CS270551B2 - Method of tetrasubstituted benzene derivatives preparation - Google Patents

Method of tetrasubstituted benzene derivatives preparation Download PDF

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CS270551B2
CS270551B2 CS818260A CS826081A CS270551B2 CS 270551 B2 CS270551 B2 CS 270551B2 CS 818260 A CS818260 A CS 818260A CS 826081 A CS826081 A CS 826081A CS 270551 B2 CS270551 B2 CS 270551B2
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hydroxy
formula
oder
nieder
methoxy
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CS826081A2 (en
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Nobuo Shinma
Morio Fujiu
Isao Umeda
Tatsuo Ohtsuka
Hideo Ishitsuka
Yasuji Suhara
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Hoffmann La Roche
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Abstract

Neue tetra-substituierte Benzolderivate der Formel worin X Sauerstoff, Schwefel oder Hydroxyimino; Y Methylen oder Imino; R1 Hydroxy, Phosphonooxy, Glycosyloxy, aciliertes Glycosyloxy, Acyloxy oder nieder-Alkoxycarbonyloxy; R2 nieder-Alkoxy, nieder-Alkenyloxy oder nieder-Alkylthio; R3 nieder-Alkoxy; R4 nieder-Alkyl, p-nieder-Alkoxybenzoyl oder substituiertes oder unsubstituiertes Phenyl, Benzyl, Pyridylmethyl, Fürturyl, Tetrahydrofurfuryl, Thenyl, Tetrahydrothenyl, Pyrrolylmethyl, Pyrrolinylmethyl oder Pyrrolidinylmethyl darstellt, mit der Bedingung, daß X nicht Methylen ist, wenn R4 Alkyl, Phenyl, substituiertes Phenyl, Benzyl oder p-Hydroxybenzyl ist und mit der weiteren Bedingung, daß R2 und R3 voneinander verschieden sind, wenn R4 p-Methoxybenzyl und Y Methylen ist, und pharmazeutisch anwendbare Salze davon, sind antiviral wirksam. Sie können nach mehreren Verfahrensweisen hergestellt werden.

Description

Vynález se týká způsobu přípravy tetrasubatituováných benzenových derivátů obecného vzorce IThe invention relates to a process for the preparation of tetrasubatituated benzene derivatives of the general formula I

(I), kde R1 představuje hydroxyskupinu, fosfonooxyskupinu, případně acetylovanou β-D-glukopyranosyloxyekupinu, alkanoyloxyskupinu se 2 až 18 atomy uhlíku, benzyloxyekupinu nebo ethoxykarbonyloxyskupinu, R2 představuje alkoxyskupinu s 1 až 6 atomy uhlíku nebo alkenyloxyskupinu se 2 až 7 atomy uhlíku, R^ představuje methyl, p-methoxyfenyl, benzyl případně substituovaný hydroxy skup lnou, chlorem, methylem, alkoxyskupinou s 1 až 6 atomy uhlíku, methylthioskupinou, dímethy lamino skupinou, allyloxy skupinou, benzyloxy skupinou nebo methylendioxyskupinou, pyridylmethyl, furfuryl, thenyl, tetrahydrothenyl nebo pyrrolylmethyl, a farmaceuticky použitelných solí.(I) wherein R 1 is hydroxy, phosphonooxy, optionally acetylated β-D-glucopyranosyloxy, C 2 -C 18 alkanoyloxy, benzyloxy or ethoxycarbonyloxy, R 2 is C 1 -C 6 alkoxy or alkenyloxy R 1 is methyl, p-methoxyphenyl, benzyl optionally substituted with hydroxy, chloro, methyl, C 1 -C 6 alkoxy, methylthio, dimethylamino, allyloxy, benzyloxy or methylenedioxy, pyridylmethyl, furfuryl, thenyl, tetrahydrothenyl or pyrrolylmethyl, and pharmaceutically usable salts.

Alkoxyskupina s 1 až 6 atomy uhlíku Je výhodně isopropoxyskupina a butoxyskupina. Příkladem alkenyloxyskupiny se 2 až 7 atomy uhlíku Je alyloxyskupina a 3- methyl -2-propenyloxyskupina. Příkladem pyridylmethylového zbytku Je 4-pyridylm ethyl. Výhodným substituovaným furfurylovým a thenylovým zbytkem a jejich nasyceným derivátem Je furfuryl, 5-siethyl-furfuryl, 2-thenyl, tetrahydro-2-thenyl a 2-pyrrolylmethyl.C 1 -C 6 -alkoxy is preferably isopropoxy and butoxy. Examples of C 2 -C 7 alkenyloxy are allyloxy and 3-methyl-2-propenyloxy. An example of a pyridylmethyl radical is 4-pyridylmethyl. Preferred substituted furfuryl and thenyl moieties and saturated derivatives thereof are furfuryl, 5-ethylfurfuryl, 2-thenyl, tetrahydro-2-thenyl and 2-pyrrolylmethyl.

Výhodnou skupinou sloučenin vzorce I Je taková, kde R2 Je alkoxyskupina s 1 až 6 atomy uhlíku a R1 a mají výše uvedený význam.A preferred group of compounds of formula I is that wherein R 2 is an alkoxy group having 1 to 6 carbon atoms and R 1 are as defined above.

Dále Jsou výhodnými sloučeninami vzorce I takové, kde R1 Je hydroxy skupin a, alkanoyloxy skupin a se 2 až 18 atomy uhlíku, benzyloxyskupina, fosfonooxyskupina, ethoxykarbonyloxy skupin a, R2 Je alkoxyskupina s 1 až 6 atomy uhlíku nebo alkenyloxyskupina se 2 až 7 atomy uhlíku a R^ Je methoxyfenyl.Further preferred compounds of formula I are those wherein R 1 is hydroxy α, C 2 -C 18 alkanoyloxy, benzyloxy, phosphonooxy, ethoxycarbonyloxy α, R 2 is C 1 -C 6 alkoxy or C 2 -C 7 alkenyloxy and R a is methoxyphenyl.

Způsob přípravy sloučenin obecného vzorce I a jejich farmaceuticky použitelných solí se vyznačuje tím, že se acetofenon obecného vzorce IIThe process for the preparation of the compounds of the formula I and their pharmaceutically usable salts is characterized in that the acetophenone of the formula II is used

kde Rj a Rp mají význam uvedený ve vzorci I, nechá reagovat výhodně při 100 °C s Jodem v terciárním aminu* a získaná sůl se nechá reagovat s aminem obecného vzorce IIIwherein Rj and Rp are as defined in formula I, reacted preferably at 100 ° C with iodine in a tertiary amine * and the obtained salt is reacted with an amine of formula III

R3 - ЯН2 (III), kde R^ má význam uvedený ve vzorci I, a získaná sloučenina se případně převede na farmaceuticky použitelnou sůl.R 3 - N 2 (III), wherein R 3 is as defined in formula I, and the compound obtained is optionally converted to a pharmaceutically acceptable salt.

