsik sympatomimetisk (p-stimulerende) aktivitet, samt forbindelser som i det vesentlige mangler en slik stimulerende aktivitet. Mange av de således kjente forbindelsene og særlig de fleste forbindelser som har blitt utviklet til godkjente farmasøytika, har den felles strukturen Since the early 1960s, a very large number of β-receptor blocking compounds have been developed. These compounds are often grouped into two compound categories, one where a degree of selective activity on <p>j receptors is shown, and one where the activity is substantially non-selective between P receptors. In both categories there are compounds that have a more or less pronounced intrinsic sympathomimetic (β-stimulating) activity, as well as compounds that essentially lack such stimulating activity. Many of the compounds thus known, and especially most of the compounds that have been developed into approved pharmaceuticals, have the common structure
hvor R er en forgrenet laverealkylgruppe slik som isopropyl eller tert.-butyl, eller iblant en substituert laverealkylgruppe, og Ar er en aromatisk eller heteroaromatisk gruppe, typisk en fenylgruppe som er substituert i 4- og/eller 2-stillingen med et alifatisk eller heteroalifatisk hydro-karbon som kan være ytterligere substituert og eventuelt et halogenatom. Variasjon i gruppen Ar illustreres ved henvisning til kjente forbindelser slik som alprenolol, atenolol, betaksolol, celiprolol, metoprolol, nadolol, oksprenolol, pafenolol, pindolol, propranolol, sotalol og timolol. where R is a branched lower alkyl group such as isopropyl or tert.-butyl, or sometimes a substituted lower alkyl group, and Ar is an aromatic or heteroaromatic group, typically a phenyl group which is substituted in the 4- and/or 2-position with an aliphatic or heteroaliphatic hydrocarbon which may be further substituted and optionally a halogen atom. Variation in the group Ar is illustrated by reference to known compounds such as alprenolol, atenolol, betaxolol, celiprolol, metoprolol, nadolol, oxprenolol, pafenolol, pindolol, propranolol, sotalol and timolol.
Formålet med foreliggende oppfinnelse er å tilveiebringe p<->adrenoseptor-blokkere som er kjennetegnet ved en meget høy selektivitet med henblikk på affinitet til perifere<p>j-adrenoseptorer og en lang virkningsvarighet. Oppfinnelsen omfatter både forbindelser med en moderat grad av intrinsik sympatomimetisk aktivitet og forbindelser uten noen reseptor-stimulerende effekter. The purpose of the present invention is to provide p<->adrenoceptor blockers which are characterized by a very high selectivity with regard to affinity to peripheral<p>j-adrenoceptors and a long duration of action. The invention encompasses both compounds with a moderate degree of intrinsic sympathomimetic activity and compounds without any receptor-stimulating effects.
En sterktPj-selektiv blokker ville være nyttig ved å forårsake en mindre grad av p-blokkade og således uønskede bivirkninger ved høyere doser. I noen situasjoner slik som markert bradikardi og forventet hjertesvikt, antas en -selektiv blokker med en moderat grad av partiell agonist-aktivitet å være terapeutisk fordelaktig. A highly β-selective blocker would be useful by causing a lesser degree of β-blockade and thus unwanted side effects at higher doses. In some situations such as marked bradycardia and anticipated heart failure, a -selective blocker with a moderate degree of partial agonist activity is thought to be therapeutically beneficial.
Ifølge foreliggende oppfinnelse er det funnet at forbindelser med den generelle formel According to the present invention, it has been found that compounds with the general formula
hvor Ri er hydrogen, har særlig høy og selektiv affinitet for & i-reseptorer, og at forbindelser med formel I hvor R<*>er en acylgruppe -C(0)pR^ kan gi forbindelser med formel I hvor R<*>er H ved bio- o transformasjon og utøve sin aktivitet etter å ha blitt transformert. where Ri is hydrogen, has particularly high and selective affinity for & i receptors, and that compounds of formula I where R<*> is an acyl group -C(0)pR^ can give compounds of formula I where R<*> is H by bio- o transformation and exercise its activity after being transformed.
Det vesentlige ved foreliggende oppfinnelse ligger i tilveiebringelsen av sidekjeden The essence of the present invention lies in the provision of the side chain
som kan benyttes på forskjellige aromatiske eller heteroaromatiske grupper Ar, hvilke er nyttige i kjente forbindelser, og som eventuelt er forestret ved OH-gruppen på piperidindelen. I formel I er således Ar en aromatisk eller heteroaromatisk gruppe som kjent innen teknikken. Ikke desto mindre gir underklasser av Ar-grupper samt spesifikke Ar-grupper forbindelser med spesielt fordelaktige egenskaper. Spesielt er Ar definert ved formelen: which can be used on various aromatic or heteroaromatic groups Ar, which are useful in known compounds, and which are optionally esterified at the OH group on the piperidine part. Thus, in formula I, Ar is an aromatic or heteroaromatic group as known in the art. Nevertheless, subclasses of Ar groups as well as specific Ar groups provide compounds with particularly advantageous properties. In particular, Ar is defined by the formula:
hvor m er et helt tall 0 eller 1, n er et helt tall fra 1 til 3, forutsatt at n er et helt tall 2 eller 3 når m er 1 og R^ er en gruppe -O-R<3>, -0-(CH2)qO-R<3>, en pyrazolgruppe eller en gruppe -NHCNHR<3>, hvor Q er et helt tall 2 eller 3, og R<3>er en rest eller forgrenet alkylgruppe med 1-8 karbonatomer eller en cykloalkylalkylgruppe med 4-8 karbonatomer, og X er N eller C-R, hvor R er H, CN eller OCH3. where m is an integer 0 or 1, n is an integer from 1 to 3, provided that n is an integer 2 or 3 when m is 1 and R^ is a group -O-R<3>, -0-( CH2)qO-R<3>, a pyrazole group or a group -NHCNHR<3>, where Q is an integer 2 or 3, and R<3> is a residual or branched alkyl group of 1-8 carbon atoms or a cycloalkylalkyl group of 4-8 carbon atoms, and X is N or C-R, where R is H, CN or OCH3.
I acylgruppen -C(0)pR<4>er p et helt tall, 0 eller 1, og R4er en ali- tt 0 In the acyl group -C(0)pR<4>p is an integer, 0 or 1, and R4 is an ali- tt 0
fatisk, cykloalifatisk eller aromatisk gruppe slik som en rett eller forgrenet alkylgruppe med 1-20 karbonatomer, en cykloalkyl- eller cykloalkylalkylgruppe inneholdende 3-20 karbonatomer, en fenyl-, fenoksy-, fenoksymetyl-, benzyl- eller fenyletylgruppe, idet hver av de nevnte gruppene eventuelt er substituert og/eller hver av de nevnte grupper eventuelt er avbrutt av heteroatomer. phatic, cycloaliphatic or aromatic group such as a straight or branched alkyl group of 1-20 carbon atoms, a cycloalkyl or cycloalkylalkyl group containing 3-20 carbon atoms, a phenyl, phenoxy, phenoxymethyl, benzyl or phenylethyl group, each of the said the groups are optionally substituted and/or each of the said groups is optionally interrupted by heteroatoms.
'Foretrukne forbindelser i foreliggende oppfinnelse er de forbindelser med formel I hvor X er CH og spesielt de forbindelser hvor Ar er Preferred compounds in the present invention are those compounds of formula I where X is CH and especially those compounds where Ar is
Forbindelsene med formel I hvor R^ er hydrogen, har den ønskede affinitet til perifere Pi-adrenoseptorer. Forbindelser hvor R^ er en acylgruppe, samt andre prolegemidler eller bioforløpere til forbindelsene hvor Rj er hydrogen, hvilke kan unnfanges i ytterligere oppfinnelser eller ved å benytte vanlig kunnskap innen teknikken, utøver sin aktivitet etter biotransformasjon i levende organismer til forbindelser hvor R^ er hydrogen eller kan til en viss grad inneha slik aktivitet i seg selv. The compounds of formula I where R 1 is hydrogen have the desired affinity for peripheral P 1 adrenoceptors. Compounds where R^ is an acyl group, as well as other prodrugs or bioprecursors to the compounds where Rj is hydrogen, which can be conceived in further inventions or by using common knowledge in the art, exert their activity after biotransformation in living organisms to compounds where R^ is hydrogen or may to some extent possess such activity in itself.
Forbindelser i foreliggende oppfinnelse kan benyttes som basene eller farmasøytisk akseptable salter derav. Compounds of the present invention can be used as the bases or pharmaceutically acceptable salts thereof.
Saltdannende syrer kan benyttes ved fremstilling av farmasøytisk akseptable salter av forbindelsene. Disse er: Hydrohalogensyrer, svovelsyre, fosforsyre, salpetersyre, perklorsyre, alifatiske, alicykliske, aromatiske eller heterocykliske karboksy- eller sulfonsyrer slik som maursyre, eddiksyre, propionsyre, ravsyre, glykolsyre, melkesyre, eplesyre, vinsyre, sitronsyre, askorbinsyre, maleinsyre, hydroksymalein-syre, eller pyrodruesyre, fenyleddiksyre, benzosyre, p-aminobenzosyre, antranilsyre, p-hydroksybenzosyre, salisylsyre eller p-aminosalisylsyre, palmoinsyre, metansulfonsyre, etansulfonsyre, hydroksyetansulfonsyre, etylensulfonsyre, halogenbenzensulfonsyre, toluensulfonsyre, naftylsulfon-syre eller sulfanilsyre, metionin, tryptofan, lysin eller arginin. Salt-forming acids can be used in the preparation of pharmaceutically acceptable salts of the compounds. These are: Hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid acid, or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, palmoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or arginine.
Forbindelsene i foreliggende oppfinnelse kan fremstilles som angitt nedenfor. The compounds in the present invention can be prepared as indicated below.
For hensiktsmessighetens skyld betegnes delen i formel I For convenience, the part is denoted by formula I
som R<N>. as R<N>.
I gruppene R<N>og Ar er R<1>, R<2>, r<3>, r<4>og n som definert i forbindelse In the groups R<N>and Ar, R<1>, R<2>, r<3>, r<4>and n are as defined in connection
med de spesifiserte formlene. with the specified formulas.
Forbindelsene med formel I oppnås i overensstemmelse med metoder slik som de følgende: The compounds of formula I are obtained in accordance with methods such as the following:
a) Omsetning av en forbindelse med formelen: a) Reaction of a compound with the formula:
eller hvor X<*>er en hydroksygruppe, Z er en hydroksygruppe eller en reaktiv, forestret hydroksygruppe, eller X^ og Z danner sammen en epoksygruppe, med en forbindelse mede formelen: or where X<*> is a hydroxy group, Z is a hydroxy group or a reactive, esterified hydroxy group, or X^ and Z together form an epoxy group, with a compound of the formula:
Når Z er en reaktiv, forestret hydroksygruppe, er den spesielt en hydroksygruppe forestret med en sterk, uorganisk syre, fortrinnsvis en hydrohalogensyre slik som saltsyre, hydrobromsyre eller hydroiodsyre, dessuten svovelsyre eller en sterk, organisk sulfonsyre, f.eks. metansulfonsyre, trifluormetansulfonsyre, benzensulfonsyre, 4-brombenzen-sulfonsyre eller 4-toluensulfonsyre. Z er spesielt klor, brom, iod, metansulfonyl, trifluormetansulfonyl eller 4-toluensulfonyl. When Z is a reactive, esterified hydroxy group, it is in particular a hydroxy group esterified with a strong inorganic acid, preferably a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, also sulfuric acid or a strong organic sulphonic acid, e.g. methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Z is in particular chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl or 4-toluenesulfonyl.
