DK158457B - METHOD OF ANALOGUE FOR THE PREPARATION OF 3,7,11,15-TETRAMETHYL-2,4,6,10,14-HEXADECAPENTA ACID OR SALTS THEREOF - Google Patents

METHOD OF ANALOGUE FOR THE PREPARATION OF 3,7,11,15-TETRAMETHYL-2,4,6,10,14-HEXADECAPENTA ACID OR SALTS THEREOF Download PDF

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DK158457B
DK158457B DK155081A DK155081A DK158457B DK 158457 B DK158457 B DK 158457B DK 155081 A DK155081 A DK 155081A DK 155081 A DK155081 A DK 155081A DK 158457 B DK158457 B DK 158457B
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compound
general formula
give
tetramethyl
formula
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DK155081A
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DK158457C (en
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Isao Yamatsu
Osamu Tagaya
Yuichi Inai
Kouichi Suzuki
Shinya Abe
Kouichi Abe
Takeshi Suzuki
Kouji Yamada
Yoshikazu Suzuki
Nozomu Koyanagi
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Eisai Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds

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  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

DK 158457© iDK 158457 © i

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaen-syre med formlen IThe present invention relates to an analogous process for the preparation of the novel compound 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid of formula I

eller farmaceutisk acceptable salte heraf, der kan anvendes som anticancermiddel og terapeutisk middel til 10 behandling af hudsygdomme med keratinisering.or pharmaceutically acceptable salts thereof, which may be used as anticancer agent and therapeutic agent for treating skin diseases by keratinization.

W. Bollag, et al. rapporterede i Europ. J. Cancer, vol. 10, p. 731 (1974)., at retinoider såsom ethyl-9-(2,3,6-trimethyl-4-methoxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoat har anticancervirkning. Disse retinoide 15 forbindelser er imidlertid i høj grad toksiske og frembyder yderligere sådanne problemer som fremkaldelse af hypervitaminosis med hensyn til vitamin A, når de administreres.W. Bollag, et al. reported in Europe. J. Cancer, Vol. 10, p. 731 (1974), that retinoids such as ethyl 9- (2,3,6-trimethyl-4-methoxyphenyl) -3,7-dimethyl-2,4,6,8 -nonatetraenoate has anticancer effect. However, these retinoid compounds are highly toxic and further present such problems as inducing hypervitaminosis with vitamin A when administered.

Den ved fremgangsmåden ifølge opfindelsen til-20 vejebragte forbindelse med den ovenstående formel I udviser anticancervirkning, fremkalder i det væsentlige ikke nogen hypervitaminosis med hensyn til vitamin A og ligger lavt med hensyn til andre toksicitetsvirkninger.The compound of the present invention provided by the method of the invention exhibits anticancer activity, does not substantially cause hypervitaminosis with respect to vitamin A, and is low with respect to other toxic effects.

25 En udførelsesform A af fremgangsmåden ifølge op findelsen er ejendommelig ved, at man (1) omsætter en forbindelse med formlen II 1 2 3 4 5 6 11 2 og et Wittig-reagens afledt af en forbindelse med den 3An embodiment A of the method according to the invention is characterized in that (1) is reacted with a compound of formula II 1 2 3 4 5 6 11 2 and a Wittig reagent derived from a compound of the 3

almene formel IIIgeneral formula III

44

X - ch2 - CO^ IIIX - ch 2 - CO ^ III

5 hvori X betegner et halogenatom, og betegner en lave- 65 wherein X represents a halogen atom and represents a low 6

re alkylgruppe, til opnåelse af en forbindelse med den almene formel IValkyl group, to give a compound of the general formula IV

( DK 158457 B(DK 158457 B

22

CO^ IVCO ^ IV

hvori R^ har den ovennævnte betydning, og (2) hydrolyserer den således opnåede forbindelse med den almene formel IV i nærværelse af en base til 5 fremstilling af forbindelsen med formlen I.wherein R 1 is as defined above and (2) hydrolyses the compound thus obtained with the general formula IV in the presence of a base for preparing the compound of formula I.

Som eksempler på Wittig-reagenser, der kan anvendes i det ovenfor beskrevne trin (1) og er afledt af en forbindelse med den almene formel III, kan der nævnes phosphorforbindelser fremstillet ved omsætning mellem 10 forbindelsen med den almene formel III og triphenylphos-phin, phenyldialkoxyphosphin, trialkylphosphit eller lignende. Fremstillingen af reagenset og Wittig-reaktionen, ved hvilken reagenset anvendes, udføres ved hjælp af konventionelle fremgangsmåder, såsom den fremgangsmåde, 15 der er angivet af Wadworth, et al. i J. Am. Chem. Soc., vol. 83, p. 1733 (1961), den fremgangsmåde, der er angivet af Greenwald, et al. i J. Org. Chem., vol. 28, p.As examples of Wittig reagents which can be used in the above-described step (1) and are derived from a compound of the general formula III, there may be mentioned phosphorus compounds prepared by reacting the compound of the general formula III with triphenylphosphine, phenyldialkoxyphosphine, trialkylphosphite or the like. The preparation of the reagent and the Wittig reaction using the reagent is carried out by conventional methods such as the method described by Wadworth, et al. in J. Am. Chem. Soc., Vol. 83, p. 1733 (1961), the method set forth by Greenwald, et al. in J. Org. Chem., Vol. 28, p.

