CA1183541A - Phenylethylene derivatives, their preparation and their use as drugs - Google Patents
Phenylethylene derivatives, their preparation and their use as drugsInfo
- Publication number
- CA1183541A CA1183541A CA000419140A CA419140A CA1183541A CA 1183541 A CA1183541 A CA 1183541A CA 000419140 A CA000419140 A CA 000419140A CA 419140 A CA419140 A CA 419140A CA 1183541 A CA1183541 A CA 1183541A
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- Prior art keywords
- methyl
- formula
- alkyl
- compound
- tetramethyl
- Prior art date
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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)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to phenylethylene derivatives of the formula (I)
The present invention relates to phenylethylene derivatives of the formula (I)
Description
~ 5 ~ ~ ~.Z. 0050/,5710/711/712 PhenyLethylene derivatives, the;r preparat;on and their use as drugs.
The present invent;on relates to phenylethylene der;vatives, processes for their preparation, and thera-peutic agents conta;n;ng these compounds and the;r use in combating disorders.
German Laid-Open Application DOS 2,854,354 d;s-closes that st;lbene der;vat;ves have pharmacolog;cal actions when used for topical and systemic therapy of neo-plasms, acne, psorias;s and other dermatological dis~
orders. Ho~ever, the pronounced toxic effect or side effect of these compounds is particularly d;sadvantageous~
and renders them substantially unsuitable as agents for the topical and systemic therapy of the above disorders.
The d;sadvantageous effect of the st;lbene derivatives of German La;d-Open Applicat1on DOS 2,854,354 is described by, for example, A. Kistler in Calcified Tissue Inter-nat;onal 33 ~ (1981), Z49-254, and is evident in particular in repeated administration to rodents by the method published by R.C. Moon et al CCancer Research 39, (1979), 1339-1346].
It is an object of the present ;nvent;on to pro-v;de compounds having a comparable intensity of action but less pronounced toxic side effects.
We have found that this object is achieved by phenylethylene derivatives of the formula ~h
The present invent;on relates to phenylethylene der;vatives, processes for their preparation, and thera-peutic agents conta;n;ng these compounds and the;r use in combating disorders.
German Laid-Open Application DOS 2,854,354 d;s-closes that st;lbene der;vat;ves have pharmacolog;cal actions when used for topical and systemic therapy of neo-plasms, acne, psorias;s and other dermatological dis~
orders. Ho~ever, the pronounced toxic effect or side effect of these compounds is particularly d;sadvantageous~
and renders them substantially unsuitable as agents for the topical and systemic therapy of the above disorders.
The d;sadvantageous effect of the st;lbene derivatives of German La;d-Open Applicat1on DOS 2,854,354 is described by, for example, A. Kistler in Calcified Tissue Inter-nat;onal 33 ~ (1981), Z49-254, and is evident in particular in repeated administration to rodents by the method published by R.C. Moon et al CCancer Research 39, (1979), 1339-1346].
It is an object of the present ;nvent;on to pro-v;de compounds having a comparable intensity of action but less pronounced toxic side effects.
We have found that this object is achieved by phenylethylene derivatives of the formula ~h
2 s o.z~ 0050~35710/711/712 C ~ C = C~ ~ ~5 1/ ~2 where A ;s alkylene wh;ch is unsubst;tuted or -s~bst;tuted by C1-C4-alkyl, R1 is hydrogen or methyl, R~ is hydrogen or methyl, R3 ;s hydrogen or C1-C~-alkyl, R4 ;s C1-C
alkyl and R5 ;s p-hydroxyphenyleneam;nocarbonyl or tetrazol-S-ylaminocarbonyl and, if R3 ;s C1-C8-aLkyl, may furthermore be carboxyl or c2-C4-carbalkoxy, and, where relevant~ their salts with phys;ologically tolerated bases.
A ;s preferably an unsubstituted or me~hyl-substituted methylene or ethylene group.
Particularly useful compounds are those in wh;ch the phenyl r;ngs are located trans to one another.
The C-C bond represented by a wavy l;ne can be either above or below t~he plane of the paper, and accord-;ngly belong to a c;s (Z) or a trans (E) compound.
Typ;cal e~amples of novel compounds are ethyl 4~C2 methyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl~-benzoate, 4-C2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl]-benzoic acid, 4-C2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzo;c acid, ethyl 4-C2-methyl-2-~1,1,o-trimethyl-1,2,3,4-tetrahydro-naphth-7-yl)-vinyl~-benzoate, ~ 3 ~ O.Z. 0050/35710/711/712 ethyl 4-C2-ethyl-2~ 1,4,4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl]-benzoate, 4-C2-ethyl-2~(1,1,4,4,6~pentamethyl-1,2,3,4-tetrahydro~
naphth-7-yl)-v;nyl~-benzoic acid, ethyl 4-C2-methyl-2-~1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benz.oate, - -4-C2-methyl-2 (1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetra-hydronaphth-7-yl)~v;nyl]-benzoic acid, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoic acid, -~
ethyl 4-C2-methylw2-(1,1,4,4-tetramethyl-6-;sopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoate, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-~etra-hydronaphth 7-yl)-vinyll-benzo;c acid, ethyl 4OC2 methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-~enzoate, methyl 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-v;nyl~-benzoate, ethyl 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoate, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-butyl.-1,2,3,4-tetrahydronaphth~7-yl)-v;nyl~-benzo;c acid~
ethyl 4-C2-methyl-2-(1,1,4,4-te~ramethyl-6-(2-methyl-6-(2-methylpropyl)-1,2~3,4-tetrahydronaphth-70yl)-v;nyl]-benzoate, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6 (Zomethylpropyl)-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoic acid, ethyl 4-C2-methyl-2-(1,1,3,4,4,6-hexamethyl-1,2,3,4-tetra hydronaphth-7-yl)-vinyl~-benzoate,
alkyl and R5 ;s p-hydroxyphenyleneam;nocarbonyl or tetrazol-S-ylaminocarbonyl and, if R3 ;s C1-C8-aLkyl, may furthermore be carboxyl or c2-C4-carbalkoxy, and, where relevant~ their salts with phys;ologically tolerated bases.
A ;s preferably an unsubstituted or me~hyl-substituted methylene or ethylene group.
Particularly useful compounds are those in wh;ch the phenyl r;ngs are located trans to one another.
The C-C bond represented by a wavy l;ne can be either above or below t~he plane of the paper, and accord-;ngly belong to a c;s (Z) or a trans (E) compound.
Typ;cal e~amples of novel compounds are ethyl 4~C2 methyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl~-benzoate, 4-C2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl]-benzoic acid, 4-C2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzo;c acid, ethyl 4-C2-methyl-2-~1,1,o-trimethyl-1,2,3,4-tetrahydro-naphth-7-yl)-vinyl~-benzoate, ~ 3 ~ O.Z. 0050/35710/711/712 ethyl 4-C2-ethyl-2~ 1,4,4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl]-benzoate, 4-C2-ethyl-2~(1,1,4,4,6~pentamethyl-1,2,3,4-tetrahydro~
naphth-7-yl)-v;nyl~-benzoic acid, ethyl 4-C2-methyl-2-~1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benz.oate, - -4-C2-methyl-2 (1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetra-hydronaphth-7-yl)~v;nyl]-benzoic acid, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoic acid, -~
ethyl 4-C2-methylw2-(1,1,4,4-tetramethyl-6-;sopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoate, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-~etra-hydronaphth 7-yl)-vinyll-benzo;c acid, ethyl 4OC2 methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-~enzoate, methyl 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-v;nyl~-benzoate, ethyl 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoate, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-butyl.-1,2,3,4-tetrahydronaphth~7-yl)-v;nyl~-benzo;c acid~
ethyl 4-C2-methyl-2-(1,1,4,4-te~ramethyl-6-(2-methyl-6-(2-methylpropyl)-1,2~3,4-tetrahydronaphth-70yl)-v;nyl]-benzoate, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6 (Zomethylpropyl)-1,2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzoic acid, ethyl 4-C2-methyl-2-(1,1,3,4,4,6-hexamethyl-1,2,3,4-tetra hydronaphth-7-yl)-vinyl~-benzoate,
3~
_ ~ ~ 0 Z~ 0050/35710/711/712
_ ~ ~ 0 Z~ 0050/35710/711/712
4-C2-methyl-2-(1,1,3,4~4,6-hexamethyl~1~2,3,4-tetrahydro-naphth~7-yl)-vinyl~-benzo;c ac;d, ethyl 4-C2-methyl-2-(1,1,2,3,3,5-hexamethylindan-6-yl~-v;nyl~benzoate, propyl 4-C2-methyl 2-(1,1,2,3,3,5-hexamethylindan-6-yl)-v;nyl~-benzoate, - -isopropyl 4-C2-methyl-2-(1,1,2,3,3,5-hexamethylindan-6-yl)-v;nyl~-benzoate, 4-t2-methyl-2-(1,1,2,3,3,5-hexamethyl;ndan-6 yl)-v;nyl~-benzo;c acid,4-C2-methyl-2-(1,1,3,3,5 pentamethyl;ndan-6-yl)-Y;nylJ-ben 2 oic acid, methyl 4 C2-methyl-2-(1,1,3,3,5-pentamethylindan-6-yl)-vinyl~-benzoate, ethyl 4-C2-methyl-2-(1,1,3,3,5-pentamethylindan-6-yl)-vinyl]-benzoate, - methyl 4-C2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl]-benzoate, propyl 4-C2-methyl-2-(1,1,4,4,6-pentamethyl~1O2,3,4-tetra-hydronaphth-7-yl)-vinyl~-benzoate, ethyl 4-C2-ethyl-2-(1,1,4,4,6-pentamethyl-1,Z,3,4-tetra-hydronaphth-7-yl)-vinyl]-benzoate, 4-C2-ethyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-vinyl]-benzoic ac;d, methyl 4-C2-ethyl-2-(1,1,4~4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl]-benzoate, 4-C2-methyl-2 (1,1,4,4-tetramethyl-6-n-butyl-1,2,3,4-tetrahydronaphth-7 yl3-vinyl~-benzo;c acid, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-n-octyl-1,2,3,4-35gL~
- S - O.Z~ 0050/35710/711/712 tetrahydronaphth-7-yl)-v;nyl]-benzoic acid, 4-CZ-methyl-2-t1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-v;nyl~-benzo;c ac;d, 4-C2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4~tetrahydro-naphth-7-yl)-vinyl]-N-~tetrazol-S-yl)-benzamide, 4-C2~methyl 2-~1,1,4,4,6-pentamethyl-t,2,3,4-t-etrahydro-naphth-7-yl)-v;nyl~-N-tetrazol-5-yl)-b2nzamide, 4-C2 methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl~-N-(tetrazol-5-yl)-benzamide, 4-C2-methyl-2-~1,1,4~4-tetramethyl-6-;sopropyl-1,Z,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl~-benzamide, 4-C2-methyl-2-~1~1,2,3,3-pentamethylindan-6-yl)-vinylJ-N-(tetrazol-S~yl~-benzamide, 4-C2-methyl-2-(1~1~3,~3-tetramethylindan-6-yl)-vinyl~-N- -(tetrazol-5-yl~--benzam;de, 4-C2-methyl 2-~1,1,4,4-tetramethyl-6~propyl~1,2,3,4-tetra-hydronaphth~7-yl)-vinyl~-N-(tetrazol 5-yl)-benzamide, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methylpropyl)-1,2,3,4~tetrahydronaphth-7-yl)-v;nyl~-N-(tetrazol-S-yl)-benzam;de, 4-C2-methyl-2-~1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl~-N~tetrazol-5-yl)-benzam;de, 4-C2-ethyl-2-~1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphth-7-yl)-vinyl~-N-(tetrazol-5-yl)-benzamide, 4~C2-ethyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphthyl-7-yl)-v;nyl~-N-(tetrazol-S-yl)-benzam1de, 4-C2-methyl-2-~1,1-dimethyl-1,2,3,4-tetrahydronaphth-7-yl~-vinyl~-N-~tetrazol-~-yl)-benzam;de, 4-C2-methyl-1,1,6-trimethyl-1,2~3,4-tetrahydronaphth-7-35~
- 6 - O.Z. 0050/35710/711/712 yl)-v;nyl]-N-ttetrazol-5-yl)-benzam;de~
4-C2 methyl-2-(1,1~3,3,5-pentamethylindan-6~yl)-v;nyl~-N-(tetrazol-5-yl)-benzam;de, 4-C2-methyl-2-(1,1,2,3,3,5-hexamethyl;ndan-6-yl)-vinyl~-N-ttetrazol-5-yl)-benzam;de, 4-C2~methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphth-7-yl) vinyl]-benzoic acid 4-hydroxyan;lide, 4-C2-methyl-2-t1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl]-benzo;c ac;d 4-hydroxyan;l;de, 4-C2-methyl-2~ 1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetra-hydronaphth-7-yl)-v;nyl~-benzo;c ac;d 4-hydroxyan;l;de, 4-C2-methyl-Z-(1,1,4,4-tetramethyl-6-;sopropyl-1~2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzo;c ac;d 4-hydroxy-an;l;de, 4-C2-methyl 2-t1,1,2,3,3-pentamethylindan-6-yl?-~inyl]-benzo;c ac;d 4-hydroxyanilide, 4-C2-methyl-Z-~1,1,3,3-tetramethyl;ndan-6-yl)-vinyl~-benzo;c ac;d 4-hydroxyan;l;de, 4-C2-methyl-2-~1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetra-hydronaphth-7-yl)-v;nyl]-benzo;c ac;d 4 hydroxyan;l;de, 4-C2-methyl-2-(1,1,4,4~tetramethyl-6-(2-methylpropyl)-1,2,3,4-tetr3hydronaphth-7-yl)-vinyl]-benzoic ac;d 4 hydroxyan;lide, 4-C2-methyl-2-(1,1,4~4-tetramethyl-6-butyl-1,2,3,4-tetra-hydronaphth-7-yl)-v;nyl]~benzo;c acid 4-hydroxyan;l;de, 4-C2-ethyl-2-t1,1,4,4-tetramethyl 1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl~-benzo;c ac;d 4-hydroxyanil;de, 4-C2-ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-te~rahydro-naphth-7-yl)-vinyl]-benzo;c acid 4-hydroxyan;lide, - 7 - O.Z. 0050i35710/711/712 4-~2-methyl~2-(1O1-d;methyl-1~2~3~4-tetrahydronaphth-7-yl)-v;nyl~-benzoic ac;d 4-hydroxyanllide~
4-C2-methyl-2-(1,1,6 trimethyl 1,2,3,4-tetrahydronaphth- -7-yl)-v;nyl~obenzoic acid 4-hydroxyan;lide, 4-C2-methyl-2~(1,1,3O3,5-pentamethyl;ndan-~ yl)-v;nyl~-benzoic ac;d 4~hydroxyan;lide and - -4-C2-methyl-Z~(1,1,2,3,3,5-hexamethylindan~6-yl)-vinyl]-benzo;c ac;d 4-hydroxyanilide.
