NO830202L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLETHYLENE DERIVATIVES - Google Patents

PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLETHYLENE DERIVATIVES

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Publication number
NO830202L
NO830202L NO830202A NO830202A NO830202L NO 830202 L NO830202 L NO 830202L NO 830202 A NO830202 A NO 830202A NO 830202 A NO830202 A NO 830202A NO 830202 L NO830202 L NO 830202L
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NO
Norway
Prior art keywords
methyl
vinyl
benzoic acid
group
tetrahydronaphth
Prior art date
Application number
NO830202A
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Norwegian (no)
Inventor
Fritz-Frieder Frickel
Axel Nuerrenbach
Original Assignee
Basf Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19823202065 external-priority patent/DE3202065A1/en
Priority claimed from DE19823202100 external-priority patent/DE3202100A1/en
Priority claimed from DE19823202118 external-priority patent/DE3202118A1/en
Application filed by Basf Ag filed Critical Basf Ag
Publication of NO830202L publication Critical patent/NO830202L/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/66—Polycyclic acids with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Foreliggende oppfinnelse angår fenyletylenderivater, fremgangsmåtet, for deres fremstilling og terapeutiske midler som inneholder slike forbindelser, samt deres anvendelse ved sykdomsbekjempelse. The present invention relates to phenylethylene derivatives, the method for their production and therapeutic agents containing such compounds, as well as their use in disease control.

Fra DE-OS 28 54 354. er det kjent at stilbenderivater har farmakologiske virkninger ved topisk og systemisk terapi, av neoplasmer, akne, psoriasis og andre dermatologiske lidelser. From DE-OS 28 54 354. it is known that stilbene derivatives have pharmacological effects in topical and systemic therapy of neoplasms, acne, psoriasis and other dermatological disorders.

De utpregede toksiske (bi-)virkninger av disse forbindelserThe pronounced toxic (side) effects of these compounds

er imidlertid en ulempe som synes å gjøre dem lite egnet som middel mot de nevnte lidelser. Svakheten ved stilbenderivatene i henhold til DE-OS 28 54 354 er f.eks. beskrevet av A. Kistler i Calcified Tissue International 33, 249-254 (1981), og viser seg spesielt ved gjentatte applikasjoner på gnagere, etter den metode som er publisert av R. C. Moon et al. [Cancer Research 39, 1339-1346 (1979)]. is, however, a disadvantage that seems to make them less suitable as a remedy for the aforementioned ailments. The weakness of the stilbene derivatives according to DE-OS 28 54 354 is e.g. described by A. Kistler in Calcified Tissue International 33, 249-254 (1981), and manifests itself particularly with repeated applications to rodents, following the method published by R. C. Moon et al. [Cancer Research 39, 1339-1346 (1979)].

Formålet med foreliggende oppfinnelse har vært å kommeThe purpose of the present invention has been to

frem til forbindelser med sammenlignbar effekt, men med mindre toksiske bivirkninger. until compounds with a comparable effect, but with less toxic side effects.

Oppfinnelsen angår fenyletylenderivater med formel:The invention relates to phenylethylene derivatives with the formula:

hvor where

A er en alkylenrest som eventuelt er substituert med en A is an alkylene residue which is optionally substituted with a

C1_4-alkylgruppe,C1_4 alkyl group,

r'' er et hydrogenatom eller en metylgruppe,r'' is a hydrogen atom or a methyl group,

2 2

R er et hydrogenatom eller en metylgruppe,R is a hydrogen atom or a methyl group,

R 3 er et hydrogenatom eller en C. ft-alkyIgruppe,R 3 is a hydrogen atom or a C 1 -C 1 -alkyl group,

R 4er en C .-alkylgruppe ogR 4 is a C 1 -alkyl group and

R 5 er en p-hydroksyfenylenaminokarbonyl-, tetrazol-5-y1-amino-karbonylgruppe eller, dersom R^ betyr en C^_g-alkylgruppe, R 5 is a p-hydroxyphenyleneaminocarbonyl, tetrazol-5-y1-aminocarbonyl group or, if R 5 means a C 1-6 alkyl group,

en karboksyl eller C2_zj~karbalkoksygruppe, og eventuelt deres salter med fysiologisk akseptable baser. a carboxyl or C2_zj~carbalkoxy group, and optionally their salts with physiologically acceptable bases.

A er fortrinnsvis en metylen- eller etylengruppe som eventuelt er substituert med en metylgruppe. A is preferably a methylene or ethylene group which is optionally substituted with a methyl group.

Spesielt verdifulle forbindelser oppnås når fenylringene befinner seg i trans-stilling i forhold til hverandre. Particularly valuable compounds are obtained when the phenyl rings are in the trans position relative to each other.

Den bølgeformig opptrukne C-C-binding kan befinne seg over eller under papirplanet og dermed tilhøre en cis-(Z-)-eller en trans-(E-)-forbindelse. The undulating C-C bond can be above or below the plane of the paper and thus belong to a cis-(Z-) or a trans-(E-) compound.

Typiske eksempler på forbindelser i henhold til opp-' finnelsen er: 4-[2-metyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyreetylester Typical examples of compounds according to the invention are: 4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)- vinyl]-benzoic acid ethyl ester

4-[2-metyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,6-trimety1-1, 2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,6-trimety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyreetyléster 4-[2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-etyl-2- (1 ,1 , 4 , 4 , 6-pentametyl-1 , 2 , 3 , 4-tetrahydronaf t-7-yl)-vinyl]-benzosyreetylester 4-[2-Ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-etyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre 4-[2-ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,4,4-tetrametyl-6-etyl-1,2,3,4-tetrahydronaf t- 7 -yl) -vinyl ] -benzo sy ree tyle st er 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-metyl-2-(1,1,4,4-tetramety1-6-etyl-1,2,3,4-tetrahydronaf t-7 -yl ) -vinyl ] -benzosyre 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,4,4-tetramety1-6-isopropyl-1,2,3,4-tetra-hydronåft-7-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl]-benzoic acid

4-t2-metyl-2-(1,1,4,4-tetramety1-6-isopropyl-1,2,3,4-tetrahydronaf t-7 -yl) -vinyl]-benzosyreetylester 4-t2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-metyl-2-(1,1,4,4-tetramety1-6-propyl-1,2,3,4-tetrahydronaf t-7 -yl )-vinyl]-benzosyre 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,4,4-tetrametyl-6-propyl-1,2,3,4-tetrahydronaf t-7-yl)-vinyl]-benzosyreetylester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-mety1-2-(1,1,4,4-tetrametyl-6-buty1-1,2,3,4-tetrahydronaf t-7-yl)-vinyl]-benzosyremetylester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid methyl ester

4-[2-metyl-2-(1,1,4,4-tetrametyl-6-butyl-1,2,3,4-tetrahydronaf t-7-yl)-vinyl]-benzosyreetylester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-metyl-2-(1,1,4,4-tetrametyl-6-butyl-1,2,3,4-tetrahydronaf t-7-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,4,4-tetramety1-6-(2-metyl-6-(2-metylpropy1)-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyreetylester 4-[ 2-metyl-2- (1,1,4 ,.4-tetrametyl-6- ( 2-metyl-propyl) - 1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre 4-[2-mety1-2-(1,1,3,4,4,6-heksametyl-1,2,3,4-tetrahydronaf t-7-yl) -vinyl]-benzosyreetylestér 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-6-(2-methylpropyl)-1,2,3,4-tetrahydronaphth-7-yl)- vinyl]-benzoic acid ethyl ester 4-[ 2-methyl-2-(1,1,4,.4-tetramethyl-6-( 2-methyl-propyl)-1,2,3,4-tetrahydronaphth-7-yl)- vinyl]-benzoic acid 4-[2-methyl-2-(1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-mety1-2-(1,1,3,4,4,6-heksametyl-1,2,3,4-tetrahydronaf t-7 -yl) -vinyl ] -benzosyre 4-[2-methyl-2-(1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-mety1-2-(1,1,2,3,3,5-heksametyl-indan-6-yl)-vinyl]-benzosyreetylestér 4-[2-methyl-2-(1,1,2,3,3,5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid ethyl ester

4-[2-mety1-2-(1,1,2,3,3,5-heksametyl-indan-6-yl)-vinyl]-benzosyrepropylester 4-[2-methyl-2-(1,1,2,3,3,5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid propyl ester

4-[2-mety1-2-(1,1,2,3,3,5-heksametyl-indan-6-yl)-vinyl]-benzosyreisopropylester 4-[2-methyl-2-(1,1,2,3,3,5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid isopropyl ester

4-[2-mety1-2-(1,1,2,3,3,5-heksametyl-indan-6-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,2,3,3,5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid

4-[2-mety1-2-(1,1,3,3,5-pentametyl-indan-6-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl)-vinyl]-benzoic acid

4-[2-mety1-2-(1,1,3,3,5-pentametyl-indan-6-y1)-viny1]-benzosyremetylester 4-[2-Methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl)-vinyl]-benzoic acid methyl ester