1128 (1963), og den fremgangsmåde, der er angivet af Horner, et al. i Ber. vol. 95, p. 581 (1962).1128 (1963), and the method set forth by Horner, et al. i Ber. Vol. 95, p. 581 (1962).

20 I det ovennævnte trin (2) udføres hydrolysen i nærværelse af en til hydrolyse af carboxylsyreestere almindeligt anvendt base, såsom natriumhydroxid og kaliumhydroxid.In the above step (2), the hydrolysis is carried out in the presence of a base commonly used for the hydrolysis of carboxylic acid esters such as sodium hydroxide and potassium hydroxide.

En anden udførelsesform B af fremgangsmåden ifølge 25 opfindelsen er ejendommelig ved, at manAnother embodiment B of the method according to the invention is characterized in that:

(1) omsætter en forbindelse med formlen V(1) reacting a compound of formula V

3030

og et Wittig-reagens afledt af en forbindelse med den almene formel VIand a Wittig reagent derived from a compound of general formula VI

35 xJvco^i hvori X betegner et halogenatom, og R1 betegner en lave-Wherein X represents a halogen atom and R

.. DK 158457 B.. DK 158457 B

3 re alkylgruppe, til opnåelse af en forbindelse med den almene formel IV, og (2) hydrolyserer den således opnåede forbindelse med den almene formel IV i nærværelse af en base til 5 fremstilling af forbindelsen med formlen I.3 alkyl group to give a compound of general formula IV and (2) hydrolyzes the thus obtained compound of general formula IV in the presence of a base for preparing the compound of formula I.

Hvert af de ovenfor beskrevne trin (1) og (2) kan udføres på samme måde som ved fremgangsmåde A.Each of the steps (1) and (2) described above can be performed in the same manner as in Method A.

En tredje udførelsesform C af fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man 10 (1) omsætter en forbindelse med den almene formelA third embodiment C of the process according to the invention is characterized in that a compound of the general formula 10 (1) is reacted.

VIIWE YOU

vii 15 hvori Y betegner en lavere alkylgruppe eller en arylgrup-pe, og en forbindelse med den almene formel VI til opnåelse af en forbindelse med den almene formel VIII 1 2 3 4 5 6vii 15 wherein Y represents a lower alkyl group or an aryl group and a compound of general formula VI to give a compound of general formula VIII 1 2 3 4 5 6

^ ^ ^ ^ ^ ^ V ^ 2 1 VIII^^^^^^ V ^ 2 1 VIII

2 hvori Y og har de ovennævnte betydninger, og 3 (2) underkaster den således opnåede forbindelse 4 med den almene formel VIII en desulfinering og ester 5 hydrolyse i nærværelse af en base til fremstilling af 6 forbindelsen med formlen I.2 wherein Y and have the above meanings, and 3 (2) the compound 4 thus obtained of the general formula VIII undergoes desulfination and ester 5 hydrolysis in the presence of a base to prepare the 6 compound of formula I.

Trinnet (1) udføres i nærværelse af en base. Som eksempler på baserne kan der nævnes n-butyllithium og phenyllithium. Som eksempler på ved omsætningen anvendte opløsningsmidler kan der nævnes tetrahydrofuran, diethyl-50 ether og 1,1-dimethoxyethan. Omsætningen udføres almindeligvis ved en lavere temperatur end stuetemperatur.The step (1) is performed in the presence of a base. Examples of the bases include n-butyllithium and phenyllithium. Examples of solvents used in the reaction include tetrahydrofuran, diethyl-50 ether and 1,1-dimethoxyethane. The reaction is usually carried out at a lower temperature than room temperature.

Trinnet (2) kan udføres på samme måde som trinnet (2) ved den ovennævnte fremgangsmåde A.The step (2) can be carried out in the same way as the step (2) by the above method A.

Som eksempler på de i de almene formler III, IV, 55 vi, VII og VIII optrædende substituenter kan der nævnes følgende: halogenatomer, såsom chlor, brom og iod for sub- kExamples of the substituents of general formulas III, IV, 55 vi, VII and VIII include the following: halogen atoms such as chlorine, bromine and iodine for sub

DK 158457BDK 158457B

4 fr'v stituenten X; lavere alkylgrupper, såsom methyl, ethyl og propyl for substituenten R^; og lavere alkylgrupper, såsom methyl, ethyl og propyl, og arylgrupper, såsom phenyl og p-tolyl, for substituenten Y.4 from the support X; lower alkyl groups such as methyl, ethyl and propyl for the substituent R and lower alkyl groups such as methyl, ethyl and propyl, and aryl groups such as phenyl and p-tolyl for the substituent Y.

5 Som eksempler på farmaceutisk acceptable salte af forbindelsen med formlen I kan der nævnes dens natriumsalt og dens kaliumsalt.Examples of pharmaceutically acceptable salts of the compound of formula I include its sodium salt and its potassium salt.

Den ved fremgangsmåden ifølge opfindelsen tilvejebragte forbindelse med den ovennævnte formel I udviser 10 også terapeutisk virkning med hensyn til behandling af hudsygdomme med keratinisering.The compound of the above formula I provided by the process of the invention also exhibits therapeutic efficacy in treating keratinization skin diseases.