Ved bruken av en reaktiv ester som et utgangsmateriale utføres reaksjonen fortrinnsvis i nærvær av et basisk kondensasjonsmiddel og/eller med hvor Ri har den ovenfor angitte betydning, og Y er en avspaltningsgruppe slik som halogen, alkoksy, aryloksy eller acyloksy. When using a reactive ester as a starting material, the reaction is preferably carried out in the presence of a basic condensing agent and/or with where Ri has the above meaning, and Y is a leaving group such as halogen, alkoxy, aryloxy or acyloxy.
f) Avspalting av en rest fra en forbindelse med formel I som angitt ovenfor, ytterligere substituert med en rest slik som en benzyl- eller •substituert benzylgruppe ved et heteroatom. f) Cleavage of a residue from a compound of formula I as indicated above, further substituted with a residue such as a benzyl or •substituted benzyl group at a heteroatom.
g) Omdannelse av en forbindelse med formelen g) Transformation of a compound with the formula
hvor X^ er en gruppe inneholdende en eller flere karbon-karbon--umetninger og kan omdannes til gruppen (0)m(CH2)n-R^ ved metning av hver slik umetning deri. where X^ is a group containing one or more carbon-carbon unsaturations and can be converted into the group (O)m(CH2)n-R^ by saturation of each such unsaturation therein.
h) Reduksjon av en Schiffs base med formelen: h) Reduction of a Schiff's base with the formula:
Denne reduksjonen utføres på vanlig måte, f.eks. ved bruk av et di-lettmetallhydrid, ved bruk av et hydrid slik som et boran med maursyre, eller ved hjelp av en katalytisk hydrogenering, f.eks. med hydrogen i nærvær av Raney-nikkel. Ved reduksjonen må det sørges for at andre grupper ikke påvirkes. This reduction is carried out in the usual way, e.g. using a di-light metal hydride, using a hydride such as a borane with formic acid, or by means of a catalytic hydrogenation, e.g. with hydrogen in the presence of Raney nickel. During the reduction, it must be ensured that other groups are not affected.
i) Reduksjon av okso-gruppen til en hydroksygruppe i en forbindelse med formelen: i) Reduction of the oxo group to a hydroxy group in a compound of the formula:
Denne reduksjonen utføres på vanlig måte, spesielt ved bruk av et hydrid, som nevnt ovenfor. Reduksjonen kan også foretas i nærvær av chirale ligander, og derved gi opphav til ulike mengder av enantiomerene. Reduksjonen kan også utføres enzymatisk. This reduction is carried out in the usual way, especially using a hydride, as mentioned above. The reduction can also be carried out in the presence of chiral ligands, thereby giving rise to different amounts of the enantiomers. The reduction can also be carried out enzymatically.
j) Reduksjon av en amidisk karbonylgruppe i en forbindelse med en av formlene j) Reduction of an amidic carbonyl group in a compound of one of the formulas
Reduksjonen kan utføres på den ovenfor beskrevne måten ved bruk av komplekse metallhydrider, f.eks. litiumaluminiumhydrid eller di-isobutyl-aluminiumhydrid. Reaksjonen finner hensiktsmessig sted i et inert oppløsningsmiddel slik som en eter, f.eks. dietyleter eller tetrahydrofuran. Komplekse borhydrider kan også anvendes spesielt når en selektiv reaksjon er ønsket. The reduction can be carried out in the manner described above using complex metal hydrides, e.g. lithium aluminum hydride or diisobutyl aluminum hydride. The reaction conveniently takes place in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran. Complex borohydrides can also be used especially when a selective reaction is desired.
k) For dannelse av en forbindelse med formel I hvor R^ er en acylgruppe -C(0)pR<4>, omsetning av den tilsvarende forbindelsen hvor Ri er H med en°syre eller et syrederivat med formelen: k) For the formation of a compound of formula I where R^ is an acyl group -C(0)pR<4>, reaction of the corresponding compound where Ri is H with an acid or an acid derivative of the formula:
hvor Z<*>er en hydroksygruppe eller en reaktiv gruppe som definert for en reaktiv forestret hydroksygruppe Z ovenfor. where Z<*> is a hydroxy group or a reactive group as defined for a reactive esterified hydroxy group Z above.
1) Omsetning av en forbindelse med formelen: 1) Reaction of a compound with the formula:
hvor nitrogenatomet tilstøtende propanolgruppen kan bære en beskyttende grupper, f.eks. en benzylgruppe, og hvor Y er en avspaltningsgruppe slik som halogen, alkoksy, aryloksy eller acyloksy, med en forbindelse med formelen: where the nitrogen atom adjacent to the propanol group can carry a protective group, e.g. a benzyl group, and where Y is a leaving group such as halogen, alkoxy, aryloxy or acyloxy, with a compound of the formula:
hvor Ri har den ovenfor angitte betydning. where Ri has the above meaning.
Avhengig av prosessbetingelsene og utgangsmaterialet oppnås sluttproduktet enten i fri form eller i form av dens syreaddisjonssalt, som omfattes av foreliggende oppfinnelse. Således kan f.eks. basiske, nøytrale eller blandede salter oppnås, samt hemiamino, sesqui- eller polyhydrater. Syreaddisjonsaltene av de nye forbindelsene kan på i og for seg kjent måte overføres til frie forbindelser ved bruk f .eks. av basiske midler, slik som alkali eller ioneutveksler. På den annen side kan de oppnådde frie baser danne salter med organiske eller uorganiske syrer. Ved fremstillingen av syreaddisjonssaltene anvendes fortrinnsvis slike syrer som danner egnede farmasøytisk akseptable salter. Eksempler på slike syrer er gitt ovenfor. Depending on the process conditions and the starting material, the end product is obtained either in free form or in the form of its acid addition salt, which is covered by the present invention. Thus, e.g. basic, neutral or mixed salts are obtained, as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds can be transferred in a manner known per se to free compounds using e.g. of basic agents, such as alkali or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of the acid addition salts, such acids are preferably used which form suitable pharmaceutically acceptable salts. Examples of such acids are given above.
Disse eller andre salter av de nye forbindelsene som f.eks. pikrater, kan tjene som rensemidler for de oppnådde frie baser når de frie basene omdannes til salter, disse separeres, og basene frigjøres deretter fra saltene igjen. Ifølge det nære slektskapet mellom de nye forbindelsene i den frie formen og i form av deres salter, vil det fra det ovenstående forstås at henvisning til den frie forbindelsen, om mulig og med mindre annet er angitt, også skal tas som en henvisning til de tilsvarende salter. These or other salts of the new compounds such as e.g. picrates, can serve as cleaning agents for the obtained free bases when the free bases are converted into salts, these are separated, and the bases are then released from the salts again. According to the close relationship between the new compounds in the free form and in the form of their salts, it will be understood from the above that reference to the free compound, if possible and unless otherwise indicated, should also be taken as a reference to the corresponding salts.
Siden forbindelsene i foreliggende oppfinnelse er minst et asymmetrisk karbonatom, omfatter oppfinnelsen alle mulige isomerer av forbindelsene. De nye forbindelsene kan således, avhengig av valget av utgangsmaterialer og fremgangsmåte, være til stede som optiske antipoder eller racemat, eller, dersom de inneholder minst to asymetriske karbonatomer, være til stede som en isomerblanding (racematblanding). Since the compounds in the present invention have at least one asymmetric carbon atom, the invention encompasses all possible isomers of the compounds. The new compounds can thus, depending on the choice of starting materials and method, be present as optical antipodes or racemate, or, if they contain at least two asymmetric carbon atoms, be present as an isomer mixture (racemate mixture).
De oppnådde isomerblandingene (racematblandinger) kan, avhengig av fysikalsk-kjemiske komponentforskjeller, separeres i de to stereoisomere (diastereoisomere) rene racematene f.eks. ved hjelp av kromatografi og/eller fraksjonert krystallisasjon. The obtained isomer mixtures (racemate mixtures) can, depending on physico-chemical component differences, be separated into the two stereoisomeric (diastereoisomeric) pure racemates, e.g. by means of chromatography and/or fractional crystallization.
De oppnådde racemater kan separeres ifølge kjente metoder, f.eks. ved hjelp av omkrystallisering fra et optisk aktivt oppløsningsmiddel, ved hjelp av mikroorganismer eller ved omsetning med optisk aktive syrer som danner salter av forbindelsen og separering av de således oppnådde salter, f.eks. ved hjelp av diastereomerenes forskjellige oppløselighet, hvorfra antipodene kan frisettes ved hjelp av et egnet middel. The racemates obtained can be separated according to known methods, e.g. by means of recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active acids which form salts of the compound and separation of the salts thus obtained, e.g. by means of the different solubility of the diastereomers, from which the antipodes can be released by means of a suitable agent.
Egnede brukbare optisk aktive syrer er f.eks. L- og D-formene av vinsyre, di-o-tolylvinsyre, eplesyre, mandelsyre, kamfersulfonsyre eller kininsyre. Den mest aktive delen av de to antipodene blir fortrinnsvis isolert. Videre kan en av de to enantiomerene oppnås ved asymetrisk reduksjon av den tilsvarende ketoforbindelsen. Suitable usable optically active acids are e.g. The L and D forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. The most active part of the two antipodes is preferably isolated. Furthermore, one of the two enantiomers can be obtained by asymmetric reduction of the corresponding keto compound.
Det blir hensiktsmessig benyttet slike materialer i de ovenfor angitte metoder som leder til grupper av sluttprodukter som primært er ønsket, og særlig til de spesielt beskrevne og foretrukne sluttproduktene. Such materials are appropriately used in the above-mentioned methods which lead to groups of end products that are primarily desired, and in particular to the specifically described and preferred end products.
Utgangsmaterialene er kjente eller kan, dersom de skulle være nye, bli oppnådd ifølge i og for seg kjente fremgangsmåter. The starting materials are known or, if they were to be new, can be obtained according to methods known per se.
Ved klinisk bruk blir forbindelsene i foreliggende oppfinnelse normalt administrert oralt, rektalt eller ved injeksjon i form av et farmasøytisk preparat som inneholder en aktiv komponent enten som fri base eller som farmasøytisk akseptable, ikke-toksiske syreaddisjonssalter, f.eks. hydrokloridet, laktatet, acetatet, sulfamatet eller lignende i kombinasjon med en farmasøytisk bærer. In clinical use, the compounds of the present invention are normally administered orally, rectally or by injection in the form of a pharmaceutical preparation containing an active component either as free base or as pharmaceutically acceptable, non-toxic acid addition salts, e.g. the hydrochloride, the lactate, the acetate, the sulfamate or the like in combination with a pharmaceutical carrier.
Bæreren kan være et fast stoff, halvfast stoff eller væskeformig for-tynningsmiddel eller en kapsel. Disse farmasøytiske preparatene omfattes også av oppfinnelsen. Vanligvis er mengden av aktiv komponent mellom 0,1 og 10 vekt-% av preparatet, hensiktsmessig mellom 0,5 og 20 vekt-% i preparater for injeksjon og mellom 2 og 50 vekt-% i preparater for oral administrasjon. The carrier may be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations are also covered by the invention. Generally, the amount of active component is between 0.1 and 10% by weight of the preparation, suitably between 0.5 and 20% by weight in preparations for injection and between 2 and 50% by weight in preparations for oral administration.
