DK165366B - 3-Piperidinecarboxylic acids or 3-tetrahydropyridine carboxylic acids which are N-substituted by a diphenyl-, dithienyl- or phenyl-thienyl-substituted ether group, a process for preparing them, and pharmaceutical preparations which comprise the compounds - Google Patents

Description

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Nærværende opfindelse angår hidtil ukendte N-substituerede 3-piperidin- eller 3-tetrahydropyridin-carboxylsyrer og estre heraf, hvori en alkylætergruppe udgør en del af 10 N-substituenten, og salte heraf med den i krav 1 angivne formel I, fremgangsmåder til fremstilling af disse forbindelser og farmaceutiske præparater hvori forbindelserne indgår.The present invention relates to novel N-substituted 3-piperidine or 3-tetrahydropyridine carboxylic acids and esters thereof, wherein an alkyl ether group forms part of the 10 N substituent and salts thereof with the formula I as claimed in claim 1 these compounds and pharmaceutical compositions comprising the compounds.

15 X de senere år har der foregået megen farmakologisk forskning omkring H -aminosmørsyre (herefter betegnet GABA), en hæmmende neurotransmitter i centralnervesystemet hos pattedyr.In recent years, much pharmacological research has been conducted on H-aminobutyric acid (hereafter referred to as GABA), an inhibitory neurotransmitter in the central nervous system of mammals.

20 Hæmning af GABA-optagelse resulterer i en øget tilgængelighed af denne hæmmende neurotransmitter i den synaptiske kløft, og dermed i øget GABA'ergisk aktivitet. Øget GABA'-ergisk aktivitet kan være nyttig i behandlingen.af f.eks. angst, smerte, epilepsi, samt muskel- og bevægelsessygdom-25 me (se f.eks. Krogsgaard-Larsen, P. et al., Progress in Medicinal Chemistry, 22 (1985) 68-112, Advances in Drug Research, 17 (1988), 381-456.Inhibition of GABA uptake results in an increased availability of this inhibitory neurotransmitter in the synaptic cleft, and thus in increased GABA'ergic activity. Increased GABA 'ergic activity may be useful in the treatment. anxiety, pain, epilepsy, and muscular and movement disorders (see, e.g., Krogsgaard-Larsen, P. et al., Progress in Medicinal Chemistry, 22 (1985) 68-112, Advances in Drug Research, 17 ( 1988), 381-456.

En velkendt og potent hæmmer af GABA-optagelse fra den 30 synaptiske kløft ind i presynaptiske nerveender og gliale celler er f.eks. piperidin-3-carboxylsyre (nipecotinsyre).A well known and potent inhibitor of GABA uptake from the synaptic cleft into presynaptic nerve endings and glial cells is e.g. piperidine-3-carboxylic acid (nipecotinic acid).

Da det imidlertid er en relativt polariseret forbindelse, og den derfor er ude af stand til at passere blod-hjerne barrieren, har piperidin-3-carboxylsyren ikke fundet nogen 35 praktisk anvendelse som et lægemiddel.However, since it is a relatively polarized compound and therefore unable to pass the blood-brain barrier, the piperidine-3-carboxylic acid has found no practical use as a drug.

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2 I US patentbeskrivelserne nr. 4,383,999 og nr. 4,514,414 (SmithKline Beckman Corporation) og europæiske offentliggørelsesskrifter nr. 236342 og nr. 231996 (Novo Industri A/S) angives aryl og hetero-aryl derivater af N-(4,4-di-5 substitueret-3-buten-l-yl)azaheterocykliske carboxylsyrer som værende GABA-optagelseshæmmere. I dansk patentansøgning nr. 2314/89 (Novo Industri A/S) angives N-alkyl-sub-stituerede azaheterocykliske carboxylsyrer, hvor alkylkæ-derr videre er substitueret med en oximætergruppe, som hæm- .2 U.S. Patent Nos. 4,383,999 and 4,514,414 (SmithKline Beckman Corporation) and European Publication Nos. 236342 and 231996 (Novo Industri A / S) disclose aryl and heteroaryl derivatives of N- (4,4-di- 5 substituted-3-buten-1-yl) azaheterocyclic carboxylic acids as GABA uptake inhibitors. Danish Patent Application No. 2314/89 (Novo Industri A / S) discloses N-alkyl substituted azaheterocyclic carboxylic acids, wherein alkyl chains are further substituted with an oximeter group which inhibits.

10 mere af GABA optagelse. Europæisk offentliggørelsesskrift nr. 221.572 og dansk ans. nr. 5280/86 (Warner-Lambert Company) angiver, at l-arylmethoxyalkylpyridin-3-carboxyl-syrer er hæmmere af GABA-optagelse.10 more of GABA recording. European Publication No. 221,572 and Danish Ans. No. 5280/86 (Warner-Lambert Company) states that 1-arylmethoxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

15 Ifølge Yunger, L.M. et al, J.Pharm.Exp.Therap. 228 (1984) 109·, er N-(4,4-diphenyl-3-buten-l-yl)nipecotinsyre (betegnet 1SK&F 89976A), N-(4,4-diphenyl-3-buten-l-yl)guvacin (betegnet SK&F 100330Aj, N-(4,4-diphenyl-3-buten-l-yl)homo-β-prolin (betegnet SK&F 100561) og N-(4-phenyl-4-(-2-thie- 20 nylH3-buten-l-yl)nipeco tinsyre (betegnet - SK&F 100604J) .. oralt;aktive hæmmere af GABA optagelse. .Disse data er· opsummeret i Krogsgaardr-Larsen, P. et al*·, Epilepsy Res. .1 (1987) 77-93.' kv ' - -v.··. : 25 Nipecotinsyre er piperidin-3-earboxylssyre, guvacine er.15 According to Yunger, L.M. et al., J.Pharm.Exp.Therap. 228 (1984) 109 ·, is N- (4,4-diphenyl-3-buten-1-yl) nipecotinic acid (designated 1SK & F 89976A), N- (4,4-diphenyl-3-buten-1-yl) guvacin (designated SK&F 100330Aj, N- (4,4-diphenyl-3-buten-1-yl) homo-β-proline (designated SK&F 100561) and N- (4-phenyl-4 - (- 2-thienylH3) -butene-l-yl) nipeco tartaric acid (designated - SK&F 100604J) .. orally; active inhibitors of GABA uptake. These data are summarized in Krogsgaardr-Larsen, P. et al. · Epilepsy Res. ) 77-93 'kv' - v. ·· .: 25 Nipecotinic acid is piperidine-3-earboxylic acid, guvacin is.

1,2,5,6-tetrdhydropyridin-3-carboxylsyre og homo-B-prolin er pyrrolidin-3-eddikesyre.1,2,5,6-tetrahydropyridine-3-carboxylic acid and homo-B-proline are pyrrolidine-3-acetic acid.

Nærværende opfindelse angår hidtil ukendte N-substitueredeThe present invention relates to novel N-substituted

30 azaheterocykliske carboxylsyrer og estre heraf, hvori en ætergruppe-indgår som’del af N-substituenten. Forbindel-serne; ifølge’ opfindelsen hår den generelle formel I30 azaheterocyclic carboxylic acids and esters thereof, wherein an ether group is included as part of the N substituent. Connecting conditions; According to the invention, the general formula I

... . *s · \ .(CH2)nC0R7 35 ’ R: R i-—: 1 II Ny ^0 . ^CH . / ~R6 ,-rx R2 ^CH ^(ΟΗ2)ρν(0Η2)ς (CH2)m ' '.... * s · \. (CH2) nC0R7 35 'R: R i-—: 1 II New ^ 0. ^ CH. / ~ R6, -rx R2 ^ CH ^ (ΟΗ2) ρν (0Η2) ς (CH2) m ''

R3 IR3 I

R4R4

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3 1 2 hvor R og "R er ens eller forskellige og hver er phenyl eller 2-thienyl, substitueret med en eller flere substitu-enter udvalgt blandt følgende atomer eller grupper: hydro- 3 gen, halogen, C^_g-alkyl, C^_g-alkoxy eller cyano; R og 5 hver for sig er hydrogen eller tilsammen danner en 5 6 binding; m er 2 og n er 0; R og R hver for sig er hydro- ' 7 gen eller danner tilsammen en binding, og R er OH eller C1_g~alkoxy, p er 0 eller 1 eller 2, q er 0 eller 1 eller 2, J.det p og q ikke samtidig er 0, og R8 er H eller 10 alkyl, eller er farmaceutisk acceptable syreaddditions-salte heraf eller, når carboxylsyregruppen ikke er for-estret, farmaceutisk acceptable metalsalte eller eventuelt alkylerede ammoniumsalte heraf. Forbindelserne med formel I har en større lipophilitet, og dermed en større 15 tilgængelighed til hjernen, samt en langt højere affinitet til GABA-optagelsesstederne end tilsvarende forbindelser uden N-substituenten (f.eks. pyrrolidin-3-eddikesyre (homo-S-prolin), piperid±n-3-carboxylsyre (nipecotinsyre) og .l,2,5,6-tetrahydropyridin-3-carboxylsyre (guvacin)).Wherein R and "R are the same or different and each is phenyl or 2-thienyl, substituted by one or more substituents selected from the following atoms or groups: hydrogen, halogen, C1-6 alkyl, C β-alkoxy or cyano; R and 5 are each hydrogen or together form a 5 6 bond; m is 2 and n is 0; R and R are each hydrogen or 7 together form a bond, and R is OH or C1-6 alkoxy, p is 0 or 1 or 2, q is 0 or 1 or 2, J. p and q are not simultaneously 0, and R8 is H or 10 alkyl, or are pharmaceutically acceptable acid addition salts. thereof, or when the carboxylic acid group is not esterified, pharmaceutically acceptable metal salts, or optionally alkylated ammonium salts thereof. without the N substituent (eg pyrrolidine-3-acetic acid (homo-S-proline), pip erid ± n-3-carboxylic acid (nipecotinic acid) and 1,2,5-tetrahydropyridine-3-carboxylic acid (guvacin)).

20 De har derfor interessante og nyttige.farmakologiske egenskaber. -20 They therefore have interesting and useful pharmacological properties. -

Forbindelserne ifølge formel I kan være geometriske og optiske isomerer og alle isomerer og blandinger heraf er 25 indeholdt heri. Isomererne kan adskilles ved hjælp af standardmetoder, såsom kromatografiske teknikker eller fraktionel krystallisering af salte med optisk aktive syrer eller baser.The compounds of formula I may be geometric and optical isomers and all isomers and mixtures thereof are contained herein. The isomers can be separated by standard methods such as chromatographic techniques or fractional crystallization of salts with optically active acids or bases.

30 Det er vist, at de omhandlede forbindelser med den generelle formel I, som hæmmer optagelse af GABA fra den syn-aptiske kløft har nyttige farmakologiske egenskaber: på centralnervesystemet, idet de forårsager en selektiv forøgelse af den GABA'ergiske aktivitet. Det har overrasken-35 de vist sig, at disse virkninger er større end virkningen af de fra bl.a. dansk ansøgning 5280/86 kendte forbindelser. Forbindelser ifølge formel I kan bruges i behandlin-The compounds of general formula I which inhibit the uptake of GABA from the synaptic cleft have been shown to have useful pharmacological properties: on the central nervous system, causing a selective increase in GABAergic activity. Surprisingly, it has been found that these effects are greater than the effects of those from e.g. Danish application 5280/86 known connections. Compounds of formula I can be used in the treatment.

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4 gen af, f.eks., smerte, angst, epilepsi og visse muskel-og bevægelsessygdomme. De kan også finde anvendelse som sedativer, hypnotika og antidepressiva.4 gene of, for example, pain, anxiety, epilepsy and certain muscle and movement disorders. They can also be used as sedatives, hypnotics and antidepressants.

5 Farmaceutisk acceptable syreadditionssalte af forbindelserne ifølge formel I inkluderer også de, der er afledt fra uorganiske eller organiske syrer, såsom salt-, hydro-genbromid-, svovl-, fosfor-, eddike-, mælke-, malein-, phthal-, citron-, og fumarsyre.Pharmaceutically acceptable acid addition salts of the compounds of formula I also include those derived from inorganic or organic acids such as salt, hydrogen bromide, sulfur, phosphorus, vinegar, milk, maleic, phthal, lemon -, and fumaric acid.

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Opfindelsen angår også en række fremgangsmåder til fremstilling af forbindelserne ifølge den foreliggende opfindelse. Disse fremgangsmåder er kendetegnet ved det i krav 10-14 angivne og uddybes nedenfor: 15The invention also relates to a variety of methods for preparing the compounds of the present invention. These methods are characterized by those set forth in claims 10-14 and elaborated below:

Metode AMethod A

Forbindelser med den generelle formel la, d.v.s. forbindelser med den generelle formel I som defineret ovenfor, 3 4 20 hvor· R og R tilsammen danner en binding, fremstilles efter følgende metode A: R Rf,(CH2)nC0R7 25 «rV° + i' />-. —_► 2 I .CH / H Vs(CH2)pVv(CH2)q (CH2)m (II) (III) *s 30 >s^(CH2)nC0R7 I1 Is r>—* tia> 1 2Compounds of the general formula Ia, i.e. Compounds of general formula I as defined above, wherein R and R together form a bond, are prepared by the following method A: R Rf, (CH2) nCO7 7 25 rV ° + i '/> -. -_► 2 I .CH / H Vs (CH2) pVv (CH2) q (CH2) m (II) (III) * s 30> s ^ (CH2) nCO07 I1 Is r> - * tia> 1 2

Et acetaldehydderivat med formel II, hvor R og R er som defineret ovenfor, omsættes med en forbindelse med formel 35An acetaldehyde derivative of formula II wherein R and R are as defined above is reacted with a compound of formula 35

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5 III, hvor Y er en egnet afgangsgruppe såsom halogen eller p-toluensulfonat. Denne omsætning kan gennemføres i et passende opløsningsmiddel, såsom acetone, tetrahydrofuran, toluen eller N,N-dimethylformamid under tilstedeværelse 5 af en stærk base, såsom natriumhydrid, ved en temperatur op til refluxtemperatur i 1 til 72 timer (for syntese af acetaldehydderivater med formel II, se Meyers, A.I. et al., J.Am.Chem. Soc. 104 (1982) 877-9 og Matteson, D.S. et al., J.Org.Chem. 45 (1980) 1091-5); Blicke, F.F. and Faust, 10 J.A., J.Amer. Chem.Soc., 16 (1954), 3156; Borch R.F.,III where Y is a suitable leaving group such as halogen or p-toluenesulfonate. This reaction may be carried out in a suitable solvent such as acetone, tetrahydrofuran, toluene or N, N-dimethylformamide in the presence of a strong base such as sodium hydride at a temperature up to reflux temperature for 1 to 72 hours (for the synthesis of acetaldehyde derivatives of formula II, see Meyers, AI et al., J. Am. Chem. Soc. 104 (1982) 877-9 and Matteson, DS et al., J. Org. Chem. 45 (1980) 1091-5); Blicke, F.F. and Faust, J.A., J.Amer. Chem.Soc., 16 (1954), 3156; Borch R.F.,

Tetrahedron Lett., 36, (1972), 3761; Martin, S.F., Synthesis, (1979), 633; Ashwood M.S. et al.. Synthesis, (1988), 379)).Tetrahedron Lett., 36, (1972), 3761; Martin, S.F., Synthesis, (1979), 633; Ashwood M.S. et al., Synthesis, (1988), 379).

15 Metode BMethod B

Forbindelser med den generelle formel I som defineret ovenfor fremstilles efter følgende generelle metode B: 20 E, E, ^.0. ^CH ^0H —-:—► tf CH ^(CH2)p(CH2)q 4 (IV) 25 p R, Ea p I 5 (CH2)nCOR7 ^°\ 'ck + r\ R2 CH (CH2)pV(CH2)q /~~R6 R, I NcH2)o 6Compounds of general formula I as defined above are prepared according to the following general method B: E, E, O. ^ CH 2 OH -: - ► tf CH 2 (CH 2) p (CH 2) q 4 (IV) 25 p R, Ea p I 5 (CH 2) nCOR 7 ^ ° \ 'ck + r \ R2 CH (CH 2) pV (CH2) q / ~ R6 R, I NcH2) o 6

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Et hydroxyæterderivat med den generelle formel IV hvor r\ R , R og R , R°, p og g er som defineret ovenfor, omsættes således, at der dannes en forbindelse med formel V, hvor R , R, R°, R , R°, p og q er som defineret ovenfor 5 og Z er en egnet afgangsgruppe (d.v.s. halogen, tosylat, mesylat). Denne omsætning kan gennemføres i et passende opløsningsmiddel (f.eks. dichlormethan, toluen, pyridin) med et passende reagens (f.eks. p-toluensulfonylchlorid, phosphoroxychlorid, phosphorpentachloridthionylhalogenid, 10 phosphortribromid eller methansulfonylchlorid) ved en tem peratur op til refluxtemperaturen i 1 til 72 timer. JEter- 1 2 3 4 8 derivatet med formel V, hvor R , R , R , R , R , Z, p og q er som defineret ovenfor omsættes med et derivat af en 5 6 azaheterocyclisk carboxylsyre med formel VI hvor R , R , 15 n og m er som defineret ovenfor, til dannelse af en forbindelse med den generelle formel I. Denne omsætning kan gennemføres i et passende opløsningsmiddel så. som acetone, tetahydrofuran, . toluen: eller . N, N- dimethylformamid under tilstedeværelse af en base, såsom...et . alkalimetalr·.A hydroxy ether derivative of the general formula IV wherein r \ R, R and R, R °, p and g are as defined above is reacted to form a compound of formula V wherein R, R, R °, R, R °, p and q are as defined above 5 and Z is a suitable leaving group (ie halogen, tosylate, mesylate). This reaction can be carried out in a suitable solvent (eg dichloromethane, toluene, pyridine) with an appropriate reagent (eg p-toluenesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride thionyl halide, phosphorus tribromide or methanesulfonyl chloride) at a temperature up to reflux temperature for 72 hours. The JEter 1 derivative of formula V wherein R, R, R, R, R, Z, p and q are as defined above is reacted with a derivative of a 5,6 azaheterocyclic carboxylic acid of formula VI wherein R, R 15 n and m are as defined above to form a compound of general formula I. This reaction may be carried out in a suitable solvent then. as acetone, tetahydrofuran ,. toluene: or. N, N-dimethylformamide in the presence of a base such as ... et. alkalimetalr ·.

20 carbonat eller en passende tertiær amin ved·en,temperatur op-til refluxtemperatur. i 1 til 72 'timer.20 carbonate or a suitable tertiary amine at a temperature up to reflux temperature. for 1 to 72 hours.

Metode C : . _ . . ' '· ·. . - ··..·' ·-·.· ; c ' "· · 25 Forbindelser med den generelle formel la som defineret ovenfor (metode A) fremstilles ifølge den nedenstående metode C: 30 f1 j8 rry° + Y\ -'“v. .^z ".'--7 2 I {αν* (ca2)q . H . . ... . , . · c,·:-.Method C:. _. . '' · ·. . - ·· .. · '· - ·. ·; Compounds of the general formula Ia as defined above (method A) are prepared according to the method below C: 30 f1 {αν * (ca2) q. H. . .... ,. · C, ·: -.

- (II) · (VII) .-v ' 35 7- (II) · (VII).-V '35 7

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Ef (CH2)»COE, i r * rv 5 Er^°-(CH->(4q (CH2)m (VIII) (VI)Ef (CH2) »COE, i r * rv 5 Is ^ ° - (CH -> (4q (CH2) m (VIII) (VI)

Es λ _(CH2)nCOR7 10 —► - *2 ^-(CH2)p^*<CH2)q (“2)· 15Es λ _ (CH2) nCOR7 10 -► - * 2 ^ - (CH2) p ^ <CH2) q (“2) · 15

Et acetaldehydderivat med formel II (som defineret i metode A) omsættes med en disubstitueret alkan med formel g VII, hvor R , p og q er som defineret ovenfor og Y og Z 20 er passende afgangsgrupper (såsom halogen, tosylat eller mesylat) (Y og Z kan være ens eller forskellige), til dannelse af et vinylæterderivat med formel VIII. Denne omsætning kan gennemføres i et passende opløsningsmiddel såsom tetrahydrofuran, toluen eller Ν,Ν-dimethylformamid under 25 tilstedeværelse af en stærk base, så som natriumhydrid eller et alkyllithium ved en temperatur op til refluxtem-peratur i 1 til 72 timer.An acetaldehyde derivative of formula II (as defined in method A) is reacted with a disubstituted alkane of formula g VII, wherein R, p and q are as defined above and Y and Z 20 are appropriate leaving groups (such as halogen, tosylate or mesylate) (Y and Z may be the same or different) to form a vinyl ether derivative of formula VIII. This reaction may be carried out in a suitable solvent such as tetrahydrofuran, toluene or Ν, Ν-dimethylformamide in the presence of a strong base such as sodium hydride or an alkyl lithium at a temperature up to reflux temperature for 1 to 72 hours.

i ii i

Vinylæterderivatet med formel VIII omsættes med et deri- 30 vat af en azaheterocyclisk carboxylsyre med formel VI (på næsten samme måde som forbindelse V omsættes med VI i metode B) til dannelse af en forbindelse med den gene- 1 2 5 6 7 8 relle formel la, hvor R , R , R , R°, R, R°, n, m, p og q er Som defineret ovenfor.The vinyl ether derivative of formula VIII is reacted with a derivative of an azaheterocyclic carboxylic acid of formula VI (in almost the same way as compound V is reacted with VI in method B) to give a compound of the general formula la, where R, R, R, R °, R, R °, n, m, p and q are As defined above.