Som eksempler på de hudsygdomme med keratinisering, der kan behandles med forbindelsen med formlen I, kan der nævnes hudsygdomme, der viser sådanne symptomer 15 som hyperkeratosis, parakeratosis og dyskeratosis. Mere konkret kan der som eksempler på hudsygdomme nævnes psoriasis, acne, acne vulgaris, Darier's sygdom, palmoplan-tar pustulosis, lichen planus, ichthyosis, erythroderma, pityriasis rubra pilaris og keratosis senilis.As examples of the keratinization skin diseases which can be treated with the compound of formula I, there may be mentioned skin diseases which show such symptoms as hyperkeratosis, parakeratosis and dyskeratosis. More specifically, examples of skin diseases include psoriasis, acne, acne vulgaris, Darier's disease, palmoplanar tar pustulosis, lichen planus, ichthyosis, erythroderma, pityriasis rubra pilaris and keratosis senilis.

20 Der anvendes præparater til udvortes brug af ste roidtypen til behandling af hudsygdomme med keratinisering. Disse præparater har imidlertid stærke bivirkninger, således at de ikke er anvendelige til gentagen administrering i et længere tidsrum og til behandling med 25 administrering af en stor mængde af præparatet.Preparations for topical use of the steroid type are used to treat skin diseases with keratinization. However, these compositions have strong side effects such that they are not useful for repeated administration for a prolonged period of time and for treatment with a large amount of the preparation.

I modsætning hertil har den omhandlede 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaensyre den virkning, at den hæmmer keratinisering af huden og udviser lav toksicitet.In contrast, the subject 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid has the effect of inhibiting keratinization of the skin and exhibiting low toxicity.

30 Resultaterne af farmakologiske prøver og toksici tetsprøver med den omhandlede forbindelse er anført nedenfor .The results of pharmacological tests and toxicity tests of the subject compound are given below.

Farmakologiske prøver (anticancervirkning) 35 (1) Forsøgsprocedure.Pharmacological tests (anticancer effect) 35 (1) Experimental procedure.

Mus (ICR, hunner, 60 dage gamle) barberedes i nak-2 ken (5 cm ). 7,12-Dimethylbenzo-[2]-anthracen opløstes i acetone til opnåelse af 75 mg/100 ml opløsning. Den såle-Mice (ICR, females, 60 days old) were shaved in the neck-2 ken (5 cm). 7,12-Dimethylbenzo [2] anthracene was dissolved in acetone to give 75 mg / 100 ml of solution. The sole

DK 158457BDK 158457B

5 des fremstillede opløsning påførtes på musene på den dag, hvor de var 60 dage gamle, og desuden på den dag, hvor de var 75 dage gamle, i en mængde på 0,2 ml pr. mus.December 5, the solution prepared was applied to the mice on the day when they were 60 days old, and in addition on the day when they were 75 days old, in an amount of 0.2 ml per day. mouse.

5 Crotonolie opløstes i acetone til opnåelse af 250 mg/100 ml opløsning, og den således fremstillede opløsning påførtes på musene i en mængde på 0,2 ml pr. mus 2 gange om ugen indtil påbegyndelsen af behandlingen. Når der var dannet 3-7 papillcmer (diameter på 3-8 mm for 10 hver, og totaldiameter på 30-60 mm) pr. mus, påbegyndtes behandlingen.Croton oil was dissolved in acetone to give 250 mg / 100 ml solution, and the solution thus prepared was applied to the mice at an amount of 0.2 ml per ml. mice twice a week until the start of treatment. When 3-7 papillae (3-8 mm diameter for 10 each and 30-60 mm total diameter) were formed per mice, treatment began.

Prøveforbindelsen opløstes i jordnødolie til opnåelse af 20 mg/ml opløsning og administreredes oralt til musene. Opløsningen administreredes 10 gange i 14 15 dage (1 gang omdagen), og diametrene af de dannede pa~ pillomer måltes på den 14. dag til bestemmelse af den totale diameter for hver mus.The test compound was dissolved in peanut oil to give 20 mg / ml solution and administered orally to the mice. The solution was administered 10 times for 14 days (once daily) and the diameters of the pills formed were measured on the 14th day to determine the total diameter of each mouse.

(2) Prøveforbindelse.(2) Sample connection.

3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapenta-20 ensyre (den omhandlede forbindelse).3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (the subject compound).

Ethyl-9-(2,3,6-trimethyl-4-methoxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoat (kontrolforbindelse).Ethyl 9- (2,3,6-trimethyl-4-methoxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoate (control compound).

(3) Resultaterne er anført i tabel 1.(3) The results are given in Table 1.

Tabel 1 25 Prøveforbindelse Antal Papilloma (total diameter/mus) mus Middel- Middel- Forøgelse elværdi værdi ler formind- ( 0'te dag) (14. dag) skelseTable 1 25 Sample Compound Number of Papilloma (Total Diameter / Mice) Mice Mean - Medium Increase Electricity Value or Decrease (Day 0) (Day 14)

Jordnødolie 30 alene 3 33,9 mm 39,7 mm + 17,1 %Peanut oil 30 alone 3 33.9 mm 39.7 mm + 17.1%

Omhandlet forbindelse 5 37,5 mm 21,3 mm - 43,2 % (200 mg/kg/dag)Compound 5 37.5 mm 21.3 mm - 43.2% (200 mg / kg / day)

Kontrolforbin- 35 delse (40 mg/kg/ 3 58,1 mm 32,7 mm - 43,7 % dag)Control compound (40 mg / kg / 3 58.1 mm 32.7 mm - 43.7% day)

Som det fremgår af ovenstående tabel 1, er den omhandlede forbindelse effektiv mod papillomer.As shown in Table 1 above, the subject compound is effective against papillomas.