4-[2-mety1-2-(1,1,3,3,5-pentametyl-indan-6-ylj-vinyl]-benzosyreetylestér 4-[2-methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl-vinyl]-benzoic acid ethyl ester

4-[2-mety1-2-(1,1,4,4,6-pentametyl-1,2,3, 4-tetrahydronaft-7-yl)-vinyl]-benzosyremetylester 4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid methyl ester

4-[2-mety1-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyrepropylester 4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid propyl ester

4-[2-etyl-2-(1,1,4,4,6-pentametyl-1,2,3, 4-tetrahydronaft-7-yl)-vinyl]-benzosyreetylester 4-[2-Ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

4-[2-etyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre 4-[2-ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-etyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyremetylester 4-[2-Ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid methyl ester

4-[2-mety1-2-(1,1,4,4-tetramety1-6-n-butyl-1,2,3,4-tetrahydronaf t-7-yl ) -vinyl ] -benzosyre 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-n-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-metyl-2-(1,1,4,4-tetrametyl-6-n-oktyl-1,2,3,4-tetrahydronaf t- 7 -yl ) -vinyl]-benzosyre 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-n-octyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-mety1-2-(1,1,6-trimety1-1; 2 , 3 ,4-tetrahydronaft-7-yl)-vinyl]-benzosyre 4-[2-methyl-2-(1,1,6-trimethyl-1;2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid

4-[2-mety1-2-(1,1,4,4-tetramety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-mety1-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-N-tetrazol-5-yl)benzosyreamid 4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-tetrazol-5-yl)benzoic acid amide

4-[2-metyl-2-(1,1,4,4-tetråmetyl-6-etyl-1,2,3,4-tetrahydronaf t-7 -yl ) -vinyl]-N-(tetrazol-5-yl)benzosyreamid 4-[2-mety1-2-(1,1,4,4-tetrametyl-6-isopropyl-1,2,3,4-tetrahydronaf t-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-mety1-2-(1,1,2,3,3-pentamety1-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5- yl)benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazole -5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,2,3,3-pentamethyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-mety1-2-(1,1,3,3-tetrametyl-indån-6-y1)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-methyl-2-(1,1,3,3-tetramethyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4- [ 2-nietyl-2- (1,1 , 4 , 4-tetrametyl-6-propyl-1 ,2,3 , 4-tetrahydronaf t-7-yl )-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-mety1-2-(1,1,4,4-tetrametyl-6-(2-mety1-propy1)-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-mety1-2-(1,1,4,4-tetrametyl-6-butyl-1,2,3,4-tetrahydro-naft-7-yl)-vinyl]-N-(tetrazol-5-yl)benzosyreamid 4-[2-etyl-2-(1,1,4,4-tetramety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-niethyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5- yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-propyl)-1,2,3,4-tetrahydronaphth-7-yl)-vinyl ]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydro-naphth-7 -yl)-vinyl]-N-(tetrazol-5-yl)benzoic acid amide 4-[2-ethyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl )-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-etyl-2- (1,1,4,4 ,6-penta/metyl'-1 ,2,3 , 4-tetrahydronaftyl-7-yl)-vinyl]-N-(tetrazol-5-y1)-benzosyreamid 4-[2-ethyl-2-(1,1,4,4,6-penta/methyl'-1,2,3,4-tetrahydronaphthyl-7-yl)-vinyl]-N-(tetrazol-5- y1)-benzoic acid amide

4-[2-mety1-2-(T,1-dimetyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-N-(tetrazol-5-y1)-benzosyreamid 4-[2-methyl-2-(T,1-dimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-metyl-1,1,6-trimety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-methyl-1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-metyl-2-(1,1,3,3,5-pentametyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-metyl-2-(1,1,2,3,3,5-heksametyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzosyreamid 4-[2-methyl-2-(1,1,2,3,3,5-hexamethyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide

4-[2-mety1-2-(1,1,4,4-tetramety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-mety1-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-metyl-2-(1,1,4,4-tetramety1-6-etyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-mety1-2-(1,1,4,4-tetramety1-6-isopropyl-1,2,3,4-tetrahydronaf t-7 -yl )-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-metyl-2-(1,1,2,3,3-pentametyl-indan-6-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,2,3,3-pentamethyl-indan-6-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-metyl-2-(1,1,3,3-tetrametyl-indan-6-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,3,3-tetramethyl-indan-6-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-metyl-2-(1,1,4,4-tetramety1-6-propyl-1,2,3,4-tetrahydronaf t-7 -yl ) -vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-mety1-2-(1,1,4,4-tetramety1-6-(2-mety1-propyl)-1,2,3,4-tetrahydronaft-7-y1)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-propyl)-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid (4-hydroxyanilide)

4-[2-mety1-2-(1,1,4,4-tetramety1-6-butyl-1,2,3,4-tetrahydronaf t-7 -yl ) -vinyl ] -benzosyre- ( 4 -hy dr oksyan i lid) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxy oxyan in lid)

4-[2-etyl-2-(1,1, 4,4-tetramety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-ethyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-etyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-Ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-mety1-2-(1,1-dimetyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1-dimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-metyl-2-(1,1,6-trimetyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-mety1-2-(1,1,3,3,5-pentametyl-indan-6-yl)-vinyl]-benzosyre-(4-hydroksyanilid) 4-[2-methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl)-vinyl]-benzoic acid-(4-hydroxyanilide)

4-[2-mety1-2 - (1 ,1,2,3,3,5-heksametyl-indan-6-y1)-vinyl]-benzosyre-(4-hydroksyanilid). 4-[2-methyl-2-(1,1,2,3,3,5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid-(4-hydroxyanilide).

Forbindelsene i henhold til oppfinnelsen, som utgjør derivater av fri benzosyre, har et surt hydrogenatom og kan følgelig på velkjent måte overføres i fysiologisk akseptable, lett vannløselige salter ved hjelp av baser. Egnede salter er for eksempel ammoniumsalter, alkalimetallsalter - spesielt natrium, kalium og litiumsalter - jprdalkalimetallsalter - spesielt kalsium eller magnesiumsalter - samt salter med egnede organiske baser, som lavere alkylaminer - f.eks. metyl-amin eller etylamin - substituerte lavere alkylaminer, spesielt hydroksysubstituerte alkylaminer - som dietanolamin, trietanol-amin eller tris-(hydroksymetyl)-aminometan-, piperidin eller morfolin . The compounds according to the invention, which are derivatives of free benzoic acid, have an acidic hydrogen atom and can therefore be transferred in a well-known manner into physiologically acceptable, easily water-soluble salts by means of bases. Suitable salts are, for example, ammonium salts, alkali metal salts - especially sodium, potassium and lithium salts - alkaline alkali metal salts - especially calcium or magnesium salts - as well as salts with suitable organic bases, such as lower alkylamines - e.g. methylamine or ethylamine - substituted lower alkylamines, especially hydroxy-substituted alkylamines - such as diethanolamine, triethanolamine or tris-(hydroxymethyl)aminomethane-, piperidine or morpholine.

Dersom de nye forbindelser inneholder en tetrazolrest, kan deres alkali- og jordalkalisalter fremstilles. If the new compounds contain a tetrazole residue, their alkali and alkaline earth salts can be prepared.

De nye forbindelsene fremstilles ved atThe new compounds are produced by

a) en forbindelse med formel II:a) a compound of formula II:

hvor A og R 1 -R 4har de betydninger som er angitt i krav 1, omsettes etter Wittig-Horner med en fosforforbindelse med formel III: where A and R 1 -R 4 have the meanings stated in claim 1, is reacted according to Wittig-Horner with a phosphorus compound of formula III:

hvor R 6 har den betydning som er angitt for R 5, eller where R 6 has the meaning given for R 5, or

står for1en cyanogruppe, og R 7utgjør en C^_4alkylgruppe, eller stands for a cyano group, and R 7 represents a C 1 -4 alkyl group, or

b) et fosfoniumsalt med formel IV:b) a phosphonium salt of formula IV:

12 3 4 hvor A, R , R , R og R har de betydninger som er angitt i krav 1, og X betyr klor eller brom, omsettes etter Wittig med et benzaldehyd-derivat med formel: 12 3 4 where A, R , R , R and R have the meanings stated in claim 1, and X means chlorine or bromine, is reacted according to Wittig with a benzaldehyde derivative of formula:

hvor R har den ovenfor angitte betydning, hvoretter, dersom R^ ikke utgjør en karboksylgruppe, den oppnådde forbindelse eventuelt forsåpes eller den derved, eller direkte, oppnådde fri syre deretter eventuelt omsettes med en C^_^-alkohol, p-hydroksyanilin eller 5-aminotetrazol og de derved oppnådde forbindelser eventuelt overføres i deres salter med fysiologisk akseptable baser. where R has the meaning given above, after which, if R^ does not constitute a carboxyl group, the compound obtained is optionally saponified or the free acid obtained thereby, or directly, is then optionally reacted with a C^_^-alcohol, p-hydroxyaniline or 5 -aminotetrazole and the compounds thus obtained are optionally transferred in their salts with physiologically acceptable bases.