The compounds accord;ng to the invent;on, ~here they are der;vat;ves of the free benzoic ac;d, possess an ac;d;c hydrogen atom, and can therefore be converted w;th a base, in a convent;onal manner~ ;nto a phys;ologically tolerated, read;ly water-soluble salt. Examples of su;t-able salts are ammon;um salts~ alkal; metal salts, ;n - -part;cular those of sodium, potassium and lithium, alka-line earth metal s,alts~ ;n particular those of calc;um and magnesium, and salts w;~h su;table organic bases, such as lower alkylam;nesD eg. methylam;ne or ethylam;ne, lower alkylam;nes wh;ch are subst;tuted, ;n particular by hydroxyl, eg. diethanolamine, triethanolzm;ne and tris-(hydroxymethyl)-am;nomethane, p;perid;ne and morpholinec If the novel compounds possess a tetrazole radical, the;r alkali metal and alkal;ne earth metal salts may be prepared.
The novel compounds n1ay be prepared by a process characterized in that a) a compound of the fo~mula II
.
~`
35~L
o 8 - O.Z. OOS0/~5710/711/712 co-~4 \~ ~ R 3 I I
R R
where A, R1, R~, R3 and R4 have the mean;ngs g;ven above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
~6 ~ CH2-Po(oR7~2 III
~here R6 has the mean;ngs g;ven for R5 or ;s cyano, and R7 ;s C1-C4-alkyl, or b) a pho~phon;um salt of the formula IY
3 ~ f 3 1 ~9 A~ C~ CH-P ( C6H5 ) 3 X~3 XV
1/ \ 2 ~here A, R1~ R2~ R3 and R4 have the mean;ngs given above and X is chlorine or bromine, is subjected to a W;tt;g react;on w;th a benzaldehyde derivat;ve of the formula :~-CO~ V
where R6 has the above mean;ngs, and thereafter, if R6 ;s not carboxyl~ the resulting jt, ~.
s~ .
~3~
- 9 - O.Z. OOS0/3571C/711/712 compound may, if des;red, be hydrolyzed and the free ac;d, obtained either ;n th;s manner or directly, may, if des;red, then be reacted with a C1-C3-alcohol, p-hydroxy aniline or 5~aminotetrazole, and the compound thus obta;ned may, ;f des;red, be converted ;nto ;ts salt ~;th phys;ol49ically tolerated bases. ~ ~
The reactions a) and b) are carried out at not more than 100C, advantageously at from 20 to 50C~ under atmospheric pressure, or under superatmospheric pressure in a closed vessel, the mixture being heated, if appro-pr;ate, to the stated ~emperature.
These react;ons can be carr;ed out in the presence of a d;luent or solvent, for example a lower saturated d;alkyl ether, d;alkyl glycol ether or cycl;c ether, eg. - ~
d;ethyl ether, ethyl tert.-butyl ether, 1,2-d;n~ethoxy-ethane, tetrahydrofuran or dioxane, an aromat;c hydro-carbon, eg. benzene, an alkylbenzene, eg. toluene or xylene, a saturated al;phat;c hydrocarbon, eg~ hexane, heptane or ;sooctane, a lo~er al;phatic ketone, eg. ace-tone, methyl ethyl ketone or methyl isobutyl ketone, or ad;alkylformam;de, egO d;methylformamide or diethylforma-m;de, or a mixture of the above solvents. A cycl;c ether, eg. d;oxane or tetrahydrofuran, or, ;n part;cular, d;methylformamide, or a mixture of these, is preferably employed, the reaction taking place ln general at not more than 30C.
The react;on is carried out in the presence of a deprotonat;ng agent for the phosphorus compound (III).
Su;table compounds of this type are alkali metal hydrides ~ ~ ~3S~
- 10 ~ O.Z. 0050/35710/711/712 and alkali metal amides~ n particular ~hose of sod;um and potass;um, the sodium and potassium salts of dimethyl-sulfoxide, alkyl-l;thium compounds, eg. n-butyl-l;th;um, and alkali metal alcoholates~ preferably sod;um methylate and sodium ethylate.
When an aliphatic epoxide compound~ preferably butylene o~ide, ;s used, it ;s poss;ble to carry out the reac~;on w;thout the addition of other agents. Al;phatic epoxide compounds are thus solvent and deprotonat;ng agent at the same t;me. When butylene ox;de ;s employed, the reaction can be carried out at the boil;ng po;nt of the react;on mixture or at about 100C, ;n a closed vessel, and at superat~aspher;c pressure.
To react an acid I, where R5 is COOH, with a C1-C3-alcohol, p-hydroxyanil;ne or 5-aminotetrazole, the ac;d is converted ;nto an act;vated derivat;ve of the formula I ~here R is COX and X is a leav;ng group.
X is an ac;d rad;cal, eg. halogen, ;n part;cular chlor;ne or brom;ne, or the N hydroxysucc;nimide radical.
The reaction is carr;ed out at not more than 50C
under atmospher;c pressure, or under superatmospher;c pressure ;n a closed vessel.
Th;s react;on can be carr;ed out in the presence of a d;luent or solvent, for example a lower saturated d;alkyl ether, d;alkyl glycol ether or cycl;c ether, such as d;ethyl ether, ethyl tert.-butyl ether, 1,2 d;methoxy-ethane, tetrahydrofuran or dioxane, an aromat;c hydro-carbon, such as benzene, an alkylbenzene, such as totuene or xylene, a saturated al;phatic hydrocarbon, such as 3~
~ O.Z. 0050/35710/711/712 hexane, heptane or isooctane, a lower aliphat;c ke~one, such as acetone, methyl ethyl ketone or methyl ;sobutyl ketone, or a d;alkylformamide, such as dimethylformam;de or diethylformamide, or a m;xture of the stated solvents~
The linear or cyclic ether, eg. d;ethyl ether or tetra-hydrofuran, or, ;n part;cular, d;~ethylformam;~ ;s pre-ferably used, the reaction ta~ing place ;n general at not more than 3ûC.
The react;on is convent;onally carr;ed out in the presence of a base as the acid acceptor~ Su;table bases are aLkali metal carbonates and b;carbonate~s, ;n part;c~-lar those of sod;um and potass;um, tert;ary organic bases, eg. pyr;d;ne, and lower tr;al~ylam;nes, eg. trimethyl-am;ne and tr;ethylam;ne. The base ;s employed in a - ~ -sto;ch;ometr;c amount or in a slight excess, based on the benzoy~ halide used.
In another possible method of preparing the novel ac;d der;vatives, the corresponding free acid I, ~here R5 is COOH, is used as a starting material, and ;s reacted with a C1-C3-alcohol, p-am;nophenol or am;notetrazole, ;n a solvent, ;n the presence of a carboxyl-activat;ng agent wh;ch el;m;nates water.
Su;table act;vat;ng reagents which e~;m;nate water are the reagents convent;onally used in pept;de synthes;s ~cf. The Pept;des, Volume I, pages 77-128, Academ;c Press, N.Y., ~965). The general pr;nciple of the react;on compr;ses activation of the carboxyl group, for example by treatment with a carbodiimide, eg. N,N3- -d;cyclohexylcarbodi;m;de, or by intermediate formation of 3~
.
- 12 - o.z. 0050/35710/711/712 an acid a2;de, a mixed anhydride ~for example with a mono- -ester of carbon;c acid), an activated ester (for example the p nitrophenyl ester) or a heterocycl;c amide (for example an im;dazolide) of the corresponding benzoic acid.
A compound in ~h;ch the carboxyl group has been activated may then be reacted with a c1-C3-alco~ol, p-aminophenol or am;notetrazole to g;ve the acid deriva-t;ve according to the invention. The activation and linkage reactions can be carried out in a solYent, pre ferably in N~N-dimethyLformamide~ tetrahydrofuran, dioxane, methylene chlor;de, n;tromethane, acetonitr;le, d;methyl-sulfox;de, N,N-d;methylacetamide or hexamethylphosphoro-tr;am;de. The two stages, ie~ the reaction of ~he ac;d w;th the coupl;ng agent and the reaction of the acti~ated- -intermed;ate ~ith p-am;nophenol may be carried out at from 20 to 100C, either stepw;se by isolat;ng the acti-vated intermed;ate before adding the p-aminophenol, or advantageously by carrying out the stages in success;on, without isolation of intermediates.
In a preferred l;nkage method, the reaction is carr;ed out using N~N-carbonyld;imidazole in dimethyl-formam;de, the react;on temperature be;ng from 20 to 60C
for both stages.
The compounds of the formula I may be pure c;s or trans iSomerS or mixtures of these. A mixture can be determined quantitatively by HPLC analysis or by a 13C-NMR
spectrum, and the particular desired ;somer can be isolated in pure form by fractional crystallizat;on,-chromatography ~;th, for example, a s;l;ca gel column, or - ~3 ~ O.Z~ 0050/35710/711/712 preparative HPLC. --The novel compounds and the;r physiologically tolerated salts can be used for the top;cal and system;c therapy and prophylaxis of ben;gn and malignant neoplasms and premal;gnant lesions, eg. precancers and c3rc;nomas of the skin, of the mucous membranes and of th~-;nternal organs~ in the top;cal and system;c therapy of acne, psor;as;s and other dermatolog;cal d;sorders accompan;ed by patholog;cally mod;f;ed keratin;zation, and for the treatment of rheumat;c disorders, ;n particular those of an ;nflammatory or degenerat;ve nature, wh;ch affect the jo;nts, musc-es, tendons and other parts of the motive apparatus. A preferred field of?iAdication, in add;t;on to the therapy of dermatolog;cal d;sorders, ;s - - -the prophylactic and therapeut;c treatment of precancers and tumors. In th;s f;eld, the lo~ toxicity of the com-pounds is advantageous.
The pharmacolog;cal actions can be demonstrated, for example, ;n the follow;ng test models:
1. Elim;nat;on of kerat;n;zat;on ;n tracheal cultures as a demonstrat;on of the ant;tumor act;on~
The test model ;s used to determine the ;ntr;ns;c property of the novel compounds of increas;ng the differ-ent;at;on of ep;thelial cells. The great sign;f;cance of th;s screen;ng method ;n pred;ct;ng the potent;al use of a new retino;d for the prevention of tumors ;n ep;thel;al t;ssue ;s generally recogn;zed. Moreover, ;t ;s known that every ;n v;tro test system has d;sadvantages ;n-respect of the pred;ction of ;n vivo act;vity. Apart from 3S9~:~
- 14 - O.Z. 0050/35710/711/712 ~hese bas;c restrict;ons, tracheal cell cultures are one of the most useful methods of deternining the biological activity of novel retinoids.