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66

Farmakologiske prøver (hæmning af keratinisering) (1) Forsøgsprocedure.Pharmacological tests (keratinization inhibition) (1) Experimental procedure.

I en Petriskål (diameter 6 cm), hvori der var anbragt 8 dækglas (diameter 15 mm), hældtes der 5 ml af en 5 suspension af den variant af epithelceller fra rotteblæ-re, der betegnes BES 20B (ca. 2 x 10 celler/ml), og in-kuberingen udførtes ved 37°C i 24 timer og med en carbondioxidkoncentration på 5%. Hvert af de således behandlede dækglas anbragtes i 2 ml af Eagle's MEM medium 10 indeholdende prøveforbindelsen i forskellige koncentrationer, og derefter udførtes der en anden inkubering ved 37°C og ved en carbondioxidkoncentration på 5%. Mediet fornyedes med mellemrum på 2-3 dage. På den 2., 5., 8. og 14. dag regnet fra inkuberingens påbegyndelse blev 15 dækglassene taget op af mediet og underkastedes Papanicolaou's farveprøve til bestemmelse af keratiniseringsgra-den. Bestemmelsen udførtes ved måling af absorptionsspektret i området 400 til 750 nm, og Kl (keratiniseringsin- dex) beregnedes ud fra følgende ligning: 20 Absorptionstop i nærheden af 490 nm tilskrevet de KI _ keratiniserede celler_In a Petri dish (diameter 6 cm), in which 8 coverslips (diameter 15 mm) were placed, 5 ml of a 5 suspension of the variant of rat bladder epithelial cells designated BES 20B (about 2 x 10 cells) was poured. / ml) and the incubation was carried out at 37 ° C for 24 hours and with a carbon dioxide concentration of 5%. Each of the coverslips thus treated was placed in 2 ml of Eagle's MEM medium 10 containing the test compound at different concentrations, and then a second incubation was performed at 37 ° C and at a carbon dioxide concentration of 5%. The media is renewed every 2-3 days. On the 2nd, 5th, 8th and 14th day from the start of the incubation, the 15 coverslips were taken from the medium and subjected to Papanicolaou's swatch to determine the degree of keratinization. The determination was performed by measuring the absorption spectrum in the range of 400 to 750 nm, and K1 (keratinization index) was calculated from the following equation: Absorption peaks near 490 nm attributed to the K1 keratinized cells.

Absorptionstop i nærheden af 640 nm tilskrevet de ikke-keratiniserede celler.Absorption peaks near 640 nm attributed to the non-keratinized cells.

En KI-værdi på 1,0 eller højere angiver høj kera-25 tinisering, og en KI-værdi på 0,5 eller mindre angiver i det væsentlige ingen keratinisering.A KI value of 1.0 or higher indicates high keratinization, and a KI value of 0.5 or less indicates essentially no keratinization.

BES 2OB cellerne inkuberedes til sammenligning i et medium, der ikke indeholdt nogen af de omhandlede forbindelser.The BES 2OB cells were incubated for comparison in a medium containing none of the subject compounds.

30 (2) Prøveforbindelse.30 (2) Sample Connection.

3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapenta-ensyre (den omhandlede forbindelse).3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (the subject compound).

(3) Forsøgsresultater.(3) Experimental results.

Resultaterne er anført i tabel 2.The results are listed in Table 2.

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77

Tabel 2Table 2

KlKl

Inkuberingsperiode 2 dage 5 dage 8 dage 14 dage 5 Kontrol 0,43 1,10 3,27 3,08Incubation period 2 days 5 days 8 days 14 days 5 Control 0.43 1.10 3.27 3.08

Omhandlet forbindelse 0,1 yg/ml 0,43 0,67 0,55 0,52 1.0 yg/ml 0,42 0,46 0,38 0,39 5.0 yg/ml 0,48 0,50 - 0,22 10 Ved kontrolforsøget oversteg KI-værdien 1,0 på den 5. dag fra inkuberingens begyndelse, hvilket angiver høj keratinisering. I modsætning til resultatet ved kontrolforsøget viste de med forskellige koncentrationer af den omhandlede forbindelse opnåede resultater KI-værdier 15 på mindre end 1,0 ved alle forsøg, hvilket angivet hæmning af keratinisering.Compound 0.1 g / ml 0.43 0.67 0.55 0.52 1.0 g / ml 0.42 0.46 0.38 0.39 5.0 g / ml 0.48 0.50 - 0.22 In the control experiment, the KI value exceeded 1.0 on the 5th day from the start of the incubation, indicating high keratinization. Contrary to the results of the control experiment, the results obtained with different concentrations of the subject compound showed KI values 15 of less than 1.0 in all experiments, indicating inhibition of keratinization.

Toksicitetsprøver (1) Forsøgsprocedure.Toxicity tests (1) Test procedure.

Prøveforbindelsen administreredes gentagne gange 20 til en gruppe på 6 mus (ICR-stammen, hunner) i 14 dage.The test compound was repeatedly administered 20 to a group of 6 mice (ICR strain, females) for 14 days.

Den administrerede mængde var 40 mg/kg/dag, 200 mg/kg/ dag og 400 mg/kg/dag for den omhandlede forbindelse og 200 mg/kg/dag for kontrolforbindélsen. I løbet af administreringen observeredes forøgelser eller formindskel-25 ser i musenes vægt, indtræden af dødsfald osv.The amount administered was 40 mg / kg / day, 200 mg / kg / day and 400 mg / kg / day for the subject compound and 200 mg / kg / day for the control compound. During administration, increases or decreases in mouse weight, onset of deaths, etc. were observed.