Omsetningene a) og b) foregår ved temperaturer opp til 100°C, f.eks. ved 20-50°C. Omsetningene kan også foretas under atmosfæretrykk, eller i en lukket beholder under høyere trykk, eventuelt under oppvarming til det angitte temperaturområde. The reactions a) and b) take place at temperatures up to 100°C, e.g. at 20-50°C. The reactions can also be carried out under atmospheric pressure, or in a closed container under higher pressure, possibly under heating to the indicated temperature range.

Omsetningene kan foretas i nærvær av et fortynnings- eller løsningsmiddel, f.eks. en lavere mettet dialkyleter, dialkylglykoleter eller cyklisk eter, som dietyleter, etyl-tert-butyleter, 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et aromatisk hydrokarbon som benzen, eller en alkylbenzen som toluen eller xylen, eller et mettet alifatisk hydrokarbon som heksan, heptan eller isooktan, et lavere alifatisk keton som acetonmetyletylketon eller metylisobutylketon, et dialkylformamid som dimetyl eller dietylformamid, eller en blanding av de nevnte løsningsmidler. Fortrinnsvis benyttes cykliske etere som dioksan eller tetrahydrofuran, og spesielt dimetylformamid eller blandinger av disse, idet omsetningen vanligvis foregår ved en temperatur opptil 30°C. The reactions can be carried out in the presence of a diluent or solvent, e.g. a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene, or an alkylbenzene such as toluene or xylene, or a saturated aliphatic hydrocarbon such as hexane , heptane or isooctane, a lower aliphatic ketone such as acetone methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide such as dimethyl or diethylformamide, or a mixture of the aforementioned solvents. Cyclic ethers such as dioxane or tetrahydrofuran, and especially dimethylformamide or mixtures thereof, are preferably used, the reaction usually taking place at a temperature of up to 30°C.

Omsetningene foretas i nærvær av et deprotoniseringsmiddel for fosforforbindelsen (III). Egnede midler er alkali-metallhydrider og alkalimetallamider, spesielt natrium og kaliumforbindelsene, natrium og kaliumsaltene av dimetylsulfoksyd, alkyllitiumforbindelser som n-butyllitium, eller alkalimetall alkoholater, fortrinnsvis natriummetanolat eller natriumetanolat. The reactions are carried out in the presence of a deprotonating agent for the phosphorus compound (III). Suitable agents are alkali metal hydrides and alkali metal amides, especially the sodium and potassium compounds, the sodium and potassium salts of dimethylsulfoxide, alkyllithium compounds such as n-butyllithium, or alkali metal alcoholates, preferably sodium methanolate or sodium ethanolate.

Ved anvendelse av en alifatisk epoksyforbindelse, fortrinnsvis butylenoksyd, lykkes reaksjonen også uten tilsetning av andre midler. Alifatiske epoksyforbindelser utgjør således både løsningsmiddel og deprotoniseringsmiddel. Ved bruk av butylenoksyd som alifatisk epoksyforbindelse, kan omsetningen utføres ved koketemperaturen for reaksjonsblandingen, eller ved en temperatur omkring 100°C under høyere trykk i en lukket beholder. When using an aliphatic epoxy compound, preferably butylene oxide, the reaction also succeeds without the addition of other agents. Aliphatic epoxy compounds thus constitute both solvent and deprotonating agent. When using butylene oxide as an aliphatic epoxy compound, the reaction can be carried out at the boiling temperature of the reaction mixture, or at a temperature of around 100°C under higher pressure in a closed container.

Omsetningen av syren I (R 5 COOH) med en Cj _3-alkohol, p-hydroksyanilin eller 5-aminotetrazol, oppnås ved å overføre syren i et aktivert derivat med formel I, hvor R står for resten COX, hvor X betyr en utgående gruppe. The reaction of the acid I (R 5 COOH) with a C 3 -alcohol, p-hydroxyaniline or 5-aminotetrazole is achieved by transferring the acid in an activated derivative of formula I, where R stands for the residue COX, where X means a leaving group .

X utgjør en syrerest, f.eks. et halogenatom, spesielt klor eller brom, eller N-oksysuccinimidresten. X constitutes an acid residue, e.g. a halogen atom, especially chlorine or bromine, or the N-oxysuccinimide residue.

Omsetningen foregår ved en temperatur på opptil 50°C ved atmosfæretrykk, eller i en lukket beholder under høyere trykk. The reaction takes place at a temperature of up to 50°C at atmospheric pressure, or in a closed container under higher pressure.

Disse omsetninger kan utføres i nærvær av et fortynnings-eller løsningsmiddel, f.eks. en lavere mettet dialkyleter, dialkylglykoleter eller cyklisk eter, som dietyleter, etyl-tert-butyleter, .1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et aromatisk hydrokarbon, som benzen eller et alkylbenzen, som toluen eller xylen, eller et mettet alifatisk hydrokarbon, som heksan, heptan eller isooktan, et lavere alifatisk keton, som aceton, metyletylketon eller metylisobutylketon, et dialkylformamid, som dimetyl eller dietylformamid, eller i blandinger av de nevnte løsningsmidler. Fortrinnsvis benyttes lineære- eller cykliske etere, så som dietyleter eller tetrahydrofuran, samt spesielt dimetylformamid, hvorved omsetningen vanligvis foregår ved en temperatur på opptil 30°C. These reactions can be carried out in the presence of a diluent or solvent, e.g. a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, ethyl tert-butyl ether, .1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon, such as benzene or an alkylbenzene, such as toluene or xylene, or a saturated aliphatic hydrocarbon , such as hexane, heptane or isooctane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide, such as dimethyl or diethylformamide, or in mixtures of the aforementioned solvents. Preferably, linear or cyclic ethers are used, such as diethyl ether or tetrahydrofuran, and especially dimethylformamide, whereby the reaction usually takes place at a temperature of up to 30°C.

Vanligvis foretas omsetningen i nærvær av en base som syrebindende middel. Egnede baser er alkalimetallkarbonater, -hydrogenkarbonater, spesielt natrium- og kaliumforbindelsene, organiske tertiære baser som pyridin eller lavere trialkyl-.aminer som trimetyl- eller trietylamin. Herunder benyttes den anvendte base i støkiometriske mengder, eller i et lite overskudd, i forhold til det brukte benzosyrehalogenid. Usually, the reaction is carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, hydrogen carbonates, especially the sodium and potassium compounds, organic tertiary bases such as pyridine or lower trialkylamines such as trimethyl or triethylamine. Below, the base used is used in stoichiometric quantities, or in a small excess, in relation to the benzoic acid halide used.

En annen fremstillingsmulighet for syrederivatene i henhold til oppfinnelsen tar utgangspunkt i de tilsvarende frie syrer I (R 5= COOH), idet disse omsettes i nærvær av et vannavspaltende middel som aktiverer karboksylgruppen, med en C^_^~alkohol, p-aminofenol eller tetrazolamin i et løsningsmiddel. Another manufacturing option for the acid derivatives according to the invention is based on the corresponding free acids I (R 5 = COOH), as these are reacted in the presence of a water-releasing agent that activates the carboxyl group, with a C^_^~alcohol, p-aminophenol or tetrazolamine in a solvent.

Som vannavspaltende aktiverende reagens kan vanlige reagenser som benyttes ved peptidsyntese, benyttes (sml. "The Peptides", bd. I, Academic Press, N. Y., 1965, s. 77-128). Det generelle prinsipp ved omsetningen består i aktivering av karboksylgruppen, f.eks. ved behandling med et karbodiimid, så som N,N'-dicykloheksylkarbodiimid, eller ved intermediær dannelse av syreazidet, et blandet anhydrid (f.eks. med karbonsyremonoesteren), en aktivert ester (f.eks. p-nitrofenyl-ester) eller et heterocyklisk amid (f.eks. et imidazolid) av den tilsvarende benzosyre. As water-splitting activating reagent, common reagents used in peptide synthesis can be used (cf. "The Peptides", vol. I, Academic Press, N.Y., 1965, pp. 77-128). The general principle of the turnover consists in activation of the carboxyl group, e.g. by treatment with a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by intermediate formation of the acid azide, a mixed anhydride (e.g. with the carboxylic acid monoester), an activated ester (e.g. p-nitrophenyl ester) or a heterocyclic amide (eg, an imidazolide) of the corresponding benzoic acid.

