CA2179314A1

CA2179314A1 - Esters and amides of 9(z)-retinoic acid

Info

Publication number: CA2179314A1
Application number: CA002179314A
Authority: CA
Inventors: Michael John; Wolfgang Siegel
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1995-06-26
Filing date: 1996-06-17
Publication date: 1996-12-27
Also published as: DE19523079A1; JPH0912538A; EP0751125A1

Abstract

Esters and amides of 9 (Z) -retinoic acid for the treatment of carcinomas, novel 9 (Z) -retinoic acid derivatives, pharmaceutical compositions containing esters and amides of 9 (Z) -retinoic acid as anticancer agents, and the use of esters and amides of 9 (Z)-retinoic acid for the treatment and prophylaxis of carcinomas.

Description

~ ~ 21~93~4 Esters and amides of 9 ( Z )-retlnoic acid The invention rRlates to esters and amides of 9 ( Z )-retinoic acid for the treatment of carcinomas, to novel 9(Z)-retinoic acid derivatives and to ph~rr~ utical compositions containing esters and amides of 9(Z)-retinoic acid, and to the use thereof for the treatment of carcinomas.
10 ~etinoic acids (vitamin A acids) are derivatives of vitamin A
( retinol ) covering a wide range of biological activities, such as cellular differentiation and many others. Their biological activ-lty is made possible by interaction with two families of nuclear receptors (RA receptor and ~X receptor) (cf. Mol. Cell. Biol. 14 No. 4 (1994) 2323 - 30).
The use of all-(E)- or 13-(Z)-retinoic acids or their derivatives in the therapy of acne has been known for a long time (cf.
US 3,729,568 and E~ 366 713). Use of 9(Z)-retinoic acid in the 20 treatment of cancer has been considered only since the identifi-cation of specific receptor systems [cf. Cell 68 (1992) 397 -406; Nature ~L (1993) 657 - 60; Nucl. Acid Research 21, No. 5 (1993) 1231 - 37; ~ifferentiation 54 (lg93) 123 - 29; J. Bio.
Chem. 26~ (1994) 16689 - 95, Blood ~2, No. 12 (1993) 35g2 - 99;
Blood ~, No. 10 (19g3) 22].
already known for the structural isomers all-E- and 13(Z)-retinoic acid, in some cases severe side effects occur on use of 9(Z)-retinoic acid too, 80 that the extent of secondary reactions 30 disproportionately overcompensates for the effect achieved. In addition, topical use of free g(Z)-ret$noic acid frequently leads to severe derm~l irrltation and pain for the patient which depends on the concentration and f requency of application . The type and number of side effects reduce the possibility of therapy with high doses of free 9 ( Z )-retlnoic acid and re3tri~ t the number of areas of application.
We have now found that certain esters and amides of 9 ( Z ) -retinoic acid can also be used for treating carcinomas but, at the same gO time, show only few, if any, side effects. The present invention therefore relates to derivatives of 9(2)-retinoic acid which can easily be prepared and are of importance for the treafment of carcinomas while simultaneously minim~7;ng the toxicological side effects of free 9(Z)-vitamin A acid.

~ 2 2~7~3~
The invention therefore relates to compounds for use for treating carcinomas, of the general formula I
X~
C~
~y (I), where Y can be the following radicals:
--O--CRI--CO--R2, where Rl i5 H or Cl-C20-alkyl or Cl-C20-alkanoyl, preferably H or 20 Cl-C4-alkyl, and R2 i8 Cl-C4-alkyl, -CH20H, 2 -CH2-o-co-R3 n ' Xn, Xn ~ Xn ~
and where R3 is H or Cl-C4-alkyl, X is H, F, Cl, E~r, I, -OH, -oR3, -NH2, -N02, -CN, -NHR3, -NR3 30 -sH, sR3, -o-co-R3, -Co-R3, -CHO or -CO-ORI, 2 and n is an integer from O to S, or else Y i8 ~ 217~314 --O--CH2~ CH3 --O--CHz~ oCH3~
--O--CH2~ F; --~--CH2--CO-- NH~--CH3 -- N~ ~ COOH ; --NH ~ ;
COOH
--O~CE~2--CO ~ OCH3 OCE;3 `J~J~l ;
~
~o.~
-- O--CHR4 O--CHR3--O--CO--oR3 ~ CHz--O--CO--R
--O--CRI--CH
O -- --CO --Rl --N~ ; _ NR3 ~ ; --NR4 ~ xn r o 4 17~
where Rl, R3, X and n have the abovementioned meanings, and R4 is -Co-oR3, -Co-R3 or -Co-R3 ~~ Xn ~
where in the compounds which contain several R~, R2, R3 and/or R4 radicals, these can be ldentical or different, or Qlse Y i8 one of the radicals ORs ORs Rs 1 Z~
ORs ORs R300C ~ O- R300C /. ~ ,~NR3--RsO ~ /, OR Rs \ ~ I~ ' ~ ORs oR5 ORs where R3 has the abovementioned meaning, and Rs is H or Cl--C4-alkyl or C~--C4-alkanoyl.
Of particular importance for use for treating carcinomas are com-30 pounds of the general formula I where Y is the radical --O--CRI--CO--~
Xn where Rl is H, X is F, -OH, -OCH3, -NHz, -CN, -NHCH3 or -N(CH3) 2, and n is an integer from 1 to 5, preferably 1 to 3, in parti~ular 40 1 to 2, and the compounds of the general ~ormula I
where Y is one of the radicals 21793I~