The abil;ty of the test substances to eliminate keratin;zation ;n a defined ;n v;tro system was determined.
Tracheae of hamsters at a very early stage of v;-tam;n A
def;c;ency were used for culture. When the trachea was removed, the an;mals~ which had been weaned at 21 days, were from 29 to 30 days old and st;ll showed an ;ncrease 10 ;n we;ght. The;r average we;ght was from 47 to 52 9 The tracheal epithelium was in general slightly columnar or pavement-like and had only ;solated areas of squamous metaplas;a. Each trachea was opened along the membrane-l;ke dorsal wall, from the larynx to the car;na, and --cultured ;n a serum-free med;um ~CMRL-1066 supplemented by 1.0 ~g/nl of crystalL;ne bov;ne ;nsulin, 0.1 ,ug/ml of hydrocort;sone hemisuccinate~ 2 mM of glutam;ne, 10~
units/ml of penicillin and 10~ ~g/ml of streptomycin).
The cultures were aerated with a m;xture of 50% of oxygen, 45X of n;trogen and 5X of carbon d;oxide, and the culture d;shes were shaken gently to br;ng the tracheae ;nto contact w;th the gas and the culture med;um. All tracheae were in;tially kept for 3 days ;n the culture med;um without the addition of ret1no;d. After this per;od, some tracheae were removed. Almost all of these exh;bited substant;al squamous metaplasia. The rema;ning tracheae were divided into groups, wh;ch were then treated with the following addit;ves: -a) The test substance d;ssolved in spectroscopically pure l ~h35~,~
15 - O.Z. 0050/35710/711/712 dimethylsulfox;de (the final concentration of dimethyl-sulfox;de ;n the culture med;um was never greater than O . 1 X ) .
b) An equ;valent amount of d;methylsulfox;de ~;thout a further add;tive.
The nutrient med;um was changed three t;mes per week. After culture for 10 days, the rema;n;ng tracheae were worked up by being f;xed in 10% strength buffered formaldehyde solut;on and embedded ;n paraff;n. 5 ~m sect;ons through the center were sta;ned w;th hexatoxyl;n and eos;n, and exam;ned under the m;croscope to determ;ne if kerat;n and keratohyal;n were present; both were observed ;n about 90X of all control cultures kept ;n the absence of test substance. Dose effect curves of the - ~ -novel compounds iere recorded. Table 1 belo~ gives the extrapolated molar doses wh;ch suppress kerat;n;2at;0n in half the cultures (ED 50X).
Table 1:
Substance of example ED50 Cmoletliter~
7 1~10 11 18 3.10 12 19 1.10 12 26 1.10 12 V;tamin A acid 1.10 11 Moreover, the compounds accord;ng to the invent;on (in particular the compound of Example 2) induce cell d;fferentiat;on to give mature granulocytes ;n leukemia 3~
- 16 - O.Z. 0053/35710/711/712 cells of patients hav;ng promyelocyt;c leukem;a~ -2. The ant;arthr;t;c act;on of the novel compounds can be determined in a conventional manner ;n an an;mal experiment based on the adjuvant arthrit;s model.
3. The dermatological activity, for example ;n the treatment of acne, can be demonst~ated, ;nter atia, by means of the comedolyt;c act;v;ty.
Th~ development of comedos was ;nduced by one top;cal appl;cat;on of 0~5 ml per day, onto both ears of alb;no rabb;ts, of 5% of tar ;n PolyanR (es~er of lanolin alcohol and l;nolen;c ac;d, produced by Amerchol Corp., U.S.A.), the application be;ng carried out on 5 successive days per week over a per;od of two weeks. Thereafter, the test substances ;n ethanol/propylene glycol (70:30, v/v, 0.5 ml) were appl;ed top;cally onto the ;nner sk;n area of one ear of each rab~;t once per day on 5 success;ve days per week over a period of t~o ~eeks. The second ear of each an;mal served as an untreated control.
After further treatment for 7Z hours ~ith the test substance, the rabb;ts were sacr;f;ced. A sk;n sample of about 6 cm2 was taken from each aur;cle just outs;de the oratory passage, and th;s sample ~as d;v;ded ;nto sect;ons of about 1 cm2. These pieces of sk;n were ;mmersed for 2 m;nutes ;n warm water at 60C. The ep;derm7s was care-fully peeled off using the flat end of a spatula and a small forceps, and was placed, dermal s;de up, on the sl;de. After dry;ng in air overn;ght, the test strips were assessed under a stereom;croscope. Follicular p;eces with keratose mater;al remained intact. The comedos were ~3~
- 17 - o~z~ 0050/35710/711/712 recognizable as discr te, cylindrical to round keratose particles ~hich ~ere of simi lar appearance and whose size and number ~ere proport;onaL to the act;v;ty of the test substance. The comedo~yt;ç effect ~3s determ;ned as the decrease ;n the number of comedos, in ~, compared ~;th the control ear (cf~ Table 2). - -Table 2:
Substance of example Comedolyt;c act;v;ty in %
2 7~
6 b8 ~2 vitam;n A ac;d - 67 4. Demonstrat;on of the ability of the compcunds to reduce the number of utricul; in the Rh;no mouse model served as a further measure of the dermatolog;cal act;v;ty.
In th;s method, ~h;ch ~as descr;bed by L.H. Kl;gman et al ;n The Journal of ~nvest;gat;ve Dermatology 73 ~1979)~
354-358, cysts wh;ch are present in Rhino mice as geneti-cally caused sk;n lesions, ;e. acne cysts, are caused to recede by adm;n;stration of the act;ve compoundr and ~he decrease ;s expressed as a %.
- 18 -O.Z. 0050/35710/711t712 TabLe 3 Substance of example Decrease ;n X
2 ~8 ~ 59 V;tam1n A ac;d 60
- S - O.Z~ 0050/35710/711/712 tetrahydronaphth-7-yl)-v;nyl]-benzoic acid, 4-CZ-methyl-2-t1,1,6-trimethyl-1,2,3,4-tetrahydronaphth-7-yl)-v;nyl~-benzo;c ac;d, 4-C2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4~tetrahydro-naphth-7-yl)-vinyl]-N-~tetrazol-S-yl)-benzamide, 4-C2~methyl 2-~1,1,4,4,6-pentamethyl-t,2,3,4-t-etrahydro-naphth-7-yl)-v;nyl~-N-tetrazol-5-yl)-b2nzamide, 4-C2 methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl~-N-(tetrazol-5-yl)-benzamide, 4-C2-methyl-2-~1,1,4~4-tetramethyl-6-;sopropyl-1,Z,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl~-benzamide, 4-C2-methyl-2-~1~1,2,3,3-pentamethylindan-6-yl)-vinylJ-N-(tetrazol-S~yl~-benzamide, 4-C2-methyl-2-(1~1~3,~3-tetramethylindan-6-yl)-vinyl~-N- -(tetrazol-5-yl~--benzam;de, 4-C2-methyl 2-~1,1,4,4-tetramethyl-6~propyl~1,2,3,4-tetra-hydronaphth~7-yl)-vinyl~-N-(tetrazol 5-yl)-benzamide, 4-C2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methylpropyl)-1,2,3,4~tetrahydronaphth-7-yl)-v;nyl~-N-(tetrazol-S-yl)-benzam;de, 4-C2-methyl-2-~1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetra-hydronaphth-7-yl)-vinyl~-N~tetrazol-5-yl)-benzam;de, 4-C2-ethyl-2-~1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphth-7-yl)-vinyl~-N-(tetrazol-5-yl)-benzamide, 4~C2-ethyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphthyl-7-yl)-v;nyl~-N-(tetrazol-S-yl)-benzam1de, 4-C2-methyl-2-~1,1-dimethyl-1,2,3,4-tetrahydronaphth-7-yl~-vinyl~-N-~tetrazol-~-yl)-benzam;de, 4-C2-methyl-1,1,6-trimethyl-1,2~3,4-tetrahydronaphth-7-35~
- 6 - O.Z. 0050/35710/711/712 yl)-v;nyl]-N-ttetrazol-5-yl)-benzam;de~
4-C2 methyl-2-(1,1~3,3,5-pentamethylindan-6~yl)-v;nyl~-N-(tetrazol-5-yl)-benzam;de, 4-C2-methyl-2-(1,1,2,3,3,5-hexamethyl;ndan-6-yl)-vinyl~-N-ttetrazol-5-yl)-benzam;de, 4-C2~methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphth-7-yl) vinyl]-benzoic acid 4-hydroxyan;lide, 4-C2-methyl-2-t1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl]-benzo;c ac;d 4-hydroxyan;l;de, 4-C2-methyl-2~ 1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetra-hydronaphth-7-yl)-v;nyl~-benzo;c ac;d 4-hydroxyan;l;de, 4-C2-methyl-Z-(1,1,4,4-tetramethyl-6-;sopropyl-1~2,3,4-tetrahydronaphth-7-yl)-vinyl~-benzo;c ac;d 4-hydroxy-an;l;de, 4-C2-methyl 2-t1,1,2,3,3-pentamethylindan-6-yl?-~inyl]-benzo;c ac;d 4-hydroxyanilide, 4-C2-methyl-Z-~1,1,3,3-tetramethyl;ndan-6-yl)-vinyl~-benzo;c ac;d 4-hydroxyan;l;de, 4-C2-methyl-2-~1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetra-hydronaphth-7-yl)-v;nyl]-benzo;c ac;d 4 hydroxyan;l;de, 4-C2-methyl-2-(1,1,4,4~tetramethyl-6-(2-methylpropyl)-1,2,3,4-tetr3hydronaphth-7-yl)-vinyl]-benzoic ac;d 4 hydroxyan;lide, 4-C2-methyl-2-(1,1,4~4-tetramethyl-6-butyl-1,2,3,4-tetra-hydronaphth-7-yl)-v;nyl]~benzo;c acid 4-hydroxyan;l;de, 4-C2-ethyl-2-t1,1,4,4-tetramethyl 1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl~-benzo;c ac;d 4-hydroxyanil;de, 4-C2-ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-te~rahydro-naphth-7-yl)-vinyl]-benzo;c acid 4-hydroxyan;lide, - 7 - O.Z. 0050i35710/711/712 4-~2-methyl~2-(1O1-d;methyl-1~2~3~4-tetrahydronaphth-7-yl)-v;nyl~-benzoic ac;d 4-hydroxyanllide~
4-C2-methyl-2-(1,1,6 trimethyl 1,2,3,4-tetrahydronaphth- -7-yl)-v;nyl~obenzoic acid 4-hydroxyan;lide, 4-C2-methyl-2~(1,1,3O3,5-pentamethyl;ndan-~ yl)-v;nyl~-benzoic ac;d 4~hydroxyan;lide and - -4-C2-methyl-Z~(1,1,2,3,3,5-hexamethylindan~6-yl)-vinyl]-benzo;c ac;d 4-hydroxyanilide.
The compounds accord;ng to the invent;on, ~here they are der;vat;ves of the free benzoic ac;d, possess an ac;d;c hydrogen atom, and can therefore be converted w;th a base, in a convent;onal manner~ ;nto a phys;ologically tolerated, read;ly water-soluble salt. Examples of su;t-able salts are ammon;um salts~ alkal; metal salts, ;n - -part;cular those of sodium, potassium and lithium, alka-line earth metal s,alts~ ;n particular those of calc;um and magnesium, and salts w;~h su;table organic bases, such as lower alkylam;nesD eg. methylam;ne or ethylam;ne, lower alkylam;nes wh;ch are subst;tuted, ;n particular by hydroxyl, eg. diethanolamine, triethanolzm;ne and tris-(hydroxymethyl)-am;nomethane, p;perid;ne and morpholinec If the novel compounds possess a tetrazole radical, the;r alkali metal and alkal;ne earth metal salts may be prepared.
The novel compounds n1ay be prepared by a process characterized in that a) a compound of the fo~mula II
.
~`
35~L
o 8 - O.Z. OOS0/~5710/711/712 co-~4 \~ ~ R 3 I I
R R
where A, R1, R~, R3 and R4 have the mean;ngs g;ven above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
~6 ~ CH2-Po(oR7~2 III
~here R6 has the mean;ngs g;ven for R5 or ;s cyano, and R7 ;s C1-C4-alkyl, or b) a pho~phon;um salt of the formula IY
3 ~ f 3 1 ~9 A~ C~ CH-P ( C6H5 ) 3 X~3 XV
1/ \ 2 ~here A, R1~ R2~ R3 and R4 have the mean;ngs given above and X is chlorine or bromine, is subjected to a W;tt;g react;on w;th a benzaldehyde derivat;ve of the formula :~-CO~ V
where R6 has the above mean;ngs, and thereafter, if R6 ;s not carboxyl~ the resulting jt, ~.
s~ .