35 835 8

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Metode DMethod D

Forbindelser med den generelle formel la som defineret ovenfor (metode A) fremstilles efter følgende metode D: 5 p R8 I1 f -► 2 I ^(CHj)p^(CHj)qCompounds of general formula Ia as defined above (Method A) are prepared according to the following Method D: 5 p R8 I1 f -► 2 I ^ (CHj) p ^ (CHj) q

HH

10 di) (vil) R, *, . \^^2)nC0R, 'ν(οίζ)ρ'ν(οζ), «0^Εί 15 (CH2)m (VIII) (VI)10 di) (will) R, * ,. \ ^^ 2) nC0R, 'ν (οίζ) ρ'ν (οζ), «0 ^ Εί 15 (CH2) m (VIII) (VI)

*S* S

t ^(CE2)nCOR7 .t ^ (CE2) nCOR7.

20 ^ ^°>v ,>CH / ~R® (ΐ3) R2 ^(CHpp^CCHjJq (CH2)m20 ° C> v,> CH / ~ R® (ΐ3) R2 ^ (CHpp ^ CCH2 Jq (CH2) m

Denne metode ligner i nogen grad metode C, men med den 25 vigtige forskel, at vinylæterderivatet med formel VIIIThis method is somewhat similar to Method C, but with the important difference that the vinyl ether derivative of formula VIII

fremstilles ved en faseoverførselsreaktion af aldehydderivatet (II) med den disubstituerede alkan med formel VII. Substituenteme er som defineret i metode C.is prepared by a phase transfer reaction of the aldehyde derivative (II) with the disubstituted alkane of formula VII. The substituents are as defined in Method C.

30 Eksempler på sådanne faseoverførselsalkyleringer kan findes i W.E. Keller, Phase Transfer Reactions, Vol. 1 og 2, Fluka, Georg Thieme Verlag, Stuttgart 1986 og 1989.Examples of such phase transfer alkylations can be found in W.E. Keller, Phase Transfer Reactions, Vol. 1 and 2, Fluka, Georg Thieme Verlag, Stuttgart 1986 and 1989.

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99

Metode EMethod E

Forbindelser med den generelle formel Ib, d.v.s. forbindelser med den generelle formel I som defineret ovenfor, 2 A s ø 5 hvor R , R , R° og R° alle er hydrogen, fremstilles ved hydrogenering af forbindelserne med formel la:Compounds of general formula Ib, i.e. compounds of the general formula I as defined above, 2 A s 5 where R, R, R ° and R ° are all hydrogen, are prepared by hydrogenating the compounds of formula Ia:

Rs 10 \.(CH2)nCOR7 XV* —► *2 ^(CH2)pX(CH2)q (CH2)b 15 (CH2)nCOR7 R8 r--Λ Λ; £> ab> 2q E2 (CH2)p (CH2)q (cH2)m 25 Hydrogeneringen udføres fortrinsvis ved stuetemperatur under tilstedeværelse af en hydrogeneringskatalysator så som en ædelmeltalskatalysator, f.eks. palladium på trækul.Rs 10 \. (CH2) nCOR7 XV * —► * 2 ^ (CH2) pX (CH2) q (CH2) b 15 (CH2) nCOR7 R8 r - Λ Λ; The hydrogenation is preferably carried out at room temperature in the presence of a hydrogenation catalyst such as a noble melt catalyst, e.g. palladium on charcoal.

Det foretrukne hydrogentryk er fra atmosfærisk tryk til omkring 5 atm., men hydrogeneringen kan også foregå ved 30 højt tryk. Ethanol og metanol er eksempler på foretrukne opløsningsmidler.The preferred hydrogen pressure is from atmospheric pressure to about 5 atm, but hydrogenation can also take place at high pressure. Ethanol and methanol are examples of preferred solvents.

For at beskytte de mellemprodukter, der bruges i ovennævnte metoder (f.eks. III eller V), kan carboxylsyregrup-35 pen for eksempel esterifiseres. Indførelse og fjernelse af beskyttelsesgrupper beskrives f.eks. i "Protective Groups in Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973).For example, to protect the intermediates used in the above methods (e.g., III or V), the carboxylic acid group can be esterified. The introduction and removal of protecting groups is described e.g. in "Protective Groups in Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973).

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Hvis estere er fremstillet efter metoderne A-E kan forbin- 7 delser med formel I, hvor R er OH, fremstilles ved hydro-5 lyse af estergruppen, fortrinsvis ved stuetemperatur i en blanding af en vandig alkalimetalhydroxidopløsning og en alkohol, såsom methanol eller ethanol, i ca. 0,5 til 6 timer.If esters are prepared according to methods AE, compounds of formula I wherein R is OH can be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol. ca. 0.5 to 6 hours.

3 10 Værdier for in vitro hæmning af [ H] -GABA optagelse for forbindelserne ifølge opfindelsen blev først og fremmest anslået ved Fjailands metode (Acta Pharmacol.Toxicol. 42 (1978) 73-76).Values for in vitro inhibition of [H] -GABA uptake for the compounds of the invention were firstly estimated by Fjayland's method (Acta Pharmacol.Toxicol. 42 (1978) 73-76).

15 Han Wistar rotters hjernebarkvæv homogeniseredes forsigtigt med håndkraft under anvendelse af en glas/PTFE homo-genisator i 10 portioner af 0,32 M sucrose. Xnkubering blev foretaget i en 40 mM tris HC1 buffer (pH 7,5 ved 3Q?C) .indeholdende 120 nM NåCl, 9,2 nM KG1, 4 mM MgS04, 20 2/3 :mM CaCl2 og 10 mM glucose i 60 min. ved 30?C: Ligand- koncentrationen var 0,2 nM. · Værdier for hæmning af GABA-optagelse for nogle repræsentative forbindelser vises i Tabel 1: 25 ··<··· 30 I t r 3515 He Wistar rat cerebral tissue was gently homogenized using a glass / PTFE homogenizer in 10 aliquots of 0.32 M sucrose. Incubation was performed in a 40 mM Tris HCl buffer (pH 7.5 at 3 ° C) containing 120 nM NaCl, 9.2 nM KG1, 4 mM MgSO 4, 20 2/3: mM CaCl2 and 10 mM glucose for 60 min. . at 30 ° C: Ligand concentration was 0.2 nM. · GABA uptake inhibition values for some representative compounds are shown in Table 1: 25 ·· <··· 30 I t r 35

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1111

Tabel 1. Hæmning af [ Hj-GABA optagelse II III i 5 1 aT ' aT3 aT1 1 af3 V- B ° ° S ® ® S ®Table 1. Inhibition of [Hj-GABA uptake II III in 5 1 aT 'aT3 aT1 1 af3 V- B ° ° S ® ® S ®

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8-¾ SSS®SSSS8-¾ SSS®SSSS

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15 H15 H

I I I I * II I I I * I

^ I I ........9 9 I I^ I I ........ 9 9 I I

20 I 1 I I f f f f acociioioiojojcs 'å · ft C rH^ 25 ^ ^ HH I H ft ft I f I i i f i i20 I 1 I I f f f f f acociioioiojojcs' å · ft C rH ^ 25 ^^ HH I H ft ft I f I i i f i i

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12 I III' ' ^ 1 ' ϊτΓ3 aT1 _ s ® s s “12 I III '' ^ 1 'ϊτΓ3 aT1 _ s ® s s “

‘"cc — o 8 o u S SS"" Cc - o 8 o u S SS

5-- 5 S S 5 6 I II II II D .5-- 5 S S 5 6 I II II II D.

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1313

Forbindelser med formel' I er nyttige, idet de udviser en tydelig farmakologisk virkning i mennesker. Især er forbindelserne med formel I nyttige i kraft af deres hæmmende virkning på GABA-optagelsen.Compounds of formula I are useful in that they exhibit a distinct pharmacological effect in humans. In particular, the compounds of formula I are useful by virtue of their inhibitory effect on GABA uptake.

55

Til ovennævnte indikationer vil dosis variere afhængigt af hvilken forbindelse med formel I der anvendes, afhængigt af indgivelsesmåden og den ønskede terapi. Generelt opnås dog tilfredsstillende resultater med en dosis på 10 fra ca. 0,5 mg til ca. 1000 mg, fortrinsvis fra ca. 1 mg til ca. 500 mg forbindelse med formel 1, hensigtsmæssigt indgivet fra 1 til 5 gange dagligt, eventuelt i form af præparater med forsinket frigivelse. Sædvanligvis er passende dosisformer ved oral indgivelse fra ca. 0,5 mg til 15 ca. 1000 mg, fortrinsvis fra ca. 1 mg til ca. 500 mg af forbindelsen med formel I, blandet med et farmaceutisk bærestof eller fortyndingsmiddel. Der er ikke observeret toksiske virkninger.For the above indications, the dose will vary depending on the compound of formula I used, depending on the mode of administration and the desired therapy. In general, however, satisfactory results are obtained with a dose of 10 from ca. 0.5 mg to approx. 1000 mg, preferably from ca. 1 mg to approx. 500 mg of compound of formula 1, conveniently administered from 1 to 5 times daily, optionally in the form of delayed release preparations. Usually, suitable dosage forms for oral administration are from about 0.5 mg to 15 approx. 1000 mg, preferably from ca. 1 mg to approx. 500 mg of the compound of formula I, mixed with a pharmaceutical carrier or diluent. No toxic effects have been observed.

’20 Forbindelserne med formel I kan indgives i form af et farmaceutisk acceptabelt syreadditionssalt,.eller hvor det er muligt som et metal- eller et lavere alkylammoniumsalt. Sådanne saltformer-udviser omtrent samme virkningsgrad som de frie base former.The compounds of formula I may be administered in the form of a pharmaceutically acceptable acid addition salt, or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit about the same efficiency as the free base forms.

2525

Denne opfindelse angår også farmaceutiske præparater indeholdende en forbindelse med formel I eller et farmaceutisk acceptabelt salt heraf, og sædvanligvis indeholder sådanne præparater også et farmaceutisk bærestof eller fortyn-30 dingsmiddel. Præparaterne indeholdende forbindelserne ifølge opfindelsen kan fremstilles ved konventionelle tek-hikker og findes i konventionelle former, f.eks. i kapsler', tabletter, opløsninger og suspensioner.This invention also relates to pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof, and usually such compositions also contain a pharmaceutical carrier or diluent. The compositions containing the compounds of the invention can be prepared by conventional techniques and are available in conventional forms, e.g. in capsules', tablets, solutions and suspensions.

35 Det benyttede farmaceutiske bærestof kan være et sædvanligt fåst eller flydende bærestof. Eksfempler på faste bærestoffer er laktose, terra alba, sucrose, talkum, gelatine,The pharmaceutical carrier used may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin,

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14 agar,, pektin, akasia, magnesiumstearat og stearinsyre. Eksempler på flydende bærestoffer er sirup, jordnøddeolie, olivenolie og vand.14 agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

5 På lignende måde kan bærestoffet eller fortyndingsmidlet indeholde ethvert stof med forsinket frigivelse, der kendes af fagfolk, såsom glycerylmonostearat eller glyceryl-distearat, alene eller blandet med en voks.Similarly, the carrier or diluent may contain any delayed release substance known to those skilled in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

10 Hvis der anvendes et fast bærestof til oral indgivelse kan præparatet tabletteres, placeres i en hård gelatinekapsel i pulver- eller pelletform , eller i form af en pastil eller en tablet. Mængden af fast bærestof vil variere meget, men vil sædvanligvis være fra omkring 25 mg 15 til omkring 1 g. Hvis der anvendes et flydende bærestof kan præparatet være i form-af en sirup, emulsion, blød gelatinekapsel eller steril injektionsvæske såsom en van- t dig eller ikke- vandig flydende suspension eller opløsning.If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a lozenge or tablet. The amount of solid carrier will vary widely, but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the composition may be in the form of a syrup, emulsion, soft gelatin capsule or sterile solution for injection such as water. you or non-aqueous liquid suspension or solution.

2020

De farmaceutiske præparater ifølge opfindelsen kaii fremstilles efter sædvanlige teknikker for farmaceutisk industri·, omfattende blanding, granulering og komprimering eller forskellige former for blanding og opløsning af in-25 gredienserne til opnåelse af det ønskede slutprodukt.The pharmaceutical compositions of the invention are prepared according to conventional techniques for the pharmaceutical industry, comprising mixing, granulating and compressing or various forms of mixing and dissolving the ingredients to obtain the desired final product.

En typisk· tablet som kan fremstilles ved sædvanlige tabletteringsteknikker indeholder: 30 Kærne:A typical · tablet that can be prepared by conventional tableting techniques contains: 30 Kernels:

Aktiv forbindelse-(som fri forbin- 100 mg delse:'eller et salt heraf)Active compound (as a free compound 100 mg: or a salt thereof)

Kolloidal siliconedioxid (Areosil ) 1,5 mg 35 Cellulose, microcryst. (Avicel ) 70 mg ' Modificeret cellulose gum (Ac-Di-Sol )· 7,5 mgColloidal Silicone Dioxide (Areosil) 1.5 mg Cellulose, microcryst. (Avicel) 70 mg 'Modified Cellulose Gum (Ac-Di-Sol) · 7.5 mg

Magnesiumstearat 1 mgMagnesium stearate 1 mg

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1515

Overtræk: HPMC ca. 9 mg * ®Coating: HPMC approx. 9 mg * ®

Mywacett 9-40 T ca. 0.9 mg 5 *Mywacett 9-40 T approx. 0.9 mg 5 *

Acyleret monoglycerid anvendt som blødgørings-middel til filmovertræk 10 Indgivelsesmåde kan være enhver måde som effektivt transporterer den aktive forbindelse til det passende eller ønskede virkningssted, så som oral eller parenteral indgi vning, hvor den orale vej foretrækkes.Acylated monoglyceride used as a film coating plasticizer. Method of administration may be any means that effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral administration, where the oral route is preferred.

1515

Fremgangsmåden til fremstilling af forbindelser med formel I og præparater indeholdende disse, er yderligere illustreret i de efterfølgende eksempler.The process of preparing compounds of formula I and compositions containing them is further illustrated in the following Examples.

20 I det følgende betegner TLC tyndtlagskromatografi, THF tetrahydrofuran, og smp. smeltepunkt. Forbindelsernes struktur bekræftes ved NMR og elementæranalyse. Hvor smeltepunkter er angivet er disse ukorrigerede. Alle temperaturer er i °C. Forbindelser, der bruges som udgangsmateri-25 aler er enten kendte forbindelser eller forbindelser, som let kan fremstilles ved kendte metoder. Hidtil ukendte diarylacetaldehyder fremstilledes efter kendte metoder (se f.eks. Blicke, FF and Faust, J.A., J.Arner.Chem.Soc., 16 (1954), 3156; Borch R.F., Tetrahedron Lett., 36, (1972), 30 3761; Martin, S.F., Synthesis, (1979), 633; Ashwood M.S.In the following, TLC denotes thin layer chromatography, THF tetrahydrofuran, and m.p. melting point. The structure of the compounds is confirmed by NMR and elemental analysis. Where melting points are indicated, these are uncorrected. All temperatures are in ° C. Compounds used as starting materials are either known compounds or compounds which can be readily prepared by known methods. Novel diaryl acetaldehydes were prepared by known methods (see, e.g., Blicke, FF and Faust, JA, J. Arner.Chem.Soc., 16 (1954), 3156; Borch RF, Tetrahedron Lett., 36, (1972), Martin, SF, Synthesis, (1979), 633; Ashwood MS

et al., Synthesis, (1988), 379); Meyers, A.I., et al., J.Amer.Chem.Soc., 104 (1982), 877-9; Matteson, D.S., et al., J.Org.Chem., 45 (1980) 1091-5)). Kolonnekromatografi udførtes ved anvendelse af den af Still, W.C. et al., 35 J.Org.Chem., 43 (1978) 2923 beskrevne teknik på Merck si-licagel 60 (Art. 9385). HPLC udførtes med en Waters model 510 kromatograf, interface via et systemmodul til en Waters 5et al., Synthesis, (1988), 379); Meyers, A.I., et al., J.Amer.Chem.Soc., 104 (1982), 877-9; Matteson, D.S., et al., J. Org. Chem., 45 (1980) 1091-5)). Column chromatography was performed using that of Still, W.C. et al., 35 J. Org.Chem., 43 (1978) 2923, described on Merck silica gel 60 (Art. 9385). HPLC was performed with a Waters model 510 chromatograph, interface via a system module to a Waters 5

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16 490 multibølgelængdedetektor til en med omvendt fase C^g kolonne (250 x 4 mml, 5 pm, 100 Å). Retentionstider angives i minutter.16 490 multi-wavelength detector for an inverted phase C ^ g column (250 x 4 mml, 5 µm, 100 Å). Retention times are given in minutes.

EKSEMPEL 1 (Metode A) (R)-l-[2- [ [ 2,2-Diphenylethenyl] oxy] ethyl] -3-piper idin carboxylsyreethylester 10 - (R)-enantiomeren af ethylnipecotat (100 g, 0,64 mol) (Akkerman, A.M. et al., Gazz. Chim. I tal., 102 (1972) 189) blandedes i tør acetone (300 ml) med 2-bromethanol (85 g, 15 0,68 mol), tørret, pulveriseret kaliumkarbonat (188 g, 1,28 mol); og kaliumjodid (21,6 g, 0,13 mol). Reaktions-blandingen, omrør tes ved stuetemperatur i .18 timer og ved reflux i >24 timer. Filtrering af reaktionsblandingen og inddampning af det fremkomne filtrat gav (R)-l-(2-hydroxy-20 ethyl)nipecotinsyreethylester som en olie, der rensedesExample 1 (Method A) (R) -1- [2- [[2,2-Diphenylethenyl] oxy] ethyl] -3-piperidine carboxylic acid ethyl ester 10 - (R) -enantiomer of ethyl nipecotate (100 g, 0.64 mol ) (Akkerman, AM et al., Gazz. Chim. In Nos. 102 (1972) 189) were mixed in dry acetone (300 ml) with 2-bromoethanol (85 g, 0.68 mol), dried, powdered potassium carbonate. (188 g, 1.28 mol); and potassium iodide (21.6 g, 0.13 mol). The reaction mixture is stirred at room temperature for 18 hours and at reflux for> 24 hours. Filtration of the reaction mixture and evaporation of the resulting filtrate gave (R) -1- (2-hydroxyethyl) nipecotinic acid ethyl ester as an oil which was purified

ved distillering in vacuo (110- 115°C, 0,1 mmHg), udbytte (72,2 g, 56%). TLC: rf 0,20 (Si0~; dichlormethan/methanol 19/1). ' : .Vby distillation in vacuo (110-115 ° C, 0.1 mmHg), yield (72.2 g, 56%). TLC: rf 0.20 (SiO ~; dichloromethane / methanol 19/1). ': .V

25 En prøve af ovennævnte alkohol (140 g, 0,70 mol) opløstes i toluen (400 ml) og thionylbromid (80 ml, 0,77 mol) tilførtes under kraftig omrøring. Efter 1,5 time var den exo-therme reaktion aftaget og diethylæter (400 ml) tilsattes.A sample of the above alcohol (140 g, 0.70 mol) was dissolved in toluene (400 ml) and thionyl bromide (80 ml, 0.77 mol) was added with vigorous stirring. After 1.5 hours, the exothermic reaction subsided and diethyl ether (400 ml) was added.