(2) Prøveforbindelse.(2) Sample connection.

Der anvendtes de ved de farmakologiske prøver (anticancervirkning) anførte forbindelser.The compounds listed in the pharmacological tests (anticancer effect) were used.

(3) Forsøgsresultater.(3) Experimental results.

30 (a) Forøgelse og formindskelse af vægten.30 (a) Increase and decrease weight.

Resultaterne er anført i tabel 3.The results are listed in Table 3.

(b) Dødsfald.(b) Deaths.

Alle musene, der behandledes med kontrolforbindelsen i en mængde på 200 mg/kg/dag, døde på den 35 8. dag, og der observeredes ingen dødsfald hos de med den omhandlede forbindelse behandlede mus.All mice treated with the control compound in an amount of 200 mg / kg / day died on day 8, and no deaths were observed in the mice treated with the subject compound.

DK 158457 BDK 158457 B

8 (c) Håraffald.8 (c) Hair loss.

Der observeredes håraffald på den 6. dag hos hver mus, der var behandlet med kontrolforbindelsen i en mængde på 200 mg/kg/dag, og der observeredes intet 5 håraffald hos de med den omhandlede forbindelse behandlede mus.Hair loss was observed on the 6th day in each mouse treated with the control compound in an amount of 200 mg / kg / day and no 5 hair loss was observed in the mice treated with the subject compound.

(d) Cyanosis.(d) Cyanosis.

Der observeredes cyanosis på den 7. dag hos hver mus, der var behandlet med kontrolforbindelsen 10 i en mængde på 200 mg/kg/dag, og der observeredes ingen cyanosis hos de med den omhandlede forbindelse behandlede mus.Cyanosis was observed on the 7th day in each mouse treated with the control compound 10 in an amount of 200 mg / kg / day and no cyanosis was observed in the mice treated with the subject compound.

DK 158457BDK 158457B

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DK 158457BDK 158457B

1010

Hos individerne ved toksicitetsprøverne ved man/ at håraffaldet og vægtændringen angiver hypervitaminosis med hensyn til vitamin A. Da håraffald og vægtformindskelse observeredes i en fremtrædende høj grad hos den 5 med kontrolforbindelsen behandlede gruppe muS/ antages det, at der indtrådte hypervitaminosis med hensyn til vitamin A. I modsætning hertil observeredes der intet sådant problem hos den med den omhandlede forbindelse behandlede gruppe mus.In the individuals in the toxicity tests, the hair loss and weight change indicate hypervitaminosis with regard to vitamin A. Since hair loss and weight loss were observed to a high degree in the 5 group treated with the control compound, hypervitaminosis with regard to vitamin A occurred. In contrast, no such problem was observed in the group of mice treated with the compound in question.

10 I betragtning af de ovenfor beskrevne farmakolo giske forsøgsresultater og toksicitetsprøveresultater anses den omhandlede forbindelse for at være i høj grad risikofri og at være værdifuld som anticancermiddel og terapeutisk middel til behandling af hudsygdomme med 15 keratinisering.10 Considering the pharmacological test results and toxicity test results described above, the subject compound is considered to be highly risk-free and valuable as an anticancer and therapeutic agent for the treatment of skin diseases with keratinization.

Den omhandlede forbindelse kan derfor anvendes til forebyggelse og behandling af cancer og præcancerøse tilstande og kan desuden anvendes til behandling af hudsygdomme med keratinisering, såsom acne og psoriasis 20 vulgaris, og til behandling af allergiske og inflammatoriske hudsygdomme. Desuden kan den omhandlede forbindelse anvendes til behandling af mucosale sygdomme forårsaget af inflammation, degeneration og dysplastiske ændringer.Therefore, the subject compound can be used for the prevention and treatment of cancer and precancerous conditions and can also be used for the treatment of skin diseases with keratinization, such as acne and psoriasis 20 vulgaris, and for the treatment of allergic and inflammatory skin diseases. In addition, the subject compound can be used to treat mucosal diseases caused by inflammation, degeneration and dysplastic changes.

25 Til anvendelserne som anticancermiddel og tera peutisk middel til behandling af hudsygdomme med keratinisering administreres den omhandlede forbindelse oralt i form af pulvere, granulater, piller, hårde kapsler osv. , eller parenteralt i form af salver, stikpiller, 30 injektionsopløsninger osv. Doseringen er almindeligvis 40 mg til 4 g pr. dag for voksne. Hvis den omhandlede forbindelse anvendes i form åf et præparat til udvortes brug, kan doseringen varieres afhængig af sygdomsomstændighederne. Den omhandlede forbindelse kan kombineres 35 med en almindeligt anvendelig bærer til medicinsk anvendelse på konventionel måde til opnåelse af de ovenfor beskrevne præparater.For the applications as anticancer and therapeutic agents for treating skin diseases by keratinization, the subject compound is administered orally in the form of powders, granules, pills, hard capsules, etc., or parenterally in the form of ointments, suppositories, 30 injection solutions, etc. The dosage is generally 40 mg to 4 g per day for adults. If the subject compound is used in the form of a composition for topical use, the dosage may be varied depending on the conditions of the disease. The present compound may be combined with a commonly used carrier for medical use in a conventional manner to obtain the compositions described above.