~3~
- 9 - O.Z. OOS0/3571C/711/712 compound may, if des;red, be hydrolyzed and the free ac;d, obtained either ;n th;s manner or directly, may, if des;red, then be reacted with a C1-C3-alcohol, p-hydroxy aniline or 5~aminotetrazole, and the compound thus obta;ned may, ;f des;red, be converted ;nto ;ts salt ~;th phys;ol49ically tolerated bases. ~ ~
The reactions a) and b) are carried out at not more than 100C, advantageously at from 20 to 50C~ under atmospheric pressure, or under superatmospheric pressure in a closed vessel, the mixture being heated, if appro-pr;ate, to the stated ~emperature.
These react;ons can be carr;ed out in the presence of a d;luent or solvent, for example a lower saturated d;alkyl ether, d;alkyl glycol ether or cycl;c ether, eg. - ~
d;ethyl ether, ethyl tert.-butyl ether, 1,2-d;n~ethoxy-ethane, tetrahydrofuran or dioxane, an aromat;c hydro-carbon, eg. benzene, an alkylbenzene, eg. toluene or xylene, a saturated al;phat;c hydrocarbon, eg~ hexane, heptane or ;sooctane, a lo~er al;phatic ketone, eg. ace-tone, methyl ethyl ketone or methyl isobutyl ketone, or ad;alkylformam;de, egO d;methylformamide or diethylforma-m;de, or a mixture of the above solvents. A cycl;c ether, eg. d;oxane or tetrahydrofuran, or, ;n part;cular, d;methylformamide, or a mixture of these, is preferably employed, the reaction taking place ln general at not more than 30C.
The react;on is carried out in the presence of a deprotonat;ng agent for the phosphorus compound (III).
Su;table compounds of this type are alkali metal hydrides ~ ~ ~3S~
- 10 ~ O.Z. 0050/35710/711/712 and alkali metal amides~ n particular ~hose of sod;um and potass;um, the sodium and potassium salts of dimethyl-sulfoxide, alkyl-l;thium compounds, eg. n-butyl-l;th;um, and alkali metal alcoholates~ preferably sod;um methylate and sodium ethylate.
When an aliphatic epoxide compound~ preferably butylene o~ide, ;s used, it ;s poss;ble to carry out the reac~;on w;thout the addition of other agents. Al;phatic epoxide compounds are thus solvent and deprotonat;ng agent at the same t;me. When butylene ox;de ;s employed, the reaction can be carried out at the boil;ng po;nt of the react;on mixture or at about 100C, ;n a closed vessel, and at superat~aspher;c pressure.
To react an acid I, where R5 is COOH, with a C1-C3-alcohol, p-hydroxyanil;ne or 5-aminotetrazole, the ac;d is converted ;nto an act;vated derivat;ve of the formula I ~here R is COX and X is a leav;ng group.
X is an ac;d rad;cal, eg. halogen, ;n part;cular chlor;ne or brom;ne, or the N hydroxysucc;nimide radical.
The reaction is carr;ed out at not more than 50C
under atmospher;c pressure, or under superatmospher;c pressure ;n a closed vessel.
Th;s react;on can be carr;ed out in the presence of a d;luent or solvent, for example a lower saturated d;alkyl ether, d;alkyl glycol ether or cycl;c ether, such as d;ethyl ether, ethyl tert.-butyl ether, 1,2 d;methoxy-ethane, tetrahydrofuran or dioxane, an aromat;c hydro-carbon, such as benzene, an alkylbenzene, such as totuene or xylene, a saturated al;phatic hydrocarbon, such as 3~
~ O.Z. 0050/35710/711/712 hexane, heptane or isooctane, a lower aliphat;c ke~one, such as acetone, methyl ethyl ketone or methyl ;sobutyl ketone, or a d;alkylformamide, such as dimethylformam;de or diethylformamide, or a m;xture of the stated solvents~
The linear or cyclic ether, eg. d;ethyl ether or tetra-hydrofuran, or, ;n part;cular, d;~ethylformam;~ ;s pre-ferably used, the reaction ta~ing place ;n general at not more than 3ûC.
The react;on is convent;onally carr;ed out in the presence of a base as the acid acceptor~ Su;table bases are aLkali metal carbonates and b;carbonate~s, ;n part;c~-lar those of sod;um and potass;um, tert;ary organic bases, eg. pyr;d;ne, and lower tr;al~ylam;nes, eg. trimethyl-am;ne and tr;ethylam;ne. The base ;s employed in a - ~ -sto;ch;ometr;c amount or in a slight excess, based on the benzoy~ halide used.
In another possible method of preparing the novel ac;d der;vatives, the corresponding free acid I, ~here R5 is COOH, is used as a starting material, and ;s reacted with a C1-C3-alcohol, p-am;nophenol or am;notetrazole, ;n a solvent, ;n the presence of a carboxyl-activat;ng agent wh;ch el;m;nates water.
Su;table act;vat;ng reagents which e~;m;nate water are the reagents convent;onally used in pept;de synthes;s ~cf. The Pept;des, Volume I, pages 77-128, Academ;c Press, N.Y., ~965). The general pr;nciple of the react;on compr;ses activation of the carboxyl group, for example by treatment with a carbodiimide, eg. N,N3- -d;cyclohexylcarbodi;m;de, or by intermediate formation of 3~
.
- 12 - o.z. 0050/35710/711/712 an acid a2;de, a mixed anhydride ~for example with a mono- -ester of carbon;c acid), an activated ester (for example the p nitrophenyl ester) or a heterocycl;c amide (for example an im;dazolide) of the corresponding benzoic acid.
A compound in ~h;ch the carboxyl group has been activated may then be reacted with a c1-C3-alco~ol, p-aminophenol or am;notetrazole to g;ve the acid deriva-t;ve according to the invention. The activation and linkage reactions can be carried out in a solYent, pre ferably in N~N-dimethyLformamide~ tetrahydrofuran, dioxane, methylene chlor;de, n;tromethane, acetonitr;le, d;methyl-sulfox;de, N,N-d;methylacetamide or hexamethylphosphoro-tr;am;de. The two stages, ie~ the reaction of ~he ac;d w;th the coupl;ng agent and the reaction of the acti~ated- -intermed;ate ~ith p-am;nophenol may be carried out at from 20 to 100C, either stepw;se by isolat;ng the acti-vated intermed;ate before adding the p-aminophenol, or advantageously by carrying out the stages in success;on, without isolation of intermediates.
In a preferred l;nkage method, the reaction is carr;ed out using N~N-carbonyld;imidazole in dimethyl-formam;de, the react;on temperature be;ng from 20 to 60C
for both stages.
The compounds of the formula I may be pure c;s or trans iSomerS or mixtures of these. A mixture can be determined quantitatively by HPLC analysis or by a 13C-NMR
spectrum, and the particular desired ;somer can be isolated in pure form by fractional crystallizat;on,-chromatography ~;th, for example, a s;l;ca gel column, or - ~3 ~ O.Z~ 0050/35710/711/712 preparative HPLC. --The novel compounds and the;r physiologically tolerated salts can be used for the top;cal and system;c therapy and prophylaxis of ben;gn and malignant neoplasms and premal;gnant lesions, eg. precancers and c3rc;nomas of the skin, of the mucous membranes and of th~-;nternal organs~ in the top;cal and system;c therapy of acne, psor;as;s and other dermatolog;cal d;sorders accompan;ed by patholog;cally mod;f;ed keratin;zation, and for the treatment of rheumat;c disorders, ;n particular those of an ;nflammatory or degenerat;ve nature, wh;ch affect the jo;nts, musc-es, tendons and other parts of the motive apparatus. A preferred field of?iAdication, in add;t;on to the therapy of dermatolog;cal d;sorders, ;s - - -the prophylactic and therapeut;c treatment of precancers and tumors. In th;s f;eld, the lo~ toxicity of the com-pounds is advantageous.
The pharmacolog;cal actions can be demonstrated, for example, ;n the follow;ng test models:
1. Elim;nat;on of kerat;n;zat;on ;n tracheal cultures as a demonstrat;on of the ant;tumor act;on~
The test model ;s used to determine the ;ntr;ns;c property of the novel compounds of increas;ng the differ-ent;at;on of ep;thelial cells. The great sign;f;cance of th;s screen;ng method ;n pred;ct;ng the potent;al use of a new retino;d for the prevention of tumors ;n ep;thel;al t;ssue ;s generally recogn;zed. Moreover, ;t ;s known that every ;n v;tro test system has d;sadvantages ;n-respect of the pred;ction of ;n vivo act;vity. Apart from 3S9~:~
- 14 - O.Z. 0050/35710/711/712 ~hese bas;c restrict;ons, tracheal cell cultures are one of the most useful methods of deternining the biological activity of novel retinoids.
The abil;ty of the test substances to eliminate keratin;zation ;n a defined ;n v;tro system was determined.
Tracheae of hamsters at a very early stage of v;-tam;n A
def;c;ency were used for culture. When the trachea was removed, the an;mals~ which had been weaned at 21 days, were from 29 to 30 days old and st;ll showed an ;ncrease 10 ;n we;ght. The;r average we;ght was from 47 to 52 9 The tracheal epithelium was in general slightly columnar or pavement-like and had only ;solated areas of squamous metaplas;a. Each trachea was opened along the membrane-l;ke dorsal wall, from the larynx to the car;na, and --cultured ;n a serum-free med;um ~CMRL-1066 supplemented by 1.0 ~g/nl of crystalL;ne bov;ne ;nsulin, 0.1 ,ug/ml of hydrocort;sone hemisuccinate~ 2 mM of glutam;ne, 10~
units/ml of penicillin and 10~ ~g/ml of streptomycin).
The cultures were aerated with a m;xture of 50% of oxygen, 45X of n;trogen and 5X of carbon d;oxide, and the culture d;shes were shaken gently to br;ng the tracheae ;nto contact w;th the gas and the culture med;um. All tracheae were in;tially kept for 3 days ;n the culture med;um without the addition of ret1no;d. After this per;od, some tracheae were removed. Almost all of these exh;bited substant;al squamous metaplasia. The rema;ning tracheae were divided into groups, wh;ch were then treated with the following addit;ves: -a) The test substance d;ssolved in spectroscopically pure l ~h35~,~
15 - O.Z. 0050/35710/711/712 dimethylsulfox;de (the final concentration of dimethyl-sulfox;de ;n the culture med;um was never greater than O . 1 X ) .
b) An equ;valent amount of d;methylsulfox;de ~;thout a further add;tive.
The nutrient med;um was changed three t;mes per week. After culture for 10 days, the rema;n;ng tracheae were worked up by being f;xed in 10% strength buffered formaldehyde solut;on and embedded ;n paraff;n. 5 ~m sect;ons through the center were sta;ned w;th hexatoxyl;n and eos;n, and exam;ned under the m;croscope to determ;ne if kerat;n and keratohyal;n were present; both were observed ;n about 90X of all control cultures kept ;n the absence of test substance. Dose effect curves of the - ~ -novel compounds iere recorded. Table 1 belo~ gives the extrapolated molar doses wh;ch suppress kerat;n;2at;0n in half the cultures (ED 50X).
Table 1:
Substance of example ED50 Cmoletliter~
7 1~10 11 18 3.10 12 19 1.10 12 26 1.10 12 V;tamin A acid 1.10 11 Moreover, the compounds accord;ng to the invent;on (in particular the compound of Example 2) induce cell d;fferentiat;on to give mature granulocytes ;n leukemia 3~
- 16 - O.Z. 0053/35710/711/712 cells of patients hav;ng promyelocyt;c leukem;a~ -2. The ant;arthr;t;c act;on of the novel compounds can be determined in a conventional manner ;n an an;mal experiment based on the adjuvant arthrit;s model.
3. The dermatological activity, for example ;n the treatment of acne, can be demonst~ated, ;nter atia, by means of the comedolyt;c act;v;ty.
Th~ development of comedos was ;nduced by one top;cal appl;cat;on of 0~5 ml per day, onto both ears of alb;no rabb;ts, of 5% of tar ;n PolyanR (es~er of lanolin alcohol and l;nolen;c ac;d, produced by Amerchol Corp., U.S.A.), the application be;ng carried out on 5 successive days per week over a per;od of two weeks. Thereafter, the test substances ;n ethanol/propylene glycol (70:30, v/v, 0.5 ml) were appl;ed top;cally onto the ;nner sk;n area of one ear of each rab~;t once per day on 5 success;ve days per week over a period of t~o ~eeks. The second ear of each an;mal served as an untreated control.