Ved fremstilling av farmasøytiske preparater inneholdende en forbindelse ifølge oppfinnelsen i form av doseringsenheter for oral administrasjon, kan den valgte forbindelse blandes med en fast, pulverformig bærer som f.eks. laktose, sakkarose, sorbitol, mannitol, stivelse, slik som potetstivelse, maisstivelse, amylopektin, cellulosederivater eller gelatin, samt med antifriksjonsmidler slik som magnesiumstearat, kalsiumstearat, polyetylenglykolvokser eller lignende, og presses til tabletter. Dersom belagte tabletter er ønsket, kan den ovenfor fremstilte kjerne belegges med en konsentrert oppløsning av sukker, hvilken oppløsning kan inneholde f.eks. gummi arabikum, gelatin, talk, titandioksyd eller lignende. Videre kan tablettene belegges med en lakk oppløst i et lett flyktig organisk oppløsningsmiddel eller blanding av oppløsningsmidler. Til dette belegget kan det tilsettes et fargestoff for lett å kunne skjelne mellom tabletter med forskjellige aktive forbindelser eller med forskjellige mengder av de aktive forbindelser til stede. When preparing pharmaceutical preparations containing a compound according to the invention in the form of dosage units for oral administration, the selected compound can be mixed with a solid, powdered carrier such as e.g. lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatin, as well as with antifriction agents such as magnesium stearate, calcium stearate, polyethylene glycol wax or the like, and pressed into tablets. If coated tablets are desired, the core prepared above can be coated with a concentrated solution of sugar, which solution can contain e.g. gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets can be coated with a varnish dissolved in a slightly volatile organic solvent or mixture of solvents. A dye can be added to this coating to easily distinguish between tablets with different active compounds or with different amounts of the active compounds present.
Ved fremstilling av myke myke gelatinkapsler (perleformede, lukkede kapsler) som består av gelatin og f.eks. glycerin eller ved fremstilling av lignende lukkede kapsler, blandes den aktive forbindelsen med en vegetabilsk olje. Harde gelatinkapsler kan inneholde granuler av den aktive forbindelsen i kombinasjon med en fast, pulverformig bærer som laktose, sakkarose, sorbitol, mannitol, stivelse (som f.eks. potetstivele, maisstivelse eller amylopektin), cellulosederivater eller gelatin. In the production of soft soft gelatin capsules (bead-shaped, closed capsules) which consist of gelatin and e.g. glycerin or when producing similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.
Doseringsenheter for rektal administrasjon kan fremstilles i form av suppositorier som inneholder det aktive stoff i en blanding med en nøytral fettbase, eller de kan fremstilles i form av gelatin-rektalkapsler som inneholder det aktive stoff i en blanding med en vegetabilsk olje eller paraffinolje. Dosage units for rectal administration can be prepared in the form of suppositories containing the active substance in a mixture with a neutral fatty base, or they can be prepared in the form of gelatin rectal capsules containing the active substance in a mixture with a vegetable oil or paraffin oil.
Flytende preparater for oral administrasjon kan være til stede i form av siruper eller suspensjoner, f.eks. oppløsninger inneholdende fra ca. 0,2 til ca. 20 vekt-% av det beskrevne aktive stoff, hvorved resten består av sukker og en blanding av etanol, vann, glycerol og propylenglykol. Om ønsket, kan slike flytende preparater inneholdende fargestoffer, smaksstoffer, sakkarin og karboksymetylcellulose som fortykningsmiddel. Liquid preparations for oral administration may be present in the form of syrups or suspensions, e.g. solutions containing from approx. 0.2 to approx. 20% by weight of the active substance described, whereby the rest consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations can contain dyes, flavourings, saccharin and carboxymethyl cellulose as a thickener.
Oppløsninger for parenteral administrasjon ved injeksjon kan fremstilles som en vandig oppløsning av et vannoppløselig farmasøytisk akseptabelt salt av den aktive forbindelsen, fortrinnsvis i en konsentrasjon fra ca. 0,1 til ca. 10 vekt-%. Disse oppløsningene kan også inneholde stabiliseringsmidler og/eller buffermidler, og kan hensiktsmessig være tilgjengelig i forskjellige doseringsenhets-ampuller. Solutions for parenteral administration by injection can be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from about 0.1 to approx. 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents, and may suitably be available in different dosage unit ampoules.
Fremstillingen av farmasøytike tabletter for peroral bruk utføres i overensstemmelse med kjente metoder. The production of pharmaceutical tablets for oral use is carried out in accordance with known methods.
Den daglige dose av det aktive stoff varierer, og er avhengig av administrasjonstype, men som en alminnelig regel er det 20-500 mg/dag ved peroral administrasjon og 10-200 mg/dag ved intravenøs administrasjon. En anbefalt dosering for behandling av glaukom er 1 dråpe (50-100 jjI) en eller to ganger pr. dag i et angrepet øye, av en oppløsning inneholdende 1-10 mg/ml aktivt stoff. The daily dose of the active substance varies and depends on the type of administration, but as a general rule it is 20-500 mg/day for oral administration and 10-200 mg/day for intravenous administration. A recommended dosage for the treatment of glaucoma is 1 drop (50-100 IU) once or twice per day. day in an affected eye, of a solution containing 1-10 mg/ml active substance.
Følgende eksempler illustrerer oppfinnelsen. Strukturer er vist i medfølgende tabeller 1-3. The following examples illustrate the invention. Structures are shown in accompanying Tables 1-3.
Eksempel 1Example 1
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3(4-(3-(cyklopropylmetoksy)propyl)fenoksy)propyl)amino)-etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3(4-(3-(cyclopropylmethoxy)propyl)phenoxy)propyl)amino)ethyl)-. (Method a)
12,9 g av hydrokloridet av N-2-aminoetylen-4-hydroksypiperidinkarboksa-mid og 2,3 NaOH ble omrørt i etanol (100 ml) ved 60°C i 1 time. Deretter ble 6,0 g 3-(4-(3-(cyklopropylmetoksy)propyl)fenoksy)-l,2-epoksypropan i 50 ml etanol tilsatt i løpet av 2 timer. Den resulterende blanding ble omrørt natten over ved 60°C, inndampet til tørrhet, oppløst i CH2CI2og ekstrahert tre ganger med vann, og inndampet til tørrhet. Resten ble kromatografert på 320 g silisiumdioksydgel 60. Kolonnen ble 12.9 g of the hydrochloride of N-2-aminoethylene-4-hydroxypiperidinecarboxamide and 2.3 NaOH were stirred in ethanol (100 ml) at 60°C for 1 hour. Then 6.0 g of 3-(4-(3-(cyclopropylmethoxy)propyl)phenoxy)-1,2-epoxypropane in 50 ml of ethanol were added over the course of 2 hours. The resulting mixture was stirred overnight at 60°C, evaporated to dryness, dissolved in CH 2 Cl 2 and extracted three times with water, and evaporated to dryness. The residue was chromatographed on 320 g of silica gel 60. The column was
først eluert med en CH2CI2/CH3OH (10:1) blanding, og de første 600 ml ble kassert. Deretter ble fraksjoner på 100 ml oppsamlet. Etter 18 fraksjoner var metanolinnholdet i den mobile fasen øket til 25%. Fraksjonene 30-36 inneholdt det ønskede produktet. Etter inndampning ved resten omkrystallisert fra acetonitril. Utbytte 2,5 g. Smeltepunkt 89°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. first eluted with a CH 2 Cl 2 /CH 3 OH (10:1) mixture, and the first 600 ml was discarded. Fractions of 100 ml were then collected. After 18 fractions, the methanol content in the mobile phase had increased to 25%. Fractions 30-36 contained the desired product. After evaporation the residue recrystallized from acetonitrile. Yield 2.5 g. Melting point 89°C (base). The structure was confirmed using NMR analysis.
Eksempel 2Example 2
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(cyklobutylmetoksy)etyl)fenoksy)propyl)amino)etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(cyclobutylmethoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a)
12,77 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksa-mid og 2,28 g NaOH ble omrørt i etanol (150 ml) i 4 timer. Deretter ble 5,1 g 3-(4-(2-(cyklobutylmetoksy)etyl)fenoksy)-l,2-epoksypropan tilsatt. Blandingen ble omrørt ved 50°C i 3 dager, filtrert, inndampet og kromatografert på silisiumdioksyd ved bruk av metanol/metylenklorid som mobil fase. På slutten ble ren metanol benyttet. Utbytte 2,54 g. Smeltepunkt 92°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. 12.77 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 2.28 g of NaOH were stirred in ethanol (150 ml) for 4 hours. Then 5.1 g of 3-(4-(2-(cyclobutylmethoxy)ethyl)phenoxy)-1,2-epoxypropane was added. The mixture was stirred at 50°C for 3 days, filtered, evaporated and chromatographed on silica using methanol/methylene chloride as mobile phase. At the end, pure methanol was used. Yield 2.54 g. Melting point 92°C (base). The structure was confirmed using NMR analysis.
Eksempel 3Example 3
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-2-((2-hydroksy-3-(4-(2-(2-(2-metylpropoksy)etoksy)etyl)fenoksy)propyl)amino)etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-2-((2-hydroxy-3-(4-(2-(2-(2-methylpropoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a)
7,6 g av hydroklordet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid og 1,36 g av NaOH ble omrørt i etanol i 1 time ved 60°C. Deretter ble 4,0 g 3-(4-(2-(2-(2-metylpropoksy)etoksy)etyl)fenoksy)-l,2-epoksypropan i 40 ml etanol tilsatt i løpet av 3 timer. Den resulterende blanding ble omrørt ved 60°C i 11 timer, inndampet, oppløst i CHq12, vasket tre ganger med vann, tørket over Na2S04, filtrert og inndampet. Resten ble kromatografert på 320 g silisiumdioksydgel 60. Kolonnen ble ført eluert med 1 liter 20% CH3OH i CH2C12og deretter med 1 liter 40% CH3OH i CH2CI2, og de føgende 1,4 liter ble oppsamlet og inndampet. Resten 7.6 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 1.36 g of NaOH were stirred in ethanol for 1 hour at 60°C. Then 4.0 g of 3-(4-(2-(2-(2-methylpropoxy)ethoxy)ethyl)phenoxy)-1,2-epoxypropane in 40 ml of ethanol was added over the course of 3 hours. The resulting mixture was stirred at 60°C for 11 h, evaporated, dissolved in CHq 2 , washed three times with water, dried over Na 2 SO 4 , filtered and evaporated. The residue was chromatographed on 320 g of silica gel 60. The column was eluted with 1 liter of 20% CH3OH in CH2Cl2 and then with 1 liter of 40% CH3OH in CH2Cl2, and the next 1.4 liters were collected and evaporated. The rest
krystalliserte ved behandling med diisopropyleter. Utbytte 3,2 g. Smeltepunkt 81°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. crystallized by treatment with diisopropyl ether. Yield 3.2 g. Melting point 81°C (base). The structure was confirmed using NMR analysis.
Eksempel 4Example 4
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(2-metylpropksy)etyl)fenoksy)pfopyl)amino)etyl)-. (Metode a). Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a).