Behandlingen av en forbindelse med aktivert karboksylgruppe med en _3~alkohol, p-aminofenol eller tetrazolin, fører deretter til et syrederivat i henhold til oppfinnelsen. Aktiverings- og koblingsreaksjonene kan foretas i løsnings-midler, fortrinnsvis i N,N-dimetylformamid, tetrahydrofuran, dioksan, metylenklorid, nitrometan, acetonitril, dimetylsulfoksyd, N,N-dimetylacetamid og heksametylfosforsyretriamid. En egnet temperatur for begge trinn, dvs. omsetningen av syren med koblingsmidlet og reaksjonen av det aktiverte mellomprodukt med p-aminofenol, ligger i området 20 til 100°C. Reaksjonen kan herunder foretas trinnvis ved at det aktiverte mellomprodukt isoleres før tilsetningen av p-aminofenolet, eller mer fordelaktig, ved å bringe reaksjonspartnerne til The treatment of a compound with an activated carboxyl group with a 3-alcohol, p-aminophenol or tetrazoline then leads to an acid derivative according to the invention. The activation and coupling reactions can be carried out in solvents, preferably in N,N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide and hexamethylphosphoric acid triamide. A suitable temperature for both steps, i.e. the reaction of the acid with the coupling agent and the reaction of the activated intermediate with p-aminophenol, is in the range 20 to 100°C. The reaction can below be carried out step by step by isolating the activated intermediate before the addition of the p-aminophenol, or more advantageously, by bringing the reaction partners to

reaksjon etter hverandre uten isolering av mellomtrinn.reaction one after the other without isolation of intermediate steps.

I henhold til en foretrukket koblingsmetode benyttes N,N-karbonyldiimidazol med dimetylformamid som løsnings-middel, hvorunder reaksjonstemperaturen for begge trinn ligger i området 20 til 60°C. According to a preferred coupling method, N,N-carbonyldiimidazole is used with dimethylformamide as solvent, during which the reaction temperature for both steps is in the range 20 to 60°C.

Forbindelsene med formel I kan ha en enhetlig cis-The compounds of formula I may have a uniform cis-

eller trans-struktur, eller utgjøre en blanding av cis-trans-isomerene. Blandingen kan bestemmes kvantitativt ved HPLC-analyse eller gjennom.<1>3C-NMR spektroskopi og de respektive isomerer eventuelt isoleres i ren tilstand ved fraksjonert krystallisasjon eller kromatografi, f.eks. på kiselgelsøyler eller ved preparativ HPLC. or trans structure, or constitute a mixture of the cis-trans isomers. The mixture can be determined quantitatively by HPLC analysis or through <1>3C-NMR spectroscopy and the respective isomers possibly isolated in a pure state by fractional crystallization or chromatography, e.g. on silica gel columns or by preparative HPLC.

Forbindelsene og deres fysiologisk akseptable salter kan benyttes ved topisk og systemisk terapi og profylakse av benigne og maligne neoplasmer og premaligne lesjoner. The compounds and their physiologically acceptable salts can be used in topical and systemic therapy and prophylaxis of benign and malignant neoplasms and premalignant lesions.

Således kan de f.eks. benyttes ved precancrøse tilstander og carsinomer i hud, slimhinner og indre organer, og ved topisk og systemisk terapi av akne, psoriasis og andre dermatologiske lidelser som følge av patologisk forandret forhorning av hud, spesielt av betent eller degenerativ art, i ledd, muskler, sener og andre deler av bevegelsesapparatet. Et foretrukket indikasjonsområde ved siden av dermatologiske lidelser er den profylaktiske og terapeutiske behandling av precancrøse tilstander og tumorer. Deres lave toksisitet er herunder fordelaktig. Thus, they can e.g. used for precancerous conditions and carcinomas of the skin, mucous membranes and internal organs, and for topical and systemic therapy of acne, psoriasis and other dermatological disorders as a result of pathologically altered keratinization of the skin, especially of an inflamed or degenerative nature, in joints, muscles, tendons and other parts of the locomotor system. A preferred indication area next to dermatological disorders is the prophylactic and therapeutic treatment of precancerous conditions and tumors. Their low toxicity is also advantageous.

De farmakologiske virkninger kan eksempelvis påvises ved bruk av følgende testmodeller: 1. Påvisning av antitumorvirkning ved at keratiniseringen i trakealkulturer stanses: I denne forsøksmodell bestemmes forbindelsenes evne til å øke differensieringen av epitelceller. Denne screening-metode er alminnelig anerkjent på grunn av høy signifikans ved vurdering av hvorvidt nye retinoider kan ha potensiell anvendelse som middel til å hindre tumorer i epitelvev. Det er selvsagt kjent at ethvert in vitro test-system er beheftet med mangler når det gjelder å forutsi in vivo aktiviteten. Bortsett fra denne prinsipielle begrensning, utgjør systemet med trakeal- cellekulturer en av de mest verdifulle metoder for å fastslå den biologiske aktivitet av nye retinoider. The pharmacological effects can, for example, be demonstrated using the following test models: 1. Demonstration of anti-tumour effect by stopping the keratinization in tracheal cultures: In this experimental model, the ability of the compounds to increase the differentiation of epithelial cells is determined. This screening method is generally recognized because of its high significance when assessing whether new retinoids may have potential application as a means of preventing tumors in epithelial tissue. It is of course known that any in vitro test system is subject to shortcomings when it comes to predicting the in vivo activity. Apart from this fundamental limitation, the tracheal cell culture system constitutes one of the most valuable methods for determining the biological activity of new retinoids.

I undersøkelsen bestemmes testsubstansenes evne til å oppheve keratiniseringen i et definert in vitro system. Trakeer fra hamstere som befinner seg i en meget tidlig tilstand av vitamin A-mangel, benyttes i kulturen. Ved tidspunktet for trakea-uttaket var dyrene 29 til 30 dager gamle (de var avvennet etter 21 dager) og de oppviste fremdeles en vektøkning. Deres gjennomsnittsvekt utgjorde 4 7 til 52 g. Trakeaepitelet var i alminnelighet et svakt In the investigation, the ability of the test substances to cancel keratinization is determined in a defined in vitro system. Tracheae from hamsters in a very early state of vitamin A deficiency are used in the culture. At the time of tracheal sampling, the animals were 29 to 30 days old (they were weaned after 21 days) and were still gaining weight. Their average weight was 4 7 to 52 g. The tracheal epithelium was generally a weak

sylinder- eller plateepitel med skjellede metaplasier columnar or squamous epithelium with squamous metaplasia

bare på enkelte steder. Hver trakea ble åpnet langs den membranaktige dorsalvegg fra strupehodet til carina, og benyttet i et serumfritt kulturmedium (CMRL-1066 supplert only in certain places. Each trachea was opened along the membranous dorsal wall from the larynx to the carina, and used in a serum-free culture medium (CMRL-1066 supplemented

med krystallinsk storfeinsulin, 1,0^ug/ml, hydrocortison-hemisuccinat, 0,1^ug/ml; glutamin 2 mmolar; penicilllin, 100 enheter/ml og streptomycin, 100 ^,ug/ml) . Hver kultur ble behandlet med en gassblanding av 50% oksygen, 4 5% with crystalline bovine insulin, 1.0 µg/ml, hydrocortisone hemisuccinate, 0.1 µg/ml; glutamine 2 mmolar; penicillin, 100 units/ml and streptomycin, 100 µg/ml). Each culture was treated with a gas mixture of 50% oxygen, 4 5%

nitrogen og 5% karbondioksyd. Kulturskålene ble forsiktig omdreid for å bringe trakeer i kontakt med gass og kulturmediet. Alle trakeer ble først holdt 3 dager uten retinoid-tilsetning i kulturmediet. Etter 3 dager ble noen trakeer tatt ut. De oppviste nesten alle tydelige skjellede nitrogen and 5% carbon dioxide. The culture dishes were gently inverted to bring tracheae into contact with gas and the culture medium. All tracheas were initially kept for 3 days without retinoid addition in the culture medium. After 3 days some tracheas were taken out. They almost all showed clear scales

metaplasier. De øvrige trakeer ble inndelt i grupper som metaplasias. The other tracheas were divided into groups such as

ble behandlet med følgende tilsetninger:was treated with the following additives:

a) Testsubstans løst i spektroskopisk ren dimetylsulfoksyd, hvor den endelige dimetylsulfoksyd i kulturmediet aldri a) Test substance dissolved in spectroscopically pure dimethylsulfoxide, where the final dimethylsulfoxide in the culture medium never

var større enn 0,i%.was greater than 0.i%.

b) Den ekvivalente mengde dimetylsulfoksyd uten ytterligere tilsetninger.. b) The equivalent amount of dimethyl sulphoxide without further additions..