After further treatment for 7Z hours ~ith the test substance, the rabb;ts were sacr;f;ced. A sk;n sample of about 6 cm2 was taken from each aur;cle just outs;de the oratory passage, and th;s sample ~as d;v;ded ;nto sect;ons of about 1 cm2. These pieces of sk;n were ;mmersed for 2 m;nutes ;n warm water at 60C. The ep;derm7s was care-fully peeled off using the flat end of a spatula and a small forceps, and was placed, dermal s;de up, on the sl;de. After dry;ng in air overn;ght, the test strips were assessed under a stereom;croscope. Follicular p;eces with keratose mater;al remained intact. The comedos were ~3~
- 17 - o~z~ 0050/35710/711/712 recognizable as discr te, cylindrical to round keratose particles ~hich ~ere of simi lar appearance and whose size and number ~ere proport;onaL to the act;v;ty of the test substance. The comedo~yt;ç effect ~3s determ;ned as the decrease ;n the number of comedos, in ~, compared ~;th the control ear (cf~ Table 2). - -Table 2:
Substance of example Comedolyt;c act;v;ty in %
2 7~
6 b8 ~2 vitam;n A ac;d - 67 4. Demonstrat;on of the ability of the compcunds to reduce the number of utricul; in the Rh;no mouse model served as a further measure of the dermatolog;cal act;v;ty.
In th;s method, ~h;ch ~as descr;bed by L.H. Kl;gman et al ;n The Journal of ~nvest;gat;ve Dermatology 73 ~1979)~
354-358, cysts wh;ch are present in Rhino mice as geneti-cally caused sk;n lesions, ;e. acne cysts, are caused to recede by adm;n;stration of the act;ve compoundr and ~he decrease ;s expressed as a %.
- 18 -O.Z. 0050/35710/711t712 TabLe 3 Substance of example Decrease ;n X
2 ~8 ~ 59 V;tam1n A ac;d 60
5. The tolerat;on of the test substances after topical adm;n;strat;on was determ;ned in exper;ments w;th
6 ~h;te male New Zealand rabbits in each case. In the case of each test animal, an area of about 6 cm2 on the back was shaved. The test substances ~ere d;ssolved in ethanol/propylene glycol ~7û:30~ v/v), and 0~2 ml of th;s solut;on was applied with an automatic micropipette on 9 success;ve days by carefully rubb;ng the solut;on ;nto a part;cular point twice daily at 6-hour ;ntervals.
aefore each applicat;on ;n the morn;ng, all test areas were assessed subjectively in respect of erythemas and scaling, a numerical scale from 0 to 3 be;ng employed ~0 = no react;on, 1 = m;ld, 2 ~ moderate and 3 a severe).
The average erythema format;on and scal;ng g;ves the rela-t;ve ;rr;tant level of the test substances ;n compar;son w;th v;tamin A ac;d.
~ ~ ~35~
~ 19 - O.Z. 0050/35710/711/712 Table 4 ~-Substance of example ErythemaScal;ng 2 2.8 2.7 ~ 3~0 3.~
8 104 1.0 V;tamin A ac;d 3.0 3.0 Accord;ngly, the present invent;on also reLates to the therapeut;c agents for topical and systemic use wh;ch ;n add;t;on to convent;onal rarr;ers or d;luents conta;n a compound of the formula ~I) as the active com~
pound, and to ~he use of a compound of- the formuLa (I) for the preparae;on of a drug.
The therapeut;c agents or formulat;ons are pre-pared using the conventional l;qu;d or sol;d carr;ers or d;luents and the convent;onal pharmaceut;cal aux;liar;es, ;n accordance ~;th the des;red route of adm;n;strat;on and us;n~ a dose! su;table for use, the preparat;on be;ng carr;ed out ;n a~ convent;onal manner~ for example by mix-;ng the act;ve compound ~;th the solid or liqu;d carrier or aux;l;ary convent;onally used ;n such ~ormulat;ons.
The drugs can accord;ngly be adm;n;stered per-orally, parenterally or top;cally. Examples of formu-lat;ons of th;s type are tablets, f;lm tablets, coated tablets, capsules, p;lls, powders, solut;on-s, suspensions, ;nfus;on solutions, ;nject;on solut;ons, pastes, oint-ments~ gels, creams, lotions, powders, solutions, emul-sions and sprays.
The therapeutic agents can contain the novel 35~
~ Z0 ~ OOZ~ 0050/35710/711/712 compounds in a concentration of from 0.001 to 1X, prefer-ably from 0~001 to 0.1%, when used locally, and preferably as an ;ndividual dose of from 0.1 to 50 mg ~hen used systemically, and may be adm;nistered daily in one or more doses, depend;ng on the nature and severity of the d;s-order. - -Examples of conventionally used pharmaceut;calaux;liar;es are alcohols, eg. ;sopropanol, oxyethylated castor o;l or oxy~thylated hydrogenated castor o;l, poly-acrylic ac;d~ glycerol monostearate, paraff;n oil~ vase-l;ne, ~ool fa~, polyethylene glycol 400, polyethylene glycol 400 stearate and oxyethylated fatty alcohols for ~ocal adm;nistration, and lactose, propylene glycol and ethanol, starch, talc and pcly~;nylpyrrolidone for sys- - -tem;c adm;nistration~ The formulations may or may not conta;n ant;ox;dants, eg. tocopherol, or butylated hydroxy-an;sole or bu~ylated hydroxy~oluene, flavor-improv;ng add;t;ves, stab;l;zers, e~uls;fiers, lubr;cants, etc. All substances used ;n the preparat;on of the pharmaceutical formulation should be toxicologically acceptable, and tolerated by the active compounds used.
The examples wh;ch follow ;llustrate the prepara-tion of the compounds accord;ng to the ;nvent;on.
Ethyl E-4-C2-~ethyl-2-(1,1~4,4~6-pentamethyl-1,ZJ3,4-tetrahydronaphth-7-yl)-v;nylJ-ben~oate A solut;on of 90 9 of d;ethyl p-carboxyethylbenzyl-phosphonate in 150 ml of dimetnylsulfox;de was added drop~
w;se, in the course of 0.5 hourO at 35oC, to a suspens;on ~3S~
- 21 ~ o.Z. 0050/35710/711/712 of 9 9 of &OX strength sodium hydr;de, ~hich had before- -hand been freed from the 20X of paraff;n ~;th petroleum ether, ;n 250 ml of dime~hylsulfox;de~ Thereafter9 the m;xture ~as st;rred for a fur~her 2 hours at 40C, and a solut;on of 36~6 g of 7-acetyl~ 4,4,6-pentamethyltetra~
l;n ;n 70 ml of d;methylsulfox;de ~as added dropw;se ;n the course of 10 m;nutes.
The m;xture ~as allo~ed to stand overn;~ht, after ~h;ch 100 ml of ethanol were added, and the mixture ~as poured onto Z l;ters of ;ce/~ater and ac;d;f;ed ~ith 2 N
hydrochlor;c ac;d. The resulting pr~cipitate ~as fil-tered off, and washed on the f;lter ~;th 150 ml of ethanol and ~;th 75 ml of methanol. 35 9 of ethyl E-4-C2-methyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth~7-yl)- -~;nyl~-benzaate of melt;ng po;nt 108-109C rema;ned.
HPLC analys;s (S; 60 5 ~m, 150 bar, 98:2 n-hep-tane/ethyl acetate, tR = 3.1 min) showed that the product conta;ned more than 98X of one ;somer.
13C-NMR spectrum ~CDCl3, data in ppm~:
(The carbon atoms were numbered arb;trar;ly ;n order to ass;gn the NMR s;gnals) ~ 20 2 ~ 21 ~35~
~ 22 O.Z. OOSO/35710/711/712 14.40 (C~ 19.74 ~Cz7); 20.35 ~C26~; 31.96 ~C25, C24~ C23~ C22); 34-02 ~C1, C4); 35~32 (C2, C3);
bO.94 ~C20); 126.11 (C8); 128.41 (C1~, C~; 128955 ~C5); 129.00 ~C14, C~g); 129-68 (~15 , C17); 131.72 ~C6); 141-98 (C13); 142-93 (C1~); 143.11 ~C10); 143.83 ~C9); 166.~0 (C19).
The s;gnal at 19.74 tCz7) conf;rms the ~ ~rans) geometry of the compound.
4.7 9 of ethyl E-4-~2-methyl-2-~1,1,4,4,6-penta-methyl-1,203,4-tetrahydronaphth-7-yl)^vinyl]-ben20ate was st;rred ~;th 1.7 9 of 86% strength potass;um hydroxide in a 0;xture of 10û ml of ethanol and 5 ml of water for 6 hours at 80C. The total react;on mass was ;ntroduced ;nto 1 l;ter of water, the m;xture was ac;d;fied w;th 2 N
hydrochlor;c ac;d, and the colorless prec;p;tate obta;ned uas f;ltered off, dr;ed and then washed on a suct;on f;l-ter w;th 100 ml of heptane. After dry;ng, 4.0 9 of E-4-C2-methyl-2-~1,t,4,4,6-pentamethyl-1~Z,3,4-tetrahydro-naphth-7-yl);v;nyl~-benzo;c ac;d of melt;ng po;nt Z06C
rema;ned.
13C-NMR spectrum ~d6-d;methylsulfoxide, data ;n ppm):
~The carbon atoms ~ere numbered arb;trar1ly ;n order to ass;gn the NMR s;gnals).
3~
- Z3 - O.Z. 0050/35710/711/712 14 ~ 19COOH
22 22 . - -19.36 (C25~; 20-17 ~C2~); 31-60 (C20~ C21' C22~ C23);
33051 ~C2~ C3)j 34~71 (C4, C1); 125~40 (C8~; 128.00 (C5, C12)~ 128.61 ~C16); 128~9j'; 129,42 (C1~, C~
129.42 ~r15, C17); 131.1Z ~C6); 141.20 ~C13); 141-70 (C7); 142.16 ~C10); 142.52 ~C11); 143.08 ~C~); 167.26 ~C19) -The s;gnal at 19.36 (Cz5) conf;rms the F ttrans) geometry of the compoundO
A. Preparation of the starting material 9 9 of 80X strength sod;um hydride wh;ch had beforehand been freed from the 20~ of paraff;n with petroleum ether was suspended in 100 ml of dimethylsuL-fox;de~ and a solut;on of 7509 9 of diethyl p-cyanobenzyl-phosphonate in 150 ml of d;methylsulfox;de was added dropw;se ;n the course of O.S hour, at about 35Cn The m;xture was st;rred for a further 2 hours at 40C, and a solut;on of 53.5 g of 7 acetyl-1,1,4,4,6-pentamethyl-tetral;n ;n 50 ml of dimethylsulfoxide was added dropw;se ;n the course of 10 m;nutes.
On the next day, the react;on m;xture was poured onto 3 l;ters of lce~wa~er, and ac;dified w;th 2 N
3~
~ 24 - O.Z. 0050/35710/711/712 hydrochloric acid~ The resulting solid ~as filtered off, and washed on the f;l.er ~;th 75 ml of methanol. After drying, 30.2 9 of ~-4-~2-methyl 2-(1,1,4,4,6-pentaethyl 1O2,3,4-tetrahydronaphth~7-yl)-v;nyl~-benzon;tr;le of melt;ng point 140-141C rema;ned.
HPLC ~nalys;s ~Si 60 5 ym, 150 bar~ Z5 cm column, 97:3 n-heptane/ethyl acetate~ tR ~ 3.2 min) showed that the product contained more than 95% of one isomer.
B. Preparation of the end product 13r5 9 of E-4-~2 methyl-2-(1,1,4,496-pentamethyl-1,Z,3,4-tetrahydronaphth-7-yl)-vinyl~-benzonitrile in a m;xture of Z00 ml of ethanol and 200 ml of 10 N sodium hydrox;de solution ~ere heated at the boil for 3 hours.
The mi~ture was then cooled, after wh;ch it ~as poured onto 1 l;ter of ~ater, and the colorless precipitate was fi~ter~d off under suction and dried to give 14.9 g of E-4-~Z-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl~-benzo;c ac;d of melt;ng point Z04-206C ~cf. Exanple 2)~
The compounds given ;n the table below ~ere pre-pare~ e;ther by a W;tt;g-Horner react;on or by hydrolys;s of the correspond;ng ester or nitrîle~
~ ~3~
-- 2~ --~o o~ ~ ~ o W ~ ~ ~
~ ~ ~N
`; '`
~1~3~
-- 2~ --~ ~b~ I~N``'~ ~`b~ ~
~ ~ r p ~ I N ~ N ` P
o ~ - N ~ ~ D r o oo o r~ O cO ~ O 1 ~ ~ I~ o~ ~ c~
~ IDN l ~1 L~ U) 1~ ~ ~ ~ ~ ~
~r ~ ~
r~ ~}N
~; ~ ~ ~ ~ ~
,9 ~ , ?
$
, .