RsO~ ~ NR -- RsO :~ 7~ z NR
ORs ORs WherQ Rs i8 H or Cl-C4-alkanoyl such as CH3_CO-, C2Hs-CO-, C3H7-CO
10 or else HCO- and R3 18 H, Cl-C4-alkyl or Cl-C4-alkanoyl, in particular compounds of the general formula I where Y is one of the radicals J ,~,~ ;

~J:~ ~
.~
O
-NH--~ ~ CO-OCH3 or CH3CO-O ~~~ O-COCH3 -NH--~ ~ CH2OH
CH3COO ~ ~-COCH3 The 9 ( Z ) -retinoic acid derivatives according to the invention can bQ used both locally, le. topically, for treating cancer of the Rkin and orally, le. systemioally, for treating carcinomas or precancerous states.
E~owever, under cQrtain conditions, local and systemic prophylaxis of carcinomas is also possible.
The invention therefore also relates to pharmaceutical compos1-10 tions containing compounds of the general formula I ln addltlon to conventlonal pharmaceutlcal exclplents or diluents and conventlonal pharmaceutical ancillary substances, and to the use of ~ ullds of the general formula I in the form of pastes, gels, ointments, oreams, lotlons, dustlng powders, solutions or emulsions containing from 0 . 001 to 5~ of these compounds for the local treatment of oarcinoman or precancerous states, and to the use of a compound of the general formula I in the form of tablQts, film-coated tablets, sugar-coated tablQts, capsulQs, pills, powders, 20 granules, solutions or suspensions for the ~ystemic treatment of carcinomas or precancerous states, and to the use of pharmaceuti-cal composltions containing compounds of the general formula }
for the local or systemic prophylaxis of carcinomas.
The therapeutic compositions or formulations containing conven-tional excipients or diluents and, wherQ appropriatQ, conven-tion~l rh~rr-^eutical ancillary substances appropriate for thQ
requirQd modQ of adm$nistration with a dosage suitable for use are produced in a conventional way, in partioular by mixing. ThQ
30 therapeutic compositions contain thQ . ~ul~ds to bo used accord-ing to the invention in amounts of from 0.001 to 5~ by wQight, prQferably from 0.001 to 1~ by weight, for local use, and preferably ln a slngle dose of from 0.1 to 10 mg ~or systemic use .
Tests relating to topical use are carried out by generally customary oncology tQsting programs.
The supprQssion of uncontrolled cell growth is tested.
The preparation of compounds according to the invention of the general formu a I is indicated by the following examples.

7 217931~
Example 1 2- [ 9 ( Z ) -Retinoyloxy ] -4 ' -methylacetophenone 50 ml of dimethylformamide were introduced into a flask and then 0.5 g of potassium carbonate and 1.12 g of 2-chloro-4'-mQthyl-acetophenone plus 2 g of 9 ( Z ) -retinoic acid were added with exclusion of light. The mixture was stirred under nitrogen at 10 room temperature (RT) for 24 hours (h). 100 ml of water were then ~dded to the reaction mixture, and stirring was continued for 2 h. The re~ulting crystals were filtered off with suction and dried under nitrogen at 30 C for 12 h. 2.4 g (~vLLe~vl~ding to a yiQld of 84& of theory) of the abovementioned product were obtained. The product was purified by recrystallization ~rom isopropanol. 'rhe melting point of the recrystallized product was 126 C. The NMR spectra agree with the proposed structure.
Example 2 2--[ 9 ( Z ) -Retinoyloxy l--4 ~ -methoxyace~nphc-~n~
A mixture of 35 ml of dimethylformamide, 0.5 g of potassium carbonate, 1. 23 g of 2-chloro-4 '-methoxyacetophenone and 2 g of 9 ( Z )-retinoic acid was stirred under N2 at RT with exclusion of light for 24 h. 100 ml of water were then added to the reaction mixture at 30 C, and stirring was continued for 2 h. The resulting crystals were filtered off with suction and dried under nitrogen for 12 h. 2.5 g (corresponding to 88.1~ of theory) of the above-30 mentioned product were obtained. The melting point afterrecrystallization from isopropanol was 124-126 C.
Example 3 2-[ 9 ( Z )-Retinoyloxy]-4 '-fluoroacetophenone A mixture of 30 ml of dimethylformamide, 0.2 g of pot~ssium carbonate, 0.54 g of 2-chloro-4'-fluoroacetophenone and 1 g of 9 ( Z ) -retinoic acid was atirred under N2 at RT with exclusion of 40 light for 24 h. 100 ml of water were then added, and stirring was continued ~or 2 h. Removal of the crystals and drying under nitrogen for 12 hours resulted in 1.1 g (84.69~ of theory) of the abovementioned product. The melting point after purification by recrystallization from methanol was 99 C.