Det fremkomne- bundfald opsamledes ved filtrering og vas^ 30 kedes med diethylæter. Det faste stof tritureredes med ethylacetat, og opsamledes igen på et filter dg tørredes til··-opnåelse af (R) -1 - (· 2 -bromethyl) nipecotinsyreethylester hydrobromid (175 g, 73%) som et hvidt faststof, smp.- 210-215°.The resulting precipitate was collected by filtration and washed with diethyl ether. The solid was triturated with ethyl acetate and again collected on a filter and dried to give (R) -1 - (2-bromoethyl) nipecotinic acid ethyl ester hydrobromide (175 g, 73%) as a white solid, m.p. 210-215 °.

Diphenylacetaldehyd (4,9 g, 0,025 mol) sattes dråbevis til en blanding af natriumhydrid (1,5 g, 0,05 mol, 80% 35Diphenyl acetaldehyde (4.9 g, 0.025 mol) was added dropwise to a mixture of sodium hydride (1.5 g, 0.05 mol, 80%).

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17 oliedispergering) og tør toluen (25 ml) ved 0°C. Denne blanding omrørtes ved stuetemperatur i 0,5 timer, opvarmedes til 50°C og fik lov til at afkøle til stuetemperatur. Ovennævnte (R)-l-(2-bromethyl)nipecotinsyreethylester 5 hydrobromid (8,6 g, 0,025 mol) tilsattes portionsvis medens temperaturen blev holdt under 30°C ved hjælp af et isvandsbad. Efter omrøring i 1 time filtreredes reaktionsblandingen, og filtratet inddampedes til tørhed. Lynchro-matografi af inddampningsresten på silica gel (200 g) med 10 en blanding af heptan og tetrahydrofuran (4/1) som elue- ringsmiddel gav titel forbindelsen (6,6 g, 69%) som en olie. Tic: rf 0,24 (Si02; heptan/THF 7/3).17 oil dispersion) and dry toluene (25 ml) at 0 ° C. This mixture was stirred at room temperature for 0.5 hours, heated to 50 ° C and allowed to cool to room temperature. The above (R) -1- (2-bromethyl) nipecotinic acid ester 5 hydrobromide (8.6 g, 0.025 mol) was added portionwise while maintaining the temperature below 30 ° C by an ice-water bath. After stirring for 1 hour, the reaction mixture was filtered and the filtrate was evaporated to dryness. Flash chromatography of the residue on silica gel (200 g) with a mixture of heptane and tetrahydrofuran (4/1) as the eluent gave the title compound (6.6 g, 69%) as an oil. Tic: rf 0.24 (SiO 2; heptane / THF 7/3).

EKSEMPEL 2 15 (R) -1- [ 2- [ £ 2,2-Diphenylethenyl] oxy] ethyl ] -3-piperidin-carboxylsyre hydrochlorid m,a............. 1 ............................ I · I .1 > 11 ·. Ϊ 1 ———' I I · 20 (R) *1*- [ 2- [ [2,2-Diphenylethenyl] oxy] ethyl] -3-piperidin carboxylsyreethylester (eksempel 1) (3,0 g, 0,079 mol) opløstes i ethanol (20 ml) og 12 N natriumhydroxidopløs- -ning (2,0 ml) tilsattes. Efter omrøring af opløsningen ved stuetemperatur i 2,5 timer tilsattes 37% saltsyre .···' 25 (ca. 2,2 ml) til en surhedsgrad målt til pH 2. Dichlorme-than (300 ml) tilsattes, og blandingen tørredes (MgSO^). Filtrering og inddampning af filtratet gav et faststof, som tritureredes med diethylæter, hvilket gav titelforbindelsen (2,65 g, 86%) som et hvidt faststof, smp. 210-216°.EXAMPLE 2 (R) -1- [2- [2,2-Diphenylethenyl] oxy] ethyl] -3-piperidine carboxylic acid hydrochloride m, a ............. 1.. .......................... I · I .1> 11 ·. Ϊ 1- (II) 20 (R) * 1 * - [2- [[2,2-Diphenylethenyl] oxy] ethyl] -3-piperidine carboxylic acid ethyl ester (Example 1) (3.0 g, 0.079 mol) was dissolved in ethanol (20 ml) and 12 N sodium hydroxide solution (2.0 ml) were added. After stirring the solution at room temperature for 2.5 hours, 37% hydrochloric acid was added. ··· 25 (about 2.2 ml) to an acidity measured to pH 2. Dichloromethane (300 ml) was added and the mixture dried ( MgSO,). Filtration and evaporation of the filtrate gave a solid which was triturated with diethyl ether to give the title compound (2.65 g, 86%) as a white solid, m.p. 210-216 °.

30 C22H25C1N03*HC1' ber©gnet: C, 68,1; H, 6,8; N, 3,6; Cl, 9,15. Fundet: C, 67,6; H, 6,7; N, 3,65; Cl, 9,0%.C22 H25 ClNO3 * HCl requires: C, 68.1; H, 6.8; N, 3.6; Cl, 9.15. Found: C, 67.6; H, 6.7; N, 3.65; Cl, 9.0%.

35 .··.35. ··.

Z-(R)-l-[2-[ [2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl] — 3-piperidincarboxylsyre hydrochlorid 5 -:- EKSEMPEL 3 18Z- (R) -1- [2- [[2- (2-Methylphenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride 5 - EXAMPLE 3 18

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Z-(R)-l-[2-[[2-( 2-Methylphenyl) - 2-phenylethenyl] oxy] ethyl]- 3-piperidincarboxylsyreethylester (2,0 g, 0,0051 mol) (fremstillet som beskrevet i metode A) opløstes i ethanol 10 (8 ml) og 12N natriumhydroxidopløsning (1,3 ml) tilsattes.Z- (R) -1- [2 - [[2- (2-Methylphenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (2.0 g, 0.0051 mol) (prepared as described in Method A) was dissolved in ethanol 10 (8 ml) and 12N sodium hydroxide solution (1.3 ml) was added.

Efter omrøring af opløsningen ved stuetemperatur i 2 timer tilsattes 37% saltsyre (ca. 1,8 ml) under afkøling, efterfulgt af dichlormethan (300 ml) og blandingen tørredes (Na2S0^). Filtrering og inddamning af filtratet gav en 15 inddampningsrest som geninddampedes med acetone. Det faste produkt tritureredes med éthylacétat, opsamledes ved filtrering og tørredes in vacuo hvilket gav titelforbindelsen (0,70 g, 34%), smp·. 206-211°. ’ ·· 20 C23H27N03*HC1' ^ere9ne-t: G,- 68,7; H, 7,0; N, 3,5; Cl, 8-, 8.After stirring the solution at room temperature for 2 hours, 37% hydrochloric acid (about 1.8 ml) was added with cooling, followed by dichloromethane (300 ml) and the mixture dried (Na 2 SO 4). Filtration and evaporation of the filtrate gave an evaporation residue which was evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to give the title compound (0.70 g, 34%), m.p. 206-211 °. 20 C23H27NO3 * HCl + 1H-g: G, - 68.7; H, 7.0; N, 3.5; Cl, 8-, 8.

Fundet: C, 67,7; H, 7,1; N, 3,5; Cl, 8,9% - EKSEMPEL 4 25 E-(R)-1-[2-[[2-(2-Methylphenyl) -2-phenylethenyl ] oxy] ethyl] - 3-piperidincarboxylsyre hydrochlorid E- (R) -1- [ 2- [ [ 2- (2-Methylphenyl) -2-phenylethenyl ] oxy] ethyl ] -3 -30 piperidincarboxylsyreethylester (1,1 g, 0,0028 mol) (frem stillet som beskrevet i metode A) opløstes i ethanol (5 ml) og 12N natriumhydroxidopløsning (0,7 ml) tilsattes.Found: C, 67.7; H, 7.1; N, 3.5; Cl, 8.9% - Example 4 E- (R) -1- [2 - [[2- (2-Methylphenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride E- (R) - 1- [2- [[2- (2-Methylphenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (1.1 g, 0.0028 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.7 ml) were added.

Efter omrøring af opløsningen ved stuetemperatur i 2 timer tilsattes 37% saltsyreopløsning (ca. 1,0 ral) (under afkø-35 ling) efterfulgt af dichlormethan (300 ml) og blandingen tørredes (Na2S04). Filtrering og inddampning af filtratet gav en inddampningsrest som geninddampedes med acetone.After stirring the solution at room temperature for 2 hours, 37% hydrochloric acid solution (about 1.0 µl) (under cooling) was added followed by dichloromethane (300 ml) and the mixture dried (Na 2 SO 4). Filtration and evaporation of the filtrate gave an evaporation residue which was evaporated with acetone.

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1919

Det faste produkt tritureredes med ethylacetat, opsamledes ved filtrering og tørredes in vacuo hvilket gav titelforbindelsen (0,70 g, 62%), smp. 195-196°.The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to give the title compound (0.70 g, 62%), m.p. 195-196 °.

5 C23H27N03*HC1' bere9net: c' 68'7'· H' 7'0'* N' 3/5; cl' 8'8C23H27NO3 * HCl 'calculated: c' 68'7 '· H' 7'0 '* N' 3/5; cl '8'8

Fundet: C, 68,1; H, 7,2; N, 3,4; Cl, 8,7%.Found: C, 68.1; H, 7.2; N, 3.4; Cl, 8.7%.

EKSEMPEL 5 10 E eller Z-(R)-1-[2-[[2-(2-Chlorphenyl)-2-phenylethenyl]-oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid E eller Z-(R)-1-[2-[[2-(2-Chlorphenyl)-2-phenylethenyl]-15 oxy]ethyl]-3-piperidincarboxylsyreethylester (1,0 g, 0,0024 mol) (fremstillet som beskrevet i metode A) opløstes i ethanol (10 ml) og 10N natriumhydroxidopløsning (2,42 ral) tilsattes. Efter omrøring af opløsningen ved stuetemperatur i 5 timer tilsattes vand (100 ml) og blan-20 dingen neutraliseredes med 2N saltsyreopløsning. Xnddamp-ning af ethanol under reduceret tryk gav en vandig opløsning, som blev gjort sur til pH 0,5 med 2N saltsyreopløsning og ekstraheret med dichlormethan (4 x 100 ml). De samlede ekstrakter tørredes (Na^SO^) og inddampedes til 25 en olie, som opløstes i meget lidt methanol. Toluen (20 ml) tilsattes og den fremkomne opløsning opvarmedes på dampbad. Efter afkøling opsamledes og tørredes stoffet in vacuo til opnåelse af titelforbindelsen (0,64 g, 62%), som et hvidt krystallinsk faststof. Smp. bliver blød ved 30 170°,smelter ved 198°.EXAMPLE 5 E or Z- (R) -1- [2 - [[2- (2-Chlorophenyl) -2-phenylethenyl] -oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride E or Z- (R) -1- [2 - [[2- (2-Chlorophenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (1.0 g, 0.0024 mol) (prepared as described in Method A) was dissolved in ethanol ( 10 ml) and 10N sodium hydroxide solution (2.42 ral) were added. After stirring the solution at room temperature for 5 hours, water (100 ml) was added and the mixture was neutralized with 2N hydrochloric acid solution. Evaporation of ethanol under reduced pressure gave an aqueous solution which was acidified to pH 0.5 with 2N hydrochloric acid solution and extracted with dichloromethane (4 x 100 ml). The combined extracts were dried (Na 2 SO 4) and evaporated to an oil which was dissolved in very little methanol. Toluene (20 ml) was added and the resulting solution was heated on a steam bath. After cooling, the substance was collected and dried in vacuo to give the title compound (0.64 g, 62%) as a white crystalline solid. Mp. becomes soft at 30 170 °, melts at 198 °.

C22H23C1N03*HC1' bere9net; c' 62*6? H, 5,7; N, 3,2; Cl, 16,8 Fundet: C, 62,5; Ή, 6,0; N, 3,2; Cl, 16,6%.C22 H23 ClNO3 * HCl calculated; c '62 * 6? H, 5.7; N, 3.2; Cl, 16.8 Found: C, 62.5; Ή, 6.0; N, 3.2; Cl, 16.6%.

35 E eller Z-(R)-l-[2-[[2-(2-Chlorphenyl)-2-phenylethenyl]- oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid 5 -E or Z- (R) -1- [2 - [[2- (2-Chlorophenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride

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EKSEMPEL 6 20 E eller Z-(R)-l-[2-[[2-(2-Chlorphenyl)-2-phenylethenyl]-oxy]ethyl]-3-piperidincarboxylsyreethylester (1,0 g, 0,0024 mol) (modsat geometrisk isomer i forhold til eks-10 empel 6) opløstes i ethanol (20 ml) og 10N natriumhydroxidopløsning (2,42 ml) tilsattes. Efter omrøring af reaktionsblandingen ved stuetemperatur i 16 timer tilsattes vand (100 ml) og blandingen neutraliseredes med 2N saltsyreopløsning. Inddampning af ethanol under reduceret tryk 15 gav en vandig opløsning, som blev gjort sur til pH 1 med 2N saltsyre og ekstraheret méd dichlormethan (4 x 100 ml).Example 6 E or Z- (R) -1- [2 - [[2- (2-Chlorophenyl) -2-phenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (1.0 g, 0.0024 mol) (opposite geometric isomer to Example 6) was dissolved in ethanol (20 ml) and 10N sodium hydroxide solution (2.42 ml) was added. After stirring the reaction mixture at room temperature for 16 hours, water (100 ml) was added and the mixture was neutralized with 2N hydrochloric acid solution. Evaporation of ethanol under reduced pressure gave an aqueous solution which was acidified to pH 1 with 2N hydrochloric acid and extracted with dichloromethane (4 x 100 ml).

De samlede ekstrakter tørredes (Na2S04) og inddampedes til et faststof som omkrystalliseredes af methanol/tolu-en.hvilket gav titelforbindelsen (0,58·g;'56%) som hvide 20 krystaller (efter tørring in vacuo),- smp.- 227-8°.The combined extracts were dried (Na 2 SO 4) and evaporated to a solid which was recrystallized from methanol / toluene to give the title compound (0.58 · g; 56%) as white crystals (after drying in vacuo), m.p. 227-8 °.

C22H23elN03'HC1/ beregneti C; 62,6; Η, 5;7; N, 3,3·;.Cl, 16,8 Fundet; C, 62,6; H* 6,1; N, 3,2;. Cl, 16,7%.C 22 H 23 El NO 3 · HCl / calculated C; 62.6; Η, 5, 7; N, 3.3 · Cl, 16.8 Found; C, 62.6; H * 6.1; N, 3.2; Cl, 16.7%.

25 EKSEMPEL 7 (R)-1-[3-[[2,2-Diphenylethenyl ] oxy ] propyl ] -3-piperidin carboxylsyre hydrochlorid 30 (R)-l-[3-[[2,2-Diphenylethenyl]oxy]propyl]-3-piperidin carboxylsyreethylester (0,60 g, 0,0015 mol) (fremstillet som beskrevet i metode A) opløstes i ethanol (5 ml)*og 12N natriumhydroxidopløsning (0,4 ml) tilsattes- Efter 35 omrøring af opløsningen ved stuetemperatur i 2 timer tilsattes 37% saltsyre (ca. 0,52 ml) under afkøling, efterfulgt af‘ dichlormethan (250 ml). Blandingen tørredes 21EXAMPLE 7 (R) -1- [3 - [[2,2-Diphenylethenyl] oxy] propyl] -3-piperidine carboxylic acid hydrochloride (R) -1- [3 - [[2,2-Diphenylethenyl] oxy] propyl] -3-piperidine carboxylic acid ethyl ester (0.60 g, 0.0015 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) * and 12N sodium hydroxide solution (0.4 ml) was added - After stirring the solution at room temperature for 2 hours, 37% hydrochloric acid (about 0.52 ml) was added with cooling, followed by dichloromethane (250 ml). The mixture was dried 21

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(Na2SO^). Filtrering og inddampning af filtratet gav en inddampningsrest som geninddampedes med acetone. Det faste produkt tritureredes med acetone, opsamlédes ved filtrering og tørredes in vacuo hvilket gav titelforbindelsen 5 (0,30 g, 50%), smp. 176-180°.(Na2 *). Filtration and evaporation of the filtrate gave an evaporation residue which was evaporated with acetone. The solid product was triturated with acetone, collected by filtration and dried in vacuo to give the title compound 5 (0.30 g, 50%), m.p. 176-180 °.

C23H27NO3.HCI.O,25Η20, beregnet: C, 68,0; H, 7,1; N, 3,45;C 23 H 27 NO 3 .HCl.O, 25-20, Calc'd: C, 68.0; H, 7.1; N, 3.45;

Cl, 8,7 Fundet: C, 67,9; H, 7,1; N, 3,4; Cl, 8,3% 10 EKSEMPEL 8 (R)-1-[2-[[2-( 2-Methylphenyl) -2- (3-methyl-2-thienyl )ethe-nyl]oxy] ethyl ]-3-piperidincarboxylsyre hydrochlorid 15 (R)-l- [2- [ [ 2- (2-Methylphenyl )-2-( 3-methyl-2-thienyl )ethe-nyl] oxy]ethyl] -3-piperidincarboxylsyreethylester (6,0 g, 0,0133 mol) (fremstillet som'beskrevet i. metode A) opløstes i ethanol (100: ml) og ION natriumhydroxidopløsning 20 (13,3 ml) tilsattes. Efter omrøring af opløsningen ved stuetemperatur i 3 timer tilsattes vand (200 ml), og etha-nolet inddampedes under reduceret tryk Den vandige opløsning blev gjort sur til pH 1 med 2N saltsyreopløsning og ekstraheret med dichlormethan (4 x 150 ml). De samlede 25 ekstrakter tørredes (MgS04) og inddampedes til et faststof, som omkrystalliseredes af methanol/toluen/cyclohexan hvilket gav titelforbindelsen (4,09 g, 68%) som hvide krystaller, smp. 207-212° (efter, tørring in vacuo).Cl, 8.7 Found: C, 67.9; H, 7.1; N, 3.4; Cl, 8.3% EXAMPLE 8 (R) -1- [2 - [[2- (2-Methylphenyl) -2- (3-methyl-2-thienyl) ethenyl] oxy] ethyl] -3- piperidinecarboxylic acid hydrochloride (R) -1- [2- [[2- (2-Methylphenyl) -2- (3-methyl-2-thienyl) ethyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (6.0 g , 0.0133 mol) (prepared as described in Method A) was dissolved in ethanol (100: ml) and ION sodium hydroxide solution 20 (13.3 ml) was added. After stirring the solution at room temperature for 3 hours, water (200 ml) was added and the ethanol was evaporated under reduced pressure. The aqueous solution was acidified to pH 1 with 2N hydrochloric acid solution and extracted with dichloromethane (4 x 150 ml). The combined extracts were dried (MgSO 4) and evaporated to a solid which was recrystallized from methanol / toluene / cyclohexane to give the title compound (4.09 g, 68%) as white crystals, m.p. 207-212 ° (after, drying in vacuo).

30 C22H2?N03S.HC1.0,33PhCH3, beregnet: C, 64,6; H, 6,8; N, 3,1; Cl, 7,8; S, 7;6 Fundet: C, 64,6; H,-6,8; N, 3;1; Cl, 7,8; S, 7,3%. ’ -.: 35 EKSEMPEL 9 E eller Z-(R)-1-[2-[[2-(3-Fluorphenyl)-2-(2-methylphenyl)- ethenyl]oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid 5 - 22C22H2NO3S.HC1.0.33PhCH3, calculated: C, 64.6; H, 6.8; N, 3.1; Cl, 7.8; S, 7.6 Found: C, 64.6; H, 6.8; N, 3, 1; Cl, 7.8; S, 7.3%. EXAMPLE 9 E or Z- (R) -1- [2 - [[2- (3-Fluorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride 5 - 22

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E eller Z-(R)-l-[2-[[2-(3-Fluorphenyl)-2-(2-methylphenyl)-ethenyl]oxy]ethyl]-3-piperidincarboxylsyreethylester (0,-40 g, 0,00097 mol) (fremstillet som beskrevet i metode 10 A) opløstes i ethanol (5 ml) og 12 N natriumhydroxidopløsning (0,3 ml) tilsattes. Efter omrøring af opløsningen ved stuetemperatur i 5 timer tilsattes 37% saltsyreopløsning indtil pH måltes til ca. 1. Dichlormethan (250 ml) tilsattes, og det fremkomne bundfald opløstes ved tilsæt-15 ning af is portionsvis under kraftig omrøring. Den organiske fase skiltes fra, tørredes'(Na2S0^) og inddampedes til et bundfald, som geninddampedes med acetone. Omkrystallisering af acetone - gav: titel forbindelsen--(0,10- g·; · 24%)-som.;et hvidt faststof; smp. l93rl95?v 20 ........ .............. ....E or Z- (R) -1- [2 - [[2- (3-Fluorophenyl) -2- (2-methylphenyl) -ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (0.40 g, O (9797) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.3 ml) was added. After stirring the solution at room temperature for 5 hours, 37% hydrochloric acid solution was added until the pH was measured to ca. 1. Dichloromethane (250 ml) was added and the resulting precipitate was dissolved by adding ice cream portionwise with vigorous stirring. The organic phase was separated, dried (Na 2 SO 4) and evaporated to a precipitate which was evaporated with acetone. Recrystallization from acetone - gave: title compound - (0.10 g ·; 24%) - as a white solid; mp. l93rl95? v 20 ........ .............. ....