Næringsmediet ble skiftet 3 ganger ukentlig. Alle gjenværende trakeer ble opparbeidet etter 10 dager i kultur. De ble fiksert i 10% buffret formaldehydløsning og innsmeltet i parafin. Snitt på 5^um gjennom sentrum ble farget med heksatoksylin og eosin og undersøkt under mikroskop på nærvær av keratin og keratohyalin. Begge deler ble observert i ca. 90% av alle kontrollkulturer uten testsubstans. Dose-virkningskurve for forbindelsene i The nutrient medium was changed 3 times weekly. All remaining tracheas were recovered after 10 days in culture. They were fixed in 10% buffered formaldehyde solution and embedded in paraffin. Sections of 5 µm through the center were stained with hexatoxylin and eosin and examined under the microscope for the presence of keratin and keratohyalin. Both parts were observed for approx. 90% of all control cultures without test substance. Dose-effect curve for the compounds i

henhold til oppfinnelsen ble satt opp. Den etterfølgende according to the invention was set up. The following one

tabell 1 inneholder ekstrapolerte molare doser som stanser keratiniseringen i halvparten av kulturene (ED 50%) . table 1 contains extrapolated molar doses that stop keratinization in half of the cultures (ED 50%).

Dessuten induserer forbindelsene (spesielt forbindelsen fra eksempel 2) celledifferensieringen til utvokste granulocytter i leukemiceller hos pasienter med promyelo-cytisk leukemi. 2. Den antiartritiske virkning av forbindelsene kan bestemmes på vanlig måte i dyreforsøk i adjuvans-artritis-modell. 3. Den dermatologiske virkning, eksempelvis ved behandling av akne, kan bl.a. påvises gjennom den comedolytiske aktivitet. Moreover, the compounds (especially the compound from example 2) induce the cell differentiation into mature granulocytes in leukemia cells of patients with promyelocytic leukemia. 2. The antiarthritic effect of the compounds can be determined in the usual way in animal experiments in the adjuvant arthritis model. 3. The dermatological effect, for example in the treatment of acne, can i.a. is demonstrated through the comedolytic activity.

Dannelsen av comedoner ble indusert ved en enkeltThe formation of comedones was induced by a single

(R) (R)

topisk applikasjon (0,5 ml pr dag) av 5% tjære i Polyan (ester av lanolinalkohol og linolensyre, produsent: Amerchol Corp., U.S.A.) på begge ørene til albino-kaniner 5 påfølgende dager pr uke i 2 uker. Deretter fulgte den topical application (0.5 ml per day) of 5% tar in Polyan (ester of lanolin alcohol and linolenic acid, manufacturer: Amerchol Corp., U.S.A.) on both ears of albino rabbits 5 consecutive days per week for 2 weeks. Then it followed

topiske behandling med testsubstansen i etanol:propylenglykol (70:30; volumdeler; 0,5 ml) som ble påført på den indre hudflaten av kaninenes ene øre. Behandlingen ble foretatt daglig over 5 påfølgende dager pr uke i 2 uker. Dyrets ubehandlede øre tjente som kontroll. topical treatment with the test substance in ethanol:propylene glycol (70:30; parts by volume; 0.5 ml) which was applied to the inner skin surface of one ear of the rabbits. The treatment was carried out daily over 5 consecutive days per week for 2 weeks. The animal's untreated ear served as a control.

Etter den derpå følgende behandling (72 timer) med prøveforbindelsen, ble kaninene avlivet. En hudprøve på After the subsequent treatment (72 hours) with the test compound, the rabbits were euthanized. A skin test on

ca. 6 cm 2 fra hver øremuskel like utenfor hørselsgangen,about. 6 cm 2 from each ear muscle just outside the auditory canal,

2 2

ble fjernet og oppdelt i ca. 1 cm store skiver. Disse hudpartier ble dyppet i 2 minutter i 6 0°C varmt vann. Etter forsiktig avskrelling ved hjelp av den flate enden av en spatel og en liten pinsett, ble epidermis anbrakt på et objektglass med dermalsiden opp. Etter lufttørking over natten ble prøvestrimlene vurdert under stereo-mikroskopet. Follikulære partier med hornaktig materiale forblir intakt. Comedonene kan sees som separate ensartede, sylindriske eller runde horndeler som i størrelse og antall er proposjonal med aktiviteten av den undersøkte forbindelse. Den comedolytiske effekt ble bestemt som den prosentvise reduksjon av comedonantallet i forhold til kontroll-øret, sml. tabell 2. was removed and divided into approx. 1 cm slices. These skin parts were dipped for 2 minutes in 60°C warm water. After careful peeling using the flat end of a spatula and small tweezers, the epidermis was placed on a glass slide with the dermal side up. After air drying overnight, the sample strips were assessed under the stereo microscope. Follicular areas of horn-like material remain intact. The comedones can be seen as separate uniform, cylindrical or round horn parts which in size and number are proportional to the activity of the investigated compound. The comedolytic effect was determined as the percentage reduction of the comedone number in relation to the control ear, sml. table 2.

4. Som et annet mål på den dermatologiske virkning tjente påvisningen av forbindelsenes evne til å redusere antall utriculi i Rhino-mus. Denne metode er beskrevet av L.H. Kligman et al. i The Journal of Investigative Dermatology, 12_, 354-358 (1 979). Tilstedeværende cyster som forekommer som genetisk betingede hudlesjoner, såkalte akne-cyster, hos forsøksdyrene, blir herunder trengt tilbake av behandlingen med virkestoffet og uttrykt som %-reduksjon. 5. Testsubstansenes toleranse etter topisk applikasjon ble bestemt i forsøk hvor grupper på 6 hvite hannkaniner (New Zealand-rase) ble benyttet. På hvert forsøksdyr ble et ca. 6 cm 2 stort ryggparti barbert. Etter oppløsning av testsubstansen i etanol:propylenglykol (70:30 volumdeler), ble 0,2 ml applisert med en automatisk mikropipette 9 dager på rad. Herunder ble et bestemt område forsiktig 4. As another measure of the dermatological effect, the demonstration of the ability of the compounds to reduce the number of utriculi in Rhino mice served. This method is described by L.H. Kligman et al. in The Journal of Investigative Dermatology, 12_, 354-358 (1979). Present cysts that occur as genetically determined skin lesions, so-called acne cysts, in the experimental animals are reduced by the treatment with the active substance and expressed as a % reduction. 5. The tolerance of the test substances after topical application was determined in experiments where groups of 6 white male rabbits (New Zealand breed) were used. On each experimental animal, an approx. 6 cm 2 large back section shaved. After dissolving the test substance in ethanol:propylene glycol (70:30 parts by volume), 0.2 ml was applied with an automatic micropipette on 9 consecutive days. Below, a certain area became cautious

inngnidd 2 ganger daglig i intervaller på 6 timer. Morgenen før hver applikasjon ble testflatene subjektivt bedømt med henblikk på erytemer og skjell-dannelse. rubbed in 2 times a day at intervals of 6 hours. The morning before each application, the test surfaces were subjectively assessed for erythema and scaling.

Til bedømmelsen ble det benyttet en numerisk skala i trinn fra 0 til 3 (0 = ingen reaksjon, 1 = mild, 2 = middels, 3 = sterk). Middélverdien for erytemdannelse og skjell-dannelse tilkjennegir testsubstansens relative irritasjons-virkning sammenlignet med vitamin A-syre. For the assessment, a numerical scale was used in steps from 0 to 3 (0 = no reaction, 1 = mild, 2 = medium, 3 = strong). The mean value for erythema formation and scale formation indicates the relative irritation effect of the test substance compared to vitamin A acid.

Foreliggende oppfinnelse angår derfor også topisk og systemisk anvendelige terapeutiske midler som inneholder en forbindelse med formel (I) som virkestoff, ved siden av vanlige bærermaterialer og fortynnihgsmidler, samt bruken av en forbindelse med formel (I) til fremstilling av legemidler. The present invention therefore also relates to topically and systemically applicable therapeutic agents which contain a compound of formula (I) as active ingredient, alongside usual carrier materials and diluents, as well as the use of a compound of formula (I) for the manufacture of pharmaceuticals.

Fremstillingen av terapeutiske midler eller preparater foretas ved hjelp av de.'vanlige flytende eller faste bærer-stoffer eller fortynningsmidler, og farmasøytisk.-tekniske hjelpestoffer anvendt på vanlig måte og i overensstemmelse med den ønskede applikasjonsart og egnede dosering. The production of therapeutic agents or preparations is carried out using the usual liquid or solid carriers or diluents, and pharmaceutical technical aids used in the usual way and in accordance with the desired type of application and suitable dosage.

Midlene kan således gis peroralt, parenteralt eller topisk. Slike preparater kan eksempelvis være tabletter, film-tabletter, drasjeer, kapsler, piller, pulvere, løsninger eller suspensjoner, infusjons- eller injeksjonsløsninger, pastaer, salver, gel, kremer, lotions, puddere, løsninger eller emulsjoner og spray. The agents can thus be administered orally, parenterally or topically. Such preparations can be, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, infusion or injection solutions, pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays.

Ved lokal anvendelse benyttes preparatene i en. konsentrasjon på 0,001 til 1%, fortrinnsvis fra 0,001 til 0,1% virkestoff, For local application, the preparations are used in a concentration of 0.001 to 1%, preferably from 0.001 to 0.1% active substance,

og ved systemisk anvendelse fortrinnsvis som enkeltdose påand for systemic use preferably as a single dose on

0,1 til 50 mg som gis en eller flere ganger daglig, avhengig av sykdommens art og grad. 0.1 to 50 mg given one or more times a day, depending on the nature and degree of the disease.