3S~3~
R
~ ~, N ~ ~ ~ t~
~ ~ I ~
~ .~ ~I N _ ' ~ I
_ t ~ t ~ ~ o O ~ ~ ~ ~
~.' o ~ ~r ~ N O
r~ ~ ~ ~
i~ ~ .
-t`
3~
o 2~ o z. 0050/35710/711/712 Gaseous hydrogen chloride was passed ;nto a solu-t;on of 4.0 9 of E-4-C2 methyl-2-(1,1 r4~4~b pentamethyl-1~2,3~4-tetrahydronaphth~7-yl)-vinyl~-ben7Oic ac;d in 300 ml of ethanol at the bo;ling poin~ of ~he react;on m;xture, until the solutjon ~as saturated. Thereafter, the m;x~ure ~Jas kept at the bo;l for a further 4 hours, cooled, flushed ~;th n;trogen and then evaporated down~
The residue ~as d;gested with 30 ml of methanol, and the product ~as filtered off and dried. 3.6 9 of ethyl ~-4-~2-methyl-2 (1,1~4,4,~-pentamethyl-1,2,3,4-tetrahydro~
naphth-7-yl) Yinyl~-benzoate of melting point 109-110C
~ere obtained ~cf. Example 1).
EXAMPLE l a A solut;on of 5~3 ml of th;onyl chtor;~e ;n 10 ml of tetrahydrofuran was added rap;dly to a suspen-sion of 20.9 9 of E-4-C2 methyl-Z;(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-ben~oic ac;d ~cf, Example 2) and 5~ ml of pyridine in 200 ml of anhydrous tetrahydrofuran, and the m;xture was stirred for two hours at room temperature. Thereafter, the prec~p;tate for~ed was filtered off and th~ filtrate was made up with tetrahydrofuran to a total volume of 240 ml.
100 ml of this solution was added a little at a time, in the course of 10 m;nutes, to a suspension of 8.2 9 of p-aminophenol in 100 ml of tetrahydrofuran, and stirr;ng was then continued for a further Z0 hours at room temperature. The react;on m;xture ~as st;rred into 1 l;ter of water, the mi~ture was ac;d;fied with 2 N
~ ~ ~3~
- 29 - O.Z. 0050/35710/711/712 hydrochloric ac;d, and the result;ng prec;p;tate ~as filtered off, and recrystall;zed from ethanoL with the add;t;on of water. The product ~as f;ltsred off and dr;ed, and 11.1 9 of E-4-CZ-~ethyl-2~ 4,4-tetrao methy~-1,2,3j4-tetrahydronaph~h-7-yl)-~;nyl3~benzo;c aci~
4-hydroxyan;L;de of melting point 252-253C remained.
3C-NMR spectrum (d~-d;methylsulfox;de) The resonance s;gn3l wh;ch appears at 17.30 ppm and may be ass;gned to the methyl group on carbon atom 2 of the olef;n;c ethylene group ;nd;cates that the com-pound obta;ned is the E (trans) isomer.
EXAMPLES 19 to 23 The compounds listed in the table below were obta;ned by a procedure s;m;lar to that described ;n - ~
ExampLe 18:
35~
n ~ .~ i~ t ~ ~ 8 ~ 8 ~
~ ~ ~ ,1~
I~Z "~
U~ ~ o ~ U7 b ~ ~- ~ _, ~ ~ ~ ,, o~ ~ ~ ~ o ~ ~S ~ l ~ N O
~ ~) ~) ~ ~
1~ ~ ~ ~N 6~ 6 ~
¢ \~
~ ~ ~ ~
~ ~ ~35~
- 31 O.Z. 0050/35710/711/712 A solut;on of 0.5 ml of th;onyl chlor;de ;n 5 ml of tetrahydrofuran ~as added rapidly to a suspension of 1,8 9 of E-4-~2~methyl 2~ 1,4,4 tetramethyl-1,293,4-tetrahydronaphth-7-yl)-vinyl]~benzoic acid ~cf. Example 2) and 0~5 ml of pyrid;ne in 15 ml of tetrahydrofuran, and the mixture ~as st;rred for 2 hours at room temperature.
Thereafter, the prec;pitate formed was f;ltered off~ the f;ltrate was added to a suspens;on of 0.5 9 of anhydrous S-am;notetrazole and 0.5 g of pyr;d;ne ;n 20 ml of tetra-hydrofuran, and the m;xture uas thén stirred ~or a furtherZ0 hours at room temperature. The reaction mass wa~
st;rred into 400 ml of ~ater and acid;f;ed with 2 ~ hydro-chloric ac;d, and the result;ng prec;p;tate ~as filtered off and washed with methanol and petroleum ether. 1.7 9 of E-4-C2-methyl-2-t1,1,4,4 ~etramethyl-1,2,3~4-tetra-hydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benza~ide of melt;ng po;nt 289-290C remained.
C-NMR spectrum td6-d;methylsulfox;de~
The resonance s;gnal ~h;ch appeared at 17.41 ppm and may be ass;gned to the methyl group on carbon atom 2 of the olefinic ethylene group ;nd;cated that the compound obta;ned was the E ~trans) isomer.
EXAMPLES 25 to Z9 The compounds listed ;n the table below were obtained by a procedure s;m;lar to that described ;n Example 1:
- 32 ~ 3~
a) b ~, l l ,, ~ ~ ~3 ~ ~
~ ~ ~ ~2 ~ O I ~ n ~ I
~i~ l ~r~ ~ 3 1 I ~
~i ~ ~ ~ ~o 3 ~ o I ~ ~ ~ I ~ ~
z ~ _" ~ ~ I ~r~ ,~
I ~ ~ I .~ _ I ~ _ _ ~,, ~1 ~ ~ ~ S~ ~ ~ I
s~l ~ I ~ ~ n ~ ~ ~
~ a) ~. ~ ~ ~,~,_ ~ ~ ~ ~
~`z ~ ~. ~,~r~ ~
~1 ~ T ~ ~ ~ ,1 ~ ~r r~ ~ ~) N ~D
O r N N I~
~ ~ ~ ~ r~
0=~, a~ u~ ~ I~ o ~_ OD C~ CO a~ a:
O > ~ ~ l O ~
~ ~ N t~l ~1 t~l N
~; ~ :q $ ~ ~' ~ ~ Y~ ~ ~
~ l l ~N
~¢ ~ 1~) ~N
O Ir) ~DI~ CO cn Z N ~1 N ~1 N
.~, ` ' ~
aefore each applicat;on ;n the morn;ng, all test areas were assessed subjectively in respect of erythemas and scaling, a numerical scale from 0 to 3 be;ng employed ~0 = no react;on, 1 = m;ld, 2 ~ moderate and 3 a severe).
The average erythema format;on and scal;ng g;ves the rela-t;ve ;rr;tant level of the test substances ;n compar;son w;th v;tamin A ac;d.
~ ~ ~35~
~ 19 - O.Z. 0050/35710/711/712 Table 4 ~-Substance of example ErythemaScal;ng 2 2.8 2.7 ~ 3~0 3.~
8 104 1.0 V;tamin A ac;d 3.0 3.0 Accord;ngly, the present invent;on also reLates to the therapeut;c agents for topical and systemic use wh;ch ;n add;t;on to convent;onal rarr;ers or d;luents conta;n a compound of the formula ~I) as the active com~
pound, and to ~he use of a compound of- the formuLa (I) for the preparae;on of a drug.
The therapeut;c agents or formulat;ons are pre-pared using the conventional l;qu;d or sol;d carr;ers or d;luents and the convent;onal pharmaceut;cal aux;liar;es, ;n accordance ~;th the des;red route of adm;n;strat;on and us;n~ a dose! su;table for use, the preparat;on be;ng carr;ed out ;n a~ convent;onal manner~ for example by mix-;ng the act;ve compound ~;th the solid or liqu;d carrier or aux;l;ary convent;onally used ;n such ~ormulat;ons.
The drugs can accord;ngly be adm;n;stered per-orally, parenterally or top;cally. Examples of formu-lat;ons of th;s type are tablets, f;lm tablets, coated tablets, capsules, p;lls, powders, solut;on-s, suspensions, ;nfus;on solutions, ;nject;on solut;ons, pastes, oint-ments~ gels, creams, lotions, powders, solutions, emul-sions and sprays.
The therapeutic agents can contain the novel 35~
~ Z0 ~ OOZ~ 0050/35710/711/712 compounds in a concentration of from 0.001 to 1X, prefer-ably from 0~001 to 0.1%, when used locally, and preferably as an ;ndividual dose of from 0.1 to 50 mg ~hen used systemically, and may be adm;nistered daily in one or more doses, depend;ng on the nature and severity of the d;s-order. - -Examples of conventionally used pharmaceut;calaux;liar;es are alcohols, eg. ;sopropanol, oxyethylated castor o;l or oxy~thylated hydrogenated castor o;l, poly-acrylic ac;d~ glycerol monostearate, paraff;n oil~ vase-l;ne, ~ool fa~, polyethylene glycol 400, polyethylene glycol 400 stearate and oxyethylated fatty alcohols for ~ocal adm;nistration, and lactose, propylene glycol and ethanol, starch, talc and pcly~;nylpyrrolidone for sys- - -tem;c adm;nistration~ The formulations may or may not conta;n ant;ox;dants, eg. tocopherol, or butylated hydroxy-an;sole or bu~ylated hydroxy~oluene, flavor-improv;ng add;t;ves, stab;l;zers, e~uls;fiers, lubr;cants, etc. All substances used ;n the preparat;on of the pharmaceutical formulation should be toxicologically acceptable, and tolerated by the active compounds used.
The examples wh;ch follow ;llustrate the prepara-tion of the compounds accord;ng to the ;nvent;on.
Ethyl E-4-C2-~ethyl-2-(1,1~4,4~6-pentamethyl-1,ZJ3,4-tetrahydronaphth-7-yl)-v;nylJ-ben~oate A solut;on of 90 9 of d;ethyl p-carboxyethylbenzyl-phosphonate in 150 ml of dimetnylsulfox;de was added drop~
w;se, in the course of 0.5 hourO at 35oC, to a suspens;on ~3S~
- 21 ~ o.Z. 0050/35710/711/712 of 9 9 of &OX strength sodium hydr;de, ~hich had before- -hand been freed from the 20X of paraff;n ~;th petroleum ether, ;n 250 ml of dime~hylsulfox;de~ Thereafter9 the m;xture ~as st;rred for a fur~her 2 hours at 40C, and a solut;on of 36~6 g of 7-acetyl~ 4,4,6-pentamethyltetra~
l;n ;n 70 ml of d;methylsulfox;de ~as added dropw;se ;n the course of 10 m;nutes.
The m;xture ~as allo~ed to stand overn;~ht, after ~h;ch 100 ml of ethanol were added, and the mixture ~as poured onto Z l;ters of ;ce/~ater and ac;d;f;ed ~ith 2 N
hydrochlor;c ac;d. The resulting pr~cipitate ~as fil-tered off, and washed on the f;lter ~;th 150 ml of ethanol and ~;th 75 ml of methanol. 35 9 of ethyl E-4-C2-methyl-2-~1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth~7-yl)- -~;nyl~-benzaate of melt;ng po;nt 108-109C rema;ned.
HPLC analys;s (S; 60 5 ~m, 150 bar, 98:2 n-hep-tane/ethyl acetate, tR = 3.1 min) showed that the product conta;ned more than 98X of one ;somer.
13C-NMR spectrum ~CDCl3, data in ppm~:
(The carbon atoms were numbered arb;trar;ly ;n order to ass;gn the NMR s;gnals) ~ 20 2 ~ 21 ~35~
~ 22 O.Z. OOSO/35710/711/712 14.40 (C~ 19.74 ~Cz7); 20.35 ~C26~; 31.96 ~C25, C24~ C23~ C22); 34-02 ~C1, C4); 35~32 (C2, C3);
bO.94 ~C20); 126.11 (C8); 128.41 (C1~, C~; 128955 ~C5); 129.00 ~C14, C~g); 129-68 (~15 , C17); 131.72 ~C6); 141-98 (C13); 142-93 (C1~); 143.11 ~C10); 143.83 ~C9); 166.~0 (C19).
The s;gnal at 19.74 tCz7) conf;rms the ~ ~rans) geometry of the compound.
4.7 9 of ethyl E-4-~2-methyl-2-~1,1,4,4,6-penta-methyl-1,203,4-tetrahydronaphth-7-yl)^vinyl]-ben20ate was st;rred ~;th 1.7 9 of 86% strength potass;um hydroxide in a 0;xture of 10û ml of ethanol and 5 ml of water for 6 hours at 80C. The total react;on mass was ;ntroduced ;nto 1 l;ter of water, the m;xture was ac;d;fied w;th 2 N
hydrochlor;c ac;d, and the colorless prec;p;tate obta;ned uas f;ltered off, dr;ed and then washed on a suct;on f;l-ter w;th 100 ml of heptane. After dry;ng, 4.0 9 of E-4-C2-methyl-2-~1,t,4,4,6-pentamethyl-1~Z,3,4-tetrahydro-naphth-7-yl);v;nyl~-benzo;c ac;d of melt;ng po;nt Z06C
rema;ned.