C23H26FN03*HC1' bere9net: c' 65,8; H' 6,5; N' 3'3; cl' 8,4. Fundet: C> 65,4; Η., · 6,6; N, ·3γ7? Cl,- 8;2%; .C 23 H 26 FNO 3 * HCl Calc'd: c '65.8; H, 6.5; N '3'3; cl '8.4. Found: C> 65.4; Η., · 6.6; N, · 3γ7? Cl - 8.2%; .

EKSEMPEL 10 25 Z eller E-(R)-l-[2-[[2-(3-Fluorphenyl)-2-(2-methylphenyl)-ethenyl]oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid 30 Z eller E-(R)-l-[2-[[2-(3-Fluorphenyl)-2-(2-methylphenyl)-ethenyl]oxy]ethyl]-3-piperidincarboxylsyreethylester (0,50 g,>0,22123 mol)(fremstillet som beskrevet i metode A)- (modsat· geometrisk·· isomer· i- forhold til eksempél 9) opløstes i éthanol (5 ml)- Og 12-N natriumhydroxidopløsning 35 (0,3 ml) tilsattes. Efter omrøring af opløsningen ved stue temperatur i 5 timer tilsattes 37% saltsyreopløsning indtil pH måltes til ca. 1. Dichlormethan (250 ml) tilsattes, 23EXAMPLE 10 Z or E- (R) -1- [2 - [[2- (3-Fluorophenyl) -2- (2-methylphenyl) -ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride Z or E- (R) -1- [2 - [[2- (3-Fluorophenyl) -2- (2-methylphenyl) -ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (0.50 g,> 0.22123 mol) ( prepared as described in Method A) - (opposite to geometric ·· isomer · relative to Example 9) was dissolved in ethanol (5 ml) - and 12-N sodium hydroxide solution 35 (0.3 ml) was added. After stirring the solution at room temperature for 5 hours, 37% hydrochloric acid solution was added until the pH was measured to ca. 1. Dichloromethane (250 ml) was added, 23

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og det fremkomne bundfald opløstes ved tilsætning af is under kraftig omrøring. Den organiske fase skiltes fra, tørredes (Na2S0^) og inddampedes til et bundfald, som gen-inddampedes med acetone. Omkrystallisation af acetone gav 5 titelforbindelsen (0,10 g, 20%) som et hvidt faststof, smp. 193-195°.and the resulting precipitate was dissolved by the addition of ice with vigorous stirring. The organic phase was separated, dried (Na 2 SO 4) and evaporated to a precipitate which was re-evaporated with acetone. Recrystallization of acetone gave the title compound (0.10 g, 20%) as a white solid, m.p. 193-195 °.

C23H26FN03*HC1' bere9net: c' 65'8? H, N, 3,3, Cl, 8,4- Fundet: C, 65,5; H, 6,6; N, 3,5; Cl, 8,3%.C23H26FNO3 * HCl 'calculated: c' 65'8? H, N, 3.3, Cl, 8.4- Found: C, 65.5; H, 6.6; N, 3.5; Cl, 8.3%.

10 EKSEMPEL 11 (Metode B) (R)-l-[2-[[2,2-bis(3-Methyl-2-thienyl)ethenyl]oxy]ethyl)- 3-piperidincarboxylsyreethylester 15 - 2-(Triphenylmethoxy)ethanol (3,98 g, 0,013 mol) opløstes i tør :THF (50 ml) og en 2,5 M opløsning af butyllithium i hexan (5,:5 ml, 0,0137 mol) tilsattes ved 0°C. En opløsning 20 af bromeddikesyre (1,81 g, 13,0 mmol) behandledes:separat med en 2,5 M opløsning af butyllithium i hexan (5,5 ml, 13,7 mmol) ved 0°C før de to opløsninger blandedes. Denne reaktionsblanding opvarmedes ved reflux i 68 timer, åfkø-ledes og vand (200 ml) tilsattes. . Der vaskedés med ethyl-25 acetat, hvorefter vandfasen blev gjort sur med 0,5 M citronsyreopløsning (50 ml). Ekstrahering med ethylacetat (2 x 100 ml) og tørring (MgS04) gav rå [2-(triphenylmethoxy )ethoxy]eddikesyre (2,78 g, 58%). Denne syre opløstes i dichlormethan (30 ml) og dicyclohexylcarbodiimid (1,72 30 g, 0,0083 mol) tilsattes, efterfulgt af 4-pyrrolidinopyri-din (0,11 g, 0,00074 mol) og ethanol (0,89 ml, 2 ækviv. ) (Ai. Hassner ét al.; Tetrahedron Lett. (1978) 4475). Reak-tionsblahdingen omrørtes i 16 timer ved stuetemperatur.og filtreredes for at fjerne dicyclohexylurinstof. Filtratet 35 inddampédes, og inddampningsresten rensedes ved lynchroma-tografipå silicagel (3 x 20 cm). Eluering med cyclohexan indeholdende 1-3% ethylacetat gav den ønskede [2-(triphe-EXAMPLE 11 (Method B) (R) -1- [2 - [[2,2-bis (3-Methyl-2-thienyl) ethenyl] oxy] ethyl) -3-piperidinecarboxylic acid ethyl ester 2- (Triphenylmethoxy) ethanol (3.98 g, 0.013 mol) was dissolved in dry: THF (50 ml) and a 2.5 M solution of butyllithium in hexane (5: 5 ml, 0.0137 mol) was added at 0 ° C. A solution of bromoacetic acid (1.81 g, 13.0 mmol) was treated: separately with a 2.5 M solution of butyllithium in hexane (5.5 ml, 13.7 mmol) at 0 ° C before mixing the two solutions . This reaction mixture was heated at reflux for 68 hours, cooled and water (200 ml) was added. . Wash with ethyl acetate and acidify the water phase with 0.5 M citric acid solution (50 ml). Extraction with ethyl acetate (2 x 100 ml) and drying (MgSO 4) gave crude [2- (triphenylmethoxy) ethoxy] acetic acid (2.78 g, 58%). This acid was dissolved in dichloromethane (30 ml) and dicyclohexylcarbodiimide (1.72 g, 0.0083 mol) was added, followed by 4-pyrrolidinopyridine (0.11 g, 0.00074 mol) and ethanol (0.89 ml , 2 equiv.) (Ai. Hassner et al .; Tetrahedron Lett. (1978) 4475). The reaction mixture was stirred for 16 hours at room temperature and filtered to remove dicyclohexylurea. The filtrate 35 was evaporated and the residue was purified by flash chromatography on silica gel (3 x 20 cm). Elution with cyclohexane containing 1-3% ethyl acetate gave the desired [2-

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24 nylmethoxy)ethoxy]eddikesyreethylester (1,5 g, 50%) som en olie.24 (methyl methoxy) ethoxy] acetic acid ethyl ester (1.5 g, 50%) as an oil.

2-Brom-3-methylthiophen (1,5 g, 0,0085 mol) og magnesium-5 spåner (0,22 g) opvarmedes forsigtigt i tør THF (30 ml) og reaktionen blev hurtigt exothermisk. Efter 0,2 timer varmedes reaktionsblandingen ved reflux i 0,5 timer, og den ovennævnte ester (1,5 g, 0,0038 mol) tilsattes som en opløsning i THF (20 ml). Blandingen varmedes igen ved re-10 flux i 0,5 timer, afkøledes og ammoniumchloridopløsning (100 ml) tilsattes. Omrøring i 0,5 timer ved stuetemperatur efterfulgtes af extrahering med ethylacetat (3 x 70 ml). De samlede ekstrakter tørredes (MgSO^) og inddampedes. Inddampningsresten opløstes i en blanding af 2N salt-15 syre (50 ml), THF (50 ral) og ethanol (50 ml) og opløsningen varmedes ved 50°C i 1 time og blev gjort basisk til pH 9,5-med natriumhydroxidopløsning. De organiske opløsningsmidler fjernedes in vacuo og det vandige bundfald ekstraheredes med ethylacetat (3 x 75 ml). Tørring af de 20 samlede ekstrakter (MgSO^) og·. inddampning gav en olie, som rensedes ved lynchromatografi på silicagel (2 x 15 cm). Eluering med cyclohexan/ethylacetat (9/1) gav 2-[2-(2-Hydroxyethoxy )-l-(3-methyl-2-thienyl )ethenyl] -3-methyl-thiophen (0,54 g, 50%) som et gummiagtigt stof.2-Bromo-3-methylthiophene (1.5 g, 0.0085 mol) and magnesium chips (0.22 g) were gently heated in dry THF (30 ml) and the reaction rapidly exothermic. After 0.2 hours, the reaction mixture was heated at reflux for 0.5 hours and the above ester (1.5 g, 0.0038 mol) was added as a solution in THF (20 ml). The mixture was again heated at reflux for 0.5 hours, cooled and ammonium chloride solution (100 ml) was added. Stirring for 0.5 hours at room temperature was followed by extraction with ethyl acetate (3 x 70 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was dissolved in a mixture of 2N hydrochloric acid (50 ml), THF (50 ml) and ethanol (50 ml) and the solution was heated at 50 ° C for 1 hour and basified to pH 9.5 with sodium hydroxide solution. The organic solvents were removed in vacuo and the aqueous precipitate extracted with ethyl acetate (3 x 75 mL). Drying the 20 total extracts (MgSO4) and ·. Evaporation gave an oil which was purified by flash chromatography on silica gel (2 x 15 cm). Elution with cyclohexane / ethyl acetate (9/1) gave 2- [2- (2-Hydroxyethoxy) -1- (3-methyl-2-thienyl) ethenyl] -3-methylthiophene (0.54 g, 50%) as a rubbery substance.

2525

Ovennævnte alkohol (0,53 g, 0,0019 mol) opløstes i tør toluen (20 ml) og opløsningen afkøledes til 0°C. En opløsning af n-butyllithium (2,5 Mi hexan) (0,9 ml, 0,0023 mol) tilsattes, og reaktionsblandingen henstod ved 0°G i 30 1 time hvorefter en opløsning af p-toluensulphonylchlorid (0,.47 g, 0,0025 mol) i toluen; (10 ml) tilsattesi Blandingen henstod ved stuetemperatur i 20 timer og til den fremkomne tosylatopløsning sattes (R)-enantiomeren af ethyl-nipecotat (0,59 g, 0,0038 møl) og pulveriseret, tørret· 35 kaliumkarbonat (1,04 g, 0,0075 mol). Temperaturen hævedes til 80°C og fastholdtes i 50 timer. Reaktionsblandingen a-fkøledes og vand (50 ml): tilsattes. Toluenefasen skiltesThe above alcohol (0.53 g, 0.0019 mol) was dissolved in dry toluene (20 ml) and the solution cooled to 0 ° C. A solution of n-butyllithium (2.5 MI hexane) (0.9 ml, 0.0023 mol) was added and the reaction mixture was allowed to stand at 0 ° G for 30 hours, after which a solution of p-toluenesulphonyl chloride (0.47 g 0.0025 mol) in toluene; (10 ml) was added. The mixture was allowed to stand at room temperature for 20 hours and to the resulting tosylate solution was added the (R) -enantiomer of ethylene nipecotate (0.59 g, 0.0038 mill) and powdered, dried potassium carbonate (1.04 g , 0.0075 mol). The temperature was raised to 80 ° C and maintained for 50 hours. The reaction mixture was cooled and water (50 ml): added. The toluene phase was separated

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25 fra og vandfasen ekstraheredes med ethylacetat (50 ml).25 and the aqueous phase was extracted with ethyl acetate (50 ml).

De samlede organiske ekstrakter tørredes (MgSO^) og inddampedes hvilket gav en olie som rensedes ved lynchroma-tografi på silicagel. Eluering med cyclohexan/ethylacetat 5 (19/1 - 5/1) gav titelforbindelsen (0,25 g, 31%) som et gummiagtigt stof. TLC: rf 0,26 (Si02; heptan/ THF 7/3).The combined organic extracts were dried (MgSO4) and evaporated to give an oil which was purified by flash chromatography on silica gel. Elution with cyclohexane / ethyl acetate 5 (19/1 - 5/1) afforded the title compound (0.25 g, 31%) as a gummy substance. TLC: rf 0.26 (SiO 2; heptane / THF 7/3).

EKSEMPEL 12 10 (R)-l-[2-[ [2,2-bis(3 -Methyl - 2 - thienyl) ethenyl ] oxy) ethyl ] - 3-piperidincarboxylsyre (R)-l-[2-[[2,2-bis( 3 -Me thy 1 - 2 - thienyl) ethenyl ] oxy] ethyl ] -15 3-piperidincarboxylsyreester (420 mg, 1 mmol) (eksempel 11) opløstes i ethanol (20 ml) og 10 N natriumhydroxidopløsning (1,00 ml) tilsattes. Efter 3 timer ved stuetemperatur indstilledes opløsningens pH til & med 2 N saltsyre. Ethanolet fjernedes ved inddampning og 1 opløsningens ;pH 20 indstilledes til 2,5- Ekstrahering med dichlormethan (4 x 15 ml), tørring af de samlede ekstrakter;(MgSO^) (trækul affarvning) og inddampning af filtratet gav et bundfald, som omkrystalliseredes af vand. Dette gav titelforbindelsen (0,34 g, 84%) som et cremeagtigt faststof, smp. 55-25 70°.· TLC: rf 0,37 (Si02, CH2Cl2/Me0H 1/1), C20H25N03S2‘3/4 H20, bere9net: 59,3; H, 6,6; N, 3,45; S, 15,8; Cl, 2,9. Fundet: C, 59,3; H, 6,6; N, 3,5; S, 15,85%.EXAMPLE 12 (R) -1- [2- [[2,2-bis (3-Methyl-2-thienyl) ethenyl] oxy) ethyl] -3-piperidinecarboxylic acid (R) -1- [2 - [[2 , 2-Bis (3-Me thyl-2-thienyl) ethenyl] oxy] ethyl] -15-piperidinecarboxylic acid ester (420 mg, 1 mmol) (Example 11) was dissolved in ethanol (20 ml) and 10 N sodium hydroxide solution (1 , 00 ml) was added. After 3 hours at room temperature, the solution pH was adjusted to & with 2N hydrochloric acid. The ethanol was removed by evaporation and in the solution; pH 20 was adjusted to 2.5. Extraction with dichloromethane (4 x 15 ml), dried over the combined extracts; (MgSO 4) (charcoal decolouration) and evaporated the filtrate to give a precipitate which of water. This gave the title compound (0.34 g, 84%) as a creamy solid, m.p. 55-25 70 °. TLC: rf 0.37 (SiO 2, CH 2 Cl 2 / MeOH 1/1), C 20 H 25 NO 3 S 2 3/4 H 2 O, calculated: 59.3; H, 6.6; N, 3.45; S, 15.8; Cl, 2.9. Found: C, 59.3; H, 6.6; N, 3.5; S, 15.85%.

30 EKSEMPEL 13 . .EXAMPLE 13. .

1 - [ 2- [ [ 2,2-bis(2-Methylphenyl )6thenyl ] oxy ] ethyl] -1,2 > 5 > 6-tétrahydro-3-pyridincarboxylsyre hydrochlorid · ' 35 --------!-:-—-:---:- l-[2-[[2,2-bis (2-Methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6- 261- [2- [[2,2-bis (2-Methylphenyl) 6thenyl] oxy] ethyl] -1,2,5 '6-tetrahydro-3-pyridinecarboxylic acid hydrochloride -: - -: ---: - 1- [2 - [[2,2-bis (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-26

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tetrahydropyridin-3-carboxylsyremethy lester (0,70 g, 0,0018 mol) (fremstillet som beskrevet i metode B) opløstes i ethanol (30 ml) og 10 N natriumhydroxidopløsning (1,79 ml) tilsattes. Reaktionsblandingen omrørtes ved 5 stuetemperatur i 2,5 timer og vand (100 ml) tilsattes, efterfulgt af 2 N saltsyreopløsning til pH 10. Ethanol fjernedes ved inddampning under reduceret tryk, og den vandige opløsning vaskedes med ethylacetat (20 ml). Vandfasen skildtes fra, blev gjort sur til pH 2 med 2 N salt-10 syreopløsning, og ekstraheredes med dichloromethan (4 x 50 ml). De samlede ekstrakter tørredes (MgSO^) og inddamp-ningsresten krystalliseredes af propanol/toluen hvilket gav titelforbindelsen (0,53 g, 76%), smp. 195-198°.tetrahydropyridine-3-carboxylic acid methyl ester (0.70 g, 0.0018 mol) (prepared as described in Method B) was dissolved in ethanol (30 ml) and 10 N sodium hydroxide solution (1.79 ml) was added. The reaction mixture was stirred at room temperature for 2.5 hours and water (100 ml) was added, followed by 2N hydrochloric acid solution to pH 10. Ethanol was removed by evaporation under reduced pressure and the aqueous solution was washed with ethyl acetate (20 ml). The aqueous phase was separated, acidified to pH 2 with 2N hydrochloric acid solution, and extracted with dichloromethane (4 x 50 ml). The combined extracts were dried (MgSO4) and the residue was crystallized from propanol / toluene to give the title compound (0.53 g, 76%), m.p. 195-198 °.

15 C^H^^NOg.HCl, beregnet: C, 69,65; H, 6,8; N, 3,4; Cl, 8,55 Fundet:* C, 69,6; H, 6,85; N, 3,2; Cl> '8,1%.C ^H ^^ NONOg.HCl, calcd: C, 69.65; H, 6.8; N, 3.4; Cl, 8.55 Found: C, 69.6; H, 6.85; N, 3.2; Cl> 8.1%.

EKSEMPEL 14 (Metode C) 20 a. 1- [ 2- (2-Bromethoxy )-!-·( 2-methylphenyl }.éthenyl ] -4-.EXAMPLE 14 (Method C) a. 1- [2- (2-Bromethoxy) -1- (2-methylphenyl} ethenyl] -4-.

fluor-2-methylbenzen ( 4*Fluor-2-methylphenyl) - (2 ^met hyIphény 1) acetaldehyd; £3,5 25 g, 0,0144 mol) opløstes i tøf THF (20 ml) og -sattes dråbevis til en suspension af natriumhydrid (60% oliedispersion) (0,63 g, 0>0158 mol) i tør tetrahydrofuran (30 ml).· Blandingen omrørtes ved stuetemperatur 1 1 time og varmedes ved reflux i 0.5 time. Efter afkøling tilsattes 1,2-30 dibroraethan (12,4 ml, 10 ækviv.) og reaktionsblandirtgen henstod ved stuetemperatur i 192 timer. Reaktionsblandingen filtreredes og inddampedes. Inddampningsresten pumpedes in vacuo, men indeholdt stadig, ca. 30% udgangsaldehyd, . hvorfor ovennævnte procedure blev gentaget.fluoro-2-methylbenzene (4 * fluoro-2-methylphenyl) - (2H with hyphenyl 1) acetaldehyde; £ 3.5 25 g, 0.0144 mol) was dissolved in tough THF (20 ml) and added dropwise to a suspension of sodium hydride (60% oil dispersion) (0.63 g, 0> 0158 mol) in dry tetrahydrofuran (30 The mixture was stirred at room temperature for 1 hour and heated at reflux for 0.5 hour. After cooling, 1.2-30 dibroroethane (12.4 ml, 10 equiv) was added and the reaction mixture was left at room temperature for 192 hours. The reaction mixture was filtered and evaporated. The evaporation residue was pumped in vacuo, but still contained, ca. 30% starting aldehyde ,. why the above procedure was repeated.