11,2 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid og 2 g NaOH ble omrørt i isopropanol (100 ml) i 1 time ved 50°C. Deretter ble 5,0 g 3-(4-(2-(2-metylpropksy)etyl)fenoksy)-l,2-epoksypropan i 50 ml isopropanol tilsatt i løpet av 2 timer. Den resulterende blanding ble omrørt ved 50°C natten over, inndampet, oppløst i 2N saltsyre og ekstrahert med eter. Det vandige laget ble ekstrahert 3 ganger med CH2CI2, og denne organiske fasen ble behandlet med ION NaOH, vasket med vann, tørket over Na2S04, filtrert og inndampet. Resten ble kromatografert på 320 g silisiumdioksydgel 60 ifølge metoden i eksempel 3. Utbytte 1 g. Smeltepunkt 94°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. 11.2 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 2 g of NaOH were stirred in isopropanol (100 ml) for 1 hour at 50°C. Then 5.0 g of 3-(4-(2-(2-methylpropoxy)ethyl)phenoxy)-1,2-epoxypropane in 50 ml of isopropanol was added over the course of 2 hours. The resulting mixture was stirred at 50°C overnight, evaporated, dissolved in 2N hydrochloric acid and extracted with ether. The aqueous layer was extracted 3 times with CH 2 Cl 2 , and this organic phase was treated with 1N NaOH, washed with water, dried over Na 2 SO 4 , filtered and evaporated. The residue was chromatographed on 320 g of silica gel 60 according to the method in example 3. Yield 1 g. Melting point 94°C (base). The structure was confirmed using NMR analysis.
Eksempel 5Example 5
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(cyklopropylmetoksy)etoksy)fenoksy)propyl)amino)etyl) -. (Metode 1) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)propyl)amino)ethyl) -. (Method 1)
5,2 g N-(benzyl)-N-(2-((2-hydroksy-3-(4-(2-(cyklopropylmetoksy)etoksy)-fenoksy)propyl)amino)etyl)fenoksykarboksamid og 1,4 g 4-hydroksy-piperidin i 75 ml toluen ble omrørt ved 80°C i 45 timer. Reaksjonsblandingen ble ekstrahert to ganger med fortynnet NaOH og vasket med vann, tørket over Na2S04, filtrert og inndampet. Resten ble oppløst i 150 ml etanol, og etter tilsetning av katalysatoren (Pd/C) ble blandingen hydrogenert i 2 timer (250 ml H2). Reaksjonsblandingen ble filtrert og inndampet. Resten ble kromatografert på vanlig måte ved bruk av silisiumdioksyd og en CII^OII/CI^C^ blanding. Etter inndamping av 5.2 g N-(benzyl)-N-(2-((2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy)-phenoxy)propyl)amino)ethyl)phenoxycarboxamide and 1.4 g 4 -hydroxy-piperidine in 75 ml of toluene was stirred at 80°C for 45 hours. The reaction mixture was extracted twice with dilute NaOH and washed with water, dried over Na 2 SO 4 , filtered and evaporated. The residue was dissolved in 150 ml of ethanol, and after addition of the catalyst (Pd/C), the mixture was hydrogenated for 2 hours (250 ml of H2). The reaction mixture was filtered and evaporated. The residue was chromatographed in the usual manner using silica and a CII^OII/CI^C^ mixture. After evaporation of
oppløsningsmidlene ble resten krystallisert fra en isopropyleter/metanol-blanding (4:1). Utbytte 1,42 g. Smeltepunkt 86°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. the solvents, the residue was crystallized from an isopropyl ether/methanol mixture (4:1). Yield 1.42 g. Melting point 86°C (base). The structure was confirmed using NMR analysis.
Eksempel 6Example 6
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(2-metylpropoksy)etoksy)fenoksy)propyl)amino)etyl) -. (Metode 1) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)-. (Method 1)
10,0 g N-(benzyl)-N-(2-((2-hydroksy-3-(4-(2-(2-metylpropoksy)etoksy)-fenoksy)propyl)amino)etyl)fenoksykarboksamid og 2,1 g 4-hydroksy-piperidin i 100 ml toluen fikk reagere ved 100°C i 8 timer. Blandingen ble deretter oppløst i CH2CI2og ekstrahert to ganger med 2M NaOH, vasket med vann, tørket og inndampet. Resten ble behandlet med trekull, filtrert og hydrogenert over 5% Pd/C i 300 1 etanol. Etter at 540 ml H2~gass var forbrukt ble oppløsningen filtrert og inndampet. Resten ble oppløst i en blanding av isopropanol og etanol (3:1) og etter filtrering ble produktet krystallisert. Produktet ble frafiltrert. Utbytte 6,3 g. Smeltepunkt 101°C (baSe). Strukturen ble bekreftet ved bruk av NMR-analyse. 10.0 g of N-(benzyl)-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)-phenoxy)propyl)amino)ethyl)phenoxycarboxamide and 2.1 g of 4-hydroxy-piperidine in 100 ml of toluene was allowed to react at 100°C for 8 hours. The mixture was then dissolved in CH 2 Cl 2 and extracted twice with 2M NaOH, washed with water, dried and evaporated. The residue was treated with charcoal, filtered and hydrogenated over 5% Pd/C in 300 1 ethanol. After 540 ml of H 2 ~ gas had been consumed, the solution was filtered and evaporated. The residue was dissolved in a mixture of isopropanol and ethanol (3:1) and after filtration the product was crystallized. The product was filtered off. Yield 6.3 g. Melting point 101°C (baseSe). The structure was confirmed using NMR analysis.
Eksempel 7Example 7
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-(((S)-2-hydroksy-3-(4-(2-(cyklopropylmetoksy) etoksy) f enoksy)propyl)amino) etyl)-. (Metode Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-(((S)-2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)propyl)amino)ethyl)-. (Method
a) a)
1,47 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid 1.47 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide
ble tilbakeløpskokt i 15 ml etanol inntil klar oppløsning ble oppnådd. Deretter ble 0,45 ml 15N NaOH oppløsning tilsatt. Deretter ble 1,26 g 3—(4-(2- (cyklopropylmeto ksy)etoksy)fenoksy) -(S) -2-hydroksypropylmetan-sulfonat i 15 ml etanol tilsatt. Reaksjonsblandingen fikk reagere i 2 dager ved 45°C. Blandingen ble deretter filtrert, inndampet og oppløst i H2O og ekstrahert med CH2CI2ved pH 10. Det organiske laget ble deretter ekstrahert med vann ved pH 3 (H2SO4), og vannfasen ble ekstrahert med etylacetat. Vannfasen ble regulert til pH 10 og ekstrahert med metylenklorid, vasket med vann, tørket, filtrert og inndampet. Utbytte 0,7 g. Smeltepunkt 83°C. Strukturen ble bekreftet ved bruk av NMR-analyse. was refluxed in 15 ml of ethanol until a clear solution was obtained. Then 0.45 ml of 15N NaOH solution was added. Then 1.26 g of 3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)-(S)-2-hydroxypropylmethanesulfonate in 15 ml of ethanol was added. The reaction mixture was allowed to react for 2 days at 45°C. The mixture was then filtered, evaporated and dissolved in H 2 O and extracted with CH 2 Cl 2 at pH 10. The organic layer was then extracted with water at pH 3 (H 2 SO 4 ), and the aqueous phase was extracted with ethyl acetate. The aqueous phase was adjusted to pH 10 and extracted with methylene chloride, washed with water, dried, filtered and evaporated. Yield 0.7 g. Melting point 83°C. The structure was confirmed using NMR analysis.
Eksempel 8Example 8
Fremstilling av 1-piperidinkarboksamid, N-(2-((3-(4-(2-amino-2-oksoetyl)-fenoksy)-2-hydroksypropyl)amino)etyl)-4-hydroksy-. (metode a) Preparation of 1-piperidinecarboxamide, N-(2-((3-(4-(2-amino-2-oxoethyl)-phenoxy)-2-hydroxypropyl)amino)ethyl)-4-hydroxy-. (method a)
8,47 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid og 1,516 g NaOH ble omrørt i 200 ml etanol i 3 timer. 3,9 g 3-(4-(karbamoylmetyl)fenoksy)-l,2-epoksypropan ble tilsatt, og den resulterende blanding fikk reagere ved 50-55°C i 3 dager. Den resulterende blanding ble filtrert og inndampet. Resten ble kromatografert på vanlig måte på silisiumdioksyd med metanol/metylenklorid som mobil fase, og ved slutten ble ren metanol benyttet som mobil fase. Etter inndampning av oppløsningsmidlene ble resten krystallisert fra eter. Utbytte 1,0 g. Smeltepunkt 105°C. Strukturen ble bekreftet av NMR-analyse. 8.47 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 1.516 g of NaOH were stirred in 200 ml of ethanol for 3 hours. 3.9 g of 3-(4-(carbamoylmethyl)phenoxy)-1,2-epoxypropane was added and the resulting mixture was allowed to react at 50-55°C for 3 days. The resulting mixture was filtered and evaporated. The residue was chromatographed in the usual way on silica with methanol/methylene chloride as mobile phase, and at the end pure methanol was used as mobile phase. After evaporation of the solvents, the residue was crystallized from ether. Yield 1.0 g. Melting point 105°C. The structure was confirmed by NMR analysis.
Eksempel 9Example 9
Fremstilling av 2-metylpropansyre, l-(((2-((2-hydroksy-3-(4-(2-(2-metylpropoksy)etoksy) fenoksy) propyl)amino)ety l)amino)karbonyl)-4-piperidinylester. (Metode e) Preparation of 2-methylpropanoic acid, l-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl l)amino)carbonyl)-4- piperidinyl ester. (Method e)
2,08 g N-benzyl-N- (aminoetyl) -3- (4- (2- (2- (2-metylpropoksy) etoksy)etyl) - fenoksy)-2-hydroksypropylamin, 1,17 g 4-(2-metylpropanoyloksy)piperidin-karbonylklorid, og 1,7 g kaliumkarbonat fikk reagere i 30 ml metylenklorid i 2 dager. Blandingen ble opparbeidet på vanlig måte og kromatografert på en Altex-kolonne (2,5 x 50 cm) i porsjoner på 1,5 g. Den mobile fasen var 2,5% metanol i metylenklorid. 1,26 g rent produkt ble oppløst i 50 ml etanol og hydrogenert (Pd/C). Blandingen ble deretter filtrert og inndampet. Resten ble omkrystallisert fra en blanding av etylacetat og isopropanol (1:1). Utbytte 0,61 g. Smeltepunkt 113°C. 2.08 g N-benzyl-N-(aminoethyl)-3-(4-(2-(2-(2-methylpropoxy)ethoxy)ethyl)-phenoxy)-2-hydroxypropylamine, 1.17 g 4-(2 -methylpropanoyloxy)piperidine carbonyl chloride, and 1.7 g of potassium carbonate were allowed to react in 30 ml of methylene chloride for 2 days. The mixture was worked up in the usual way and chromatographed on an Altex column (2.5 x 50 cm) in portions of 1.5 g. The mobile phase was 2.5% methanol in methylene chloride. 1.26 g of pure product was dissolved in 50 ml of ethanol and hydrogenated (Pd/C). The mixture was then filtered and evaporated. The residue was recrystallized from a mixture of ethyl acetate and isopropanol (1:1). Yield 0.61 g. Melting point 113°C.