Reakce acetofenonu vzorce II s Jodem se provádí při teplotě 100 °C v terciárním aminu, Jako pyridinu nebo lutidinu, získaná sůl se nechá reagovat s aminem vzorce III a získaná sloučenina vzorce I se případně převede na farmaceuticky použitelnou sůl.The reaction of acetophenone of formula II with iodine is carried out at 100 ° C in a tertiary amine, such as pyridine or lutidine, the resulting salt is reacted with an amine of formula III and the resulting compound of formula I is optionally converted into a pharmaceutically usable salt.

S výhodou se připraví N-p-(dimethylamino)-benzyl-2-hydroxy-4,6-dimethoxýbenzamid, přičemž se použijí Jako výchozí látky sloučeniny vzorce II а III, kde R^ Je hydroxyskupina, R2 Je methoxyskupina a R^ je p-dimethylaminobenzyl; dále 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl) benzamid, přičemž se použijí Jako výchozí látky sloučeniny vzorce IIPreferably, Np- (dimethylamino) -benzyl-2-hydroxy-4,6-dimethoxybenzamide is prepared, starting from compounds of formula II and III, wherein R 1 is hydroxy, R 2 is methoxy and R 1 is p- dimethylaminobenzyl; 4-ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl) benzamide, starting from compounds of formula II

CS 270 551 B2 а III, kde R1 je hydroxy skupin a, Rg Je methoxyskupina a R^ je methoxybenzyl; a 2-hydroxy-6-methoxy-4-(3-«ethyl-2-butenyloxy)-N-(p-methoxybenzyl)benzarnid, přičemž se použijí jako výchozí látky sloučeniny vzorce II а III, kde R1 je hydroxyskupina, Rg je 3-methyl-2-butenyloxyskupina R^ je p-methoxybenzyl.CS 270 551 B2 and III, wherein R 1 is hydroxy α, R 8 is methoxy and R 6 is methoxybenzyl; and 2-hydroxy-6-methoxy-4- (3-ethyl-2-butenyloxy) -N- (p-methoxybenzyl) benzamide, starting from compounds of formula II and III, where R 1 is hydroxy, R 8 R 3 is 3-methyl-2-butenyloxy R 1 is p-methoxybenzyl.

Sloučeniny vzorce I projevují antivirální aktivitu, obzvláště brzdí replikaci lidských rhinovirů v kulturách Hela - buněk v koncentraci 0,001 až 2,7 /Ug/ml.The compounds of formula I exhibit antiviral activity, in particular inhibiting the replication of human rhinoviruses in Hela cell cultures at a concentration of 0.001 to 2.7 [mu] g / ml.

Vynález se dále týká antivirálního prostředku, který obsahuje sloučeninu vzorce I nebo její farmaceuticky přijatelnou sůl. Sloučeniny vzoroe I jsou obzvláště účinné vůči určitým virům Pikorna-skupiny. Následující sloučeniny projevují obzvláště silnou antivirální aktivitu.The invention further relates to an antiviral composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. The compounds of formula I are particularly active against certain Pikorna viruses. The following compounds exhibit particularly potent antiviral activity.

-(4-ethoxy-2-hydroxy-6-methoxyfenyl)-3-(4-methoxyfenyl)-1 -propanon,- (4-ethoxy-2-hydroxy-6-methoxyphenyl) -3- (4-methoxyphenyl) -1-propanone,

5-ethoxy-3-nethoxy-2-/3-(p-methoxyfenyl)-propionyl7fenyl-acetát,5-Ethoxy-3-methoxy-2- [3- (p-methoxyphenyl) propionyl] phenyl acetate,

4- ethoxy-2-hydroxy-6-methoxy-N-(p-methoxýbenzyl)-benzamid,4-ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl) -benzamide,

2-hydroxy-4,6-dimethoxy-N-^p-(methylthio)benzyl7-benzamid,2-hydroxy-4,6-dimethoxy-N- [beta] - (methylthio) benzyl7-benzamide,

2- {/Tp-( allyloxy/benzyl) amino7karbonyl)-3·, 5-dimethoxyfenyl-benzoát,2- {N - (allyloxy / benzyl) amino7carbonyl) -3,5,5-dimethoxyphenyl benzoate,

-(4-ethoxy-2-hydroxy-6-methoxyfenyl)-3-C4-methoxy-fenyl)-1-propanthion,- (4-ethoxy-2-hydroxy-6-methoxyphenyl) -3-C4-methoxyphenyl) -1-propanethion,

5- ethoxy-3-methoxy-2-/3-( 4-methoxyf enyl)propionyl7-fenylethylkarbonát, 2-/Гр- ani syl amino) karb onyj7-5-ethoxy-3-»ethoxyfenyldihydrogen- fosfát, dvoj sodný 2-/Tp-anisylamino)karbonyl7-5-ethoxy-3-ioethoxyfenyl-fo8fát> 2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxýbenzyl)-benzamid,5-Ethoxy-3-methoxy-2- [3- (4-methoxyphenyl) propionyl7-phenylethyl carbonate, 2- (N-butylamino) carbonyl] -5-ethoxy-3- »ethoxyphenyldihydrogen phosphate, disodium 2- (Β-Anisylamino) carbonyl-5-ethoxy-3-thioethoxyphenyl phosphate > 2-hydroxy-6-methoxy-4-propoxy-N- (p-methoxybenzyl) -benzamide,

4- (al lyloxy) - 2-hydroxy- 6-®ethoxy-N- (p-methoxybenzyl) -benz amid, 2-hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl)benzamid a dvoj sodný 2-/Tp-anisylamlno)karbonyl7-3-iaethoxy-5-propoxyf exxyl-fosfát ·4- (al lyloxy) -2-hydroxy-6-ethoxy-N- (p-methoxybenzyl) -benzamide, 2-hydroxy-6-methoxy-4- (3-methyl-2-butenyloxy) -N- ( p-methoxybenzyl) benzamide and disodium 2- (β-anisylamino) carbonyl7-3-ethoxy-5-propoxyphexyl phosphate ·

Antivirální účinnostAntiviral activity

Suspenze HeLa-buněk (6x10^) se smíchala se Rhinoviry HGP (3x10^ jednotek tvořících destičky, PFU) a nanesla na mikrozkušební desku, která obsahovala zkoušené sloučeniny ve stoupajícím zředění. Buňky se potom kultivovaly v Eglově roztoku minimální výživy, který obsahoval 2 % telecího séra, 1 % tryptosefosfátové polévky, 100 /Ug/ml streptomycinu a 20 jednotek/ml penicilinu G. Po 2 dnech kultivace při 33 °C se potom mikroskopicky pozoroval virální cytopathogenický účinek a cytotoxicita. Antivirální účinnost (I zkoušených sloučenin je taková koncentrace, při které je cytopathogenický účinek zbrzděn o 50 % proti kontrolní kultuře. Cytotoxicita je dána jako minimální koncentrace, při které byly pozorovány toxické symptomy (cytotoxická dávka).HeLa-cell suspension (6x10 6) was mixed with Rhinovirus HGP (3x10 6 platelet forming units, PFU) and plated on a microtest plate containing test compounds in increasing dilution. The cells were then cultured in Egl's minimal nutrient solution containing 2% calf serum, 1% tryptosephosphate soup, 100 µg / ml streptomycin and 20 units / ml penicillin G. After 2 days of culture at 33 ° C, viral cytopathogenic was then observed microscopically. effect and cytotoxicity. Antiviral activity (also of the test compounds is the concentration at which the cytopathogenic effect is inhibited by 50% against the control culture. Cytotoxicity is given as the minimum concentration at which toxic symptoms (cytotoxic dose) were observed.