Fremgangsmåderne til fremstilling af den omhand-The methods of preparing the present invention

DK 158457BDK 158457B

11 lede forbindelse belyses nærmere ved hjælp af de efterfølgende eksempler..11 lead connection is elucidated with the help of the following examples.

Eksempel 1Example 1

Til en suspension af 5/0 g 55%1 s natriumhydrid 5 (i olie) i 60 mg n-hexan sattes 28,6 g triethylphospho-noacetat. Blandingen opvarmedes derefter under tilbage-svaling, og 20 g 6,10,14-trimethyl-3,5,9,13-pentadeca-tetraen-2-on sattes dråbevis til blandingen under omrøring. Efter 30 minutters forløb hældtes reaktionsvæsken 10 ud i 200 ml vand, og derefter tilsattes der 500 mg n-hexan til ekstraktion. n-Hexanfasen fraskiltes, vaskedes med to 100 ml portioner af en blanding af methanol og vand (2:1) og koncentreredes. Det således opnåede koncentrat rensedes ved chromatografi på en silicagelkolon-15 ne til opnåelse af 18 g ethyl-3,7,ll,15-tetramethyl- 2.4.6.10.14- hexadecapentaenoat.To a suspension of 5/0 g of 55% 1s sodium hydride 5 (in oil) in 60 mg of n-hexane was added 28.6 g of triethylphosphonoacetate. The mixture was then heated under reflux and 20 g of 6,10,14-trimethyl-3,5,9,13-pentadeca-tetraen-2-one was added dropwise to the mixture with stirring. After 30 minutes, the reaction liquid 10 was poured into 200 ml of water and then 500 mg of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml portions of a mixture of methanol and water (2: 1) and concentrated. The concentrate thus obtained was purified by chromatography on a silica gel column to give 18 g of ethyl 3,7,11,15-tetramethyl hexadecapentaenoate 2.4.6.10.14.

Til 10 g af det ovenfor opnåede ethyl-3,7,11,15-tetramethy1-2,4,6,10,14-hexadecapentaenoat sattes der en opløsning af 3,9 g kaliumhydroxid i 30 ml isopropylal-20 kohol, og blandingen omrørtes ved 50°C i 1 time. Reaktionsvæsken hældtes derpå ud i isvand, syrnedes ved tilsætning af saltsyre og ekstraheredes med 100 ml ethyl-ether. Etherfasen vaskedes med vand, tørredes over magner-siumsulfat og koncentreredes til opnåelse af 9,0 g af en 25 olie. Olien opløstes i 50 ml n-hexan og krystalliseredes ved -20°C til opnåelse af 4,0 g 3,7,11,15-tetramethyl- 2.4.6.10.14- hexadecapentaensyre i form af lysegule nåle.To 10 g of the above-obtained ethyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate was added a solution of 3.9 g of potassium hydroxide in 30 ml of isopropyl alcohol and the mixture stirred at 50 ° C for 1 hour. The reaction liquid was then poured into ice water, acidified by the addition of hydrochloric acid and extracted with 100 ml of ethyl ether. The ether phase was washed with water, dried over magnesium sulfate and concentrated to give 9.0 g of an oil. The oil was dissolved in 50 ml of n-hexane and crystallized at -20 ° C to give 4.0 g of 3,7,11,15-tetramethyl-2.4.6.10.14-hexadecapentaenoic acid in the form of light yellow needles.

Smp.: 78,4°CMp: 78.4 ° C

Massespektrum (m/e): 302 (M ) 30 Infrarødt absorptionsspektrum (cm- , KBr-tablet): 3450, 2900, 1680, 1595 NMR-spektrum (6, CDC13) :1,61 (6H, s) , 1,68 (3H, s), 1,86 (3H, s), 1,92 - 2,24 (8H, b), 2,35 (3H, s), 5,10 (2H, b), 5,76 (IH, bs), 5,98 35 (IH, d, J = 11 Hz), 6,20 (IH, d, J = 15 Hz), 6,90 (IH, dd, J = 11 Hz, 15 Hz), 11,63 (IH, b).Mass Spectrum (m / e): 302 (M) Infrared Absorption Spectrum (cm, KBr Tablet): 3450, 2900, 1680, 1595 NMR Spectrum (6, CDCl3): 1.61 (6H, s), 1, 68 (3H, s), 1.86 (3H, s), 1.92 - 2.24 (8H, b), 2.35 (3H, s), 5.10 (2H, b), 5.76 (1H, bs), 5.98 (1H, d, J = 11 Hz), 6.20 (1H, d, J = 15 Hz), 6.90 (1H, dd, J = 11 Hz, 15 Hz) ), 11.63 (1H, b).

DK 158457 BDK 158457 B

1212

Ultraviolet absorptionsspektrum: xmetkano^ 304 nm.Ultraviolet Absorption Spectrum: xmetkano ^ 304 nm.