Eksempel 10Example 10
Fremstilling av fenoksyetansyre, l-(((2-((2-hydroksy-3-(4-(2-(2-metylpropoksy)etoksy) fenoksy) propyl) a mino)etyl)amino) karbonyl)-4-piperidinylester. 10 g N- (benzyl) -N- (2- ((2-hydroksy-3- (4- (2-metylpropoksy)etoksy) - - fenoksy)propyl)amino)etyl)-4-hydroksypiperidinkarboksamid i 100 ml CH2CI2og 2,96 ml pyridin ble tilbakeløpskokt, og 3,45 fenoksyetanoyl-klorid i 25 ml CH2CI2ble tilsatt i løpet av 15 min. Reaksjonsblandingen ble hensatt under tilbakeløp i 1 time. Deretter ble den vasket tre ganger med fortynnet svovelsyre, og deretter to ganger med fortynnet Na2C03-oppløsning. Det organiske laget ble tørket, filtrert og inndampet. Resten ble kromatografert på silisiumdioksyd ved bruk av CH2CI2inneholdende 2-4% CH3OH som mobil fase. Utbytte 5,2 g. Dette produktet ble oppløst i etanol, behandlet med trekull, filtrert og hydrogenert over Pd/C. Stoffet forbrukte 190 ml H2. Blandingen ble filtrert og inndampet. Resten ble deretter krystallisert fra en blanding av isopropanol og etanol (4:1). Utbytte 2,6 g. Smeltepunkt 87°C. Strukturen ble bekreftet ved bruk av NMR-analyse. Preparation of phenoxyethanoic acid, 1-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)amino)carbonyl)-4-piperidinyl ester. 10 g of N-(benzyl)-N-(2- ((2-hydroxy-3- (4-(2-methylpropoxy)ethoxy) - - phenoxy)propyl)amino)ethyl)-4-hydroxypiperidinecarboxamide in 100 ml CH 2 Cl 2 and 2 .96 ml of pyridine was refluxed, and 3.45 of phenoxyethanol chloride in 25 ml of CH 2 Cl 2 was added over 15 min. The reaction mixture was allowed to reflux for 1 hour. It was then washed three times with dilute sulfuric acid, and then twice with dilute Na 2 CO 3 solution. The organic layer was dried, filtered and evaporated. The residue was chromatographed on silica using CH2Cl2 containing 2-4% CH3OH as mobile phase. Yield 5.2 g. This product was dissolved in ethanol, treated with charcoal, filtered and hydrogenated over Pd/C. The substance consumed 190 ml of H2. The mixture was filtered and evaporated. The residue was then crystallized from a mixture of isopropanol and ethanol (4:1). Yield 2.6 g. Melting point 87°C. The structure was confirmed using NMR analysis.
Eksempel 11Example 11
Fremstilling av karbonsyre, l-(((2-((2-hydroksy-3-(4-(2-(2-metylpropoksy )etoksy) fenoksy )propyl) amino)ka rbonyl)—4—piperidinylfenylester Preparation of carboxylic acid, 1-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)carbonyl)-4-piperidinylphenyl ester
(metode k)(method k)
Tittelforbindelsen ble fremstilt ifølge eksempel 10 ovenfor ved bruk av fenylklorformiat. Utbytte 0,5 g (fra 5,2 g utgangsmateriale og 1,72 g fenylklorformiat). Smeltepunkt 92°C (base). Strukturen ble bekreftet ved NMR-analyse. The title compound was prepared according to Example 10 above using phenyl chloroformate. Yield 0.5 g (from 5.2 g starting material and 1.72 g phenyl chloroformate). Melting point 92°C (base). The structure was confirmed by NMR analysis.
Eksempel 12Example 12
Fremstilling av benzenpropansyre, l-(((-2((2-hydroksy3(4— (—(2—metyl-propksy) etoksy)f enoksy)p ropyl)am ino)etyl )amino)k arbonyl)-4—piperidinyl-ester. (metode k). Preparation of benzenepropanoic acid, l-(((-2((2-hydroxy3(4- (—(2-methyl-propoxy) ethoxy) phenoxy) propyl) amino) ethyl ) amino) carbonyl)-4-piperidinyl -ester. (method k).
Tittelforbindelsen som ble fremstilt ifølge eksempel 10 ovenfor ved bruk av 6,5 g av det benzylbeskyttede utgangsmaterialet og 2,22 g 3-fenyl-propanoylklorid som utgangsmaterialer. Utbytte 0,5 g. Smeltepunkt 87°C (base). Strukturen ble bekreftet ved NMR-analyse. The title compound which was prepared according to Example 10 above using 6.5 g of the benzyl-protected starting material and 2.22 g of 3-phenyl-propanoyl chloride as starting materials. Yield 0.5 g. Melting point 87°C (base). The structure was confirmed by NMR analysis.
Eksempel 13Example 13
Fremstilling av karbonsyre, etyl-l-(((2-((2-hydroksy-3-(4-(2-(2-metylpropoksy) etoksy) fenoksy)propyl)amino) etyl) amino)—karbonyl)-4—piperidinyl-ester. (Metode k) Preparation of carboxylic acid, ethyl-1-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)amino)—carbonyl)-4— piperidinyl ester. (Method k)
Tittelforbindelsen ble fremstilt ifølge eksempel 10 ovenfor ved bruk av 11,1 g av det benzylbeskyttede utgangsmateriale og 2,14 ml etylklor-formiat som utgangsmaterialer. Utbytte 2,0 g. Smeltepunkt 87°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 10 above using 11.1 g of the benzyl-protected starting material and 2.14 ml of ethyl chloroformate as starting materials. Yield 2.0 g. Melting point 87°C (base). The structure was confirmed using NMR analysis.
Eksempel 14Example 14
Fremstilling av butansyre, l-(((2-((2-hydroksy-3-(4-(2-(2-metylpropoksy)-etoksy) fenoksy )p rop yl) am ino )etyl )ami no)k arbonyl) -4-piper idin yles ter. Preparation of butanoic acid, l-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)-ethoxy)phenoxy)propyl)amino)ethyl)amino)carbonyl) -4-pipe idin yles ter.
(Metode k)(Method k)
Tittelforbindelsen ble fremstilt ifølge eksempel 10 ovenfor ved bruk av 7,25 g av det benzylbeskyttede utgangsmaterialet og 1,56 g butanoyl-klorid som utgangmaterialer. Utbytte 1,2 g. Smeltepunkt 81°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 10 above using 7.25 g of the benzyl-protected starting material and 1.56 g of butanoyl chloride as starting materials. Yield 1.2 g. Melting point 81°C (base). The structure was confirmed using NMR analysis.
Eksempel 15Example 15
Fremstilling avheksansyre, 1 - (((2- ((2-hydroksy-3- (4-(2-(2-metylpropoksy) - etoksy) fenoksy )p rop yl) am ino) et yl )ami no) k arbonyl) -4-piper idin yles ter. Preparation of hexanoic acid, 1 - (((2- ((2-hydroxy-3- (4-(2-(2-methylpropoxy) - ethoxy) phenoxy ) propyl) amino) ethyl ) amino) carbonyl) -4-pipe idin yles ter.
(Metode k)(Method k)
Tittelforbindelsen ble fremstilt ifølge eksempel 10 ovenfor ved bruk av 4,0 g av benzylbeskyttet utgangsmateriale og 1,12 ml heksanylklorid som utgangsmaterialer. Utbytte 1,5 g. Smeltepunkt 81°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 10 above using 4.0 g of benzyl-protected starting material and 1.12 ml of hexanyl chloride as starting materials. Yield 1.5 g. Melting point 81°C (base). The structure was confirmed using NMR analysis.
Eksempel 16Example 16
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4- (2- (2 -metylpropoksy )etyl )-2 -m etoksy fe nok sy) propyl)amino )etyl)-. Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4- (2-(2-methylpropoxy)ethyl)-2-methoxyphenoxy)propyl)amino)ethyl )-.
(Metode a)(Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 2 ovenfor. Reaksjonstid 12 timer ved 60°C. Utbytte 3,9 g (52%) av et oljeaktig produkt, n<20>=1,5372. Strukturen ble bekreftet ved bruk av NMR-analyse. ° The title compound was prepared according to Example 2 above. Reaction time 12 hours at 60°C. Yield 3.9 g (52%) of an oily product, n<20>=1.5372. The structure was confirmed using NMR analysis. °
Eksempel 17Example 17
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(2-metoksyetoksy)etyl)fenoksy)propyl)amino)etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methoxyethoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 16 ovenfor. Produktet ble krystallisert fra diisopropyleter inneholdende 20% acetonitril. Utbytte 1.5 g (18,8%). Smeltepunkt 76°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 16 above. The product was crystallized from diisopropyl ether containing 20% acetonitrile. Yield 1.5 g (18.8%). Melting point 76°C (base). The structure was confirmed using NMR analysis.
Eksempel 18Example 18
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4- (2- (2-(cyklobutylmetoksy )etok sy) etyl) fenoksy )propyl) amino)etyl). Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-(cyclobutylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl).
(Metode a)(Method a)
18,6 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid og 3,0 g NaOH ble omrørt i etanol(200 ml) i 3 timer ved 40°C. Deretter ble 8,97 g 3-(4-(2-(2-(cyklobutylmetoksy)etoksy)etyl)fenoksy)-l,2-epoksy-propan i 50 ml etanol tilsatt. Blandingen ble omrørt i 3 dager ved 45°C. Deretter ble den filtrert, inndampet og oppløst i kloroform. Det organiske laget ble deretter vasket tre ganger med vann, tørket og inndampet. Resten ble omkrystallisert fra etylacetat/lettbensin 40/60. Utbytte 5,7 g. Smeltepunkt 76°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. 18.6 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 3.0 g of NaOH were stirred in ethanol (200 ml) for 3 hours at 40°C. Then 8.97 g of 3-(4-(2-(2-(cyclobutylmethoxy)ethoxy)ethyl)phenoxy)-1,2-epoxy-propane in 50 ml of ethanol were added. The mixture was stirred for 3 days at 45°C. It was then filtered, evaporated and dissolved in chloroform. The organic layer was then washed three times with water, dried and evaporated. The residue was recrystallized from ethyl acetate/petrol 40/60. Yield 5.7 g. Melting point 76°C (base). The structure was confirmed using NMR analysis.
Eksempel 19Example 19
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2(((R)-2-hydroksy-3-(4-(2-(2-metylpropoksy)etoksy)fenoksy)propyl)amino)etyl)-. (Metoder e + Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2(((R)-2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)-. (Methods e +
f) f)
2.6 g N-benzyl-N- (2-aminoetyl) -1 - (4- (2- (2-metylpropoksy)epoksy)fenoksy-3-aminopropan-(R)-2-ol og 1,6 g 4-benzyloksypiperidinkarbonylklorid ble hensatt i 25 ml mctylcnklcrid og 2 ml trietylamin natten over ved 2.6 g of N-benzyl-N-(2-aminoethyl)-1-(4-(2-(2-methylpropoxy)epoxy)phenoxy-3-aminopropane-(R)-2-ol and 1.6 g of 4-benzyloxypiperidinecarbonyl chloride was placed in 25 ml of mctylcnklcrid and 2 ml of triethylamine overnight at
romtemperatur. Den organiske fasen ble vasket med fortynnet NaOH, tørket, filtrert og inndampet. Utbytte 3,9 ga et oljeaktig produkt som ble oppløst i etanol og 2 M HCl (til pH= 1). Pd/C ble tilsatt, og blandingen ble hydrogenert, filtrert og inndampet. Resten ble behandlet med 2M NaOH og ekstrahert med metylenklorid, filtrert og inndampet. Blandingen ble krystallisert fra en 1:1-blanding av etylacetat og diisopropyleter. Krystallene ble renset ved oppløsning i IM HCl, vasket to ganger med eter, gjort alkalisk med 10M NaOH. Krystallene ble frafiltrert, vasket med vann og tørket. Utbytte 1,29 g. Smeltepunkt 93°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. room temperature. The organic phase was washed with dilute NaOH, dried, filtered and evaporated. Yield 3.9 gave an oily product which was dissolved in ethanol and 2 M HCl (to pH= 1). Pd/C was added and the mixture was hydrogenated, filtered and evaporated. The residue was treated with 2M NaOH and extracted with methylene chloride, filtered and evaporated. The mixture was crystallized from a 1:1 mixture of ethyl acetate and diisopropyl ether. The crystals were purified by dissolving in 1M HCl, washed twice with ether, made alkaline with 10M NaOH. The crystals were filtered off, washed with water and dried. Yield 1.29 g. Melting point 93°C (base). The structure was confirmed using NMR analysis.