Den filtrerede reaktionsblanding inddampedes og til ind-dampningsrestvandet (100 ml) sattes mættet saltvandsopløs- 35 27The filtered reaction mixture was evaporated and to the evaporated residual water (100 ml) saturated brine solution was added.

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ning (100 ml) og ethylacetat (200 ml). Vandfasen skiltes fra og vaskedes med ethylacetat (100 ml). De samlede ethyl-acetatekstrakter vaskedes med saltvandsopløsning (100 ml), tørredes (MgS04) og inddampedes. Den rå titelforbindelse 5 (2,3 g, ca. 46%) blev brugt i næste trin, uden yderligere rensning.(100 ml) and ethyl acetate (200 ml). The aqueous phase was separated and washed with ethyl acetate (100 ml). The combined ethyl acetate extracts were washed with brine (100 mL), dried (MgSO 4) and evaporated. The crude title compound 5 (2.3 g, about 46%) was used in the next step, without further purification.

b. (R)-l-[2-[ [2-(4-Fluor-2-methylphenyl)-2-(2-methylphe-nyl )ethenyl] oxy] ethyl] -3-piperidincarboxylsyreethyl- 10 ester 1 - [ 2 - (2-Bromethoxy )-1-( 2 -methyl phenyl) etheny 1 ]-4-fluor-2-methylbenzen (1,15 g, 0,0033 mol), (R)-enantiomeren af 15 ethylnipecotat hydrochlorid (se eksempel 1) (1,92 g, 0,0099 mol) og tørret kaliumcarbonat (2,28 g, 0,0165 :mol) orarørtes i acetone (100 ml) ved refluxtemperatur i 54 : timer.; :· ’.· · 20 Den afkølede reaktionsblanding filtrerédes, og filtratet inddampedes. Xnddampningsresten rensedes ved lynchroma-tografi på silicagel (4,5 x 15 cm) og eluerede med heptan/ ethylacetat (9:1 ->.4:1·)· hvilket gav titelforbindélsen som et gummiagtigt stof' (0,57 g, 40%), TLC rf 0,4 (Si02, 25 ethylacetat/heptan 1/1).b. (R) -1- [2- [[2- (4-Fluoro-2-methylphenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester 1 - [ 2- (2-Bromethoxy) -1- (2-methylphenyl) ethenyl] -4-fluoro-2-methylbenzene (1.15 g, 0.0033 mol), (R) -enantiomer of ethylnipecotate hydrochloride (see Example 1) (1.92 g, 0.0099 mol) and dried potassium carbonate (2.28 g, 0.0165: mol) were stirred in acetone (100 ml) at reflux temperature for 54 hours; The cooled reaction mixture was filtered and the filtrate was evaporated. The evaporation residue was purified by flash chromatography on silica gel (4.5 x 15 cm) and eluted with heptane / ethyl acetate (9: 1 -> 4: 1 ·) to give the title compound as a gummy substance (0.57 g, 40 %), TLC rf 0.4 (SiO 2, ethyl acetate / heptane 1/1).

c. (R)-1-[2-[[2-(4-Fluor-2-methylphenyl)-2-(2-methylphe-nyl)ethenyl]oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid 30 -:---·-:- ‘ i é’ " . ; · ‘ (R>)-1- [2- [ [2-<-4-Fluor-2-methylphenyl 2-methylphenyl)-ethényl ] oxy] ethyl ] -3-pipef idincarboxylsyreethylester (0,56 g, 0,0013 mol) opløstes i ethanol (6 ml) og 10 N 35 natriumhydroxid tilsattes. Efter omrøring af opløsningen ved · stuetemperatur i 2 timer tilsattes vand (200 mml) og ethanolet inddampedes under reduceret tryk. Den vandigec. (R) -1- [2 - [[2- (4-Fluoro-2-methylphenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride (R>) - 1- [2- [[2 - <- 4-Fluoro-2-methylphenyl 2-methylphenyl) -ethenyl] oxy] ethyl] -3 -piperidinecarboxylic acid ethyl ester (0.56 g, 0.0013 mol) was dissolved in ethanol (6 ml) and 10 N sodium hydroxide was added. After stirring the solution at room temperature for 2 hours, water (200 mml) was added and the ethanol was evaporated under reduced pressure. The watery

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28 opløsning blev gjort sur til pH 5 med 2N saltsyreopløsning og ekstraheredes med dichlormethan (3 x 100 ml).28 solution was acidified to pH 5 with 2N hydrochloric acid solution and extracted with dichloromethane (3 x 100 ml).

De samlede ekstrakter tørredes (MgSO^) og inddampedes til 5 en inddampningsrest som behandledes med toluen (20 ml) og blandingen filtreredes. Methanol (0.06 ml) og chlortrime-thylsilan (0,20 ml) sattes til filtratet, og hydrochlo-ridsaltet bundfældedes. Inddampning af blandingen, efterfulgt af krystallisation af inddampningsresten fra meget 10 lidt methanol/toluen gav titel forbindelsen (0,38 g, 67%), smp. bliver blød ved 195°, smelter endeligt ved 210°.The combined extracts were dried (MgSO4) and evaporated to a residue which was treated with toluene (20 ml) and the mixture was filtered. Methanol (0.06 ml) and chlorotrimethylsilane (0.20 ml) were added to the filtrate and the hydrochloride salt precipitated. Evaporation of the mixture, followed by crystallization of the residue from very little methanol / toluene gave the title compound (0.38 g, 67%), m.p. becomes soft at 195 °, finally melts at 210 °.

C24H28FN °3·HC1· beregnet: C, 66,4; H, 6,7; N, 3,2; Cl, 8,2 Fundet: C, 66,3; H, 6,8; N, 3,1; Cl 8,4%.C24H28FN ° 3 · HCl · Calcd: C, 66.4; H, 6.7; N, 3.2; Cl, 8.2 Found: C, 66.3; H, 6.8; N, 3.1; Cl 8.4%.

15 ' EKSEMPEL 15 1“ [2- [ [2- (4-Fluor-2-methylphenyl)-2-(2-methyl-phenyl) -ethenyl] oxy] ethyl] -1,2,5,6r-tetrahydro-3~pyridincarboxyl-20 syre. hydrochlorid l-r.[2- [ [2-r (4-Fluor-2-methylphenyl) -2-( 2-méthyl-phenyl) -. ethenyl]oxy]ethyl ] -1,2,5,6-tetrahydro-3-pyridincarboxyl-25 syremethylester (0,74 g, 0,0018 mol) (fremstillet som beskrevet i metode C) opløstes i ethanol- (15 ml) og 10 N natriumhydroxidopløsning (1,8 ml) tilsattes. Efter omrøring af reaktionsblandingen i 2 timer ved stuetemperatur viste TLC at forsæbningen ikke var fuldstændig, hvor-30 for yderligere 10 N natriumhydroxidopløsning (1,8 ml) tilsattes, og reaktionsblandingen varmedes i 10 min. ved 40°C. Vand (400 ml) tilsattes, og opløsningen ekstraheredes med diethylæter (100 ml).· Den vandige fase blev gjort sur til pH 5 med 2N saltsyreopløsning og.:ekstraheredes' · 35 med dichlormethan (4 x 50 ml). De samlede ekstrakter tørredes (MgSO^) og inddampedes til en inddampningsrest (0,61 g) som opløstes i toluen (50 ml). Methanol (0,2 ml) ogEXAMPLE 15 1 "[2- [[2- (4-Fluoro-2-methylphenyl) -2- (2-methyl-phenyl) -ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-hydroxyl 3 ~ pyridinecarboxylic acid. hydrochloride 1- [2- [[2-r (4-Fluoro-2-methylphenyl) -2- (2-methylphenyl) -. ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (0.74 g, 0.0018 mol) (prepared as described in Method C) was dissolved in ethanol (15 ml) and 10N sodium hydroxide solution (1.8 ml) was added. After stirring the reaction mixture for 2 hours at room temperature, TLC showed that the saponification was not complete, adding an additional 10 N sodium hydroxide solution (1.8 ml) and heating the reaction mixture for 10 minutes. at 40 ° C. Water (400 ml) was added and the solution extracted with diethyl ether (100 ml). The aqueous phase was acidified to pH 5 with 2N hydrochloric acid solution and extracted with dichloromethane (4 x 50 ml). The combined extracts were dried (MgSO4) and evaporated to a residue (0.61 g) which was dissolved in toluene (50 ml). Methanol (0.2 ml) and

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29 chlortrimethylsilan (0,216 ml) tilsattes, og efter blanding tilsattes et lag af cyclohexan (ca. 30 ml). Efter henstand af blandingen ved 4° i 18 timer, opsamledes titelforbindelsen ved filtrering n (0,60 g, 77%), smp. 190-201° 5 (efter tørring in vacuo).29 chlorotrimethylsilane (0.216 ml) was added and after mixing a layer of cyclohexane (about 30 ml) was added. After standing the mixture at 4 ° for 18 hours, the title compound was collected by filtration n (0.60 g, 77%), m.p. 190-201 ° 5 (after drying in vacuo).

C24H26FN03*HC1,0'1PhCB3' bere9net: c/ 67,3; H, 6,4; N, 3,2; Cl, 8,0 Fundet: C, 67,1; H, 6,4; N, 3,1; Cl, 8,1% 10 EKSEMPEL 16 (Metode D) a. l-[2-(2-Bromethoxy)-l-(3-fluorphenyl)ethenyl]-3-fluorbenzen 15 bis(3-Fluorphenyl)acetaldéhyd (4,82 g, 0,0208 mol) opløstes i dichlormethan (50 ml) ogtetra-n-butylammoniumbro-mid (0,67 g, 0,00208 mol) tilsattes. 12 N natriumhydroxidopløsning (50 ml) og l;2-dibromethan (17,9 ml, 0,208 mol) 20 tilsattes og blandingen omrørtes kraftigt ved stuetemperatur i 20 timer. Dichlormethan (100 ml) og mættet saltvandsopløsning (50 ml) tilsattes og faserne adskiltes. Den vandige fase ekstraheredes yderligere med dichlormethan (50 ml) og de samlede dichlormethan ekstrakter vaskedes med 25 vand (2 x 75 ml) og mættet saltvandsopløsning (50 ml).C24H26FNO3 * HC1.0'1PhCB3 'calculated: c / 67.3; H, 6.4; N, 3.2; Cl, 8.0 Found: C, 67.1; H, 6.4; N, 3.1; Cl, 8.1% EXAMPLE 16 (Method D) a. 1- [2- (2-Bromethoxy) -1- (3-fluorophenyl) ethenyl] -3-fluorobenzene bis (3-fluorophenyl) acetaldehyde (4, Dissolve 82 g, 0.0208 mol) in dichloromethane (50 ml) and tetra-n-butylammonium bromide (0.67 g, 0.00208 mol) was added. 12N sodium hydroxide solution (50 ml) and 1; 2-dibromoethane (17.9 ml, 0.208 mol) were added and the mixture was stirred vigorously at room temperature for 20 hours. Dichloromethane (100 ml) and saturated brine (50 ml) were added and the phases separated. The aqueous phase was further extracted with dichloromethane (50 ml) and the combined dichloromethane extracts were washed with 25 water (2 x 75 ml) and saturated brine (50 ml).

Tørring af dichlormethanopløsning (Na2S0^) og inddampning gav titelforbindelsen som en olie (6,66 g, 95%), TLC rf 0,71 (Si02: dichlormethan).Drying of dichloromethane solution (Na 2 SO 4) and evaporation gave the title compound as an oil (6.66 g, 95%), TLC rf 0.71 (SiO 2: dichloromethane).

30 b. l-[2-[[2,2-bis(3-Fluorphenyl)ethenyl]oxy]ethyl]-l,2,5,6-tetrahydropyridin-3-carboxylsyremethylesterhydrochloridB. 1- [2 - [[2,2-Bis (3-Fluorophenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride

Til 1- [ 2- (2-Bromethoxy )-1-( 3-f luorphenyl )ethenyl ] -3-f luor-35 benzen (6,57 g, 0,0194 mol) i acetone (100 ml) sattes 1,2,5,6-tetrahydro-3-pyridincarboxylsyremethylester hydro-chlorid (guvacinmethylester hydrochlorid) (5,57 g, 0,0291 30To 1- [2- (2-Bromethoxy) -1- (3-fluorophenyl) ethenyl] -3-fluorobenzene (6.57 g, 0.0194 mol) in acetone (100 ml) was added 1, 2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (guvacin methyl ester hydrochloride) (5.57 g, 0.0291)

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mol), tørret kaliumkarbonat (8,03 g, 0,0581 mol) og kalium-jodid (0,32 g, 0,0019 mol). Suspensionen omrørtes ved stuetemperatur i 50 timer og filtreredes. Filtratet inddampedes til en olie (8,2 g) som opløstes i ethylacetat (100 5 ml). Vand (40 ml) tilsattes, og den vandige fases pH indstilledes til 4 med 34% vandig vinsyre. Den vandige fase skiltes fra, og den organiske fase vaskedes med vandig vinsyre (20 ml)pH 4, hvorefter vand (40 ml) tilsattes.dried potassium carbonate (8.03 g, 0.0581 mole) and potassium iodide (0.32 g, 0.0019 mole). The suspension was stirred at room temperature for 50 hours and filtered. The filtrate was evaporated to an oil (8.2 g) which was dissolved in ethyl acetate (100 ml). Water (40 ml) was added and the pH of the aqueous phase was adjusted to 4 with 34% aqueous tartaric acid. The aqueous phase was separated and the organic phase was washed with aqueous tartaric acid (20 ml) of pH 4 and then water (40 ml) was added.

Den. vandige fases pH-værdi indstilledes til ca. 8 med 2 N 10 natriumhydroxidopløsning, og faserne adskiltes. Den organiske fase vaskedes med mættet saltvandsopløsning (10 ml), tørredes (Na2S0^) og inddampedes til en olie.The. the pH of aqueous phase was adjusted to approx. 8 with 2 N 10 sodium hydroxide solution and the phases separated. The organic phase was washed with saturated brine (10 mL), dried (Na 2 SO 4) and evaporated to an oil.

Til denne olie i toluen (20 ml) sattes ved 45° methanol 15 (0,68 ml, 0,0167 mol) efterfulgt af chlortrimethylsilan (1,173 g,.0,0156 mol). Efter omrøring.ved stuetemperatur i 18 timer, var esterhydrochløridet bundfældet, og suspen-, sionen. af køledes T:til0°C i 2'timer;'Faststoffet opsamle- -des ved filtrering, vaskedes med kold toluen (15 .ml) og 20 suspenderedes i tør diethylæter (25 ml).. Filtrering gav titelforbindelsen (3,56 g, 59%) som et.hvidt faststof,..· TLC rf! 0> 68 (SiO^rdichlormethan/methanol/eddikésyre 20:2:1). ... = . . ------ .· - - 25 c. 1- [2- [ [2,2-bis( 3-Fluorphenyl )ethenyl]oxy]ethyl] -1,2,5,6-tetrahydro-3-pyridincarboxylsyre hydrochloridTo this oil in toluene (20 ml) was added at 45 ° methanol 15 (0.68 ml, 0.0167 mol) followed by chlorotrimethylsilane (1.173 g, 0.0156 mol). After stirring at room temperature for 18 hours, the ester hydrochloride was precipitated, and the suspension. of cooled T: to 0 ° C for 2 hours; The solid was collected by filtration, washed with cold toluene (15 ml) and suspended in dry diethyl ether (25 ml). Filtration gave the title compound (3.56 g , 59%) as a white solid, .. · TLC rf! 0> 68 (SiO4 radichloromethane / methanol / acetic acid 20: 2: 1). ... =. . 1- [2- [[2,2-bis (3-Fluorophenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride

Til 1- [ 2- [ [ 2,2-bis (3-Fluorphenyl )ethenyl ] oxy] ethyl] -1,2,5,6-30 tetrahydro-3-pyridincarboxylsyremethylester hydrochlorid (3,50 g, 0,0078 mol) i 96% vandig ethanol (25 ml) ved 5° sattes 12'N natriumhydroxidopløsning (2,1 ml). Efter omrøring af: opløsningen véd stuetemperatur-i 4,5 timer^ind-Stillédes'pH til 6 med 4 N- saltsyréopløsning, og blandin-35 gen inddampedes til en olie. Ethylacetet (50 ml) og vand (20 ml) 'tilsattes, og den organiske fase skiltes fra. Den vandige fase vaskedes med-ethylacetat (25 ml) og de sam- 31To 1- [2- [[2,2-bis (3-Fluorophenyl) ethenyl] oxy] ethyl] -1,2,5,6-30 tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (3.50 g, 0.0078 mol ) in 96% aqueous ethanol (25 ml) at 5 ° was added 12'N sodium hydroxide solution (2.1 ml). After stirring: the solution at room temperature-for 4.5 hours, stir-still-pH to 6 with 4N-hydrochloric acid solution and the mixture was evaporated to an oil. The ethyl acetate (50 ml) and water (20 ml) were added and the organic phase was separated. The aqueous phase was washed with ethyl acetate (25 mL) and they were combined

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lede organiske faser vaskedes med mættet saltvands opløsning (10 ml). Ethylacetatfasen tørredes (Na2S0^) og bundfalset geninddampedes med dichlormethan (3 x 15 ml).The organic phase was washed with saturated brine (10 ml). The ethyl acetate phase was dried (Na 2 SO 4) and the precipitate was evaporated with dichloromethane (3 x 15 ml).

5 Til bundfaldet i toluen (22 ml) sattes ved 45° methanol (0,225 ml) og chlortrimethylsilan (0,705 ml). Efter afkøling og omrøring ved stuetemperatur i 18 timer var det fremkomne hydrochlorid bundfældet, og suspensionen afkøle-des- til 0° i 1,5 timet. Faststoffet opsamledes ved filtre-10 ring og tørredes in vacuo hvilket gav det ønskede produkt (2,65 g, 80%). Omkrystallisering af vand gav titelforbindelsen (1,60 g, 53%), smp. 158-159°.To the precipitate in toluene (22 ml) was added at 45 ° methanol (0.225 ml) and chlorotrimethylsilane (0.705 ml). After cooling and stirring at room temperature for 18 hours, the resulting hydrochloride was precipitated and the suspension was cooled to 0 ° for 1.5 hours. The solid was collected by filtration and dried in vacuo to give the desired product (2.65 g, 80%). Recrystallization of water gave the title compound (1.60 g, 53%), m.p. 158-159 °.

C22H2rF2N03*HC1*°'3H20' bere9neti C' 61,8? H, 5,1; N, 15 3,3; Cl, 8,3 Fundet: C, 61,5; H, 5,3; N, 3,1; Cl, 8,4%.C22H2rF2NO3 * HCl * ° '3H2O' calcd at C '61.8? H, 5.1; N, 3.3; Cl, 8.3 Found: C, 61.5; H, 5.3; N, 3.1; Cl, 8.4%.

EKSEMPEL 17 (R)-l-[2-[[2,2-bis(2-Methylphenyl)ethenyl]oxy]ethyl]-3-20 piperidincarboxylsyre hydrochlorid" (R:)-l- [2- [ [2,2-bis( 2-Methylphenyl )ethenyl] oxy] ethyl] -3-' piperidincarboxylsyreethylester:(2>20 g,.0,0054 mol) 25 (fremstillet som beskrevet i metode D) Opløstes :i ethanol (20 ml) og 10 N natriumhydroxidopløsning (7 ral) tilsattes. Efter omrøring af opløsningén ved stuetemperatur i 3 timer tilsattes vand (300 ml), og opløsningen vaskedes med di-ethylæter (100 ml). Den vandige fase vaskedes yderligere 30 med diethylæter (100 ml). Den vandige fases pH-værdi indstilledes til 5 og ekstraheredes derefter med dichlormethan (4 x 100 ml). De samlede ekstrakter tørredes (MgS04), inddampedes, og inddampningsresten opløstes i toluen (50 ml). Methanol (0,4 ml) og chlortrimethylsilan (0,7 ml) 35 tilsattes, og produktet bundfældedes. Dette faststof opsamledes ved filtrering og omkrystalliseredes af vand hvilket gav titelforbindelsen (1,4 g, 62%), smp. 217-226°Example 17 (R) -1- [2 - [[2,2-bis (2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride "(R:) - 1- [2- [[2, 2-bis (2-Methylphenyl) ethenyl] oxy] ethyl] -3- 'piperidinecarboxylic acid ethyl ester: (2> 20 g, 0.0054 mol) (prepared as described in Method D) Dissolve: in ethanol (20 ml) and 10 N sodium hydroxide solution (7 ral) was added After stirring the solution at room temperature for 3 hours, water (300 ml) was added and the solution was washed with diethyl ether (100 ml) and the aqueous phase was further washed with diethyl ether (100 ml). The pH of the aqueous phase was adjusted to 5 and then extracted with dichloromethane (4 x 100 ml), the combined extracts dried (MgSO 4), evaporated and the residue dissolved in toluene (50 ml). Methanol (0.4 ml) and chlorotrimethylsilane. (0.7 ml) was added and the product precipitated This solid was collected by filtration and recrystallized from water to give the title compound (1.4 g, 62%), mp 217-226 °

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32 (efter tørring in vacuo).32 (after drying in vacuo).