Výsledky jsou uvedeny v tabulce 1 a ukazují, že sloučeniny podle vynálezu projevují anti-rhinovirovou aktivitu při koncentracích, které byly 10 až 10 000 krát nižší než cytotoxické dávky.The results are shown in Table 1 and show that the compounds of the invention exhibit anti-rhinoviral activity at concentrations that were 10 to 10,000 times lower than the cytotoxic doses.

Dále jsou udána v tabulce 2 antivirální apektra 1-(4-ethoxy-2-hydroxy-6-methoxyfenyl)-3-(4-methoxyfenyl)-1-propanonu (sloučenina A) a 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)benz amidu (sloučenina B) vůči různým serotypům rhinovirů.The antiviral apects of 1- (4-ethoxy-2-hydroxy-6-methoxyphenyl) -3- (4-methoxyphenyl) -1-propanone (compound A) and 4-ethoxy-2-hydroxy-6- methoxy-N- (p-methoxybenzyl) benzamide (compound B) against various rhinovirus serotypes.

Tabulka 1Table 1

SloučeninaCompound

1-(2-hydroxy-4,6-dimethoxyfenyl)-3-(3>4-)methylendioxy(fenyl)-1-propanon1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (3,4-) methylenedioxy (phenyl) -1-propanone

1-(2-hydroxy-4,6-dimethoxyfenyl)-3-/7-methylthio)fenyl7-1-propanon1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (7-methylthio) phenyl-7-propanone

-(2-hydroxy-4,6-dimethoxy fenyl )-3-( 4-methyl fenyl )-1-propanon- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-methylphenyl) -1-propanone

I050 (/ug/el) I0 50 (ug / el) cytotoxicita (/Ug/ml) cytotoxicity (/ Ug / ml) 0,03-0,1 0,03-0,1 >8 > 8 0,01-0,03 0.01-0.03 8 8 0,01-0,03 0.01-0.03 7*8 7 * 8

CS 270 551 B2CS 270 551 B2

1.( 4-ethoxy-2-hydroxy-6-methoxyf enyl)-3-( 4-methoxyfenyl)-1-propanon 1. (4-Ethoxy-2-hydroxy-6-methoxyphenyl) -3- (4-methoxyphenyl) -1-propanone 0,002 0,002 . >e . > e 5-ethoxy-3-methoxy-2-/3-(p-methoxyfenyl)propionyl7fenyl-dihydrogenfosfát 5-Ethoxy-3-methoxy-2- [3- (p-methoxyphenyl) propionyl] phenyl dihydrogen phosphate 0,3-0,8 0,3-0,8 >10 > 10 5-éthoxy-3-methoxy-2-/3-(p-methoxyfenyli>ropionyl7fenylасеtát 5-Ethoxy-3-methoxy-2- / 3- (p-methoxyphenyl) ropionyl 7-phenyl mesylate 0,001 0.001 >8 > 8 1-(2-hydroxy-4,6-dime thoxyfenyl)-3-(4-methoxyf enyl)-1-propanon-oxim (Z-isomer) 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-methoxyphenyl) -1-propanone oxime (Z-isomer) 0,03 0.03 >10 > 10 1-(2-hydroxy-4,6-dimethoxyfenyl)-3-(4-methoxyf enyl)-1-propanon-oxim (E isomer) 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-methoxyphenyl) -1-propanone oxime (E isomer) 0,03-0,9 0,03-0,9 >10 > 10 2-hydro xy-4,6-dimethoxy-N-(p-methoxybenzyl)-benzamid 2-Hydroxy-4,6-dimethoxy-N- (p-methoxybenzyl) -benzamide 0,002 0,002 8 8 3-(4-chlonfenyl)-1-(2-hydroxy-4,6-dimethoxyfenyl)-1-propanon 3- (4-Chlorophenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) -1-propanone 0,1 0.1 10 10 1-(2-hydroxy-4,6-dimethoxyfenyl)-3-(5-metbyl-2-fůry 1)-1-propanon 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (5-methyl-2-furyl) -1-propanone 0,9 0.9 >8 > 8 1-(2-ethoxy-6-hydroxy-4-methoxyfenyl)-3-(4-methoxyfenyl)-1-propanon 1- (2-ethoxy-6-hydroxy-4-methoxyphenyl) -3- (4-methoxyphenyl) -1-propanone 0,01-0,03 0.01-0.03 0,9 0.9 1 -(2-hydroxy-4,6-dimethoxyfenyl)-3-(4-methoxyfenyl)-1,3-propandion 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-methoxyphenyl) -1,3-propanedione 0,01-0,03 0.01-0.03 8 8 1 - (2-hydroxy-6-methoxy-4-propoxyfenyl) -3-( 4-methoxyfenyl)-1-propanon 1- (2-Hydroxy-6-methoxy-4-propoxyphenyl) -3- (4-methoxyphenyl) -1-propanone 0,004-0,01 0,004-0,01 2,7 2.7 1 - (2-hydroxy- 4-i sopropoxy- 6-me thoxy f enyl) -3- (4-methoxyfenyl)—1—propanon 1- (2-Hydroxy-4-isopropoxy-6-methoxyphenyl) -3- (4-methoxyphenyl) -1-propanone 0,03-0,1 0,03-0,1 8 8 4-e thoxy- 2 - hydro xy- 6-me thoxy-N- ( p-me t hoxybenzyl)benzamid - 4-ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl) benzamide - 0,002 0,002 >10 > 10 1 -(2-hydroxy-4,6-dimethoxyfenyl )-3-( tetrahydro-5-methyl-2-furyl)-1-propanon 1- (2-Hydroxy-4,6-dimethoxyphenyl) -3- (tetrahydro-5-methyl-2-furyl) -1-propanone 0,9 0.9 > 8 > 8 2-hydroxy-4,6-dime thoxy-N- (4-methoxyfenyl)benzamid 2-hydroxy-4,6-dimethoxy-N- (4-methoxyphenyl) benzamide 0,03-0,1 0,03-0,1 >10 > 10 N-benzyl-2-hydroxy-4,6-dimethoxýbenzamid N-benzyl-2-hydroxy-4,6-dimethoxybenzamide 0,03-0,1 0,03-0,1 > 8 > 8 2-hydroxy-4,6-dimethoxy-N-(m,p-(methylendioxy) -benzyl)benzamid 2-hydroxy-4,6-dimethoxy-N- (m, p- (methylenedioxy) benzyl) benzamide 0,003-0,01 0,003-0,01 > 8 > 8 2-hydroxy-4,6-dimethoxy-N-(m-methoxybenzyl)-benzamid 2-hydroxy-4,6-dimethoxy-N- (m-methoxybenzyl) benzamide 0,002 0,002 >8 > 8 2-hydroxy-4,6-dimethoxy-N-(p-methylbenzyl)-benzamid 2-hydroxy-4,6-dimethoxy-N- (p-methylbenzyl) -benzamide 0,01-0,03 0.01-0.03 8 8 N-(p-chlorobenzyl)-2-hydroxy-4 , 6-dimethoxy-benzamid N- (p-chlorobenzyl) -2-hydroxy-4,6-dimethoxybenzamide 0,01-0,03 0.01-0.03 > 2,4 > 2,4 N-furfuryl-2-hydroxy-4 , 6-dimethoxybenzamid N-furfuryl-2-hydroxy-4,6-dimethoxybenzamide 0,03-0,1 0,03-0,1 > 8 > 8 2-hydroxy-4,6-dimethoxy-N-methylbenzamid 2-hydroxy-4,6-dimethoxy-N-methylbenzamide 0,9 0.9 > 8 > 8 2-hydroxy-N-(m-hydroxy-p-methoxybenzyl)-4 , 6-dimethoxybenzamid 2-hydroxy-N- (m-hydroxy-p-methoxybenzyl) -4,6-dimethoxybenzamide 0,1-0,3 0,1-0,3 2,7 2.7 N-(m,p-dimethoxybenzyl)-2-hydroxy-4, 6-dimethoxybenzamid N- (m, p-dimethoxybenzyl) -2-hydroxy-4,6-dimethoxybenzamide 0,3 0.3 8 8 2-hydroxy-4,6-dimethoxy-N-/T4-pyridyl)methyl7-benzamid 2-hydroxy-4,6-dimethoxy-N- (η 4 -pyridyl) methyl 7-benzamide 0,9 0.9 8 8 N-( p-butoxybenzyl )-2-hydroxy-4,6-dimethoxybenzamid N- (p-butoxybenzyl) -2-hydroxy-4,6-dimethoxybenzamide 0,3 0.3 8 8 2-hydroxy-N-(p-hydroxy-benzyl)-4 , 6-dimothoxy-benzwnid 2-hydroxy-N- (p-hydroxybenzyl) -4,6-dimethoxybenzamide 0,3 0.3 >8 > 8