IftcLX »IftcLX »

Eksempel 2Example 2

Til en suspension af 4,8 g natriumethanolat i 100 ml n-hexan sattes 18 g diethyl-3-ethoxycarbonyl-2-methyl-5 2-propenylphosphonat. Til blandingen sattes 10 g 3,7,11-trimethyl-2,6,10-dodecatrien-l-al under omrøring ved stuetemperatur. Efter 1 times forløb hældtes reaktionsvæsken ud i 50 ml vand, og n-hexanfasen fraskiltes, n-Hexanfasen vaskedes med to 50 ml portioner af en blanding 10 af methanol og vand (2:1) og koncentreredes. Det således opnåede koncentrat rensedes ved chromatografi på en si-licagelkolonne til opnåelse af 14,5 g ethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoat.To a suspension of 4.8 g of sodium ethanolate in 100 ml of n-hexane was added 18 g of diethyl-3-ethoxycarbonyl-2-methyl-5-2-propenylphosphonate. To the mixture was added 10 g of 3,7,11-trimethyl-2,6,10-dodecatrien-1-al with stirring at room temperature. After 1 hour, the reaction liquid was poured into 50 ml of water and the n-hexane phase was separated, the n-hexane phase washed with two 50 ml portions of a mixture of methanol and water (2: 1) and concentrated. The concentrate thus obtained was purified by chromatography on a silica gel column to give 14.5 g of ethyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate.

10 g af den ovenfor opnåede ethylester hydrolyse-15 redes på samme måde som i eksempel 1 til opnåelse af 3,5 g 3,7,ll,15-tetramethyl-2,4,6,10,14-hexadecapentaen-syre i form af gule nåle.10 g of the above-obtained ethyl ester are hydrolyzed in the same manner as in Example 1 to give 3.5 g of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid in the form of yellow needles.

Det således opnåede produkt identificeredes på samme måde som i eksempel 1, nemlig ved hjælp af smel-20 tepunkt, massespektrum, NMR-spektrum, infrarødt absorptionsspektrum og ultraviolet absorptionsspektrum.The product thus obtained was identified in the same manner as in Example 1, namely by melting point, mass spectrum, NMR spectrum, infrared absorption spectrum and ultraviolet absorption spectrum.

Eksempel 3 i 100 ml tetrahydrofuran opløstes 10 g 1-p-tolyl-sulfonyl-3,7,ll-trimethyl-2,6,10-dodecatrien, og opløs-25 ningen afkøledes til -50°C. Til opløsningen sattes der dråbevis 18,5 ml 15%'s n-butyllithium-n-hexan-opløsning under omrøring og i en nitrogenstrøm, idet opløsningens temperatur holdtes på -50°C. Til den således opnåede opløsning tilsattes der derpå dråbevis 300 ml tetrahydro-30 furanopløsning indeholdende 5,7 g ethyl-4-brom-3-methyl- 2-butenat. Efter 30 minutters forløb tilsattes der 100 ml 10%'s vandig ammoniumchloridopløsning, og derpå behandledes opløsningen til opnåelse af stuetemperatur. Blandingen ekstraheredes derefter med to 200 ml portio-35 ner n-hexan. n-Hexanfasen vaskedes med tre 100 ml portioner vand, tørredes over magnesiumsulfat og koncentrere- 13Example 3 in 100 ml of tetrahydrofuran was dissolved 10 g of 1-p-tolylsulfonyl-3,7,11-trimethyl-2,6,10-dodecatriene and the solution cooled to -50 ° C. To the solution was added dropwise 18.5 ml of 15% n-butyllithium-n-hexane solution with stirring and in a stream of nitrogen, keeping the temperature of the solution at -50 ° C. To the solution thus obtained was added dropwise 300 ml of tetrahydrofuran solution containing 5.7 g of ethyl 4-bromo-3-methyl-2-butenate. After 30 minutes, 100 ml of 10% aqueous ammonium chloride solution was added and then the solution was treated to obtain room temperature. The mixture was then extracted with two 200 ml portions of n-hexane. The n-hexane phase was washed with three 100 ml portions of water, dried over magnesium sulfate and concentrated.

DK 1584 5 7 BDK 1584 5 7 B

des til opnåelse af 13 g ethyl-3,7,ll,15-tetramethyl-5-p-tolylsulfony1-2,6,10,14-hexadecatetraenoat.des to give 13 g of ethyl 3,7,11,15-tetramethyl-5-p-tolylsulfonyl-2,6,6,10,14-hexadecatetraenoate.

Til 10 g af den ovenfor opnåede ethylester sattes en opløsning af 4,6 g kaliumhydroxid i 50 ml isopropyl-5 alkohol, og blandingen omrørtes ved 50°C i 3 timer. Reaktionsvæsken hældtes derefter ud i isvand, syrnedes ved tilsætning af saltsyre og ekstraheredes med 100 ml ethylether. Ethyletherfasen vaskedes med vand, tørredes over magnesiumsulfat og koncentreredes til opnåelse af 6 10 g af en olie. Olien opløstes i 30 ml n-hexan og krystalliseredes ved -20°C til opnåelse af 1,8 g 3,7,11,15-te-tramethyl-2,4,6,10,14-hexadecapentaensyre i form af lysegule nåle.To 10 g of the ethyl ester obtained above was added a solution of 4.6 g of potassium hydroxide in 50 ml of isopropyl alcohol and the mixture was stirred at 50 ° C for 3 hours. The reaction liquid was then poured into ice water, acidified by the addition of hydrochloric acid and extracted with 100 ml of ethyl ether. The ethyl ether phase was washed with water, dried over magnesium sulfate and concentrated to give 6 10 g of an oil. The oil was dissolved in 30 ml of n-hexane and crystallized at -20 ° C to give 1.8 g of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid in the form of light yellow needles .

Det således opnåede produkt identificeredes på 15 samme måde som i eksempel 1, nemlig ved hjælp af smeltepunkt, massespektrum, NMR-spektrum, infrarødt absorptionsspektrum og ultraviolet absorptionsspektrum.The product thus obtained was identified in the same way as in Example 1, namely by melting point, mass spectrum, NMR spectrum, infrared absorption spectrum and ultraviolet absorption spectrum.