C24H29N03*HC1, bere9net: C, 69,3; H, 7,3; N, 3,4; Cl, 8,5 Fundet; C, 69,4; H, 7,4; N, 3,3; Cl, 8,5%.C 24 H 29 NO 3 * HCl Calc'd: C, 69.3; H, 7.3; N, 3.4; Cl, 8.5 Found; C, 69.4; H, 7.4; N, 3.3; Cl, 8.5%.

5 EKSEMPEL 18 (R)-1-[2-[[2,2-bis (4-Fluor-2 -me t hy lpheny 1 )ethenyl] oxy] -ethyl]-3-piperidincarboxylsyre hydrochlorid 10 -------—---:--- (R)-l- [2- [ [2,2-bis( 4-Fluor-2-methylphenyl )ethenyl]oxy] -ethyl]-3-piperidincarboxylsyreethylester (1,72 g, 0,0039 mol) (fremstillet som beskrevet i metode D) opløstes i 15 ethanol (20 ml) og 10 N natriumhydroxidopløsning (4 ml) tilsattes:. Opløsningen omrørtes ved stuetemperatur i 3 timer og vand (100 ml) tilsattes. Opløsningen ekstrahere-des .med . diethylæter (2 x 100 iral) og. dén vandigef asé. blev g$ort "sur til pH 5 med ·2 N saltsyreopløsriing. Ekstrahering 20 med dichlormethan (4 x 80 ml) og tørring af de samlede ekstrakter (MgSO^) efterfulgt af ! inddampning gav en ind-dampningsrest som opløstes i toluen (50 ml). Methanol (0,16 ml) og chlortrimethylsilan (0,51 ml) -tilsattes, og produktet; bundfældedes. Blandingen^inddampedes til et fast-25 stof og omkrystalliseredes af toluen-hvilket-gav titelforbindelsen som et hvidt krystallisk faststof (0,78 g, 44%), smp. 175-185° (sønderdeling).EXAMPLE 18 (R) -1- [2 - [[2,2-Bis (4-Fluoro-2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride - (-) - (R) -1- [2- [[2,2-bis (4-Fluoro-2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (1.72 g, 0.0039 mol) (prepared as described in Method D) was dissolved in 15 ethanol (20 ml) and 10 N sodium hydroxide solution (4 ml) was added :. The solution was stirred at room temperature for 3 hours and water (100 ml) was added. The solution is extracted with. diethyl ether (2 x 100 iral) and. the watery ase. was acidified to pH 5 with · 2 N hydrochloric acid solution. Extraction 20 with dichloromethane (4 x 80 ml) and drying of the total extracts (MgSO4) followed by evaporation gave an evaporation residue which was dissolved in toluene (50 Methanol (0.16 ml) and chlorotrimethylsilane (0.51 ml) were added and the product precipitated. The mixture was evaporated to a solid and recrystallized from toluene to give the title compound as a white crystalline solid ( 0.78 g, 44%), mp 175-185 ° (dec.).

C24H27FNO3.HC1, beregnet; C, 63,8; Η, 6,2> Ν,-3ν1; Cl, 30 7,8 Fundet; C, 64,1; H, 6,3; N, 3,0? Cl, 7,3% j. · i: . . . 1 35 EKSEMPEL 19 33C24H27FNO3.HCl, calcd; C, 63.8; Η, 6.2> Ν, -3ν1; Cl, 7.8 Found; C, 64.1; H, 6.3; N, 3.0? Cl, 7.3% j. · I:. . . EXAMPLE 19 33

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E eller Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl ) etheny 1 ] oxy] ethyl ] -3-piperidincarboxylsyre hydro-5 chlorid E eller Z-(R)-l-[2-[[2—(3-Methoxyphenyl)-2-(2-methylphenyl)-ethenyl] oxy] ethyl ] -3-piperidincarboxylsyreethylester (0,50 10 g, 0,0012 mol) (fremstillet som beskrevet 1 metode D) opløstes i ethanol (15 ml) og 12 N natriumhydroxidopløsning (0,2 ml) tilsattes. Efter omrøring af opløsningen ved stuetemperatur i 6 timer tilsattes is (100 g) og reaktionsblandingens pH-værdi indstilledes til ca. 7 med 37% saltsyre-15 opløsning. Dichlormethan (200 ml) tilsattes, og pH indstilledes yderligere til <2 med 37% saltsyreopløsning. Dichlormethanfasen tørredes (Na2S04) og inddampedes til ét ^.faststof-(0,.3 :g> 60%), srap .::188^192°. %.:>'· » ·; * , i ;“·*»; m '· V ' · v ' ‘ ·*'. *j ’•„.VV·* -· · ·- . - c-- - .·* v · ·, ..E or Z- (R) -1- [2 - [[2- (3-Methoxyphenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride E or Z- ( R) -1- [2 - [[2- (3-Methoxyphenyl) -2- (2-methylphenyl) -ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (0.50 g, 0.0012 mol) (prepared as described in Method D) was dissolved in ethanol (15 ml) and 12 N sodium hydroxide solution (0.2 ml) was added. After stirring the solution at room temperature for 6 hours, ice (100 g) was added and the pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added and the pH was further adjusted to <2 with 37% hydrochloric acid solution. The dichloromethane phase was dried (Na 2 SO 4) and evaporated to one solid (0.1%: g> 60%), srap .: 188 ° 192 °. %.:> '· »·; *, i; “· *”; m '· V' · v '' · · * '. * j '• „.VV · * - · · · -. - c-- -. · * v · ·, ..

• *. : > . · . · ·, i l · · » * » . ·.- * . · */ . . * * * m * ·>»«.• *. :>. ·. · ·, I l · · »*». · .- *. · * /. . * * * m * ·> »«.

20 C2iH29N04’HC'L*®'^5H20, beregnet: C, 66,0; H, 7,0; N, 3,2;C₂iH29NNO4’HC'L * ® 5H₂O, calculated: C, 66.0; H, 7.0; N, 3.2;

Cl>- 8,-2-Fundet: C, 66>1;-H, 7,2; N, 3,-1; Cl, -8,1%^..............Cl - 8, -2-Found: C, 66> 1; -H, 7.2; N, 3, -1; Cl, -8.1% ^ ..............

• - EKSEMPEL :20 Λ,; · 25 E eller Z-(R)-1-(2-[f2-r(3-Methoxyphenyl)-:2-(2-methylphenyl)-ethenyl]oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid E·eller Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)-30 ethenyl]oxy]ethyl]-3-piperidincarboxylsyreethylester (0,80 g, 0,0019 mol) (modsat geometrisk isomer i forhold til éksempel 19) opløstes i ethanol (15 ml) og 12:Nnatrium-hydroxidopløsnirig (0/3 ml) tilsattes; Efter omrøring af opløsningen ved stuetemperatur i 6 timer tilsattes is (50 35 g), og"reaktionsblandingens pH indstilledes til ca. 7 med 37% saltsyreopløsning. Dichlormethan (200 ml) tilsattes, og pH indstilledes yderligere til <2 med 37% saltsyreop- 34• - EXAMPLE: 20 Λ,; E or Z- (R) -1- (2- [[2- (3-Methoxyphenyl) -: 2- (2-methylphenyl) -ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride E · or Z (R) -1- [2 - [[2- (3-Methoxyphenyl) -2- (2-methylphenyl) -ethhenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (0.80 g, 0.0019 mol) ( opposite geometric isomer to Example 19) was dissolved in ethanol (15 ml) and 12: Sodium hydroxide solution (0/3 ml) was added; After stirring the solution at room temperature for 6 hours, ice (50 g) was added and The pH was adjusted to about 7 with 37% hydrochloric acid solution, dichloromethane (200 ml) was added and the pH was further adjusted to <2 with 37% hydrochloric acid.

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løsning. Dichlormethanfasen tørredes (Na2S0^) og inddampedes til et. faststof (0,35 g, 44%), smp. 198-202°.solution. The dichloromethane phase was dried (Na 2 SO 4) and evaporated to a. solid (0.35 g, 44%), m.p. 198-202 °.

C24H29N04*HC1' beregneti C, 66,7; H, 7,0; N, 3,2; Cl, 8,2 5 Fundet: C, 66,5; H, 7,2; N, 3,0; Cl, 7,6.C 24 H 29 NO 4 * HCl calculated C, 66.7; H, 7.0; N, 3.2; Cl, 8.2 Found: C, 66.5; H, 7.2; N, 3.0; Cl, 7.6.

EKSEMPEL 21 1- [-2- [ [ 2- (3-Methoxyphenyl) -2- (2-methylphenyl )ethenyl] oxy] -10 ethyl ] -1,2,5,6 - tetrahydro- 3 -pyridincarboxylsyre hydro-chlorid · l_[2-[[2-( 3-Methoxyphenyl) -2- (^2-methylphenyl )ethenyl ] oxy] -15 ethyl] -1,2,5,6-tetrahydro-3-pyridincarboxylsyremethylester (1;-15-gy 0,0027 mol) (fremstillet som beskrevet i metode D> opløstes i ethanol (15 ml) 'og 12 N natriumiiydroxidop-løsning (0,5 ml) tilsattes. Efter omrøring af opløsningen ved "stuetemperatur-ir 4!.timer‘‘tilsattes is (30 g), og reak-20 tionsblandingens pH indstilledes til ca. 7 med 37% saltsyreopløsning. Dichlormethan (200 ml) tilsattes, og pH indstilledes yderligere til ca. 1 med 37% saltsyreopløsning. Vand tilsattes indtil det faste stof var opløst, og dichlormethanfasen tørredes - (Na^SO^) 'og inddampedes-til" 25 en olie; som .geninddampedes tre .gange med-acetonev lnd-dampningsresten tritureredes med diethylæter til opnåelse af titelforbindelsen (0,60 g, 52%), hvilket gav HPLC retentionstider på 17,1 og 17,6 min* for de geometriske iso-merer.(gradient eluering, vand/20-80% acetonitril,.begge 30 indeholdende 0,1% TFA).EXAMPLE 21 1- [-2- [[2- (3-Methoxyphenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride 1- [2 - [[2- (3-Methoxyphenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1; -15 0.0027 mol) (prepared as described in Method D> was dissolved in ethanol (15 ml) and 12 N sodium hydroxide solution (0.5 ml) was added. After stirring the solution at room temperature for 4 hours. Ice was added (30 g) and the pH of the reaction mixture was adjusted to about 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added and the pH was further adjusted to about 1 with 37% hydrochloric acid solution. substance was dissolved and the dichloromethane phase was dried - (Na 2 SO 4) and evaporated to an oil; %), giving HPLC retention times of 17.1 and 17.6 min * for the geometric isomers (gradient elution, water / 20-80% acetonitrile, both containing 0.1% TFA).

C24H2gNO^.0,8HC1.0,8H2°, beregnet: C, 65?8;"H,7.,; N, 3,2? Cl, 6,3 Fundet: C, 65,3; H, 7,0,-^3,2,- Cl, 6,9%.C24H2GNO4.0.8HC1.0.8H2 °, Calc'd: C, 65.8; "H, 7.n; N, 3.2? Cl, 6.3 Found: C, 65.3; H, 7, 0, - 3.2, Cl, 6.9%.

. . . . . ; 1 ‘ . » * * \ ; ♦.. . . . . ; 1 '. »* * \; ♦.

35 EKSEMPEL 22 35EXAMPLE 22 35

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l-[2-[ C 2— (3-Chlorphenyl )-2-( 2-methylphenyl )ethenyl] oxy] -ethyl) -1,2,5,6-tetrahydro-3-pyridincarboxylsyre hydro-5 chlorid 1- [ 2- [ [ 2- (3-Chlorphenyl) -2- (2-methylphenyl) ethenyl] oxy ] -ethyl] -1,2,5,6-tetrahydro-3-pyridincarboxylmethylester 10 (0,60 g, 0,0014 mol) (fremstillet som beskrevet 1 metode D) opløstes i ethanol (5 ml) og 12 N natriumhydroxidopløs-ning (0,35 ml) tilsattes- Efter omrøring af opløsningen ved stuetemperatur i 3 timer tilsattes 37% saltsyreopløsning indtil pH måltes til ca. 1. Dichlormethan (200 ml) 15 tilsattes, og blandingen tørredes (Na2S04), filtreredes og inddampedes til en ihddampningsrest, som geninddampe-des to gange med acetone. Inddampningsresten omkrystalliseredes * af · acetone/e thylacetat hvilket · gav titelforbindelsen (0£33.g, '55%) som hvide krystaller/ smp. 168-170°.1- [2- [C 2- (3-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl) -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride 1- [ 2- [[2- (3-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylmethyl ester (0.60 g, 0.0014 mole) (prepared as described in Method D) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.35 ml) was added. After stirring the solution at room temperature for 3 hours, 37% hydrochloric acid solution was added until the pH was measured to ca. 1. Dichloromethane (200 ml) was added and the mixture dried (Na 2 SO 4), filtered and evaporated to an evaporation residue which was twice evaporated with acetone. The residue was recrystallized * from acetone / e thylacetate to give the title compound (0.33g, 55%) as white crystals / m.p. 168-170 °.

20 HPLC·retentionstider 16,12 and 18,42 for de geometriske isomerer- -(gradient· eluering, vand/20-80%- aeetonitrdl, begge faser indeholdende 0,1% TFA).20 HPLC retention times 16.12 and 18.42 for the geometric isomers - (gradient elution, water / 20-80% - aeetonitrile, both phases containing 0.1% TFA).

E eller Z-=l-[2- [ [2-(3-Chlorphenyl)-2-(2-methylphényl )ethen-25 yl]oxy]ethyl) -1,2,5,6-tetrahydro-3-pyridincarboxylsyre hydrochlorid E eller Z-l-£2-[ [2-(3-Chlorphenyl)-2-(2-methylphenyl)ethen-30 yl] oxy) ethyl] -1,2/5,6-tetrahydro-3-pyridincarboxylsyreme-thylester (0,55 g, 0,0013 mol) (fremstillet som.beskrevet i metode D) opløstes i ethanol (5 ml) og 12 N natriumhy-droxidopiøsning >(0,33 ml) tilsattes.-Efter omrøring.af opløsningen véd stuetemperatur i 3 timer-tilsattes 37% salt-35 syreopløsning indtil pH måltes til ca. 1. Dichlormethan (200 ml) tilsattes, og blandingen tørredes (Na2S04), filtreredes og inddampedes til en inddampningsrest, som gen-E or Z- = 1- [2- [[2- (3-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl) -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride E or Z1- [2- ([2- (3-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy) ethyl] -1,2 / 5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (0.55 g, 0.0013 mol) (prepared as described in Method D) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution> (0.33 ml) was added. - After stirring the solution at room temperature for 3 hours, 37% hydrochloric acid solution was added until the pH was measured to ca. 1. Dichloromethane (200 ml) was added and the mixture dried (Na 2 SO 4), filtered and evaporated to an evaporation residue which was recovered by evaporation.

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36 inddampedes to gange med acetone. Omkrystallisering af acetone/ethylacetat gav titelforbindelsen (0,17 g, 30%) som et hvidt faststof, srap. 214-215°.36 was evaporated twice with acetone. Recrystallization of acetone / ethyl acetate gave the title compound (0.17 g, 30%) as a white solid, srap. 214-215 °.

5 C23H2C1N03.HC1, beregnet: C, 63,6? H, 5,8; N, 3,2; Cl, 8,2 Fundet: C, 63,2; H, 5,8; N, 3,4; Cl, 8,0%.C23H2C1N03.HC1, calculated: C, 63.6? H, 5.8; N, 3.2; Cl, 8.2 Found: C, 63.2; H, 5.8; N, 3.4; Cl, 8.0%.

EKSEMPEL 23 10 l-[2-[ [2,2-bis( 2-Ethylphenyl )ethenyl]oxy] ethyl] -1,2,5,6- tetrahydro-3-pyridin carboxylsyrehydrochlorid l-[2-[[2,2-bis (2-Ethylphenyl )ethenyl ] oxy] ethyl] -1,2,5,6-15 tetrahydro-3-pyridincarboxylsyremethylester (1,40 g, 0,00323 mol) (fremstillet som beskrevet i metode D)t opløstes i:ethanol (10 ml) og 12 N natriumhydroxidopløsning (0,8-ml) · tilsattes. Efter .omrøring af opløsningen ved stuetemperatur i 5 timer, tilsattes 37% saltsyreopløsning ind-20 til hpH måltes vtil "ca*. :1:,. :Dichl6rmethan:';(250: ml) tilsattes, og 'blandingen tørredes (Na^SO^), f iltreredes1 og inddampedes til en inddampningsrest som geninddampedes med acetone. Omkrystallisering af ^acetone gav titelforbindelsen (0,80 g, 57%) som et hvidt faststof, smp. 162-165°.EXAMPLE 23 1- [2- [[2,2-Bis (2-Ethylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride 1- [2 - [[2, 2-Bis (2-Ethylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1.40 g, 0.00323 mol) (prepared as described in Method D) was dissolved. in: ethanol (10 ml) and 12 N sodium hydroxide solution (0.8 ml) were added. After stirring the solution at room temperature for 5 hours, 37% hydrochloric acid solution was added to 20 hp. Measured until "ca *: 1: 1: Dichloromethane: (250: ml) was added and the mixture dried (Na ), Filtered and evaporated to a residue evaporated with acetone Recrystallization of 3-acetone afforded the title compound (0.80 g, 57%) as a white solid, mp 162-165 °.

25 : -- : · · · C2gHt3iN03.HCl, beregnet: C; 70,7; H, 7,3; N, 3,2; Cl, 8,0 Fundet: C, 70;5; H, 7,4; N, 3,6; Cl, 8,0%. - - EKSEMPEL 24 30 (R)-l-[2-{ [2,2-bis( 2-Ethylphenyl )ethenyl]oxy]ethyl]-3-piperidincarboxylsyre hydrochlorid - : 35 (R) -1 -[ 2 - [ [ 2,2 -bis (-2 - E thy lpheny 1) etheny1]oxy ] ethyl ] -3 - piperidincarboxylsyreéthylester (1,20 g, 0,00275 mol)' · (fremstillet som beskrevet i metode D) opløstes i ethanol 3725: - · · · C2gHt3iN03.HCl, calculated: C; 70.7; H, 7.3; N, 3.2; Cl, 8.0 Found: C, 70.5; H, 7.4; N, 3.6; Cl, 8.0%. EXAMPLE 24 (R) -1- [2- {[2,2-bis (2-Ethylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride -: (R) -1 - [2 - [ [2,2-Bis (-2-E thylpheny 1) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (1.20 g, 0.00275 mol) (prepared as described in Method D) was dissolved in ethanol 37

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(10 ml) og 12 N natriumhydroxidopløsning (0,7 ml) tilsat tes. Efter omrøring af opløsningen ved stuetemperatur i 5 timer tilsattes 37% saltsyreopløsning indtil pH måltes til ca. 1. Dichlormethan (250 ml) tilsattes, og blandin-5 gen tørredes (Na2S04), filtreredes og inddampedes til en inddampningsrest som geninddampedes med acetone. Omkrystallisering af acetone, gav titelforbindelsen (0,85 g, 70%) som et hvidt faststof, smp. 205-206°.(10 ml) and 12 N sodium hydroxide solution (0.7 ml) were added. After stirring the solution at room temperature for 5 hours, 37% hydrochloric acid solution was added until the pH was measured to ca. 1. Dichloromethane (250 ml) was added and the mixture was dried (Na 2 SO 4), filtered and evaporated to a residue evaporated with acetone. Recrystallization of acetone gave the title compound (0.85 g, 70%) as a white solid, m.p. 205-206 °.