13C-NMR spectrum ~d6-d;methylsulfoxide, data ;n ppm):
~The carbon atoms ~ere numbered arb;trar1ly ;n order to ass;gn the NMR s;gnals).
3~
- Z3 - O.Z. 0050/35710/711/712 14 ~ 19COOH
22 22 . - -19.36 (C25~; 20-17 ~C2~); 31-60 (C20~ C21' C22~ C23);
33051 ~C2~ C3)j 34~71 (C4, C1); 125~40 (C8~; 128.00 (C5, C12)~ 128.61 ~C16); 128~9j'; 129,42 (C1~, C~
129.42 ~r15, C17); 131.1Z ~C6); 141.20 ~C13); 141-70 (C7); 142.16 ~C10); 142.52 ~C11); 143.08 ~C~); 167.26 ~C19) -The s;gnal at 19.36 (Cz5) conf;rms the F ttrans) geometry of the compoundO
A. Preparation of the starting material 9 9 of 80X strength sod;um hydride wh;ch had beforehand been freed from the 20~ of paraff;n with petroleum ether was suspended in 100 ml of dimethylsuL-fox;de~ and a solut;on of 7509 9 of diethyl p-cyanobenzyl-phosphonate in 150 ml of d;methylsulfox;de was added dropw;se ;n the course of O.S hour, at about 35Cn The m;xture was st;rred for a further 2 hours at 40C, and a solut;on of 53.5 g of 7 acetyl-1,1,4,4,6-pentamethyl-tetral;n ;n 50 ml of dimethylsulfoxide was added dropw;se ;n the course of 10 m;nutes.
On the next day, the react;on m;xture was poured onto 3 l;ters of lce~wa~er, and ac;dified w;th 2 N
3~
~ 24 - O.Z. 0050/35710/711/712 hydrochloric acid~ The resulting solid ~as filtered off, and washed on the f;l.er ~;th 75 ml of methanol. After drying, 30.2 9 of ~-4-~2-methyl 2-(1,1,4,4,6-pentaethyl 1O2,3,4-tetrahydronaphth~7-yl)-v;nyl~-benzon;tr;le of melt;ng point 140-141C rema;ned.
HPLC ~nalys;s ~Si 60 5 ym, 150 bar~ Z5 cm column, 97:3 n-heptane/ethyl acetate~ tR ~ 3.2 min) showed that the product contained more than 95% of one isomer.
B. Preparation of the end product 13r5 9 of E-4-~2 methyl-2-(1,1,4,496-pentamethyl-1,Z,3,4-tetrahydronaphth-7-yl)-vinyl~-benzonitrile in a m;xture of Z00 ml of ethanol and 200 ml of 10 N sodium hydrox;de solution ~ere heated at the boil for 3 hours.
The mi~ture was then cooled, after wh;ch it ~as poured onto 1 l;ter of ~ater, and the colorless precipitate was fi~ter~d off under suction and dried to give 14.9 g of E-4-~Z-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl)-v;nyl~-benzo;c ac;d of melt;ng point Z04-206C ~cf. Exanple 2)~
The compounds given ;n the table below ~ere pre-pare~ e;ther by a W;tt;g-Horner react;on or by hydrolys;s of the correspond;ng ester or nitrîle~
~ ~3~
-- 2~ --~o o~ ~ ~ o W ~ ~ ~
~ ~ ~N
`; '`
~1~3~
-- 2~ --~ ~b~ I~N``'~ ~`b~ ~
~ ~ r p ~ I N ~ N ` P
o ~ - N ~ ~ D r o oo o r~ O cO ~ O 1 ~ ~ I~ o~ ~ c~
~ IDN l ~1 L~ U) 1~ ~ ~ ~ ~ ~
~r ~ ~
r~ ~}N
~; ~ ~ ~ ~ ~
,9 ~ , ?
$
, .
3S~3~
R
~ ~, N ~ ~ ~ t~
~ ~ I ~
~ .~ ~I N _ ' ~ I
_ t ~ t ~ ~ o O ~ ~ ~ ~
~.' o ~ ~r ~ N O
r~ ~ ~ ~
i~ ~ .
-t`
3~
o 2~ o z. 0050/35710/711/712 Gaseous hydrogen chloride was passed ;nto a solu-t;on of 4.0 9 of E-4-C2 methyl-2-(1,1 r4~4~b pentamethyl-1~2,3~4-tetrahydronaphth~7-yl)-vinyl~-ben7Oic ac;d in 300 ml of ethanol at the bo;ling poin~ of ~he react;on m;xture, until the solutjon ~as saturated. Thereafter, the m;x~ure ~Jas kept at the bo;l for a further 4 hours, cooled, flushed ~;th n;trogen and then evaporated down~
The residue ~as d;gested with 30 ml of methanol, and the product ~as filtered off and dried. 3.6 9 of ethyl ~-4-~2-methyl-2 (1,1~4,4,~-pentamethyl-1,2,3,4-tetrahydro~
naphth-7-yl) Yinyl~-benzoate of melting point 109-110C
~ere obtained ~cf. Example 1).
EXAMPLE l a A solut;on of 5~3 ml of th;onyl chtor;~e ;n 10 ml of tetrahydrofuran was added rap;dly to a suspen-sion of 20.9 9 of E-4-C2 methyl-Z;(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-ben~oic ac;d ~cf, Example 2) and 5~ ml of pyridine in 200 ml of anhydrous tetrahydrofuran, and the m;xture was stirred for two hours at room temperature. Thereafter, the prec~p;tate for~ed was filtered off and th~ filtrate was made up with tetrahydrofuran to a total volume of 240 ml.
100 ml of this solution was added a little at a time, in the course of 10 m;nutes, to a suspension of 8.2 9 of p-aminophenol in 100 ml of tetrahydrofuran, and stirr;ng was then continued for a further Z0 hours at room temperature. The react;on m;xture ~as st;rred into 1 l;ter of water, the mi~ture was ac;d;fied with 2 N
~ ~ ~3~
- 29 - O.Z. 0050/35710/711/712 hydrochloric ac;d, and the result;ng prec;p;tate ~as filtered off, and recrystall;zed from ethanoL with the add;t;on of water. The product ~as f;ltsred off and dr;ed, and 11.1 9 of E-4-CZ-~ethyl-2~ 4,4-tetrao methy~-1,2,3j4-tetrahydronaph~h-7-yl)-~;nyl3~benzo;c aci~
4-hydroxyan;L;de of melting point 252-253C remained.
3C-NMR spectrum (d~-d;methylsulfox;de) The resonance s;gn3l wh;ch appears at 17.30 ppm and may be ass;gned to the methyl group on carbon atom 2 of the olef;n;c ethylene group ;nd;cates that the com-pound obta;ned is the E (trans) isomer.
EXAMPLES 19 to 23 The compounds listed in the table below were obta;ned by a procedure s;m;lar to that described ;n - ~
ExampLe 18:
35~
n ~ .~ i~ t ~ ~ 8 ~ 8 ~
~ ~ ~ ,1~
I~Z "~
U~ ~ o ~ U7 b ~ ~- ~ _, ~ ~ ~ ,, o~ ~ ~ ~ o ~ ~S ~ l ~ N O
~ ~) ~) ~ ~
1~ ~ ~ ~N 6~ 6 ~
¢ \~
~ ~ ~ ~
~ ~ ~35~
- 31 O.Z. 0050/35710/711/712 A solut;on of 0.5 ml of th;onyl chlor;de ;n 5 ml of tetrahydrofuran ~as added rapidly to a suspension of 1,8 9 of E-4-~2~methyl 2~ 1,4,4 tetramethyl-1,293,4-tetrahydronaphth-7-yl)-vinyl]~benzoic acid ~cf. Example 2) and 0~5 ml of pyrid;ne in 15 ml of tetrahydrofuran, and the mixture ~as st;rred for 2 hours at room temperature.
Thereafter, the prec;pitate formed was f;ltered off~ the f;ltrate was added to a suspens;on of 0.5 9 of anhydrous S-am;notetrazole and 0.5 g of pyr;d;ne ;n 20 ml of tetra-hydrofuran, and the m;xture uas thén stirred ~or a furtherZ0 hours at room temperature. The reaction mass wa~
st;rred into 400 ml of ~ater and acid;f;ed with 2 ~ hydro-chloric ac;d, and the result;ng prec;p;tate ~as filtered off and washed with methanol and petroleum ether. 1.7 9 of E-4-C2-methyl-2-t1,1,4,4 ~etramethyl-1,2,3~4-tetra-hydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benza~ide of melt;ng po;nt 289-290C remained.
C-NMR spectrum td6-d;methylsulfox;de~
The resonance s;gnal ~h;ch appeared at 17.41 ppm and may be ass;gned to the methyl group on carbon atom 2 of the olefinic ethylene group ;nd;cated that the compound obta;ned was the E ~trans) isomer.
EXAMPLES 25 to Z9 The compounds listed ;n the table below were obtained by a procedure s;m;lar to that described ;n Example 1:
- 32 ~ 3~
a) b ~, l l ,, ~ ~ ~3 ~ ~
~ ~ ~ ~2 ~ O I ~ n ~ I
~i~ l ~r~ ~ 3 1 I ~
~i ~ ~ ~ ~o 3 ~ o I ~ ~ ~ I ~ ~
z ~ _" ~ ~ I ~r~ ,~
I ~ ~ I .~ _ I ~ _ _ ~,, ~1 ~ ~ ~ S~ ~ ~ I
s~l ~ I ~ ~ n ~ ~ ~
~ a) ~. ~ ~ ~,~,_ ~ ~ ~ ~
~`z ~ ~. ~,~r~ ~
~1 ~ T ~ ~ ~ ,1 ~ ~r r~ ~ ~) N ~D
O r N N I~
~ ~ ~ ~ r~
0=~, a~ u~ ~ I~ o ~_ OD C~ CO a~ a:
O > ~ ~ l O ~
~ ~ N t~l ~1 t~l N
~; ~ :q $ ~ ~' ~ ~ Y~ ~ ~
~ l l ~N
~¢ ~ 1~) ~N
O Ir) ~DI~ CO cn Z N ~1 N ~1 N
.~, ` ' ~
Claims (24)
1. A process for the preparation of phenylethylene derivatives of the formula I
I
where A is alkylene which is unsubstituted or substituted by C1-C4-alkyl, R1 is hydrogen or methyl, R2 is hydro-gen or methyl, R3 is hydrogen or C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxyphenyleneaminocarbonyl or tetrazol-5-ylaminocarbonyl and, if R3 is C1-C8-alkyl, may furthermore be carboxyl or C2-C4-carbalkoxy, and, where relevant, its salts with physiologically tolerated bases, characterized in that a) a compound of the formula II
II
where A, R1, R2, R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 has the meanings given for R5 or is cyano, and R7 is C1-C4-alkyl, or b) a phosphonium salt of the formula IV
IV
where A, R1, R2, R3 and R4 have the meanings given above and X is chlorine or bromine, is subjected to a Wittig reaction with a benzaldehyde derivative of the formula V
V
where R6 has the above meanings, and thereafter, if R6 is not carboxyl, the resulting compound may, if desired, by hydrolyzed and the free acids, obtained either in this manner or directly, may, if desired, then be reacted with a C1-C3-alcohol, p-hydroxy-aniline or 5-aminotetrazole, and the compound thus obtained may, if desired, be converted into its salt with a physiologically tolerated base.
I
where A is alkylene which is unsubstituted or substituted by C1-C4-alkyl, R1 is hydrogen or methyl, R2 is hydro-gen or methyl, R3 is hydrogen or C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxyphenyleneaminocarbonyl or tetrazol-5-ylaminocarbonyl and, if R3 is C1-C8-alkyl, may furthermore be carboxyl or C2-C4-carbalkoxy, and, where relevant, its salts with physiologically tolerated bases, characterized in that a) a compound of the formula II
II
where A, R1, R2, R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 has the meanings given for R5 or is cyano, and R7 is C1-C4-alkyl, or b) a phosphonium salt of the formula IV
IV
where A, R1, R2, R3 and R4 have the meanings given above and X is chlorine or bromine, is subjected to a Wittig reaction with a benzaldehyde derivative of the formula V
V
where R6 has the above meanings, and thereafter, if R6 is not carboxyl, the resulting compound may, if desired, by hydrolyzed and the free acids, obtained either in this manner or directly, may, if desired, then be reacted with a C1-C3-alcohol, p-hydroxy-aniline or 5-aminotetrazole, and the compound thus obtained may, if desired, be converted into its salt with a physiologically tolerated base.