CS 270 551 B2CS 270 551 B2

N-/p-dimethylamino/benzyl7-2-hydroxy-4,6-dimethoxy-benzamid N- (p-dimethylamino) benzyl-7-hydroxy-4,6-dimethoxybenzamide 0,01 0.01 >8 > 8 2-hydroxy-4 > 6-dimethoxy-N-/p- (methyl thio)benzyl7benz amid 2-hydroxy-4,6-dimethoxy-N- [p - (methylthio) benzyl] benzamide 0,002 0,002 >8 > 8 H-/p-(benzyloxy)benzyl7-2-hydroxy-4>6-dimethoxy-benzemid N - [- (benzyloxy) benzyl] -2-hydroxy-4,6-dimethoxybenzemide 0,3-0,9 0,3-0,9 >8 > 8 2-hydroxy-4 , 6-dimethoxy-N-( 2-thenyl)benzamid 2-hydroxy-4,6-dimethoxy-N- (2-thenyl) benzamide 0,03 0.03 8 8 N-/p-( allyloxy)benzyl7-2-hydroxy-4 , 6-dimethoxy-benzamid N- [p- (allyloxy) benzyl] -2-hydroxy-4,6-dimethoxybenzamide 0,01 0.01 6 6 2-hydroxy-4 > 6-dimethoxy-N-( tetrahydro«2-thenyl)-benzamid 2-hydroxy-4,6-dimethoxy-N- (tetrahydro-2-thenyl) -benzamide 0,004-0,01 0,004-0,01 8 8 2-hydroxy-4t6-dimethoxy-N-/T2-pyrrolyl)methyl7-benzamid2-hydroxy-4- ( 6-dimethoxy-N- (T2-pyrrolyl) methyl7-benzamide) 2,7 2.7 >8 > 8 2-/Tp-ani 8ylamino)-karbonyl7-5-ethoxy-3-methoxyfenyl-acetdt 2- (N-amino) carbonyl-5-ethoxy-3-methoxyphenyl acetic acid 0,3 0.3 >8 > 8 2-Л Г /р-( allyloxy)benzyl7-amino7karbonyl7-3 , 5-dimethoxyfenyl-benzoát 2-N, N - (allyloxy) benzyl-7-amino-7-carbonyl-3,5-dimethoxyphenyl benzoate 0,002 0,002 2,7 2.7 2- /p-( allyloxy )benzyl7-amino7karbonyl} -3 > 5-dimethoxy- feny1-oktadekanoát 2- / p- (allyloxy) benzyl-7-amino-7-carbonyl} -3,5-dimethoxy- phenyl-octadecanoate 0,3 0.3 >8 > 8 1 -(4-ethoxy-2-hydroxy-6-aethoxyfenyl)-3-(4-methoxyfenyl) 1-propanthion 1- (4-Ethoxy-2-hydroxy-6-ethoxyphenyl) -3- (4-methoxyphenyl) 1-propanthion 0,002 0,002 2,7 2.7 4- e thoxy-2-hydroxy- 6-methoxy-N- ( p-methoxybenzyl) thio-benzamid 4- ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl) thiobenzamide 0,01 0.01 >8 > 8 1 -/2-hydroxy-6-methoxy-4-(methylthio) fenyl7-3-4-methoxyfenyl)-1-propanon 1- (2-Hydroxy-6-methoxy-4- (methylthio) phenyl7-3-4-methoxyphenyl) -1-propanone 0,1 0.1 1 1 5- e thoxy-3 -me thoxy-2-^3- ( 4-methoxy fenyl) propionyl7 fenyl- e t hy lkarb onát 5-Methoxy-3-methoxy-2- [3- (4-methoxyphenyl) propionyl] phenyl-ethylcarbonate 0,002 0,002 8 8 5-ethoxy-3-methoxy-2-/l-( 4-methoxyfenyl)propionyl7fenyl-oktadekanoát 5-Ethoxy-3-methoxy-2- [1- (4-methoxyphenyl) propionyl] phenyl octadecanoate 0,9 0.9 >8 > 8 5-ethoxy-3-methoxy-2-/3-(4-methoxyfenyl)-propionyl7fenyl- -benzoát 5-Ethoxy-3-methoxy-2- [3- (4-methoxyphenyl) -propionyl] phenyl- -benzoate 0,01 0.01 >8 > 8 2-/Tp-anisylamino)karbonyl7-3 > 5-dimethoxyfenyl-ethylkarbonát 2- (β-Anisylamino) carbonyl-7-5,5-dimethoxyphenyl ethyl carbonate 0,1 0.1 >8 > 8 2-/Tp-anisylamino)karbonyl7-3 > 5-dimethoxyfenyl-benzoát 2- (β-Anisylamino) carbonyl-7-5,5-dimethoxyphenyl benzoate 0,03 0.03 >8 > 8 2-/Г p— ani sylamino) karbonyl7-3 > 5-dimethoxy f enyl-okt adekanoát 2- (β-α-amino) carbonyl-7-5,5-dimethoxyphenyl-octadecanoate 0,3-0,9 0,3-0,9 ?8 ? 8 2-/Tp-anisylamino)karbonyl7-3,5-dimethoxyfenyl tetra-0-acetyl- β-D-glukopyranosid 2- (β-Anisylamino) carbonyl7-3,5-dimethoxyphenyl tetra-O-acetyl-β-D-glucopyranoside 2,7 2.7 >10 > 10 2 - /Г - ani sylamino) karbony17-3 , 5-dimethoxyfenyl - β -D-glukopyrano sid 2 - (- - nor sylamino) carbones17-3,5-dimethoxyphenyl - β-D-glucopyranoside 2,7 2.7 >10 > 10 5-ethoxy-3-methoxy-2-/3-( 4-methoxy fenyl) propionyl7fenyl - /3-D-glukopyranosid 5-ethoxy-3-methoxy-2- [3- (4-methoxyphenyl) propionyl] phenyl - β-D-glucopyranoside 2,7 2.7 >10 > 10 Dvoj sodný 5-ethoxy-3-methoxy-2-/3~( 4-methoxyfenyl)propiony17 fenyl-fo s fát Disodium 5-ethoxy-3-methoxy-2- [3- (4-methoxyphenyl) propiones] 17-phenylphosphate 0,03-0,1 0,03-0,1 >10 > 10 2-^Tp-ani sylamino )karbonyl7-3 > 5-dimethoxy fenyl- di hydro genfosfát 2- (5-dimethylamino) carbonyl-7, 5-dimethoxyphenyl dihydrogenphosphate 0,006-0,01 0,006-0,01 • >8 •> 8 2-/Vp-anisylamino)karbonyl7-5-ethoxy-3-»ethoxyfenyl-dihydrogenfosfát 2- (N-anisylamino) carbonyl7-5-ethoxy-3- »ethoxyphenyl dihydrogenphosphate 0,01-0,03 0.01-0.03 >8 > 8 dvoj sodný 2-/5’p-anisylamino)karbonyl7-5-ethoxy-3-»ethoxyf eny1-fosfát disodium 2- (5'p-anisylamino) carbonyl7-5-ethoxy-3- »ethoxyphenyl phosphate 0,01-0,03 0.01-0.03 >8 > 8