Eksempel 20Example 20
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-(((S)-2-hydroksy-3-(4-(2-(2-metylpropoksy)etoksy)fenoksy)propyl)amnino)etyl)-. (Metoder e + f) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-(((S)-2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amnino)ethyl)-. (Methods e + f)
Tittelforbindelsen ble fremstilt ifølge eksempel 19 ovenfor. Produktet ble krystallisert fra etylacetat. Utbytte 6,5 g (72%). Smeltepunkt 94°C. Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 19 above. The product was crystallized from ethyl acetate. Yield 6.5 g (72%). Melting point 94°C. The structure was confirmed using NMR analysis.
Eksempel 21Example 21
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-metoksyetyl)fenoksy)propyl)amino)etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-methoxyethyl)phenoxy)propyl)amino)ethyl)-. (Method a)
7,0 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid og 1,2 g NaOH ble omrørt i etanol i 2 timer ved romtemperatur. Deretter ble 3,1 g 3-(4-(2-metoksyetyl)fenoksy)-l,2-epoksypropan i 30 ml tilsatt. Blandingen ble omrørt natten over ved 60°C, filtrert og inndampet. Resten ble oppløst i etylacetat og ekstrahert med 2M HCl. Deretter ble den vandige fasen regulert til pH 7,5 og ekstrahert med CHCI3. Deretter ble pH-verdien hevet til 10, og den vandige fasen igjen ekstrahert med CHCI3. Denne metoden ble gjentatt tre ganger. Den kombinerte kloroforrnfiscn ble deretter inndampet. Resten ble om- 7.0 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 1.2 g of NaOH were stirred in ethanol for 2 hours at room temperature. Then 3.1 g of 3-(4-(2-methoxyethyl)phenoxy)-1,2-epoxypropane in 30 ml was added. The mixture was stirred overnight at 60°C, filtered and evaporated. The residue was dissolved in ethyl acetate and extracted with 2M HCl. The aqueous phase was then adjusted to pH 7.5 and extracted with CHCl 3 . The pH was then raised to 10, and the aqueous phase was again extracted with CHCl3. This method was repeated three times. The combined chloroform fraction was then evaporated. The rest were re-
krystallisert fra toluen. Utbytte 1,5 g. Smeltepunkt 74°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. crystallized from toluene. Yield 1.5 g. Melting point 74°C (base). The structure was confirmed using NMR analysis.
Eksempel 22Example 22
Fremstilling av 1-piperidinkarboksamid, N-(2-((3-(4-(2-(2-(2-amino-kar bon yl) fe nok sy) et oks y) ety 1) f en oks y) - 2- hyd rok sy pro pyl )am ino) -4- - hydroksy-. (Metode a) Preparation of 1-piperidine carboxamide, N-(2-((3-(4-(2-(2-(2-amino-carbonyl) fe nok sy) et ox y) ethy 1) f en ox y) - 2- hydroxy propyl )amino) -4- - hydroxy-. (Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 2 ovenfor. Reaksjonstid 6 timer ved 60°C. Produktet ble krystallisert fra acetonitril inneholdende 0,5% metanol. Utbytte 2,0 g (25%). Smeltepunkt 110°C (base). Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 2 above. Reaction time 6 hours at 60°C. The product was crystallized from acetonitrile containing 0.5% methanol. Yield 2.0 g (25%). Melting point 110°C (base). The structure was confirmed using NMR analysis.
Eksempel 23Example 23
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(2-metylpropoksy)etyl)-3-cyanofenoksy)propylamino)etyl)-. (Metode Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethyl)-3-cyanophenoxy)propylamino)ethyl)-. (Method
a) Tittelforbindelsen ble fremstilt ifølge og i samme målestokk som eksempel a) The title compound was prepared according to and on the same scale as the example
2 ovenfor. Utbytte 2,7 g av et oljeaktig produkt. n^<O>= 1,5545. Strukturen ble bekreftet ved bruk av NMR-analyse. 2 above. Yield 2.7 g of an oily product. n^<0>= 1.5545. The structure was confirmed using NMR analysis.
Eksempel 24Example 24
Fremstilling av 2-metylpropansyre, l-(((2-(((S)-2-hydroksy-3-(4-(2-(2-metylp ro pok sy) etoksy) f enoksy)p ro pyl )am ino) etyl )a min o)k arbonyl) -4-piperidinylester. (Metode e + f) Preparation of 2-methylpropanoic acid, l-(((2-(((S)-2-hydroxy-3-(4-(2-(2-methylprop oxy)ethoxy)phenoxy)prop yl)amino ) ethyl )a min o)carbonyl)-4-piperidinyl ester. (Method e + f)
8,33 g N-benzyl-N-(2-aminoetyl)-l-(4-(2-metylpropoksy)etoksy)fenoksy-3-aminopropan-(S)-2-ol og 4,67 g 4-(l-metyletylkarbonyloksy)piperidin-karbonylklorid, og 5,53 g K2CO3ble omrørt i 50ml metylenklorid i 2 dager ved romtemperatur. Reaksjonsblandingen ble vasket to ganger med 8.33 g of N-benzyl-N-(2-aminoethyl)-1-(4-(2-methylpropoxy)ethoxy)phenoxy-3-aminopropane-(S)-2-ol and 4.67 g of 4-(l -methylethylcarbonyloxy)piperidinecarbonyl chloride, and 5.53 g of K 2 CO 3 were stirred in 50 ml of methylene chloride for 2 days at room temperature. The reaction mixture was washed twice with
vann og inndampet. Resten ble kromatografert på 800 g silisiumdioksydgel. Utbytte 8,05 g. 3,22 g av dette produktet ble oppløst i 125 ml etanol og hydrogenert over 10% Pd/C. 155 ml hydrogen ble forbrukt. Blandingen ble filtrert inndampet, og resten krystallisert to ganger fra etylacetat. Utbytte 1,63 g. Smeltepunkt 84°C. Strukturen ble bekreftet ved bruk av NMR-analyse. water and evaporated. The residue was chromatographed on 800 g of silica gel. Yield 8.05 g. 3.22 g of this product was dissolved in 125 ml of ethanol and hydrogenated over 10% Pd/C. 155 ml of hydrogen were consumed. The mixture was filtered evaporated, and the residue crystallized twice from ethyl acetate. Yield 1.63 g. Melting point 84°C. The structure was confirmed using NMR analysis.
Eksempel 25Example 25
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(2-(2-pyridinyloksy)etoksy)etyl)fenoksy)propyl)amino)etyl) -. (Metode Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-(2-pyridinyloxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl) - . (Method
a) a)
Tittelforbindelsen ble fremstilt ifølge eksempel 18 ovenfor. Produktet ble The title compound was prepared according to Example 18 above. The product was
krystallisert fra acetonitril. Utbytte 1,4 g (19,5%). Smeltepunkt 75°C. Strukturen ble bekreftet ved bruk av NMR-analyse. crystallized from acetonitrile. Yield 1.4 g (19.5%). Melting point 75°C. The structure was confirmed using NMR analysis.
Eksempel 26Example 26
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(2 -(2-cyclopropylm etoksy)etoksy)etyl)fenok sy)propyl)amino) etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2 -(2-cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl )-. (Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 18 ovenfor ved bruk av 22,4 g av hydrokloridet av N-2-aminoetyl-4-hydroksypiperidinkarboksamid, 4 g NaOH og 11,1 g 3-(4-(2-(cyklopropylmetoksy) etyl) fenoksy)-1,2-epoksypropan. Produktet ble omkrystallisert fra etylacetat. Utbytte 4 g. Smeltepunkt 72°C Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 18 above using 22.4 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide, 4 g of NaOH and 11.1 g of 3-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy) -1,2-epoxypropane. The product was recrystallized from ethyl acetate. Yield 4 g. Melting point 72°C The structure was confirmed using NMR analysis.
Eksempel 27Example 27
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4- ((2 -cyklopr op ylm etok sy)etoksy)metyl) fenoksy) propyl)amino )etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4- ((2 -cyclopropylethoxy)ethoxy)methyl)phenoxy)propyl)amino)ethyl)-. (Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 22 ovenfor. Produktet ble krystallisert fra diisopropyleter inneholdende 25% acetonitril. Utbytte 1,5 g (15,3%). Smeltepunkt 72°C. Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 22 above. The product was crystallized from diisopropyl ether containing 25% acetonitrile. Yield 1.5 g (15.3%). Melting point 72°C. The structure was confirmed using NMR analysis.
Eksempel 28Example 28
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4-(2-(lH-pyrazol-l-yl)etoksy)fenoksy)propyl)amino)etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(1H-pyrazol-1-yl)ethoxy)phenoxy)propyl)amino)ethyl)-. (Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 2 ovenfor. Utbytte 1,0 g (6%). Smeltepunkt 94°C. Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 2 above. Yield 1.0 g (6%). Melting point 94°C. The structure was confirmed using NMR analysis.
Eksempel 29Example 29
Fremstilling av 1-piperidinkarboksamid, 4-hydroksy-N-(2-((2-hydroksy-3-(4- (2- ((((1 -metyletyl)a mino) kar bonyl)am ino)etyl)fenoksy )propyl) amino) - etyl)-. (Metode a) Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4- (2- ((((1 -methylethyl)amino)carbonyl)amino)ethyl)phenoxy ) propyl) amino) - ethyl) -. (Method a)
Tittelforbindelsen ble fremstilt ifølge eksempel 2 ovenfor. Utbytte 3 g (43%), krystallisert fra eter. Smeltepunkt 117°C. Strukturen ble bekreftet ved hjelp av NMR-analyse. The title compound was prepared according to Example 2 above. Yield 3 g (43%), crystallized from ether. Melting point 117°C. The structure was confirmed by NMR analysis.