2. A process as defined in claim 1, wherein a phenylethylene derivative of the formula I as defined in claim 1, or where relevant its salt with a physiologically tolerated base, is prepared, where A is ethylene, R1 and R2 are each methyl, R3 is C1-C8-alkyl, R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy.
3. A compound of the formula I as defined in claim 1 and where relevant its salts with physiologically tolerated bases whenever obtained by a process as defined in claim 1 or by an obvious chemical equivalent thereof.
4. A compound of the formula I as defined in claim 1 and where relevant its salts with physiologically tolerated bases wherein A is ethylene, R1 and R2 are each methyl, R3 is C1-C8-alkyl R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy whenever obtained by a process as defined in claim 2 or by an obvious chemical equivalent thereof.
5. A process for the preparation of phenylethylene derivatives of the formula I
I
where R3 is hydrogen or C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxyphenyleneaminocarbonyl or tetrazol-5-ylamino-carbonyl and, if R3 is C1-C8-alkyl, may furthermore be carboxyl or C2-C4-carbalkoxy, and, where relevant, its salts with physiologically tolerated bases, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 has the meanings given for R5 or is cyano, and R7 is C1-C4-alkyl, and thereafter, if R6 is not carboxyl, the resulting compound may, if desired, be hydrolyzed and the free acid, obtained either in this manner or directly, may if desired, then be reacted with a C1-C3-alcohol, p-hydroxy-aniline or 5-aminotetrazole, and the compound thus obtained may, if desired, be converted into its salt with a physio-logically tolerated base.
I
where R3 is hydrogen or C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxyphenyleneaminocarbonyl or tetrazol-5-ylamino-carbonyl and, if R3 is C1-C8-alkyl, may furthermore be carboxyl or C2-C4-carbalkoxy, and, where relevant, its salts with physiologically tolerated bases, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 has the meanings given for R5 or is cyano, and R7 is C1-C4-alkyl, and thereafter, if R6 is not carboxyl, the resulting compound may, if desired, be hydrolyzed and the free acid, obtained either in this manner or directly, may if desired, then be reacted with a C1-C3-alcohol, p-hydroxy-aniline or 5-aminotetrazole, and the compound thus obtained may, if desired, be converted into its salt with a physio-logically tolerated base.
6. A compound of the formula I as defined in claim 5 and where relevant its salts with physiologically tolerated bases whenever obtained by a process as defined in claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of phenylethylene derivatives of the formula I
I
where R3 is C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxyphenyleneaminocarbonyl, tetrazol-5-ylaminocarbonyl, carboxyl ox C2-C4-carbalkoxy, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 is C2-C4-carbalkoxy and R7 is C1-C4-alkyl, and thereafter, the resulting compound may, if desired, be hydrolyzed and the free acid obtained may, if desired, then be reacted with a C1-C3-alcohol, p-hydroxyaniline or 5-aminotetrazole.
I
where R3 is C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxyphenyleneaminocarbonyl, tetrazol-5-ylaminocarbonyl, carboxyl ox C2-C4-carbalkoxy, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 is C2-C4-carbalkoxy and R7 is C1-C4-alkyl, and thereafter, the resulting compound may, if desired, be hydrolyzed and the free acid obtained may, if desired, then be reacted with a C1-C3-alcohol, p-hydroxyaniline or 5-aminotetrazole.
8. A process as defined in claim 7, wherein a phenylethylene derivative of the formula I as defined in claim 7 is prepared, where R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy.
9. A compound of the formula I as defined in claim 7 whenever obtained by a process as defined in claim 7 or by an obvious chemical equivalent thereof.
10. A compound of the formula I as defined in claim 7 where R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy whenever obtained by a process as defined in claim 8 or by an obvious chemical equivalent thereof.
11. A process for the preparation of phenylethylene derivatives of the formula I
I
where R3 is C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxy-phenyleneaminocarbonyl, tetrazol-5-ylaminocarbonyl, carboxyl or C2-C4-carbalkoxy, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 is cyano, and R7 is C1-C4-alkyl, and thereafter, the resulting compound hydrolyzed and the free acid, obtained may, if desired, then be reacted with a C1-C3-alcohol , p-hydroxyaniline or 5-aminotetrazole.
I
where R3 is C1-C8-alkyl, R4 is C1-C4-alkyl and R5 is p-hydroxy-phenyleneaminocarbonyl, tetrazol-5-ylaminocarbonyl, carboxyl or C2-C4-carbalkoxy, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 is cyano, and R7 is C1-C4-alkyl, and thereafter, the resulting compound hydrolyzed and the free acid, obtained may, if desired, then be reacted with a C1-C3-alcohol , p-hydroxyaniline or 5-aminotetrazole.
12. A process as defined in claim 11, wherein a phenylethylene derivative of the formula I as defined in claim 11 is prepared, where R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy.
13. A compound of the formula I as defined in claim 11 whenever obtained by a process as defined in claim 11 or by an obvious chemical equivalent thereof.
14. A compound of the formula I as defined in claim 11 wherein R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy whenever obtained by a process as defined in claim 12 or by an obvious chemical equivalent thereof.
15. A process for the preparation of phenylethylene derivatives of the formula I
I
where R3 is C1-C8-alkyl,R4 is C1-C4-alkyl and R5 is p-hydroxy-phenyleneaminocarbonyl, tetrazol-5-ylaminocarbonyl, carboxyl or C2-C4-carbalkoxy, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 is carboxyl and R7 is C1-C4-alkyl, and thereafter, the resulting free acid may, if desired, then be reacted with a C1-C3-alcohol, p-hydroxyaniline or 5-aminotetrazole.
I
where R3 is C1-C8-alkyl,R4 is C1-C4-alkyl and R5 is p-hydroxy-phenyleneaminocarbonyl, tetrazol-5-ylaminocarbonyl, carboxyl or C2-C4-carbalkoxy, characterized in that a compound of the formula II
II
where R3 and R4 have the meanings given above is subjected to a Wittig-Horner reaction with a phosphorus compound of the formula III
III
where R6 is carboxyl and R7 is C1-C4-alkyl, and thereafter, the resulting free acid may, if desired, then be reacted with a C1-C3-alcohol, p-hydroxyaniline or 5-aminotetrazole.
16. A process as defined in claim 15 wherein a phenylethylene derivative of the formula I as defined in claim 15 is prepared, where R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy.
17. A compound of the formula I as defined in claim 15 whenever obtained by a process as defined in claim 15 or by an obvious chemical equivalent thereof.
18. A compound of the formula I as defined in claim 15 wherein R4 is methyl and R5 is carboxyl or C2-C4-carbalkoxy whenever obtained by a process as defined in claim 16 or by an obvious chemical equivalent thereof.
19. A Process for the preparation of E-4-?2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl? benzoic acid characterized in that 7-acetyl-1,1,4,4-tetramethyl-6 isopropyl-1,2,3,4-tetrahydronaphthalene is subjected to a Wittig-Horner reaction with diethyl p-carboxyethylbenzylphosphonate to obtain ethyl E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydro-naphth-7-yl)-vinyl]-benzoate, said benzoate being subjected to hydrolysis to obtain E-4-[2 methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid.
20. E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)vinyl] benzoic acid whenever obtained by a process as defined in claim 19 or an obvious chemical equivalent thereof.
21. A process for the preparation of E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl] benzoic acid characterized in that 7-acetyl-1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphthalene is subjected to a Wittig-Horner reaction with diethyl p-cyanobenzylphosphonate to obtain E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzonitrile, said benzonitrile being subjected to hydrolysis to obtain E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid.
22. E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]benzoic acid whenever obtained by a process as defined in claim 21 or an obvious chemical equivalent thereof.
23. A process for the preparation of E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl] benzoic acid characterized in that 7-acetyl-1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphthalene is subjected to a Wittig-Horner reaction with diethyl p-carboxy-benzylphosphonate to obtain E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,3-tetrahydronaphth-7-yl)-vinyl]-benzoic acid.
24. E-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl] benzoic acid whenever obtained by a process as defined in claim 23 or an obvious chemical equivalent thereof.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823202065 DE3202065A1 (en) | 1982-01-23 | 1982-01-23 | Substituted N-(5-tetrazolyl)benzamides, the preparation thereof and pharmaceutical compositions containing these |
| DEP3202118.6 | 1982-01-23 | ||
| DEP3202100.3 | 1982-01-23 | ||
| DEP3202065.1 | 1982-01-23 | ||
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1183541A true CA1183541A (en) | 1985-03-05 |
Family
ID=27189859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000419140A Expired CA1183541A (en) | 1982-01-23 | 1983-01-10 | Phenylethylene derivatives, their preparation and their use as drugs |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0084667B1 (en) |
| AU (1) | AU1069583A (en) |
| CA (1) | CA1183541A (en) |
| DE (1) | DE3266442D1 (en) |
| FI (1) | FI830163L (en) |
| IL (1) | IL67618A0 (en) |
| NO (1) | NO830202L (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4714786A (en) * | 1986-01-28 | 1987-12-22 | Basf Aktiengesellschaft | Vinylphenol derivatives, their preparation and their use |
| US5061705A (en) * | 1989-02-10 | 1991-10-29 | Basf Aktiengesellschaft | Diaryl-substituted heterocyclic compounds, drugs and cosmetics obtained therefrom |
| US5087637A (en) * | 1989-08-08 | 1992-02-11 | Basf Aktiengesellschaft | Diarylacetylenes, the preparation and use thereof |
| US5206242A (en) * | 1989-02-10 | 1993-04-27 | Basf Aktiengesellschaft | Diaryl-substituted pyrazole compounds and drugs and cosmetics obtained therefrom |
| US5326900A (en) * | 1989-02-10 | 1994-07-05 | Basf Aktiengesellschaft | Aromatic keto compounds, the preparation thereof, and drugs and cosmetics containing these |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| DE3434944A1 (en) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | L-SUBSTITUTED TETRALIN DERIVATIVES, THEIR PRODUCTION AND USE |
| DE3434942A1 (en) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | TETRALINE 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 |
| GB2218416A (en) * | 1988-05-13 | 1989-11-15 | Bayer Ag | Leukotriene disease antagonists |
| US5221760A (en) * | 1988-05-13 | 1993-06-22 | Bayer Aktiengesellschaft | Alkenoic acid derivatives |
| FR2656608B1 (en) * | 1989-12-28 | 1992-04-24 | Roussel Uclaf | NOVEL BENZOYLATED POLYAMINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS FUNGICIDES. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK159967C (en) * | 1977-12-22 | 1991-06-03 | Hoffmann La Roche | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE STYLE BENDER DERIVATIVES |
-
1982
- 1982-12-23 DE DE8282111928T patent/DE3266442D1/en not_active Expired
- 1982-12-23 EP EP82111928A patent/EP0084667B1/en not_active Expired
-
1983
- 1983-01-04 IL IL67618A patent/IL67618A0/en unknown
- 1983-01-10 CA CA000419140A patent/CA1183541A/en not_active Expired
- 1983-01-18 FI FI830163A patent/FI830163L/en not_active Application Discontinuation
- 1983-01-21 NO NO830202A patent/NO830202L/en unknown
- 1983-01-21 AU AU10695/83A patent/AU1069583A/en not_active Abandoned
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4714786A (en) * | 1986-01-28 | 1987-12-22 | Basf Aktiengesellschaft | Vinylphenol derivatives, their preparation and their use |
| US5061705A (en) * | 1989-02-10 | 1991-10-29 | Basf Aktiengesellschaft | Diaryl-substituted heterocyclic compounds, drugs and cosmetics obtained therefrom |
| US5206242A (en) * | 1989-02-10 | 1993-04-27 | Basf Aktiengesellschaft | Diaryl-substituted pyrazole compounds and drugs and cosmetics obtained therefrom |
| US5326900A (en) * | 1989-02-10 | 1994-07-05 | Basf Aktiengesellschaft | Aromatic keto compounds, the preparation thereof, and drugs and cosmetics containing these |
| US5087637A (en) * | 1989-08-08 | 1992-02-11 | Basf Aktiengesellschaft | Diarylacetylenes, the preparation and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0084667A2 (en) | 1983-08-03 |
| EP0084667B1 (en) | 1985-09-18 |
| EP0084667A3 (en) | 1984-03-07 |
| IL67618A0 (en) | 1983-05-15 |
| DE3266442D1 (en) | 1985-10-24 |
| NO830202L (en) | 1983-07-25 |
| AU1069583A (en) | 1983-07-28 |
| FI830163A0 (en) | 1983-01-18 |
| FI830163L (en) | 1983-07-24 |
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