10 C26H33N03*HC1, bere9net: c' 70'3? H' 7'7'* N' 3,2; Cl, 8,0C26H33NO3 * HCl, calculated: c '70'3? H '7'7' * N '3.2; Cl, 8.0

Fundet: C, 70,0; H,7,8; N, 3,4; Cl, 7,9%.Found: C, 70.0; H, 7.8; N, 3.4; Cl, 7.9%.

EKSEMPEL 25 15 l-[2-[ [2,2-Diphenylethenyl]oxy]ethyl]-l,2,5,6-tetrahydro- 3-*pyridincarboxylsyre hydrochlorid 1*[2-[[2,2-Diphénylethenyl Joxy]ethyl] -1,2,5,6-tetrahydro-20 3-pyridincarboxylsyrémethylester (4,33 g, 0,01147 mol) · (fremstillet som beskrevet-i metode D) opløstes i-ethanol (50 ml): og 10 N natriumhydroxidopløsning (11,5 ml·) tilsat-tes, .efterfulgt af vand (5 ml). Opløsningen omrørtes ved stuetemperatur i 2,5 timer og henstod ved 4° C i 18 25 timer. 2 N saltsyreopløsning tilsattes indtil pH nåede ca. 2, og blandingen ekstraheiedes med dichlormethan (3 x 60 ml). De samlede ekstrakter tørredes (MgSO^) og inddampedes hvilket gav et skummende produkt (4,24 g), som krystalliseredes af 2-propanol hvilket gav titelforbindelsen 30 (2,32 g, 52%) som et hvidt faststof, smp. 173-176°.EXAMPLE 25 1- [2- [[2,2-Diphenylethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3- * pyridinecarboxylic acid hydrochloride 1 * [2 - [[2,2-Diphenylethenyl Joxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (4.33 g, 0.01147 mol) · (prepared as described in Method D) dissolved in ethanol (50 ml): and 10 N sodium hydroxide solution (11.5 ml ·) was added, followed by water (5 ml). The solution was stirred at room temperature for 2.5 hours and left at 4 ° C for 18 hours. 2N hydrochloric acid solution was added until the pH reached ca. 2 and the mixture was extracted with dichloromethane (3 x 60 ml). The combined extracts were dried (MgSO4) and evaporated to give a foamy product (4.24 g) which was crystallized from 2-propanol to give the title compound 30 (2.32 g, 52%) as a white solid, m.p. 173-176 °.

C22H23N®3‘RC1 *0,2870, beregnet: C; 67,8; H, 6,3; N, · 3,6;C22 H23 N®3 RCl1 0.2870, calculated: C; 67.8; H, 6.3; N, 3.6;

Cl, 9,1 Fundet: C, 67,7; H, 6,3; N,* 3,4;. Cl, 8,8%.Cl, 9.1 Found: C, 67.7; H, 6.3; N, * 3.4; Cl, 8.8%.

* ·' · ( 1 35 38* · '· (1 35 38

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EKSEMPEL 26 1— [ 2— [ [2-( 2-Fluorphenyl) -2- (2-methylphenyl )ethenyl]oxy] -ethyl]-1,2,5,6-tetrahydro-3-pyridincarboxylsyre hydro-5 chlorid 1- C 2- [ [2- (2-Fluorphenyl) -2- (2-methylphenyl Jethenyl] oxy] -ethyl] -1,2,5, 6-tetrahydro-3-pyridincarboxylsyremethyl-10 ester hydrochlorid (2,18 g, 0,0049 mol) (fremstillet som beskrevet i metode D) opløstes i ethanol (24 ml) og 12 N natriumhydroxidopløsning (1,83 ml) tilsattes ved 5°. Opløsningen omrørtes ved stuetemperatur i 2,5 timet og hen-stod ved -10° i 18 timer. Reaktionsblandingen inddampe-15 des til en inddampningsrest efter at pH var blevet indstillet til 6,5 med 4 N :saltsyreopløsning. Vand (20 ml) og ethylacetat (50 ml) tilsattes, og den vandige fase skiltes fra og .ekstraheredes. igen med; .ethylacetat. (25 ral).EXAMPLE 26 1- [2- [[2- (2-Fluorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride 1 - C 2- [[2- (2-Fluorophenyl) -2- (2-methylphenylethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (2.18 g 0.0049 mol) (prepared as described in Method D) was dissolved in ethanol (24 ml) and 12N sodium hydroxide solution (1.83 ml) was added at 5 °. The solution was stirred at room temperature for 2.5 hours and allowed to stand at The reaction mixture was evaporated to an evaporation residue after the pH was adjusted to 6.5 with 4 N: hydrochloric acid solution. Water (20 ml) and ethyl acetate (50 ml) were added and the aqueous phase was separated. and extracted again with ethyl acetate (25 ral).

De :samléde. ethylacetatékstrakter * -vaskedes med mættétosalt-20 vandsopløsning (40 ml), tørredes (MgSO^) og inddampedes til en inddampningsrest som- geninddampedes med-dichlor-methan (3 x 40 ml). Denne inddampningsrest (1,9 g) opløstes^! 'toluen- (15'ml).og méthanol!(0,2 ml) tilsattes oefterfulgt :af chlortrimethylsilan (0,r 62; ml). Blandingen* omrør-25 tes i 18 timer ved stuetemperatur'og af køledes til .0° i. 2 timer. 'Titelforbindelsen (1,9 g, 91%) blev opnået'som hvide krystaller, . smp. 183-185°, efter, tørring in vacuo.They: assembled. Ethyl acetate extracts * were washed with saturated methosalt-aqueous solution (40 ml), dried (MgSO 4) and evaporated to an evaporation residue which was then evaporated with dichloromethane (3 x 40 ml). This residue (1.9 g) was dissolved Toluene (15ml) and methanol (0.2ml) were added followed by chlorotrimethylsilane (0.62mL). The mixture * is stirred for 18 hours at room temperature and cooled to .0 ° for 2 hours. The title compound (1.9 g, 91%) was obtained as white crystals. mp. 183-185 °, after drying in vacuo.

C23H24F^°3*1'2^HC1' beregnet: :C, 64,7; H,. 6,0; N, 3;3; .C23H24F3 ° 3 * 1 2 HCl Calc'd: C, 64.7; H ,. 6.0; N, 3, 3; .

30 Cl, 10,4 Fundet: C, 64,3; H, 6,0; N, 3,1; Cl, 9,9% 35 EKSEMPEL 27 39Cl, 10.4 Found: C, 64.3; H, 6.0; N, 3.1; Cl, 9.9% EXAMPLE 27 39

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1-[2-[[2-(2,4-Dichlorphenyl)-2-(2-methylphenyl)ethenyl]-oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridincarboxylsyre 5 hydrochlorid 1-[2-[[2-(2,4-Dichlorphenyl)-2-(2-methylphenyl)ethenyl]-oxy-]ethyl] -1,2,5,6-tetrahydro-3-pyridincarboxylsyreme-10 thylester hydrochlorid (2,76 g, 0,0055 mol) (fremstillet som beskrevet i metode D) opløstes i ethanol (30 ml) og 12 N natriumhydroxidopløsning (2,1 ml) tilsattes ved 5°. Opløsningen omrørtes ved stuetemperatur i 3 timer og hen-stod ved -10° i 18 timer. Reaktionsblandingen inddampedes 15 til et en inddampningsrest efter at pH var blevet indstillet til 6,5 med 4 N saltsyréopløsning. Vand (50 ml), ethyl-acetat (50 ml) og dichlormethan (50 ml) tilsattes og den organiske:fase skiltes fra; Den vandige fase ekstraheredes yderligeré med ethylacetat-:(50.ml) dichloirmethan (50 ml) 20 og de samlede organiske ekstrakter tørredes (MgS04) og inddampedes. Det fremkomne bundfald geninddampedes to gange med methanol og to gange med carbontetrachlorid hvilket gav et skummende produkt f2,7-g).- 25 Dette skummende produkt opløstes i toluen (20'ml·) og methanol (0,23 ml) tilsattes efterfulgt af chlortrimethyl-silan (0,71 ml) ved 35°. Produktet begyndte at krystallisere ved ca. 40° og blandingen omrørtes i 18 timer ved stuetemperatur og afkøledes til 0° i 2 timer. Titelforbin-30 delsen (2,20 g, 84%) blev opnået som hvide krystaller, smp. 187-190° (sønderdeling) efter tørring in vacuo.1- [2 - [[2- (2,4-Dichlorophenyl) -2- (2-methylphenyl) ethenyl] -oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride 1- [ 2 - [[2- (2,4-Dichlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (2, 76 g, 0.0055 mol) (prepared as described in Method D) were dissolved in ethanol (30 ml) and 12 N sodium hydroxide solution (2.1 ml) was added at 5 °. The solution was stirred at room temperature for 3 hours and left at -10 ° for 18 hours. The reaction mixture was evaporated to a one evaporation residue after the pH was adjusted to 6.5 with 4 N hydrochloric acid solution. Water (50 ml), ethyl acetate (50 ml) and dichloromethane (50 ml) were added and the organic: phase separated; The aqueous phase was further extracted with ethyl acetate: (50 ml) of dichloromethane (50 ml) and the combined organic extracts dried (MgSO 4) and evaporated. The resulting precipitate was re-evaporated twice with methanol and twice with carbon tetrachloride to give a foamy product (2.7 g). This foamy product was dissolved in toluene (20ml) and methanol (0.23ml) added followed by chlorotrimethylsilane (0.71 ml) at 35 °. The product began to crystallize at approx. 40 ° and the mixture was stirred for 18 hours at room temperature and cooled to 0 ° for 2 hours. The title compound (2.20 g, 84%) was obtained as white crystals, m.p. 187-190 ° (dec.) After drying in vacuo.

C23H23C12°3*1'1HC1' beregnet: C, 58,5; Hy--5>2; N, 3,0; Cl 8,3 Pundet: C, 58,2; H; 5,1; N, 2,8; Cl, -8,1%. ·' 35 ' EKSEMPEL 28 40C 23 H 23 Cl 2 ° 3 * 1HCl 1: C, 58.5; Hy - 5> 2; N, 3.0; Cl 8.3 Pound: C, 58.2; H; 5.1; N, 2.8; Cl, -8.1%. EXAMPLE 28 40

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l-[2- [ [ 2 ,· 2 -bis (2 -Chlorphenyl) etheny 1 ] oxy ] ethyl ]-1;2,5,6-tetrahydro-3-pyridincarboxylsyre hydrochlorid 5 --- 1- [ 2- [ [ 2,2-bis (2-Chlorphenyl )ethenyl]oxy] ethyl]-1,2,5,6-tetrahydro-3-pyridincarboxylsyremethylester hydrochlorid (3,j50 g, 0,0075 mol) (fremstillet som beskrevet i metode 10 D) opløstes i ethanol (40 ml) og 12 N natriumhydroxidopløsning (2,5 ml) tilsattes ved 5°. Opløsningen omrørtes ved stuetemperatur i 6 timer og henstod ved -10° i 18 timer. Reaktionsblandingen inddampedes til en inddampningsrest efter at pH var blevet indstillet til 6,5 med 4 N salt-15 syreopløsning. Vand (10 ml) og ethyllcetat (50 ml) tilsattes, og ethylacetatet adskiltes. Ethylacetatfasen vaskedes med mættet saltvandsopløsning (10 ml) tørredes (iNa^SO^) og . inddampedes. Den f remkomne >:rest inddarapedes hvilketr; gav. et. skummende * produkt (3>1 g).‘ JDette skummende 20 produkt opløstes i-toluen (23 ml) og methanol-(Q>3Q-ml)-tilsattes efterfulgt af chlortrimethylsilan (0,94 ml) ved 35° ► Produktet- < begyndte at . krystallisere, ved vaa» ;40.° og · blandingen omrørtes .1· .48 timerved i stuetemperatur ·. .og o afkøledes til OvC i 2~timeri Titelforbindelsen ::(.-2y5' g,'73%··)’·' 25 blev'opnået som hvide krystaller, smp. 200-203°· (sønder-, deling). -TLC rf 0,16 (S1O2, dichlormethan/methanol/eddike- syre:'80/8/4). ..c • EKSEMPEL 29 . .1- [2- [[2,2-bis (2-Chlorophenyl) ethenyl] oxy] ethyl] -1; 2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride 5 - 1- [2- [2,2-Bis (2-Chlorophenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (3.50 g, 0.0075 mol) (prepared as described in Method 10 D) was dissolved in ethanol (40 ml) and 12N sodium hydroxide solution (2.5 ml) was added at 5 °. The solution was stirred at room temperature for 6 hours and left at -10 ° for 18 hours. The reaction mixture was evaporated to an evaporation residue after the pH was adjusted to 6.5 with 4N hydrochloric acid solution. Water (10 ml) and ethyl acetate (50 ml) were added and the ethyl acetate separated. The ethyl acetate phase was washed with saturated brine (10 ml), dried (Na 2 SO 4) and dried. evaporated. The resulting>: residue was included which; yield. one. This foamy product was dissolved in i-toluene (23 ml) and methanol (Q> 3Q-ml) added followed by chlorotrimethylsilane (0.94 ml) at 35 ° ► The product <began to. crystallize, at a temperature of: 40 ° and · the mixture was stirred .1 · .48 at room temperature ·. and cooled to OvC for 2 h in the title compound :: (. 2y5 'g, '73% ··)' · '25 was obtained as white crystals, m.p. 200-203 ° (decomposition, division). -TLC rf 0.16 (S1O2, dichloromethane / methanol / acetic acid: '80 / 8/4). ..c • EXAMPLE 29. .

30 · ....30 · ....

l-[2-[[2,2-bis(4-Fluor-2-methylphenyl)ethenyl]oxy]ethyl]-1,2/5,6-tetrahydro-3-pyridincarboxylsyre hydrochlorid 35 l-[2-[[2,2-bis(4-Fluor-2-methylphenyl)ethenyl]oxy]ethyl]- 1,2,5,6-tetrahydro-3-pyridincarboxylsyreethylester (1,27 g, 0,0029·mol) (fremstillet som'beskrevet·i metode D) op- -·}-_· · - - · · · « '« 411- [2 - [[2,2-bis (4-Fluoro-2-methylphenyl) ethenyl] oxy] ethyl] -1,2 / 5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride 1- [2 - [[ 2,2-bis (4-Fluoro-2-methylphenyl) ethenyl] oxy] ethyl] 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid ethyl ester (1.27 g, 0.0029 · mol) (prepared as described · in Method D) op- - ·} -_ · · - - · · · «'' 41

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løstes i ethanol (30 ml) og 10 N natriumhydroxidopløsning (10 ml) tilsattes. Efter omrøring af opløsningen ved stuetemperatur i 1 time tilsattes vand (500 ml) og opløsningen vaskedes med diethylæter (2 x 100 ml). Den vandige fases 5 pH-værdi indstilledes til 5 med 2 N saltsyreopløsning og ekstraheredes med dichlormethan (3 x 200 ml). De samlede ekstrakter tørredes (MgSO^), inddampedes og inddampnings-resten opløstes i toluen (50 ml) og sattes til en opløsning af chlortrimethylsilan (0,47 ml) og methanol (0,15 10 ml) i toluen (100 ml). Bundfaldet opsamledes ved filtrering efter at blandingen havde henstået ved stuetemperatur i 18 timer. Faststoffet omkrystalliseredes tre gange af toluen/en spormængde af methanol hvilket gav titelforbindelsen (0,85 g, 65%) som hvide krystaller, smp. 195-15 209° (sønderdeling).dissolved in ethanol (30 ml) and 10N sodium hydroxide solution (10 ml) was added. After stirring the solution at room temperature for 1 hour, water (500 ml) was added and the solution was washed with diethyl ether (2 x 100 ml). The pH of the aqueous phase was adjusted to 5 with 2N hydrochloric acid solution and extracted with dichloromethane (3 x 200 ml). The combined extracts were dried (MgSO4), evaporated and the residue dissolved in toluene (50 ml) and added to a solution of chlorotrimethylsilane (0.47 ml) and methanol (0.15 10 ml) in toluene (100 ml). The precipitate was collected by filtration after standing at room temperature for 18 hours. The solid was recrystallized three times by toluene / a trace amount of methanol to give the title compound (0.85 g, 65%) as white crystals, m.p. 195-15 209 ° (decomposition).

C24H25F2N03*HC1*°r2H2G^·beregneti C/ 63/6; H, 5,9; N, 3>1; Cl, .’7,9. -Fundet: C, 63;·*?' H, 5,9; N; 3,1;. Cl·, ^7,9%, ; ·- ;··'.·*:/* ' ·* *. ) ·??ΓΙ '.ί'ΙΓΙ** ·, '* ·; 20 : -EKSEMPEL 30 :v;:.·:··.' ·.* : r;··:.: " .-T. ..... ·. . Vi’-V· ·...· , ·- /3:5,;.C24H25F2NO3 * HCl * ° r2H2G ^ calculated C / 63/6; H, 5.9; N, 3> 1; Cl, 7'7. Found: C, 63; H, 5.9; N; 3.1 ;. Cl · 7.9%; · -; ·· '. · *: / *' · * *. ) · ?? ΓΙ '.ί'ΙΓΙ ** ·,' * ·; 20: -Example 30: v;:. ·: ··. ' ·. *: R; ··:.: ".-T. ..... ·.. We'-V · · ... ·, · - / 3: 5,;.

(R)-l-[2*· [ [2-( 2-iChlorphenyl )-2-r(2-r4nethylphenyl )ethen-v ' yljoxy] ethyl] -3-piperidincarboxylsyre:hydrochlorid-.(R) -1- [2 * · [[2- (2-Chlorophenyl) -2- [2- (4-methylphenyl) ethenyl] yl] oxy] ethyl] -3-piperidinecarboxylic acid: hydrochloride.

25 t: .25 t :.

(R)-l-[2-[ [2-(2-Chlorphenyl)-2-(2-methylphenyl)ethen-yl]oxy3ethyl]-3-piperidincarboxylsyreethylester (4,1 g, 0,0096 mol) (fremstillet Som beskrevet i metode D) opløstes i ethanol (100 ml) og 18 N natriurahydroxidopløsning 30 (10 ml) tilsattes. Efter omrøring af opløsningen ved stue temperatur i 1 time tilsattes vand (500 ml) og opløsningen vaskedes méd diethylæter (2 x 100 ml). De vandige fasers pH-værdi indstillédes til 1 med 2 N saltsyreopløsning og ekstraheredes med dichlormethan (4 x 200 ml). De sam-35 lede ekstrakter tørredes *(MgSO^), inddampedes og inddamp-ningsresten krystalliseredes af toluen/en spormængde af methanol hvilket gav titelforbindelsén (3;47 g, 87%) som 42(R) -1- [2- [[2- (2-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -3-piperidinecarboxylic acid ethyl ester (4.1 g, 0.0096 mol) (prepared as described in Method D) was dissolved in ethanol (100 ml) and 18 N sodium hydroxide solution 30 (10 ml) was added. After stirring the solution at room temperature for 1 hour, water (500 ml) was added and the solution was washed with diethyl ether (2 x 100 ml). The pH of the aqueous phases was adjusted to 1 with 2N hydrochloric acid solution and extracted with dichloromethane (4 x 200 ml). The combined extracts were dried * (MgSO 4), evaporated and the residue was crystallized by toluene / a trace amount of methanol to give the title compound (3; 47 g, 87%) as 42

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et hvidt krystallinsk faststof, smp. 231-234°.a white crystalline solid, m.p. 231-234 °.

C23H26C1N03*HC1/ bere9net: c' 63,3; Η, 6>2; N, 3,2; Cl, 16.3. Pundet: C, 63,2; H, 6,4; N, 3,1; Cl, 16,3%.C 23 H 26 ClNO 3 * HCl / calcd: c '63.3; Η, 6> 2; N, 3.2; Cl, 16.3. Pound: C, 63.2; H, 6.4; N, 3.1; Cl, 16.3%.

5 EKSEMPEL 31 1- [2- [ [ (2- (2-Chlorphenyl) -2-( 2-methylphenyl )ethenyl] oxy] -ethyl] -1,2,5,6-tetrahydro-3-pyridincarboxylsyre hydro-10 chlorid .EXAMPLE 31 1- [2- [[(2- (2-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydro-10 chloride.