Eksempel 30Example 30
Fremstilling av cykloheksankarboksylsy re, 1 - (((2- (((S) -2-hydroksy-3- (4- (2-(2-(cyclopropylmetoksy)etoksy) etyl )fenoksy)propyl)amino)etyl) karbonyl)-4- piperidinylester. (Metode e) Preparation of cyclohexanecarboxylic acid, 1 - (((2- (((S) -2-hydroxy-3- (4- (2-(2-(cyclopropylmethoxy)ethoxy) ethyl )phenoxy)propyl)amino)ethyl)carbonyl) -4- piperidinyl ester (Method e)
Tittelforbindelsen ble fremstilt ifølge eksempel 9 ovenfor ved bruk av N-benzyl -N-(2-aminoetyl) -3 -(4 -(2- (2-( cyklopropylm etok sy)etoksy)etyl)-fenoksy)-2-(S)-hydroksypropylamin (4,2 g) og 4-cykloheksylkarbonyloksy-piperidinkarbonylklorid (2,1 g) som utgangsmeterialer. Utbytte 2,9 g av en gul olje.<*>HNMR (500 MHz, CDC13). S 7,1 2H, 6,8, 2H, 5,5 1H 4,9 1H, 4,1 1H) 3,9 2H, 3,6 8H, 3,3 4H, 3,2 3H, 2,8 7H 2,3 1H, 1,9 2H 1,8 2H, 1,7 2H, 1,6 3H, 1,4 2H, 1,25 3H, 1,05 1H, 0,5 2H, 0,2 2H. The title compound was prepared according to Example 9 above using N-benzyl -N-(2-aminoethyl)-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)-phenoxy)-2-(S )-hydroxypropylamine (4.2 g) and 4-cyclohexylcarbonyloxy-piperidinecarbonyl chloride (2.1 g) as starting materials. Yield 2.9 g of a yellow oil.<*>HNMR (500 MHz, CDC13). S 7.1 2H, 6.8, 2H, 5.5 1H 4.9 1H, 4.1 1H) 3.9 2H, 3.6 8H, 3.3 4H, 3.2 3H, 2.8 7H 2.3 1H, 1.9 2H 1.8 2H, 1.7 2H, 1.6 3H, 1.4 2H, 1.25 3H, 1.05 1H, 0.5 2H, 0.2 2H.
Eksempel 31Example 31
Fremstilling av 2,2-dimetylpropionsyre, l-(((2-(((S)-2-hydroksy-3-(4-(2-(2-(cyk lopr opyl meto ksy) eto ksy) etyl) fenoksy )propyl) amino) et yl) karbo nyl) -4-piperidinylester. (Metode e) Preparation of 2,2-dimethylpropionic acid, 1-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropyl methoxy) ethoxy) ethyl) phenoxy ) propyl)amino)etyl)carbonyl)-4-piperidinyl ester (Method e)
Tittelforbindelsen ble fremstilt ifølge eksempel 9 ovenfor ved bruk av N-benzyl -N -(2 -aminoetyl) -3 -(4 -(2- (2-( cyklopropylm etok sy)etoksy)etyl)-fenoksy)--2-(S)-hydroksypropylamin (5,0 g) og 4-(2,2-dimetylpropionyl-oksy)piperidinkarbonylklorid (2,8 g) som utgangsmaterialer. Utbytte 3,0 g av en gul olje.<*>HNMR (500 MHz, CDCI3): S 7,1 2H, 6,8 2H, 5,35 1H, 4,85 1H, 4,05 1H, 3,9 2H, 3,6 6H, 3,5 2H, 3,25 6H 3.26H, 1,8 2H, 1,6 2H, 1,15 9H, 1,05 1H, 0,5 2H, 0,2 2H. The title compound was prepared according to Example 9 above using N-benzyl-N-(2-aminoethyl)-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)-phenoxy)--2-( S)-hydroxypropylamine (5.0 g) and 4-(2,2-dimethylpropionyloxy)piperidinecarbonyl chloride (2.8 g) as starting materials. Yield 3.0 g of a yellow oil.<*>HNMR (500 MHz, CDCl3): S 7.1 2H, 6.8 2H, 5.35 1H, 4.85 1H, 4.05 1H, 3.9 2H, 3.6 6H, 3.5 2H, 3.25 6H 3.26H, 1.8 2H, 1.6 2H, 1.15 9H, 1.05 1H, 0.5 2H, 0.2 2H.
Eksempel 32Example 32
Fremstilling av fenyleddiksyre, l-(((2-(((S)-2-hydroksy-3-(4-(2-(2-(cyklopropylmetoksy^ toksy)et yl) f enok sy)propy 1)amino) etyl)ami no) karbonyl)-4-piperidinylester. (Metode e). Preparation of phenylacetic acid, 1-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy^toxy)ethyl)phenoxy)propyl)amino)ethyl )amino)carbonyl)-4-piperidinyl ester (Method e).
Tittelforbindelsen ble fremstilt ifølge eksempel 9 ovenfor ved bruk av N-benzyl -N-(2-aminoetyl) -3 -(4 -(2- (2-( cyklopropylm etok sy)etoksy)etyl) - fenoksy)-2-(S)-hydroksypropylpropylamin (4,4 g) og 4-benzylkarbonyloksy-piperidinkarbonylklorid (2,8 g) og 4-benzylkarbonyloksypiperidinkarbonyl-klorid (2,8 g) som utgangmaterialer. Utbytte 2,6 g av en gul olje.<i>HNMR (CDCI3, 500 MHz): S 7,3 2H, 7,25 3H, 7.12H, 6,8 2H, 5,55 1H, 4,9 1H, 4,1 1H, 3,9 2H, 3,6 8H, 3,5 3H, 3,3 4H, 3,15 2H 2,8 3H, 2,75 3H, 1,75 2H, 1,55 2H, 1,05 1H, 0,5 2H, 0,2 2H. The title compound was prepared according to Example 9 above using N-benzyl -N-(2-aminoethyl)-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)-phenoxy)-2-(S )-hydroxypropylpropylamine (4.4 g) and 4-benzylcarbonyloxypiperidinecarbonyl chloride (2.8 g) and 4-benzylcarbonyloxypiperidinecarbonyl chloride (2.8 g) as starting materials. Yield 2.6 g of a yellow oil.<i>HNMR (CDCl 3 , 500 MHz): S 7.3 2H, 7.25 3H, 7.12H, 6.8 2H, 5.55 1H, 4.9 1H, 4.1 1H, 3.9 2H, 3.6 8H, 3.5 3H, 3.3 4H, 3.15 2H 2.8 3H, 2.75 3H, 1.75 2H, 1.55 2H, 1 .05 1H, 0.5 2H, 0.2 2H.
Eksempel 33Example 33
Fremstilling av 2,3-diklorbenzosyre, l-(((2-(((S)-2-hydroksy-3-(4-(2-(2-(cyklopropylmetoksy) etok sy) etyl) f enok sy) propylamino) etyl) amino) karbonyl) - 4-piperidinylester. Preparation of 2,3-dichlorobenzoic acid, l-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propylamino) ethyl) amino) carbonyl) - 4-piperidinyl ester.
2,5gN-(2 - aminoetyl )-3-(4-(2-(2-(cyklop ropy lm etok sy) etok sy) etyl) f enok sy) - 2.5gN-(2 - aminoethyl )-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy) -
(S)-2-hydroksypropylamin, 25 ml tørr THF og 0,92 g diisopropyletylamin ble blandet og 2,39 g 4-(2,3-diklorfenylkarbonyloksy)piperidinkarbonyl-klorid ble tilsatt i porsjoner under omrøring. Blandingen ble inndampet etter 3 timers reaksjonstid. Resten ble oppløst i en l:l-blanding av metylenklorid og eter og vasket med vann, tørket over Na2S04, filtrert og inndampet til tørrhet. Syntesen ble gjentatt, og de kombinerte restene ble kromatografert på SiC>2og CH2Cl2lMeOH 9:1 som mobil fase. Utbytte 0,9 g.<*>HNMR (CDCI3, 500 MHz, HCl-salt): S 7,6 2H, 7,25 1H, 7,05 2H, 6,8 2H, 6,65 1H, 5,2 1H, 4,55 1H, 4,05 1H, 3,95 1H, 3,7 4H, 3,6 6H, 3,4 3H, 3,3 6H, 2,8 2H, 1,95 2H, 1,8 2H, 1,05 1H, 0,55 2H, 0,2 2H. (S)-2-Hydroxypropylamine, 25 ml of dry THF and 0.92 g of diisopropylethylamine were mixed and 2.39 g of 4-(2,3-dichlorophenylcarbonyloxy)piperidinecarbonyl chloride was added in portions with stirring. The mixture was evaporated after a reaction time of 3 hours. The residue was dissolved in a 1:1 mixture of methylene chloride and ether and washed with water, dried over Na 2 SO 4 , filtered and evaporated to dryness. The synthesis was repeated, and the combined residues were chromatographed on SiC>2 and CH2Cl2lMeOH 9:1 as mobile phase. Yield 0.9 g.<*>HNMR (CDCl 3 , 500 MHz, HCl salt): S 7.6 2H, 7.25 1H, 7.05 2H, 6.8 2H, 6.65 1H, 5.2 1H, 4.55 1H, 4.05 1H, 3.95 1H, 3.7 4H, 3.6 6H, 3.4 3H, 3.3 6H, 2.8 2H, 1.95 2H, 1.8 2H, 1.05 1H, 0.55 2H, 0.2 2H.
Eksempel 34 Example 34
Fremstilling av 4-hydroksy-N- (2- (((S) -hydroksy-3-(4-(2-(2-(2-cyklopropylmetoksy)etoksy)etyl)fenoksy)propyl)amino)etyl. (Metode 1) Preparation of 4-hydroxy-N-(2- (((S)-hydroxy-3-(4-(2-(2-(2-cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl. (Method 1 )
Tittelforbindelsen ble fremstilt ifølge eksempel 5 ovenfor ved bruk av N(benzyl)-N- (2-( ((S) -2-hydroksy-3-(4-(2- (cyklopropylmetoksy) etoksy-fenoksy)propyl)amino)etyl)fenoksykarboksamid (13,0 g) og 4-hydroksy-piperidin (3,27 g) som utgangsmaterialer. Utbytte 3,1 g. Smeltepunkt 77-78°C. Strukturen ble bekreftet ved bruk av NMR-analyse. The title compound was prepared according to Example 5 above using N(benzyl)-N-(2-(((S)-2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy-phenoxy)propyl)amino)ethyl )phenoxycarboxamide (13.0 g) and 4-hydroxy-piperidine (3.27 g) as starting materials.Yield 3.1 g.M.P. 77-78°C.The structure was confirmed using NMR analysis.
Eksempel 35Example 35
Fremstilling av heksansyre, l-(((2-(((S)-2-hydroksy-3-(4-(2-(2-(cyklopropylmetoksy) etoksy ) etyl) f eno ksy )prop yl) amino )etyl)am ino) karbonyl)— 4—piperidinylester. Preparation of hexanoic acid, l-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl) amino)carbonyl)— 4—piperidinyl ester.
Tittelforbindelsen ble fremstilt ifølge eksempel 9 ovenfor ved bruk av N-benzyl -N -(2 -aminoetyl) -3 -(4 -(2- (2-(cyklopropylm etok sy) etoksy) etyl)-fenoksy)—2—(S)-hydroksypropylamin (4,5 g) og 4-heksanoyloksypiperidinkarbonylklorid (4,5 g) og 4-heksanoyloksypiperidinkarbonylklorid (2,64 g) som utgangsmateriale. Utbytte 3,1 g. Smeltepunkt 25-30°C.<*>HNMR (500 MHz, CDC13): s 7,1 2H, 6,8 2H, 5,25 1H, 4,9 1H, 4,1 1H, 3,95 2H, 3,6 8H, 3,35 2H, 3,3 2H, 3,2 2H, 2,85 8H, 2,3 2H, 1,85 2H, 1,6 4H, 1,3 4H, 1,1 1H, 0,9 3H, 0,5 2H, 0,2 2H. The title compound was prepared according to Example 9 above using N-benzyl-N-(2-aminoethyl)-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)-phenoxy)-2-(S )-hydroxypropylamine (4.5 g) and 4-hexanoyloxypiperidinecarbonyl chloride (4.5 g) and 4-hexanoyloxypiperidine carbonyl chloride (2.64 g) as starting material. Yield 3.1 g. Melting point 25-30°C.<*>HNMR (500 MHz, CDC13): s 7.1 2H, 6.8 2H, 5.25 1H, 4.9 1H, 4.1 1H, 3.95 2H, 3.6 8H, 3.35 2H, 3.3 2H, 3.2 2H, 2.85 8H, 2.3 2H, 1.85 2H, 1.6 4H, 1.3 4H, 1.1 1H, 0.9 3H, 0.5 2H, 0.2 2H.