CS 270 551 B2CS 270 551 B2

2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxy-benzyl)benzamid 2-hydroxy-6-methoxy-4-propoxy-N- (p-methoxybenzyl) benzamide 0,001-0,003 0,001-0,003 20 20 May 4- (al lyloxy) -2 -hydroxy- 6-me thoxy-N- (p-me thoxy-benzyl )benzamid 4- (allyloxy) -2-hydroxy-6-methoxy-N- (p-methoxybenzyl) benzamide 0,002 0,002 8 8 2-hy droxy- 6-m e thoxy- 4-( 3-m e thyl-2 -but enyloxy) -N- ( p-methoxybenzyl)-benzamid 2-Hydroxy-6-methoxy-4- (3-methyl-2-butyloxy) -N- (p-methoxybenzyl) -benzamide 0,001-0,002 0,001-0,002 8 8 dvojsodný 2-/rp-anisylamino)karbonyl7-3-methoxy-5-propoxy- fenyl-fosfát disodium 2- (β-anisylamino) carbonyl7-3-methoxy-5-propoxy- phenyl phosphate 0,01-0,02 0.01-0.02 200 200

Tabulka 2Table 2

Virový kmen Virus strain 1050 10 50 Sloučenina A Compound A Sloučenina В Compound В Rhinovirus 1A Rhinovirus 1A 0,03-0,09 0,03-0,09 0,009-0,027 0,009-0,027 1B 1B 0,03-0,09 0,03-0,09 0,003-0,009 0,003-0,009 2 2 0,001 0.001 0,001 0.001 9 9 0,012-0,037 0,012-0,037 0,003 0.003 14 14 0,1-0,3 0,1-0,3 0,009-0,027 0,009-0,027 1 6 1 6 - - 0,003 0.003 21 21 <0,001 <0.001 <0,001 <0.001 23 23 0,004 0.004 - - 24 24 0,01-0,03 0.01-0.03 - - 25 25 0,01-0,09 0.01-0.09 - - 30 30 - - 0,001-0,003 0,001-0,003 31 31 0,03-0,09 0,03-0,09 0,081-0,24 0,081-0,24 32 32 - - 0,003-0,009 0,003-0,009 36 36 - · - · 0,009-0,027 0,009-0,027 39 39 0,012-0,037 0,012-0,037 0,003 0.003 44 44 - - 0,003 0.003 46 46 0,037-0,11 0,037-0,11 - - 47 47 - - 0,003 0.003 50 50 0,004-0,012 0,004-0,012 0,01 0.01 55 55 0,009 0.009

Cytotoxické dávky, které brzdí růst HeLa-buněk, jsou 60 /Ug/ml pro sloučeninu A a 40 /Ug/ml pro sloučeninu B.Cytotoxic doses that inhibit the growth of HeLa cells are 60 µg / ml for compound A and 40 µg / ml for compound B.

Jak bylo výře uvedeno, mohou se sloučeniny vzoroe I a jejich farmaceuticky použitelné soli použít jako léčiva proti virovým onemocněním, obzvláště při nachlazení ve formě farmaceutických přípravků.As mentioned above, the compounds of formula I and their pharmaceutically usable salts can be used as medicaments against viral diseases, in particular in the form of cold preparations in the form of pharmaceutical preparations.

Farmaceutické přípravky obsahují alespoň jednu ze zmíněných antivirálních sloučenin nebo jejich farmaceuticky použitelných solí společně · vhodným farmaceutickým nosičem. Mohou také obsahovat dalfií farmaceuticky účinné sloučeniny, jako prostředek snižující teplotu, prostředek stiěující bolest, protizánětlivý prostředek, antihistamin nebo interferonový induktor· Farmaceutické přípravky mohou být v pevné formě pro orální podání, např. jako tablety, kapsle, pilulky, práěek nebo granulát, v kapalné formě pro nasální nebo orální podání, např. Jako roztoky, suspense nebo sirupy, pro parenterální podání jako sterilní roztoky, suspense nebo emulse nebo pro topické podání ve formě roztoků, emulsí, mikronisovaných prášků, mastí a také jako kloktadla nebo aerosoly.The pharmaceutical compositions comprise at least one of said antiviral compounds or pharmaceutically acceptable salts thereof together with a suitable pharmaceutical carrier. They may also contain alpha-pharmaceutically active compounds, such as a temperature lowering agent, a pain relieving agent, an anti-inflammatory agent, an antihistamine or an interferon inducer. The pharmaceutical preparations may be in solid form for oral administration, eg as tablets, capsules, pills, powders or in liquid form for nasal or oral administration, e.g. as solutions, suspensions or syrups, for parenteral administration as sterile solutions, suspensions or emulsions or for topical administration in the form of solutions, emulsions, micronized powders, ointments, as well as gargles or aerosols.