Vanlig anvendte farmasøytiske tekniske hjelpestoffer er for eksempel alkoholer, som isopropanol, oksetylert ricinusolje eller oksetylert hydrert ricinusolje, polyakrylsyre, glyserinmonostearat, parafinolje, vaselin, ullfett, polyetylenglykol 400, polyetylenglykol 400-stearat og etoksylert fett-alkohol for lokal anvendelse, og melkesukker, propylenglykol og etanol, stivelse, talkum og polyvinylpyrrolidon for systemisk anvendelse. Preparatene kan eventuelt tilsettes antioksydasjons-midler, f.eks. tocoferol, butylert hydroksyanisol eller butylert hydroksytoluen,eller smaksforbedrende tilsetninger, stabiliseringsmidler, emulgeringsmidler, glattemidler osv. Commonly used pharmaceutical technical aids are, for example, alcohols, such as isopropanol, oxytylated castor oil or oxytylated hydrogenated castor oil, polyacrylic acid, glycerin monostearate, paraffin oil, vaseline, wool fat, polyethylene glycol 400, polyethylene glycol 400 stearate and ethoxylated fatty alcohol for local use, and milk sugar, propylene glycol and ethanol, starch, talc and polyvinylpyrrolidone for systemic use. Antioxidants can optionally be added to the preparations, e.g. tocopherol, butylated hydroxyanisole or butylated hydroxytoluene, or flavor-improving additives, stabilizers, emulsifiers, smoothing agents, etc.

Det er herunder en forutsetning at alle benyttede stoffer er toksisk ubetenkelige og er forlikelige med de anvendte virkestoffer. It is therefore a prerequisite that all substances used are toxicologically harmless and are compatible with the active substances used.

Eksempel 1 Example 1

(E)-4-[2-mety1-2-(1, 1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyreetylester (E)-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester

Til en suspensjon av 250 ml dimetylsulfoksyd og 9 g 80% natriumhydrid, som på forhånd var befridd for sin 20% andel av parafin ved hjelp av petroleter, ble i løpet av 0,5 timer tilsatt en løsning av 90 g p-karboksyetyl-benzyl-fosfonsyredietyl-ester i 150 ml DMSO ved 35°C. Blandingen ble deretter omrørt 2 timer til ved 40°C, og i løpet av 10 minutter dråpevis tilsatt To a suspension of 250 ml of dimethyl sulphoxide and 9 g of 80% sodium hydride, which had previously been freed of its 20% proportion of paraffin by means of petroleum ether, a solution of 90 g of p-carboxyethyl-benzyl was added over the course of 0.5 hours -phosphonic acid diethyl ester in 150 ml DMSO at 35°C. The mixture was then stirred for a further 2 hours at 40°C, and in the course of 10 minutes added dropwise

en løsning av 36,6 g 7-acetyl-1,1,4,4,6-pentametyltetralin ia solution of 36.6 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in

70 ml dimetylsulfoksyd.70 ml of dimethyl sulfoxide.

Etter henstand over natten ble blandingen tilsatt 100 ml etanol, og helt over i 2 liter is-vann og surgjort med 2N saltsyre. Det resulterende bunnfall ble frafiltrert, spylt på filteret med 150 ml etanol og vasket med 75 ml metanol. Det gjenværende utgjorde 35 g (E)-4-[2-mety1-2-(1,2,4,4,6-pentametyl-1 ,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyreetylestér, smp. 108 til 109°C. After standing overnight, the mixture was added with 100 ml of ethanol, and poured into 2 liters of ice-water and acidified with 2N hydrochloric acid. The resulting precipitate was filtered off, rinsed on the filter with 150 ml of ethanol and washed with 75 ml of methanol. The remainder was 35 g of (E)-4-[2-methyl-2-(1,2,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester , m.p. 108 to 109°C.

HPLC-analyse (Si 60, 5 ^um, 150 bar, n-heptan/eddiksyre-etylester (98:2), tD = 3,1 min.) viste at forbindelsen besto av mer enn 98% av en enkelt isomer. HPLC analysis (Si 60, 5 µm, 150 bar, n-heptane/acetic acid ethyl ester (98:2), tD = 3.1 min.) showed that the compound consisted of more than 98% of a single isomer.

1 3 1 3

C-NMR-spektrum (CDCl3, angivelser i ppm):C-NMR spectrum (CDCl3, values in ppm):

(Besiffringen av C-atomene er foretatt vilkårlig i forhold til tilordningen av NMR-signalene) (The numbering of the C atoms has been done arbitrarily in relation to the assignment of the NMR signals)

14,40 (C21); 19,74 (C2?); 20 ,35 (C2g); 31,96 (C25, C24 , C23, 14.40 (C21); 19.74 (C2?); 20.35 (C2g); 31.96 (C25, C24, C23,

C22); 34,02 (C1, C4>; 35,32 (C2, C3); 60,94 (C2Q); 126,11 (Cg);128,41 (C16, C12); 1 28 , 55 (C5); 1 29 ,00 (C^, C^); 1 29 ,68 (C15, C17); 131,72 (C6); 141,98 ( C^) ; 1 42,93 (C^l; 143,11 (C^); C22); 34.02 (C1, C4>; 35.32 (C2, C3); 60.94 (C2Q); 126.11 (Cg); 128.41 (C16, C12); 1 28 , 55 (C5); 1 29 .00 (C^, C^); 1 29 .68 (C15, C17); 131.72 (C6); 141.98 (C^) ; 1 42.93 (C^l; 143.11 (C ^);

143,83 (C9); 166,80 (C19); 143.83 (C9); 166.80 (C19);

Signalet ved 19,74 (C27) viser forbindelsens E-(trans-)-geometri. The signal at 19.74 (C27) shows the E-(trans-) geometry of the compound.

Eksempel 2Example 2

4,7 g (E)-4-[2-metyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-ylJ-vinyl]-benzosyreetylestér ble omrørt med 1,7 g 86% kaliumhydroksyd i en blanding av 100 ml etanol og 5 ml vann i 6 timer ved 80°C. Etter, overføring av hele reaksjonsblandingen i 1 liter vann, ble den surgjort med 2N saltsyre, hvorpå det oppnådde fargeløse bunnfall ble frafiltrert, og etter tørking på filtertrakten, vasket med 100 ml heptan. Etter tørkingen ble det igjen 4,0 g (E)-4-[2-mety1-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre, 4.7 g of (E)-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-ylJ-vinyl]-benzoic acid ethyl ester was stirred with 1.7 g of 86% potassium hydroxide in a mixture of 100 ml of ethanol and 5 ml of water for 6 hours at 80° C. After, transferring the entire reaction mixture into 1 liter of water, it was acidified with 2N hydrochloric acid, whereupon colorless precipitates were obtained was filtered off, and after drying on the filter funnel, washed with 100 ml of heptane. After drying, 4.0 g of (E)-4-[2-methyl-2-(1,1,4,4,6-pentamethyl- 1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid,

smp. 206°C.m.p. 206°C.

1 3 1 3

H-NMR-spektrum (dg-DMSO, angivelser i ppm):H-NMR spectrum (dg-DMSO, values in ppm):

(Besiffringen av C-atomene er foretatt vilkårlig i forhold til tilordningen av NMR-signalene) (The numbering of the C atoms has been done arbitrarily in relation to the assignment of the NMR signals)

19,36MC25); 20,17 (C24); 31,60 (^0' C21'<C>22'<C>23)<;>33,51 (C2, C3); 34,71 (C4, C^; 1 25 ,40 (Cg); 1 28 , 00 (C5, C12); 128,61 (<C>16); 1 28 ,95 ; 1 29 , 42 (C^, C18)<;>1 29,42 (C15, C^) ; 131,12 (C6); 141,20 (C13); 141,70 (C ?) ; 14 2,16 (C1Q); 142,52 (C11) ; 1 43 , 08 (C9) ; 1 67 , 26 (C19) . 19.36MC25); 20.17 (C24); 31.60 (^0' C21'<C>22'<C>23)<;>33.51 (C2, C3); 34.71 (C4, C^; 1 25 .40 (Cg); 1 28 . 00 (C5, C12); 128.61 (<C>16); 1 28 .95 ; 1 29 . 42 (C^, C18)<;>1 29.42 (C15, C^) ; 131.12 (C6); 141.20 (C13); 141.70 (C ?) ; 14 2.16 (C1Q); 142.52 ( C11) ; 1 43 , 08 (C9) ; 1 67 , 26 (C19) .

Signalet ved 19,36 (C25> viser forbindelsens E-(trans-)-geometri. The signal at 19.36 (C25>) shows the E-(trans-) geometry of the compound.