Eksempel 36Example 36
Fremstilling av 2-metylpropansyre, l-(((2-(((S)-2-hydroksy-3-(4-(2-(2-(cyklopropylmetoksy) etok sy)etyl) f eno ksy) propyl)amino) etyl)ami no) kar-bonyl)-4-piperidinylester. Preparation of 2-methylpropanoic acid, 1-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino) ethyl)amino)carbonyl)-4-piperidinyl ester.
Tittelforbindelsen ble fremstilt ifølge eksempel 9 ovenfor ved bruk av N-be nzyl -N- (2-am inoe tyl) -3- (4- (2 - (2- cykl opro pylm etok sy) e tok sy) etyl) - fenoksy)-2-(S)-hydroksypropylamin (5 g) og 4-(metylpropionyloksy)-piperidinkarbonylklorid (2,6 g) som utgangsmateriale. Utbytte 2,4 g.<*>HNMR (CDCI3, 500 MHz): S 7,1 2H, 6,8 2H, 6,25 1H, 4,9 1H, 4,0 2H, 3,65 10H, 3,3 4H, 3,15 4H, 2,8 211, 2,5 111,1,85 2H, 1,65 2H, 1,15 6H, 0,9 1H, 0,55 2H, 0,2 2H. The title compound was prepared according to Example 9 above using N-benzyl -N-(2-aminoethyl)-3-(4-(2 - (2-cyclopropylmethoxy)ethoxy)ethyl)-phenoxy )-2-(S)-hydroxypropylamine (5 g) and 4-(methylpropionyloxy)-piperidinecarbonyl chloride (2.6 g) as starting material. Yield 2.4 g.<*>HNMR (CDCl3, 500 MHz): S 7.1 2H, 6.8 2H, 6.25 1H, 4.9 1H, 4.0 2H, 3.65 10H, 3, 3 4H, 3.15 4H, 2.8 211, 2.5 111, 1.85 2H, 1.65 2H, 1.15 6H, 0.9 1H, 0.55 2H, 0.2 2H.
Eksempel 37Example 37
En injeksjonsoppløsning ble fremstilt ved oppløsning av 1-piperidinkarboksamid, 4-hydroksy-N-((2-hydroksy-3-(4-(3-(cyklopropylmetoksy)propyl)-fenoksy)propyl)amino)etyl)hydroklorid (0,1 g) natriumklorid (0,8 g) og askorbinsyre (0,1 g) i en tilstrekkelig mengde destillert vann for oppnåelse av 100 ml oppløsning. Denne oppløsning, som inneholder 1 mg aktivt stoff pr. hver ml, ble benyttet for fylling av ampuller som ble sterilisert. An injection solution was prepared by dissolving 1-piperidinecarboxamide, 4-hydroxy-N-((2-hydroxy-3-(4-(3-(cyclopropylmethoxy)propyl)-phenoxy)propyl)amino)ethyl)hydrochloride (0.1 g) sodium chloride (0.8 g) and ascorbic acid (0.1 g) in a sufficient amount of distilled water to obtain 100 ml of solution. This solution, which contains 1 mg of active substance per each ml, was used for filling ampoules which were sterilized.
Eksempel 38Example 38
En sirup inneholdende 2% (vekt pr. volum) aktivt stoff ble fremstilt fra følgende bestandeler A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients
Sukker, sakkarin og ammoniumsaltet ble oppløst i 60 g varmt vann. Etter avkjøling ble glycerin og en oppløsning av smaksstoffer oppløst i etanol tilsatt. Til blandingen ble vann deretter tilsatt til 100 ml. Sugar, saccharin and the ammonium salt were dissolved in 60 g of hot water. After cooling, glycerin and a solution of flavors dissolved in ethanol were added. To the mixture, water was then added to 100 ml.
Eksempel 39Example 39
2-metylpropansyre, 1 - (((2- ((2-hydroksy-3- (4- (2-metylpropoksy) etoksy) - f enoksy)propyl) amino) karbonyl)-4-piperidinylesterklorid (250 g) ble blandet med laktose (175,8 g), potetstivelse, 169,7 g og kolloidal kiselsyre (32 g). Blandingen ble fuktet med 10% oppløsning av gelatin og ble granulert gjennom en 12-mesh sikt. Etter tørking ble potetstivelse (160 2-Methylpropanoic acid, 1 - (((2- ((2-hydroxy-3-(4-(2-methylpropoxy)ethoxy)-phenoxy)propyl)amino)carbonyl)-4-piperidinyl ester chloride (250 g) was mixed with lactose (175.8 g), potato starch, 169.7 g and colloidal silicic acid (32 g). The mixture was moistened with a 10% solution of gelatin and was granulated through a 12-mesh sieve. After drying, potato starch (160
g), talk (50 g) og magnesiumstearat (5 g) sammenblandet, og den således oppnådde blanding ble presset til tabletter (10.000) som inneholder 25 mg g), talc (50 g) and magnesium stearate (5 g) were mixed together, and the mixture thus obtained was pressed into tablets (10,000) containing 25 mg
stoff. Tablettene selges på markedet forsynt med bruddmerking for oppnåelse av en annen dose enn 25 mg eller for oppnåelse av flere slike ved oppdeling. fabric. The tablets are sold on the market provided with break markings to obtain a dose other than 25 mg or to obtain several such by dividing.
Eksempel 40Example 40
Granuler ble fremstilt fra 2-metylpropansyre, l-(((2-((2-hydroksy-3-(4-(2-(2-metylpropoksy )eto ksy) f eno ksy) propyl)amino) etyl)amino)karbonyl)-4-piperidinylesterhydroklorid (250 g), laktose (175,9 g) og en alkoholisk oppløsning av polyvinylpyrrolidon (25 g). Etter tørking ble granulene blandet med talk (25 g), potetstivelse (40 g) og magnesiumstearat (2,50 g) og ble presset til 10.000 tabletter som var bikonvekse. Disse tablettene blir primært belagt med en 10% alkoholisk oppløsning av skjellakk og deretter med en vandig oppløsning inneholdende sakkarose (45%) gummi arabikum (5%), gelatin (4%) og fargestoff (0,2%). Talk og pulverisert sukker ble benyttet for pulverbehandling etter de første fem beleggene. Belegget ble deretter belagt med en 66% sukkersirup og polert med en 10% oppløsning av karnaubavoks i karbontetraklorid. Granules were prepared from 2-methylpropanoic acid, 1-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)amino)carbonyl )-4-piperidinyl ester hydrochloride (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying, the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and pressed into 10,000 biconvex tablets. These tablets are primarily coated with a 10% alcoholic solution of shellac and then with an aqueous solution containing sucrose (45%), gum arabic (5%), gelatin (4%) and dye (0.2%). Talc and powdered sugar were used for powder treatment after the first five coatings. The coating was then coated with a 66% sugar syrup and polished with a 10% solution of carnauba wax in carbon tetrachloride.
Eksempel 41Example 41
En øyedråpeoppløsning kan fremstilles med følgende sammensetning: An eye drop solution can be prepared with the following composition:
Eksempel 42 Example 42
En øyedråpeoppløsning kan fremstilles med følgende sammensetning: An eye drop solution can be prepared with the following composition:
Claims (9)
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SE8503088A SE8503088D0 (en) | 1985-06-20 | 1985-06-20 | NEW PARA-SUBSTITUTED 3-PHENOXY-1-PIPERIDINECARBONYL-AMINOALKYLAMINO-PROPANOL-2-S HAVING BETA RECEPTOR BLOCKING PROPERTIES |
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NO862241D0 NO862241D0 (en) | 1986-06-05 |
NO862241L true NO862241L (en) | 1986-12-22 |
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NO862241A NO862241L (en) | 1985-06-20 | 1986-06-05 | NEW PARA-SUBSTITUTED 3-PHENOXY-1-PIPERIDINE CARBONYLAMINOALKYLAMINO-PROPANOL-2 COMPOUNDS WITH BETA-RECEPTOR BLOCKING PROPERTIES AND PROCEDURES FOR THEIR PREPARATION. |
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JP (1) | JPS61293968A (en) |
KR (1) | KR870000297A (en) |
CN (1) | CN86104789A (en) |
AU (1) | AU5850586A (en) |
DD (1) | DD246109A5 (en) |
DK (1) | DK287486A (en) |
FI (1) | FI862601A (en) |
GR (1) | GR861584B (en) |
HU (1) | HUT42067A (en) |
IL (1) | IL79037A0 (en) |
NO (1) | NO862241L (en) |
PT (1) | PT82812B (en) |
SE (1) | SE8503088D0 (en) |
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CN103804349A (en) * | 2012-11-01 | 2014-05-21 | 杨子娇 | Compounds for treatment of glaucoma and their use |
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1985
- 1985-06-20 SE SE8503088A patent/SE8503088D0/en unknown
-
1986
- 1986-06-04 ZA ZA864173A patent/ZA864173B/en unknown
- 1986-06-04 IL IL79037A patent/IL79037A0/en unknown
- 1986-06-05 NO NO862241A patent/NO862241L/en unknown
- 1986-06-10 AU AU58505/86A patent/AU5850586A/en not_active Abandoned
- 1986-06-17 DD DD86291378A patent/DD246109A5/en unknown
- 1986-06-18 FI FI862601A patent/FI862601A/en not_active Application Discontinuation
- 1986-06-18 GR GR861584A patent/GR861584B/en unknown
- 1986-06-19 JP JP61141544A patent/JPS61293968A/en active Pending
- 1986-06-19 HU HU862587A patent/HUT42067A/en unknown
- 1986-06-19 KR KR1019860004877A patent/KR870000297A/en not_active Application Discontinuation
- 1986-06-19 DK DK287486A patent/DK287486A/en not_active Application Discontinuation
- 1986-06-20 PT PT82812A patent/PT82812B/en unknown
- 1986-06-20 CN CN198686104789A patent/CN86104789A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
HUT42067A (en) | 1987-06-29 |
ZA864173B (en) | 1987-02-25 |
FI862601A (en) | 1986-12-21 |
FI862601A0 (en) | 1986-06-18 |
NO862241D0 (en) | 1986-06-05 |
DK287486D0 (en) | 1986-06-19 |
IL79037A0 (en) | 1986-09-30 |
DK287486A (en) | 1986-12-21 |
CN86104789A (en) | 1987-02-04 |
GR861584B (en) | 1986-10-21 |
KR870000297A (en) | 1987-02-17 |
JPS61293968A (en) | 1986-12-24 |
AU5850586A (en) | 1987-01-15 |
DD246109A5 (en) | 1987-05-27 |
SE8503088D0 (en) | 1985-06-20 |
PT82812A (en) | 1986-07-01 |
PT82812B (en) | 1988-06-17 |
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