Dávkování pro léčení závisí na způsobu podávání, stáří, hmotnosti a stavu pacienta a na бThe dosage to be treated depends on the route of administration, age, weight and condition of the patient and on б

CS 270 551 В2 léčené nemoci. Obecně se doporučuje pro dospělé při nachlazení dávka 100-2000 mg 3x-6x denně při orálním podání a 0,1-100 /Ug/cm2 3x-6x denně v případě topického podání.CS 270 551 В2 treated diseases. In general, a dose of 100-2000 mg 3x-6x daily for oral administration and 0.1-100 / µg / cm 2 3x-6x daily for topical administration is recommended for adults with colds.

Způsob podle vynálezu je objasněn v následujících příkladech.The process of the invention is illustrated in the following examples.

Příklad 1Example 1

К roztoku 980 mg 2 '-hydroxy-4 ',6'-dimethoxyacetofenonu ve 20 ml pyridinu se přidá 1,27 g jodu. Smě в se zahřívá 1 hodinu na 100 °C, přičemž se vytvoří pevná hmota. Po ochlazení se pevná látka promyje postupně 50 ml etheru a troškou studené vody a potom se suší za sníženého tlaku. Získají se 2 g surového 1-/T2-hydroxy-4,6-dimethoxybenzoyl) methyl7 pyridiniumjodidu ve formě hnědého prášku.1.27 g of iodine was added to a solution of 980 mg of 2'-hydroxy-4 ', 6'-dimethoxyacetophenone in 20 ml of pyridine. The mixture was heated at 100 ° C for 1 hour, forming a solid. After cooling, the solid is washed successively with 50 ml of ether and a little cold water and then dried under reduced pressure. 2 g of crude 1- [(2-hydroxy-4,6-dimethoxybenzoyl) methyl] pyridinium iodide are obtained in the form of a brown powder.

g této pyridiniové soli se přidá к 515 »g p-methoxýbenzylaminu a směs se zahřívá 72 hodin na 80 °C. Po ochlazení se směs nalije do 20 ml IN kyseliny solné. Získaná suspenze se extrahuje 2x 100 ml dichlormethanu, extrakty se promyjí vodou, suší se síranem sodným a odpaří se. Získá se 945 mg olejovitého zbytku, který se čistí chromatografií na silikagelu se směsí hexan/ethyl асе tát (3 : 1 objemových dílů) jako eluens. Odstraněním rozpouštědla z eluátu a následujícím překryštalováním z methanolu se získá 316 mg 2-hydroxy-4,6-dimethoxy-N-(p-methoxy-benzyl) benzamidu o teplotě tání 108-109 °C.g of this pyridinium salt is added to 515 g of p-methoxybenzylamine and the mixture is heated at 80 ° C for 72 hours. After cooling, the mixture is poured into 20 ml of 1N hydrochloric acid. The suspension obtained is extracted twice with 100 ml of dichloromethane, the extracts are washed with water, dried over sodium sulphate and evaporated. 945 mg of an oily residue is obtained, which is purified by chromatography on silica gel with hexane / ethyl acetate (3: 1 by volume) as eluent. Removal of the solvent from the eluate followed by recrystallization from methanol gave 316 mg of 2-hydroxy-4,6-dimethoxy-N- (p-methoxybenzyl) benzamide, m.p. 108-109 ° C.

Příklad 2Example 2

Analogicky podle příkladu 10 se získají z pyridiniové soli aminů uvedených v tabulce 5 sloučeniny I uvedené v tabulce 5·Analogously to Example 10, the pyridine salts of the amines listed in Table 5 are obtained as Compounds I listed in Table 5

Tabulka 5Table 5

Amin Amin Sloučeniny vzorce I Compounds of formula I 4-(aminome thyl)pyridin 4- (aminomethyl) pyridine 2-hydroxy-4,6-dimethoxy-N-/t4-pyridyl)methyl7benz amid; teplota tání 114-115 °C (z etheru) 2-hydroxy-4,6-dimethoxy-N- (4-pyridyl) methyl7-benzamide; mp 114-115 ° C (from ether) p-(allyloxy)benzylamin p- (allyloxy) benzylamine N-/p-(allyloxy)benzyl7-2-hydroxy-4,6-dimethoxybenzamid; teplota tání 93-93 °C (methanol) N- [p- (allyloxy) benzyl] -2-hydroxy-4,6-dimethoxybenzamide; melting point 93-93 ° C (methanol) 2-(aminomethyl)pyrro1 2- (aminomethyl) pyrrole 2-hydroxy-4,6-dimethoxy-N-(2-pyrrolylmethyl)benzamid; teplota tání 116-117 °C (ether) 2-hydroxy-4,6-dimethoxy-N- (2-pyrrolylmethyl) benzamide; mp 116-117 ° C (ether)

Příklad 3Example 3

Roztok 9,8 g -4*-ethoxy-2'-hydroxy-ó'-methoxyacetofenonu a 12 g jodu ve 22 ml pyridinu se zahřívá 1 hodinu na 100 °C. Získaná pevná hmota se ochladí, práěkuje a znovu se zahřívá 1 hodinu na 100 °C. Po ochlazení se směs filtruje a pevný zbytek se promyje postupně 100 ml etheru a 100 ml vody a potom se suší 3 hodiny při 60 °C za sníženého tlaku. Získá se 18,2 g 1-/T4-ethoxy-2-hydroxy-6-methoxýbenzoyl)methyl7 pyridiniumjodidu jako světle hnědé látky.A solution of 9.8 g of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone and 12 g of iodine in 22 ml of pyridine was heated at 100 ° C for 1 hour. The solid obtained was cooled, dusted and reheated to 100 ° C for 1 hour. After cooling, the mixture was filtered and the solid residue was washed successively with 100 ml of ether and 100 ml of water and then dried at 60 ° C for 3 hours under reduced pressure. 18.2 g of 1- (N-ethoxy-2-hydroxy-6-methoxybenzoyl) methyl] pyridinium iodide are obtained as a light brown solid.

15,4 g této piridiniové soli se přidá ke 100 ml p-methoxybenzylaminu a směs se zahřívá 18 hodin pod dusíkem a za míchání na 80 °C. Po ochlazení se ke směsi přidá 200 ml ethylacetátu a 150 ml vody. Ethylасеtátová fáze se oddělí a vodná fáze se extrahuje 150 ml ethylacetátu. Spojené ethylасеtátové roztoky se promyjí postupně 2x 150 ml zředěné kyseliny sodné, 150 ml vodného roztoku uhličitanu sodného a roztokem kuchyňské soli, suší se přes noc a odpaří se. Získá se 15 g oleje, který se čistí chromatografií na silikagelu směsí hexan/ethylacetát. Odpařením rozpouštědla z eluátu a krystalizací zbytku z methanolu se získá 6,3 g 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)-benzamidu ve formě bezbarvých jehliček o t. t. 87-88 °C.15.4 g of this piridinium salt are added to 100 ml of p-methoxybenzylamine and the mixture is heated under nitrogen and stirred at 80 ° C for 18 hours. After cooling, 200 ml of ethyl acetate and 150 ml of water were added to the mixture. The ethyl acetate phase is separated and the aqueous phase is extracted with 150 ml of ethyl acetate. The combined ethyl acetate solutions were washed successively with 2 x 150 ml dilute sodium acid, 150 ml aqueous sodium carbonate solution and brine, dried overnight and evaporated. 15 g of an oil are obtained which is purified by chromatography on silica gel with hexane / ethyl acetate. Evaporation of the solvent from the eluate and crystallization of the residue from methanol gave 6.3 g of 4-ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl) -benzamide as colorless needles, mp 87-88 ° C.