Eksempel 3 • Example 3 •

A. Fremstilling av utgangsmaterialetA. Preparation of the starting material

Av 9 g 80% natriumhydrid, som først var befridd for sin parafinandel på 20% ved hjelp av petroleter, ble det fremstillet en suspensjon i 100 ml dimetylsulfoksyd, som i løpet av 0,5 timer, ved ca. 35°C, dråpevis ble tilsatt en løsning av 75,9 g p-cyanobenzylfosfonsyredietylester i 150 ml dimetylsulfoksyd. Blandingen ble omrørt i ytterligere 2 timer ved 40°C, og i løpet av 10 minutter dråpevis tilsatt en løsning av 53,5 g 7-acetyl-1,1,4,4,6-pentametyltetralin i 50 ml dimetylsulfoksyd. Den neste dag ble reaksjonsblandingen helt over i 3 liter is-vann, og surgjort med 2N saltsyre. Det oppnådde faststoff ble frafiltrert og vasket med 75 ml metanol på filteret. Etter tørking ble det tilbake 30,2 g (E)-4-[2-mety1-2-(1,1,4,4,6-pentaetyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzonitril, From 9 g of 80% sodium hydride, which was first freed of its 20% paraffin content using petroleum ether, a suspension was prepared in 100 ml of dimethylsulfoxide, which in the course of 0.5 hours, at approx. 35°C, a solution of 75.9 g of p-cyanobenzylphosphonic acid diethyl ester in 150 ml of dimethylsulfoxide was added dropwise. The mixture was stirred for a further 2 hours at 40°C, and during 10 minutes a solution of 53.5 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in 50 ml of dimethylsulfoxide was added dropwise. The next day, the reaction mixture was poured into 3 liters of ice water and acidified with 2N hydrochloric acid. The solid obtained was filtered off and washed with 75 ml of methanol on the filter. After drying, 30.2 g of (E)-4-[2-methyl-2-(1,1,4,4,6-pentaethyl-1,2,3,4-tetrahydronaphth-7-yl)- vinyl]-benzonitrile,

smp. 140 til 141°C.m.p. 140 to 141°C.

HPLC-analysen (Si 60, 5^um, 150 bar, 25 cm søyle, n-heptan/eddiksyreetylester (97:3), t K = 3,2 min) viste en isomer-renhet på mer enn 95%. The HPLC analysis (Si 60, 5 µm, 150 bar, 25 cm column, n-heptane/ethyl acetate (97:3), t K = 3.2 min) showed an isomer purity of more than 95%.

B. Fremstilling av sluttproduktet.B. Manufacture of the final product.

13,5 g (E)-4-[2-méty1-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzonitril ble oppvarmet i 3 timer til kokepunktet i en blanding av 200 ml etanol og 200 ml 10N natronlut. Etter avkjølingen ble blandingen helt over i 1 liter vann, hvorpå det fargeløse bunnfall, som ble suget av, etter tørking utgjorde 14,9 g (E)-4-[2-metyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre, 13.5 g of (E)-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzonitrile were heated for 3 hours to the boiling point in a mixture of 200 ml of ethanol and 200 ml of 10N caustic soda. After cooling, the mixture was poured into 1 liter of water, whereupon the colorless precipitate, which was sucked off, after drying amounted to 14.9 g of (E)-4-[2-methyl-2-(1,1,4,4, 6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid,

smp. 204 til 206°C sml. eksempel 2.m.p. 204 to 206°C m.p. example 2.

Forbindelsene som er angitt i den etterfølgende tabell, ble fremstillet ved en Wittig-Horner-reaksjon eller ved forsåpning av de korresponderende estere eller nitriler. The compounds indicated in the following table were prepared by a Wittig-Horner reaction or by saponification of the corresponding esters or nitriles.

Eksempel 17 Example 17

I en løsning av 4,0 g (E)-4-[2-metyl-2-(1,1,4,4,6-pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre i 300 ml etanol ble det ved reaksjonsblandingens kokepunkt ledet inn gassformig hydrogenklorid inntil metning. Blandingen ble deretter holdt i ytterligere 4 timer ved kokepunktet, og etter avkjøling spylt med nitrogen. Etter inndampning ble reaksjonsblandingen utgnidd med 30 ml metanol, frafiltrert og tørket. Det ble derved oppnådd 3,6 g (E)-4-[2-metyl-2-(1 ,1,4,4,6 -pentametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]— benzosyreetylestér, smp. 109 til 110°C sml. eksempel 1. In a solution of 4.0 g of (E)-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl ]-benzoic acid in 300 ml of ethanol, at the boiling point of the reaction mixture, gaseous hydrogen chloride was introduced until saturation. The mixture was then kept for a further 4 hours at the boiling point and, after cooling, flushed with nitrogen. After evaporation, the reaction mixture was triturated with 30 ml of methanol, filtered off and dried. 3.6 g of (E)-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl were thereby obtained ]— benzoic acid ethyl ester, m.p. 109 to 110°C m.p. example 1.

Eksempel 18Example 18

Til en suspensjon av 20,9 g (E)-4-[2-mety1-2-(1,1,4,4,-tetrametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre (sml. eksempel 2) og 5,8 ml pyridin i 200 ml vannfri tetra-hydrof uran, ble en løsning av 5,3 ml tionylklorid i 10 ml tetrahydrofuran raskt tilsatt. Etter omrøring i 2 timer ved romtemperatur, ble det resulterende bunnfall frafiltrert og filtratet fylt opp med tetrahydrofuran til et totalvolum på 240 ml. To a suspension of 20.9 g of (E)-4-[2-methyl-2-(1,1,4,4,-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl] -benzoic acid (cf. Example 2) and 5.8 ml of pyridine in 200 ml of anhydrous tetrahydrofuran, a solution of 5.3 ml of thionyl chloride in 10 ml of tetrahydrofuran was quickly added. After stirring for 2 hours at room temperature, the resulting precipitate was filtered off and the filtrate made up with tetrahydrofuran to a total volume of 240 ml.

100 ml av denne løsning ble litt etter litt, i løpet av 10 minutter, tilsatt til en suspensjon av 8,2 g p-aminofenol i 100 ml tetrahydrofuran. Deretter ble blandingen omrørt i 100 ml of this solution was added little by little, over 10 minutes, to a suspension of 8.2 g of p-aminophenol in 100 ml of tetrahydrofuran. The mixture was then stirred in

20 timer ved romtemperatur. Reaksjonsblandingen ble rørt inn20 hours at room temperature. The reaction mixture was stirred

i 1 liter vann, surgjort med 2N saltsyre, hvorpå det resulterende bunnfall ble frafiltrert og omkrystallisert fra etanol under tilsetning av vann. in 1 liter of water, acidified with 2N hydrochloric acid, after which the resulting precipitate was filtered off and recrystallized from ethanol with the addition of water.

Etter frafiltrering og tørking ble det igjen 11,1 g (E)-4-[2-mety1-2-(1,1,4,4-tetramety1-1,2,3,4-tetrahydronaft-7-yl)-vinyl]-benzosyre-(4-hydroksyanilid), smp. 252 til 253°C. After filtering off and drying, 11.1 g of (E)-4-[2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)- vinyl]-benzoic acid-(4-hydroxyanilide), m.p. 252 to 253°C.

1 3 1 3

C-NMR-spektrum (dg -DMSO)C-NMR spectrum (dg-DMSO)

Resonanssignalet ved 17,30 ppm for metylgruppen ved karbonatom nr. 2 i etylengruppen viser at den oppnådde forbindelse er E-(trans-)-isomeren. The resonance signal at 17.30 ppm for the methyl group at carbon atom no. 2 in the ethylene group shows that the compound obtained is the E-(trans-) isomer.

Eksempel 19 til 21 Examples 19 to 21

Forbindelsene oppført i den etterfølgende tabell ble fremstillet analogt med eksempel 18. The compounds listed in the following table were prepared analogously to Example 18.

Eksempel 24 Example 24

Til en suspensjon av 1,8 g (E)-4- 2-metyl-2-(1,1,4,4-tetrametyl-1,2,3,4-tetrahydronaft-7-yl)-vinyl -bensosyre To a suspension of 1.8 g of (E)-4-2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl-benzoic acid

(sml. eksempel 2), og 0,5 ml pyridin i 15 ml tetrahydrofuran ble hurtig tilsatt en løsning av 0,5 ml tionylklorid i 5 ml tetrahydrofuran. Etter 2 timers omrøring ved romtemperatur ble det resulterende bunnfall frafiltrert, filtratet tilsatt til en suspensjon av 0,5 g vannfri 5-aminotetrazol og 0,5 g pyridin i 20 ml tetrahydrofuran og deretter omrørt i ytterligere 20 timer ved romtemperatur. Reaksjonsblandingen ble rørt inn i 400 ml vann, surgjort med 2N saltsyre, hvorpå det utfelte bunnfall ble frafiltrert og vasket med metanol og petroleter. Det ble herved oppnådd 1,7 g (E)-4-[2-metyl-2-(1,1,4,4-tetra-mety 1-1,2,3,4-tetrahydronaft-7-yl)-vinyl] -N-(tetrazol-5-yl)-benzosyreamid. Smp. 289-290°C. (cf. example 2), and 0.5 ml of pyridine in 15 ml of tetrahydrofuran was quickly added to a solution of 0.5 ml of thionyl chloride in 5 ml of tetrahydrofuran. After stirring for 2 hours at room temperature, the resulting precipitate was filtered off, the filtrate added to a suspension of 0.5 g of anhydrous 5-aminotetrazole and 0.5 g of pyridine in 20 ml of tetrahydrofuran and then stirred for a further 20 hours at room temperature. The reaction mixture was stirred into 400 ml of water, acidified with 2N hydrochloric acid, after which the precipitate that had formed was filtered off and washed with methanol and petroleum ether. 1.7 g of (E)-4-[2-methyl-2-(1,1,4,4-tetramethyl 1-1,2,3,4-tetrahydronaphth-7-yl)- vinyl] -N-(tetrazol-5-yl)-benzoic acid amide. Temp. 289-290°C.