Eksempel 4Example 4

Pille.Pill.

20 3,7,11,15-Tetramethyl-2,4,6,10,14- hexadecapentåensyre 50 g3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentanoic acid 50 g

Kiselsyreanhydrid 30 gSilicic anhydride 30 g

Krystallinsk cellulose 50 gCrystalline cellulose 50 g

Majsstivelse 36 g 25 Hydroxypropylcellulose 10 gCorn starch 36 g Hydroxypropyl cellulose 10 g

Magnesiumstearat 4 gMagnesium stearate 4 g

Den ovenstående sammensætning oparbejdedes på konventionel måde til opnåelse af en pille (180 mg pr. pille).The above composition was worked up in a conventional manner to obtain one pill (180 mg per pill).

Claims (1)

DK 158457B Analogifremgangsmåde til fremstilling af 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaensyre med formlen I eller farmaceutisk acceptable salte heraf, kendetegnet ved, at man enten (1) omsætter en forbindelse med formlen II og et Wittig-reagens afledt af en forbindelse med den 15 almene formel III x - ch2 - co2r1 III hvori X betegner et halogenatom, og R.^ betegner en lavere alkylgruppe, til opnåelse af en forbindelse med den 20 almene formel IV hvori R^ har den ovennævnte betydning, og hydrolyserer 25 den således opnåede forbindelse i nærværelse af en base, eller (2) omsætter en forbindelse med formlen V 30 og et Wittig-reagens afledt af en forbindelse med den almene formel VI 1 X\^%/C02E1 VI hvori X betegner et halogenatom, og R-^ betegner en lavere alkylgruppe, til opnåelse af en forbindelse med den almene formel IV DK 158457B C°2El IV hvori R^ har den ovennævnte betydning, og hydrolyserer 5 den således opnåede forbindelse i nærværelse af en base, eller (3) omsætter en forbindelse med den almene formel VII 10 so2y vii hvori Y betegner en lavere alkylgruppe eller en arylgrup-pe, og en forbindelse med den almene formel VI 15 x\^V'002bi VI hvori X betegner et halogenatom, og betegner en lavere alkylgruppe, til opnåelse af en forbindelse med den almene formel VIII 20 so2y Jv\xV\xV/v ^ VIII hvori Y og har de ovennævnte betydninger, og under-25 kaster den således opnåede forbindelse en desulfinering og esterhydrolyse i nærværelse af en base.DK 158457B Analogous process for preparing 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid of formula I or pharmaceutically acceptable salts thereof, characterized in that either (1) is reacted with a compound of formula II and a Wittig reagent derived from a compound of the general formula III x - ch2 - co2r1 III wherein X represents a halogen atom and R 1 represents a lower alkyl group to give a compound of the general formula IV wherein R has the aforementioned meaning, and hydrolyzes the compound thus obtained in the presence of a base, or (2) converts a compound of formula V 30 and a Wittig reagent derived from a compound of general formula VI CO 2 E 1 VI wherein X represents a halogen atom and R 1 represents a lower alkyl group to give a compound of the general formula IV wherein R 1 has the above meaning and hydrolyzes the compound thus obtained in the presence of a base, or (3) reacting a compound of the general formula VII in which Y represents a lower alkyl group or an aryl group, and a compound of the general formula VI wherein X represents a halogen atom, and represents a lower alkyl group, to give a compound of the general formula VIII 20 so2y Jv \ xV \ xV / v ^ VIII wherein Y and have the above meanings, and the compound thus obtained undergoes desulfination and ester hydrolysis in the presence of a base.
DK155081A 1980-04-07 1981-04-06 METHOD OF ANALOGUE FOR THE PREPARATION OF 3,7,11,15-TETRAMETHYL-2,4,6,10,14-HEXADECAPENTA ACID OR SALTS THEREOF DK158457C (en)

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JP4455880 1980-04-07
JP4455880A JPS56140949A (en) 1980-04-07 1980-04-07 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenic acid
JP10442080 1980-07-31
JP10442080A JPS5731615A (en) 1980-07-31 1980-07-31 Remedy for skin disease with keratinization

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JPS56140949A (en) * 1980-04-07 1981-11-04 Eisai Co Ltd 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenic acid
EP0059258B1 (en) * 1980-12-24 1984-05-30 Eisai Co., Ltd. Pharmaceutical preparations comprising polyprenyl compounds, especially as anti-cancer agents, and pharmaceutical compositions for the prevention and treatment of cancer and skin diseases
JPS57106638A (en) * 1980-12-24 1982-07-02 Eisai Co Ltd Conjugated polyprenylcarboxylic acid and its derivative
JPS58164508A (en) * 1982-03-26 1983-09-29 Eisai Co Ltd Composition for external use containing isoprenyl-carboxylic acid
JPS5973516A (en) * 1982-10-21 1984-04-25 Eisai Co Ltd Antiphlogistic agent
JPS6160612A (en) * 1984-08-31 1986-03-28 Eisai Co Ltd Carcinostatic intensifier
IL107587A (en) * 1993-11-12 1998-08-16 Univ Ramot Farnesyl geranyl or geranyl-geranyl derivatives pharmaceutical compositions containing them and methods for their preparation
CA2407421C (en) 2000-04-24 2009-11-03 Nikken Chemicals Co., Ltd. Activators of peroxisome proliferator-activated receptors
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NL191744C (en) 1996-06-04
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