1- [2- [ [ (2- (2-Chlorphenyl )-2-( 2-methylphenyl )ethenyl] oxy] -ethyl] -1,2,5,6-tetrahydro-3-pyridincarboxylsyreethy lester 15 (3,35 g, 0,0079 mol) (fremstillet som beskrevet i metode D) opløstes i ethanol (100 ml) og.18 N. natriumhydroxidopløsning (10 ml) tilsattes. Efter omrøring af opløsningen vted--?stuetémpératur .i ;2-timer tilsattes vand (500.ml) og ieaktionsblandingen, vaskedes-tmed dfethylæter- (2.x 100 ml).1- [2- [[(2- (2-Chlorophenyl) -2- (2-methylphenyl) ethenyl] oxy] ethyl] -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid ethyl ester (3.35 g, 0.0079 mol) (prepared as described in Method D) was dissolved in ethanol (100 ml) and 1.8 N sodium hydroxide solution (10 ml) was added. After stirring the solution at room temperature, 2 hours was added. water (500 ml) and the reaction mixture, washed with diethyl ether (2.x 100 ml).

20 Den vandige fases pH-værdi indstilledes til 1 med 2 N saltsyreopløsning og ekstraheredés med dichlormethan (4 x 100 ml). De samlede ekstrakter tørredes (MgSO^), inddampedes og s' Sen L f åste ihddarapningsrést · ©mkrystalliseredfes laf 1 toluen/en; sppimængde : af '. methanol hvilket‘ gav. titelforbindel-25 sen (2,2 g, 64%) som et hvidt krystallinsk faststof, smp. 196-1-96°.-.........-.......................................The pH of the aqueous phase was adjusted to 1 with 2N hydrochloric acid solution and extracted with dichloromethane (4 x 100 ml). The combined extracts were dried (MgSO4), evaporated, and the Late was added to the residue or crystallized to afford 1 toluene / one; amount of spppy: of '. methanol to give. the title compound (2.2 g, 64%) as a white crystalline solid, m.p. 196-1-96 °.-.........-................................ .......

e23^2ClN03*HC1> b6r®9net: C, 63;6; H;.5;8; N, 3;2;G1, 16.3. Fundet: C, 63,6; H, 5,9?-N, 3,1; Cl, · 16;3%.e23 C2ClNO3 * HCl> b6r®9net: C, 63.6; H; 0.5; 8; N, 3; 2; G1, 16.3. Found: C, 63.6; H, 5.9? -N, 3.1; Cl, · 16; 3%.

30 · '· *‘-o-. - ··'· EKSEMPEL 32- - ··: Λ- . - · (R)-l- E3«‘[* [2,-2-bis( 4-Flu6rphenyl )ethenyl]oxy] prbpyl] -3-plpéridincarboxylsyre' hydrochlorid ·-·>.' 35 ---;--— (R) -1 - [ 3 - [ [ 2-, 2 -bis (4 - Fluor phenyl -) etheny 1 ] oxy ] propyl ] - 3 - 4330 · '· *' - o-. EXAMPLE 32- - ··: Λ-. - ((R) -1- E3- [[[2,2-bis (4-Fluorophenyl) ethenyl] oxy] prbpyl] -3-piperidinecarboxylic acid hydrochloride · - ·>. -; - (R) -1 - [3 - [[2-, 2-bis (4-Fluoro-phenyl-)-ethenyl-1] oxy] -propyl] -3-43

DK 165366 BDK 165366 B

piperidincarboxylsyreethylestertartrat (3,8 g, 0,0065 mol) (fremstillet som beskrevet i metode D) opløstes i ethanol (25 ml) og 12 N natriumhydroxidopløsning (2,2 ml) tilsattes ved 5°. Efter omrøring af opløsningen ved stue-5 temperatur i 4,8 timer, justeredes reaktionsblandingens pH til ca. 7 med 4 N saltsyreopløsning og blandingen inddampedes til en inddampningsrest in vacuo. Vand (25 ml) tilsattes og blandingen ekstraheredes med dichlormethan (3 x 50 ml). De samlede ekstrakter tørredes (MgSO^) og 10 inddampedes til et skummende produkt som opløstes i toluen (1,5 ml) og opvarmedes til 40°. Methanol (0,27 ml) tilsattes efterfulgt af chlortrimethylsilan (0,83 ml). Produktet bundfældedes langsomt og efter at suspensionen havde fået lov at henstå i 18 timer ved stuetemperatur op-15 samledes den ved filtrering. Titelforbindelsen (2,9 g, guant.);opnåedes som hvide.krystaller, smp. 177-180°: (efter:tørring in vacuo). HPLC retentionstid 12,55 (gradient eluering, vand/35-50% acetonitril, den vandige fase Indeholdende'0pi M åmmoniumsulfatopløsning). » 20 '.v·· · - ·· --Μ. .-- ΐ··Λ.·ί.γ-,Ά;-- .EKSEMPEL 33 (Metode E> (R)-1 - [ 2~> [ [ 2,2-Diphenylethyl 3 oxy ] ethyl ]-3-piperidin-. carboxylsyre ‘ : 25 - -—--—-—-———- (R) -1- [2- [ [ 2,2-Diphenylethenyl] oxy] ethyl] -3-piperidincar-boxylsyre hydrochlorid (120 mg, 0,31 mmol) opløstes i methanol (5 ml) og omrørtes under en hydrogenatmosfære i 2 30 timer ved stuetemperatur i nærværelse af en 5% palladium på- barbon-katalysator (52% vandig pasta) hvorefter der filtreredes s. Filtratet inddampedes til tørhed-hvilket ef terlod en inddampningsrest som opløstes i vand.' Den vandige Opløsning blev lyophiliseret hvilkeUr gav titelforbin-35 delsen (80 mg, 58% af det teoretiske udbytte) som et faststof, TLC rf 0,32 (Si02, methanol).piperidine carboxylic acid ethyl ester tartrate (3.8 g, 0.0065 mol) (prepared as described in Method D) was dissolved in ethanol (25 ml) and 12 N sodium hydroxide solution (2.2 ml) was added at 5 °. After stirring the solution at room temperature for 4.8 hours, the pH of the reaction mixture was adjusted to ca. 7 with 4 N hydrochloric acid solution and the mixture was evaporated to a residue in vacuo. Water (25 ml) was added and the mixture extracted with dichloromethane (3 x 50 ml). The combined extracts were dried (MgSO4) and evaporated to a foamy product which was dissolved in toluene (1.5 ml) and heated to 40 °. Methanol (0.27 ml) was added followed by chlorotrimethylsilane (0.83 ml). The product precipitated slowly and after allowing the suspension to stand for 18 hours at room temperature, it was collected by filtration. The title compound (2.9 g, guant) was obtained as white crystals, m.p. 177-180 °: (after: drying in vacuo). HPLC retention time 12.55 (gradient elution, water / 35-50% acetonitrile, the aqueous phase Containing'0pi M ammonium sulfate solution). »20 '.v ·· · - ·· --Μ. EXAMPLE 33 (Method E> (R) -1 - [2 ~> [[2,2-Diphenylethyl 3 oxy] ethyl] -3- piperidine carboxylic acid 25 - - - - - - - (-) - [2- [[2,2-Diphenylethenyl] oxy] ethyl] -3-piperidinecarboxylic acid hydrochloride (120 (0.31 mmol) was dissolved in methanol (5 ml) and stirred under a hydrogen atmosphere for 2 hours at room temperature in the presence of a 5% palladium on-barbon catalyst (52% aqueous paste) and then filtered. to dryness, leaving an evaporation residue which was dissolved in water. The aqueous solution was lyophilized which gave the title compound (80 mg, 58% of theoretical yield) as a solid, TLC rf 0.32 (SiO 2, methanol). .

Claims (17)

1. N-substituerede 3-piperidin- eller 3-tetrahydropyri-din-carboxylsyrer og estre heraf, KENDETEGNET VED, at de 5 har den generelle formel· I Rs \.(CH2)nC0R7 JLi i8 fV 10 ^0. ^CH /~R6 ‘ (I) R2 XH ^(CH2)p^(CH2)q (CH2>m R3 I R4 1 2 15 hvor R og R er ens eller forskellige og hver betegner pheriyl eller 2-thienyl, substitueret med en eller flere substituenter valgt blandt følgende atomer eller grupper: hydrogen, halogen, C..-C;.-alkyl, C, -C^-alkoxy eller cyano; 3. x o id R- og :R hver for sig-er hydrogen eller tilsammen danner 5 6 20 én binding; m .er 2 og n er 0 ; R og R hver for sig er 7 hydrogen eller danner tilsammen en binding, og R er OH eller C^-Cg-alkoxy, p er 0 eller 1 eller 2, q er 0 eller 1 eller 2, idet p og q ikke samtidig er 0, R® er H eller C1_4-alkyl, og farmaceutisk acceptable syreadditionssal-25 te eller,· når carboxylsyregruppen ikke er esterifiseret, farmaceutisk acceptable metalsalte eller eventuelt alky lerede ammoniumsalte heraf. 1 21. N-substituted 3-piperidine or 3-tetrahydropyridine carboxylic acids and esters thereof, CHARACTERIZED THAT they have the general formula · In Rs \. (CH2) nC0R7 JLi i8 fV 10 ^ 0. (CH2) p ^ (CH2) q (CH2> m R3 I R4 1 2 15 where R and R are the same or different and each represents pheryl or 2-thienyl, substituted by one or more substituents selected from the following atoms or groups: hydrogen, halogen, C ..-C; alkyl, C,-C ^ alkoxy or cyano; 3. xo id R- and: R each are hydrogen or together form 5 6 20 one bond; m is 2 and n is 0; R and R are each 7 hydrogen or together form a bond and R is OH or C 1 -C 6 alkoxy, p is 0 or 1 or 2, q is 0 or 1 or 2, where p and q are not simultaneously 0, R® is H or C1-4 alkyl and pharmaceutically acceptable acid addition salt or, when the carboxylic acid group is not esterified, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts thereof 1 2 2. Forbindelser ifølge krav 1, hvor R og R uafhængigt 30 er phenyl, 2-methylphenyl, 2-chlorphenyl, 4-fluor-2-methyl-phehyl, 3-methoxyphenyl, 3-fluorphenyl, 3-chlorphenyl, 2- ethylphenyl, 2-fluorphenyl, 2,4-dichlorphenyl eller 3- methyl-2-thienyl. 3 4 35 3^_ Forbindelser ifølge krav 1 eller 2, hvor R og R hver repræsenterer hydrogen. 45 DK 165366 BCompounds according to claim 1, wherein R and R are independently phenyl, 2-methylphenyl, 2-chlorophenyl, 4-fluoro-2-methyl-pheyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 2-ethylphenyl, 2-fluorophenyl, 2,4-dichlorophenyl or 3-methyl-2-thienyl. Compounds according to claim 1 or 2, wherein R and R each represent hydrogen. 45 DK 165366 B 4. Forbindelser ifølge krav 1 eller 2, hvor R8 og tilsammen danner en binding.Compounds according to claim 1 or 2, wherein R8 and together form a bond. 5. Forbindelser ifølge et vilkårligt af kravene 1 til 4, 5 hvor p er 0 og q er 1 eller 2 og R8 er H.Compounds according to any one of claims 1 to 4, 5 wherein p is 0 and q is 1 or 2 and R8 is H. 6. Forbindelser ifølge et vilkårligt af de foregående krav, hvor R8 og R8 hver repræsenterer hydrogen. 10 7^ Forbindelser ifølge et vilkårligt af kravene 1 til 5, 5 6 hvor R og R tilsammen danner en binding.Compounds according to any one of the preceding claims, wherein R 8 and R 8 each represent hydrogen. Compounds according to any one of claims 1 to 5, 5 6 wherein R and R together form a bond. 8. Forbindelser ifølge et vilkårligt af de foregående 7 krav hvor R er OH. 15Compounds according to any one of the preceding claims wherein R is OH. 15 9. Forbindelser ifølge et vilkårligt af kravene 1 til 7, 7 hvor R er G^-Cg-alkoxy, fortrinsvis ethoxy eller methoxy.Compounds according to any one of claims 1 to 7, 7 wherein R is G 1 -C 6 alkoxy, preferably ethoxy or methoxy. 10. Fremgangsmåde til-fremstilling af en forbindelse med 3 20 den generelle formel · I -som defineret i krav 1, hvor R 4 og R tilsammen danner en binding, KENDETEGNET ved omsætning af: et iacetaldehydderivat med formlen II. - - <v H <ii) 1 2 30 hvor R og R er som defineret i krav 1, med en forbindelse medr'fornilen III - ' (CH2)nCOR7 |8 j—\ 35 Υ^(0Η2Τρ^ (CK2)T* (ch2)o ·'· -· - (III) 46 DK 165366 B hvor Y er en egnet afgangsgruppe, fortrinsvis halogen 5 6 7 8 eller p-toluensulfonat og R , R , R , R°, p, q, m og n er som defineret i krav 1.A process for the preparation of a compound of general formula · I as defined in claim 1, wherein R 4 and R together form a bond, CHARACTERIZED by the reaction of: an iacetaldehyde derivative of formula II. wherein R and R are as defined in claim 1, with a compound having the formula III - '(CH2) nCOR7 | 8 j - \ 35 Υ ^ (0Η2Τρ ^ (CK2) T * (ch 2) o · - · - (III) 46 where Y is a suitable leaving group, preferably halogen 5 6 7 8 or p-toluenesulfonate and R, R, R, R °, p, q, m and n is as defined in claim 1. 11. Fremgangsmåde til fremstilling af en forbindelse med den generelle formel i som defineret i krav 1, KENDETEGNET ved omsætning af et hydroxyæterder i vat med den generelle formel IV RiA process for preparing a compound of the general formula i as defined in claim 1, characterized by reacting a hydroxy ether in cotton with the general formula IV Ri 10. I ^0 ^CH ^0H R^ ^CH (CH2)p (CH2)q R3 1 E* (IV) 15 12 3 4 8 hvor R , R , R y R ,· R°, •pog-.q er som defineret i krav 1, med et'pasende reagens til dannélse af en forbindelse med formlen.V 20 . .. ,· . . R1 ' . . I*. ... • R f CH . XCH2).p . (CH2)q .. - *-1 (V) 25 hvor Z er en passende afgangsgruppe, fortrinsvis halogen, tosylat eller mesylat, hvorefter V omsættes med et derivat af en azaheterocyclisk· carboxylsyre med formlen VI 30 (CH2)nC0R7 ryR .. • · HN ’ · ^(CH2)m (VI) 5 6 7 hvor R , R , R , n og m er som defineret i krav 1, til dannelse af en forbindelse med den generelle formel I. 35 47 DK 165366 B10. I ^ 0 ^ CH ^ 0H R ^^ CH (CH2) p (CH2) q R3 1 E * (IV) 15 12 3 4 8 where R, R, R y R, · R °, • pog-. q is as defined in claim 1, with a suitable reagent to form a compound of the formula. .., ·. . R1 '. . IN*. ... • R f CH. XCH2) .p. (CH2) q .. - * -1 (V) where Z is a suitable leaving group, preferably halogen, tosylate or mesylate, after which V is reacted with a derivative of an azaheterocyclic carboxylic acid of formula VI 30 (CH2) nCO07. (CH 2) m (VI) 5 6 7 wherein R, R, R, n and m are as defined in claim 1, to form a compound of the general formula I. 12. Fremgangsmåde til fremstilling af en forbindelse med den generelle formel I som defineret i krav 1, hvori og R^ tilsammen danner en binding, KENDETEGNET ved omsætning af et acetaldehydderivat med formlen II <v H 10 (II) 1 2 hvor R og R er som defineret i krav 1, med en disubsti-tueret alkan med formlen vil 15 j* Y\ >Z >,(CH2)p^(CH2)q . '5 . - . ; · <VII) ,. · ; . 20 8 hvor R , p og q er som defineret i krav 1, og Y og Z er passende afgangsgrupper, fortrinsvis halogen, tosylat eller mesylat, til dannelse af et vinylæterderivat med formlen VIII 25 R1 R8 I . I , Rf (CH2)p^(CH2)q 30 (VIII) 12 8 hvor R , R , R , p og q er som defineret i krav 1, hvorefter vinylæterderivatet med formlen VIII omsættes med et derivat af en azaheterocyclisk carboxylsyre med formlen 35 VI DK 165366B 48 (CH2)nCOR7 rv, HN- / 6 ^(CH,)m 5 2 (VI) til dannelse af en forbindelse med den generelle formel I, hvori Rg og R4 tilsammen danner en binding. 10A process for preparing a compound of general formula I as defined in claim 1, wherein and R 2 together form a bond, CHARACTERISTICS by reacting an acetaldehyde derivative of formula II <v H 10 (II) 1 2 wherein R and R is as defined in claim 1, with a disubstituted alkane of the formula, 15 j * Y \> Z>, (CH2) p ^ (CH2) q. '5. -. ; · <VII) ,. ·; . Wherein R, p and q are as defined in claim 1 and Y and Z are appropriate leaving groups, preferably halogen, tosylate or mesylate, to form a vinyl ether derivative of formula VIII. I, Rf (CH 2) p 2 (CH 2) q 30 (VIII) 12 8 wherein R, R, R, p and q are as defined in claim 1, wherein the vinyl ether derivative of formula VIII is reacted with a derivative of an azaheterocyclic carboxylic acid of formula (CH2) nCOR7 rv, HN- / 6 ^ (CH2) m 5 2 (VI) to form a compound of general formula I wherein Rg and R4 together form a bond. 10 13. Fremgangsmåde ifølge krav 12, KENDETEGNET VED, at vi-nylæterderivatet med formlen VIII 15 i1 !! (VIII) 20 fremstilles ved faseoverførselsreaktion af aldehydderivatet med formlen II13. A process according to claim 12, characterized in that the vinyl ether derivative of formula VIII is prepared. (VIII) 20 is prepared by phase transfer reaction of the aldehyde derivative of formula II 25. I H + · ^ di)· 1 2 hvor R og R er som defineret i krav 1, med den disubsti-30 tuerede alkan med formlen VII V f CH Z 35 ^(CH^p^CCH^q (VII) DK 165366B 49 hvor Y og Z er egnede afgangsgrupper, såsom halogen, og Θ R , p og q er som defineret i krav 1.25. IH + · (di) · 1 wherein R and R are as defined in claim 1, with the disubstituted alkane of formula VII V f CH Z 35 ^ (CH Wherein Y and Z are suitable leaving groups such as halogen and Θ R, p and q are as defined in claim 1. 14. Fremgangsmåde til fremstilling af forbindelser med 3 5 den generelle formel I som defineret i krav 1, hvor R , 4 5 6 R , R og R alle er hydrogen, KENDETEGNET ved hydrogenering af forbindelser med formlen la h 10 \ .(CH2)nCOR7 r o *’ O-* <*> *2 (CH2)pX(CH2)q (CH2)m 15 1 2 5 6 7 8 hvor R , R , R , R , R , r°, p, q, m og n er som defineret i krav 1. ..... 20 i···A process for the preparation of compounds of general formula I as defined in claim 1, wherein R, 4,5, R, R and R are all hydrogen, CHARACTERISTICS of hydrogenation of compounds of formula la h 10 \. (CH2) nCOR7 ro * 'O- * <*> * 2 (CH2) pX (CH2) q (CH2) m 15 1 2 5 6 7 8 where R, R, R, R, R, r °, p, q, m and n is as defined in claim 1. ..... 20 in ··· 15. Farmaceutisk præparat, KENDETEGNET VED, at det som aktiv komponent indeholder en N-substitueret 3-piperidin-eller 3-tetrahydropyridin-carboxylsyre eller en ester 25 heraf ifølge et vilkårligt af kravene 1 til 7.A pharmaceutical composition, characterized in that it contains as an active component an N-substituted 3-piperidine or 3-tetrahydropyridine carboxylic acid or an ester thereof according to any one of claims 1 to 7. 16. Farmaceutisk præparat ifølge krav 15, KENDETEGNET VED, at det indeholder mellem 0,5 mg og 1000 mg, fortrinsvis mellem 1 mg og 500 mg af forbindelsen med den generel- 30 le formel 1 per enhedsdosis.Pharmaceutical composition according to claim 15, characterized in that it contains between 0.5 mg and 1000 mg, preferably between 1 mg and 500 mg of the compound of the general formula 1 per unit dose. 17. Anvendelse af en forbindelse ifølge et vilkårligt af kravene 1-7 til fremstilling af et farmaceutisk præparat til brug-'-som analgesicum, anxiolyticum, antidepressivum 35 eller hypnotikum eller ved behandling af epilepsi eller muskel- eller bevægelsessygdomme.Use of a compound according to any one of claims 1-7 for the manufacture of a pharmaceutical composition for use as analgesic, anxiolytic, antidepressant or hypnotic, or in the treatment of epilepsy or muscular or movement disorders.