C-NMR-spektrum (dg-DMSO)C-NMR spectrum (dg-DMSO)

Resonanssignalet ved 17,41 ppm for metylgruppen ved karbonatom nr. 2 i etylengruppen viser at den oppnådde forbindelse er E-(trans-)-isomeren. The resonance signal at 17.41 ppm for the methyl group at carbon atom no. 2 in the ethylene group shows that the compound obtained is the E-(trans-) isomer.

Eksempel 25 til 29Examples 25 to 29

Forbindelsene oppført i den etterfølgende tabell ble fremstillet analogt med eksempel 1. The compounds listed in the following table were prepared analogously to example 1.

Claims (5)

1. Fremgangsmåte for fremstilling av fenyletylenderivater med formel: 1. Process for the production of phenylethylene derivatives with formula: hvor A er en alkylenrest som eventuelt er substituert med en C1_4~alkylgruppe, R1 er et hydrogenatom eller en metylgruppe, R <2> er et hydrogenatom eller en metylgruppe, R 3 er et hydrogenatom eller en C1_„-alkylgruppe, R er en C._ .-alkylgruppe og R 5 er en p-hydroksyfenylenaminokarbonyl- eller tetrazol-5-yl- aminokarbonylgruppe. eller, dersom R 3 betyr en C^ _g-alkylgruppe, en karboksyl- eller C^.^ -karbalkoksygruppe, og eventuelt deres salter med fysiologisk akseptable baser, karakterisert ved ata) en forbindelse med formel II: where A is an alkylene residue which is optionally substituted with a C1_4~alkyl group, R1 is a hydrogen atom or a methyl group, R <2> is a hydrogen atom or a methyl group, R 3 is a hydrogen atom or a C1_„-alkyl group, R is a C 1-6 alkyl group and R 5 is a p-hydroxyphenyleneaminocarbonyl- or tetrazol-5-yl- aminocarbonyl group. or, if R 3 means a C 1 -g alkyl group, a carboxyl or C 1 -carbaloxy group, and optionally their salts with physiologically acceptable bases, characterized by ata) a compound of formula II: 14 hvor A og R til R har de ovenfor angitte betydninger, omsettes etter V/ittig-Horner med en fosforforbindelse med formel III 14 where A and R to R have the meanings given above, are reacted according to V/ittig-Horner with a phosphorus compound with formula III hvor R har den betydning som er angitt for R , eller står for-en cyanogruppe, og R 7utgjør en C^ _^ -alkylgruppe, ellerb) et fosfoniumsalt med formel IV: where R has the meaning given for R, or stands for a cyano group, and R 7 represents a C 1 -alkyl group, orb) a phosphonium salt of formula IV: 12 3 4 hvor A, R , R , R og R har de ovenfor angitte betydninger og X betyr klor eller brom, omsettes etter Wittig med et benzaldehyd-derivat med formel V: 12 3 4 where A, R , R , R and R have the above-mentioned meanings and X means chlorine or bromine, converted according to Wittig with a benzaldehyde derivative of formula V: hvor R 6 har den ovenfor angitte betydning, hvoretter, dersom R ikke utgjør en karboksylgruppe, den oppnådde forbindelse eventuelt forsåpes og den derved, eller direkte, oppnådde fri syre deretter eventuelt omsettes med en C^ _^~ alkohol, p-hydroksyanilin eller 5-aminotetrazol og de derved oppnådde forbindelser eventuelt overfø res i deres salter med fysiologisk akseptable baser.where R 6 has the meaning given above, after which, if R does not constitute a carboxyl group, the compound obtained is optionally saponified and the free acid obtained thereby, or directly, is then optionally reacted with a C^_^~ alcohol, p-hydroxyaniline or 5 -aminotetrazole and the compounds thus obtained are optionally transferred in their salts with physiologically acceptable bases. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at det fremstilles fenyletylenderivater med formel I eller salter av disse med fysiologisk akseptable.syrer, hvor A er en etylenrest,2. Process as stated in claim 1, characterized in that phenylethylene derivatives of formula I or salts thereof with physiologically acceptable acids are prepared, where A is an ethylene residue, 1 2 R og R er en metylgruppe,1 2 R and R are a methyl group, 3 R er en C. Q-alkylgruppe,3 R is a C. Q-alkyl group, 41 _a R er en metylgruppe og41 _a R is a methyl group and 5 R er en karboksyl- eller C2 _4 -karbalkoksygruppe.5 R is a carboxyl or C 2 -4 carboxy group.
NO830202A 1982-01-23 1983-01-21 PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLETHYLENE DERIVATIVES NO830202L (en)

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DE19823202065 DE3202065A1 (en) 1982-01-23 1982-01-23 Substituted N-(5-tetrazolyl)benzamides, the preparation thereof and pharmaceutical compositions containing these
DE19823202100 DE3202100A1 (en) 1982-01-23 1982-01-23 SUBSTITUTED 4-HYDROXYANILIDES, ITS PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
DE19823202118 DE3202118A1 (en) 1982-01-23 1982-01-23 Substituted vinylbenzoic acid derivatives, their preparation and pharmaceutical compositions containing them

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EP0155940A1 (en) * 1983-08-08 1985-10-02 Sri International Benzonorbornenyl, benzopyranyl and benzothiopyranyl retinoic acid analogues
FR2562539B1 (en) * 1984-04-06 1987-04-17 Chauvin Blache Lab NOVEL VINYL-4 BENZOIC ACID DERIVATIVES, PREPARATION METHOD THEREOF AND THERAPEUTIC APPLICATIONS THEREOF AND AS LIGANDS
DE3434944A1 (en) * 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen L-SUBSTITUTED TETRALIN DERIVATIVES, THEIR PRODUCTION AND USE
DE3434946A1 (en) 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen DIARYLACETYLENE, THEIR PRODUCTION AND USE
DE3434948A1 (en) * 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen VINYLTETRAZOLYLPHENYL DERIVATIVES, THEIR PRODUCTION AND USE
DE3434942A1 (en) * 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen TETRALINE DERIVATIVES, THEIR PRODUCTION AND USE
DE3602473A1 (en) * 1986-01-28 1987-07-30 Basf Ag VINYLPHENOL DERIVATIVES, THEIR PRODUCTION AND USE
ZW6587A1 (en) * 1986-05-13 1987-12-02 Hoffmann La Roche Tetrahydro naphthanline derivatives
ZW10287A1 (en) * 1986-07-15 1988-01-13 Hoffmann La Roche Tetrahydronaphthaline and indane derivatives
US5084476A (en) * 1986-07-15 1992-01-28 Hoffmann-La Roche Inc. Tetrahydronaphthalene and indane derivatives
CA1298309C (en) * 1987-11-06 1992-03-31 Michael Klaus Benzocycloheptene derivatives
US5221760A (en) * 1988-05-13 1993-06-22 Bayer Aktiengesellschaft Alkenoic acid derivatives
GB2218416A (en) * 1988-05-13 1989-11-15 Bayer Ag Leukotriene disease antagonists
DE3903993A1 (en) * 1989-02-10 1990-08-16 Basf Ag DIARYL SUBSTITUTED HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND MEDICINAL PRODUCTS THEREOF
US5206242A (en) * 1989-02-10 1993-04-27 Basf Aktiengesellschaft Diaryl-substituted pyrazole compounds and drugs and cosmetics obtained therefrom
US5194664A (en) * 1989-02-10 1993-03-16 Basf Aktiengesellschaft Aromatic keto compounds, the preparation thereof, and drugs and cosmetics containing these
DE3926148A1 (en) * 1989-08-08 1991-02-28 Basf Ag DIARYLACETYLENE, THEIR MANUFACTURE AND USE
FR2656608B1 (en) * 1989-12-28 1992-04-24 Roussel Uclaf NOVEL BENZOYLATED POLYAMINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS FUNGICIDES.

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