Příklad 4Example 4

Analogicky podle příkladu 3 se získá s 2'-hydroxy-6?-methoxy-4'-(3-»ethyl-2-butenyloxy)acetofenonem místo 4'-ethoxy-2*-hydroxy-6*-methoxyacetofenonu 2-hydroxy-6-methoxyCS 270 551 B2Analogously to Example 3, 2'-hydroxy-6 ? -methoxy-4 '- (3- »ethyl-2-butenyloxy) acetophenone instead of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone 2-hydroxy-6-methoxyCS 270 551 B2

-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl) bensamidve formě bezbarvýoh krystalů o teplotě tání 48-46,5 °C (z petroletheru).-4- (3-methyl-2-butenyloxy) -N- (p-methoxybenzyl) benzamide as colorless crystals, m.p. 48-46.5 ° C (from petroleum ether).

Analogicky podle příkladu 1 ee připraví;Analogously to Example 1 ee was prepared;

, -^Γρ-ηιΗ «уl-twiino)karbonyl7-3-ethoxy-3-methoxyfenyXacetát, t. t. 121 už 122 °U| ?-/Γρ-αηίeylamino)karbonyl7-3,5-dimethoxyfenyl-ethyXkarbonát, t· t· 123 až 124>5 °0| ?.-/Гр-anisylamino)karbonyl7-3,5-dimethoxyfenyl-oktadekanoát, t. t. 88 až 89 °C;, - (4-chloro-2-ylamino) carbonyl-3-ethoxy-3-methoxyphenyl acetate, m.p. ? - (Γρ-αηίeylamino) carbonyl7-3,5-dimethoxyphenyl-ethylcarbonate, mp 123-124> 5 ° 0 | R-N (N-anisylamino) carbonyl-3,5-dimethoxyphenyl octadecanoate, mp 88-89 ° C;

2-{/~/p-(allyloxy)benzyl7 omino7karbonyX )-3,5-dimethoxyfenyX-oktadekanoát, t· t. 88 až °C;2 - {[p - (allyloxy) benzyl (omino) carbonyl] -3,5-dimethoxyphenyl] octadecanoate, m.p. 88 DEG-C;

- Д’p-an i sy 1 am ino) к arb ony 17-3,5-dimethoxy feny lbenzoát, t· t. 124,5 až 125>5 °C|- Д'p-an i sy 1 am ino) k arbony 17-3,5-dimethoxyphenylbenzoate, mp 124,5 to 125> 5 ° C |

2-{/*/₽-( allyloxy)benzyl7amino7karbonyl}-3>5-dimethoxyfenylbenzoát, t· t. 105 až 106 °0;2 - {(R) - (allyloxy) benzyl7-aminocarbonyl} -3,5-dimethoxyphenylbenzoate, mp 105-106 ° C;

2-/rp-anisylamino)karbonyl7-5-ethoxy-3-ttethoxyrenyl-dihydrogenfosfát, t· t. 162 až2- (β-anisylamino) carbonyl7-5-ethoxy-3-tethoxyrenyl dihydrogen phosphate, mp 162-

163,5 °C;163.5 ° C;

2-/Тp-anisylamino)karbony17-3,5-dimethoxyfenyl-dihydrogenfosfát, t. t. 160,5 až 162,5 °C; 2-/rp-anÍ8ylamino)karbonyl7-3,5-dimethoxyfenyl-tetra-0-aoetyl-p-D-glukopyranoeid, t. t. 73*až 76 °C;2- (β-anisylamino) carbonyl-3,5-dimethoxyphenyl dihydrogen phosphate, m.p. 160.5-162.5 ° C; 2- (β-amino (carbamino) carbonyl) -3,5,5-dimethoxyphenyl-tetra-O-acetyl-β-D-glucopyranoeid, mp 73 ° -76 ° C;

2-Др-ani syl amino) karbonyl7*3,5-dimethoxy fenyl-/J-D-glukopyranosid, t· t< 132 až 133 °C| 2-hydroxy-6-methoxy-4-propoxy-N(p-methoxybenzyl)benzamid, t· t. 96,5 až 97,5 °C; 4-(allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)benzamid, t. t· 69>5 až 70 0Q, dvojsodná sůl 2-/rp-anisylamino)karbonyl7-3-»ethoxy-5-pikopoxyfenylfosfátu, t· t· 116 až 1 19 °C.2-D-α-amino amino) carbonyl 7 * 3,5-dimethoxyphenyl- N -dlucopyranoside, mp <132-133 ° C | 2-hydroxy-6-methoxy-4-propoxy-N (p-methoxybenzyl) benzamide, mp 96.5-97.5 ° C; 4- (allyloxy) -2-hydroxy-6-methoxy-N- (p-methoxybenzyl) benzamide, m.p. 69 > 5 to 70 ° C, 2- (β-anisylamino) carbonyl-3- (ethoxy) disodium salt -5-pi to opoxyphenyl phosphate, mp 116-119 ° C.

Příklad AExample A

Obvyklým způsobem se připraví tablety a následujícím složením složek:Tablets are prepared in the usual manner with the following composition of ingredients:

účinná složka (sloučenina vzorce I) 300 mg suchá laktóza 200 mg mikrokrystalická celulóza 30 mg polyvinylpyrrolidon 5 ng stearan hořečnatý 4 mgactive ingredient (compound of formula I) 300 mg dry lactose 200 mg microcrystalline cellulose 30 mg polyvinylpyrrolidone 5 ng magnesium stearate 4 mg

Příklad ВExample В

Známým způsobem ee mohou připravit kapky pro intranasální podání e následujícím obsahem složek:In a known manner, ee can prepare drops for intranasal administration with the following ingredients:

účinná složka (sloučenina I) 0,1 mg povrchově aktivní prostředek 0,05 mg propylenglykol/voda (1 ; 1 obj,. dílů) do 1 mlActive ingredient (Compound I) 0.1 mg surfactant 0.05 mg propylene glycol / water (1; 1 v / v) per ml

Příznivé koncentrační rozmezí pro účinnou složku je 0,001-1 mg/ml·A favorable concentration range for the active ingredient is 0.001-1 mg / ml ·

Příklad CExample C

Známým způsobem se mohou připravit pastilky a následujícím obsahem složek:In a known manner, lozenges can be prepared with the following ingredients:

účinná složka (sloučenina vzorce I) 0,1g práškový cukr 1,6g arabská guma 0,2g dextrin 0,1g chuíové látky 0,001 gactive ingredient (compound of formula I) 0.1g powdered sugar 1.6g gum arabic 0.2g dextrin 0.1g flavor 0.001 g

CS 270 551 B2CS 270 551 B2

Claims (6)

1. Způsob přípravy tetrasubstituovaných benzenových derivátů obecného vzorce I (I), kde.Rj představuje hydroxyskupinu, fosfonooxyskupinu, případně acetylovanouy3-D-glukopyranosyloxyskupinu, alkanoyloxy skupinu se 2 až 18 atomy uhlíku, benzyloxy ekupinu nebo ethoxykarbonyloxyskupinu, R2 představuje alkoxyskupinu s 1 až 6 atomy uhlíku nebo alkenyloxyskupinu se 2 až 7 atomy uhlíku, Rj představuje methyl, p-methoxyfenyl, benzyl případně substituovaný hydroxyskupinou, chlorem, methylem, alkoxyskupinou s 1. až 6 atomy uhlíku, methylthio skupinou, dime thy lamino skupinou, allyloxy skupinou, benzyloxy skupinou nebo methylendioxyskupinou, pyridylmethyl, furfuryl, thenyl, tetrahydrothenyl nebo pyrrolylmethyl, a farmaceuticky použitelných solí, vyznačující se tím, že se acetofenon obecného vzorce II (II), kde Rj a R^ mají význam uvedený ve vzorci I, nechá reagovat výhodně při 100 °C s jodem v terciárním aminu a získaná sůl se nechá reagovat s aminem obecného vzorce IIIA process for the preparation of tetrasubstituted benzene derivatives of the general formula I (I), wherein R 1 is hydroxy, phosphonooxy, optionally acetylated β-D-glucopyranosyloxy, C 2 -C 18 alkanoyloxy, benzyloxy or ethoxycarbonyloxy, R 2 is alkoxy Or Ceny-C alk alk alkenyloxy, Rj is methyl, p-methoxyphenyl, benzyl optionally substituted by hydroxy, chloro, methyl, C až-C alko alko alkoxy, methylthio, dimethylamino, allyloxy, benzyloxy or a methylenedioxy group, pyridylmethyl, furfuryl, thenyl, tetrahydrothenyl or pyrrolylmethyl, and pharmaceutically usable salts, characterized in that the acetophenone of formula II (II), wherein R1 and R1 are as defined in formula I, is preferably reacted at 100%. ° C with iodine in a tertiary amine and the obtained salt is reacted with amines III R3 - NH2 (III), kde R^ má význam uvedený ve vzorci I, a získaná sloučenina se případně převede na farmaceuticky použitelnou sůl·R 3 - NH 2 (III), wherein R 3 is as defined in formula I, and the compound obtained is optionally converted to a pharmaceutically acceptable salt; 2. Způsob podle bodu 1, vyznačující se tím, že se použijí sloučeniny vzorce II а III, kde Rj a R^ mají výěe uvedený význam a R2 je alkoxyskupina a 1 až 6 atomy uhlíku.2. A process according to claim 1, wherein R @ 1 and R @ 2 are as defined above and R @ 2 is alkoxy having 1 to 6 carbon atoms. 3. Způsob podle bodu 1, vyznačující se tím, že se použijí sloučeniny vzorce II a IIX, kde Rj je hydroxyskupina, alkanoyloxyskupina se 2 až 18 atomy uhlíku, benzyloxyskupina, fosfonooxyskupina, ethoxykarbonyloxyskupina, H2 je alkoxyskupina s 1 až 6 atomy uhlíku nebo alkonyloxyskupina se 2 až 7 atomy uhlíku a R^ je methoxyfenyl.3. The method according to claim 1, characterized in that the compounds of formula II and IIx, wherein R is hydroxy, alkanoyloxy having 2 to 18 carbon atoms, benzyloxy, phosphonooxy, ethoxycarbonyloxy, H 2 is alkoxy of 1 to 6 carbon atoms or (C až-Ckon) alkyloxy group and R ^ is methoxyphenyl. 4· Způsob podle bodu 1, vyznačující se tím, Že se к přípravě N-p-(dimethylanino)-benzyl-2-hydroxy-4,6-dimethoxýbenzamidu použijí jako výchozí látky sloučeniny vzorce II а III, kde R^ je hydroxyskupina, R2 je methoxyskupina a je p-dimethylaminobenzyl.4 · A method according to claim 1, characterized in that the preparation of ß к (dimethylanino) -benzyl-2-hydroxy-4,6-dimethoxybenzamide used as starting material a compound of formula II а III wherein R is hydroxy, R 2 is methoxy and is p-dimethylaminobenzyl. 5. Způsob podle bodu 1, vyznačující se tím, že se к přípravě 4-ethoxy-2-hydroxy-6-methoxy-N-(p-rnethoxýbenzyl) benzamidu použijí jako výchosí látky sloučeniny vzorce II а III, kde Rj je hydroxyskupina, R2 je methoxyskupina a R^ je methoxybenzyl.5. A process according to claim 1, wherein the starting materials of the compounds of formula II and III are used as starting materials for the preparation of 4-ethoxy-2-hydroxy-6-methoxy-N- (p-methoxybenzyl) benzamide, wherein R1 is hydroxy, R 2 is methoxy and R is methoxybenzyl. 6. Způsob podle bodu 1, vyznačující se tím, že se к přípravě 2-hydroxy-6-methoxy~4-(3-methyl-2-butenyloxy)-N-(p-methoxýbenzyl) benzamidu použijí jako výchozí látky sloučeniny vzorce II а III, kde R^ je hydroxyskupina, R2 je 3-methyl-2-butenyloxyskupina a R^ je p-methoxybenzyl·6. The process of claim 1, wherein the starting materials of the compound of formula II are used to prepare 2-hydroxy-6-methoxy-4- (3-methyl-2-butenyloxy) -N- (p-methoxybenzyl) benzamide. and III, where R 1 is hydroxy, R 2 is 3-methyl-2-butenyloxy and R 1 is p-methoxybenzyl;
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ES8308839A1 (en) 1983-10-01
ES8308841A1 (en) 1983-10-01
IL64266A (en) 1985-12-31
GR81318B (en) 1984-12-11
EP0051819A2 (en) 1982-05-19
ZW26281A1 (en) 1982-06-02
BR8107320A (en) 1982-08-03
FI813543L (en) 1982-05-13
CA1206964A (en) 1986-07-02
CU21424A (en) 1983-05-05
ES516194A0 (en) 1983-10-01
DK465581A (en) 1982-05-13
HU189991B (en) 1986-08-28
ES8308840A1 (en) 1983-10-01
NO813828L (en) 1982-05-13
NZ198879A (en) 1985-02-28
AU7730581A (en) 1982-05-20
AU543311B2 (en) 1985-04-18
ES516193A0 (en) 1983-10-01

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