ExamplQ 4 2--[9(Z)-Retinoyloxy]--3'--fluoroacetophenone A mixture of 50 ml of dimethylformamide, 0.75 g of potassium carbonate, 1. 8 g of 2-chloro-3 '-fluoroacetophenone and 3 g of 9 ( Z )-retinoic acid was stirred under nitrogen at RT with exclusion of light for 24 h. 100 ml of water were then added to the reaction mixture, and stirring was continued for 2 h. The 10 resulting crystals were filtered off with suction and recrystal-lized from isopropanol. 3.3 g (85% of theory) of the abovementioned product were obtained with a melting point of 76-79 C.
Example 5 2--[ 9 ( Z ) -Retinoyloxy ] -N- ( 2, 6-dimethylphenyl ) acetamide A mixture of 35 ml of dimethylformamide, 0 . 5 g of potassium 20 carbonate, 1.3 g of 2-chloro-N-(2,6-dimethylphenyl)acQtamide and 2 g of 9 ( Z )-retinoic acid was stirred under nitrogen at RT with exclu~ion of light for 24 h. 100 ml of water were then added to the reaction mixture, and the mixture was thQn stirred for 2 h.
The resulting crystals were dried under nitrogen for 12 h.
Recrystalli2ation from isopropanol resulted in 2.4 g (91% of theory) of the abovementioned product with a solidification point of 147-148 C.
Example 6 N- ( p-Carboxyphenyl ) -9 ( Z ) -retinoamide A mixture of 10 g of 9 ( Z )-retinoic acid and 2 . 9 g of pyridine in 650 ml of diethyl ether was cooled to 0 C. Then, at 0 C, 3.5 g of thionyl chloride were added dropwise, and the mixture was stirred at 0 C for 2 h. Precipitated pyridinium hydrochloridQ was removed.
The filtrate waD then cooled to -25 C and a solution of 4.1 g of p-aminobenzoic acid in 150 ml of diethyl ether and 2.9 g of pyridine was added. The mixture was stirred at RT for 2 h. For 40 workup, the reaction mixture was qxtracted with ice-cold 1 N i~Cl and saturated NaCl solution. The aqueous phase was separated of f ~nd the solvent was removed under reduced pressure to result in 11.7 g (93r of theory) of the abovementioned product which, after recrystallization from isopropanol/ethanol, had a solidification point of 187 C.

9 3 I ~
Example 7 2- [ 9 ( Z ) -Retinoyloxy ]--3 ', 4 ' -dimethoxyacetophenone A mixture of 50 ml of dimethylformamide, 0.75 g of potassium carbonate, 2 . 2 g of 2-chloro-3 ', 4 ' -dimethoxyacetophenone and 3 g of 9 ( Z ) -retinoic acid was stirred under nitrogen at RT with excluslon of light for 24 h. For workup, 100 ml of water were added to the reaction mixture, which was then stirred at RT for 10 2 h. The precipitated crystals were filtered off with suction, recrystallized from isopropanol and dried under nitrogen. This resulted in 3.6 g (969~ of theory) of crystallized product of melting point 130-C.
Example 8 N- [ 1--( D-Glucopyranosyluronosyl ) ] -9 ( Z ) -retinoamide A mixture of 10 g of 9(Z)-retinoic acid and 2.9 g of pyridine in 20 500 ml of diethyl ether was cooled to 0 C under N2 with exclusion of light. Then, at 0 C, 3.5 g of thionyl chloride were added dropwise, and the mixture was stirred at 0 C for 2 h. Precipitated pyridinium hydrochlorida was removed. The filtrate was then cooled to --25 C and a solution of 10 g of methyl (2,3,4-tri-o-acetyl-f~--D--glucopyranosyluronosyl)amine in 150 ml of diethyl ether and 4 . 2 g of potassium carbonate were added. The mixture was stirred at -25 C fo 2 h and warmed to 0 C over the course of 1 h. Then 2 g of potassium carbonate and 100 ml of methanol were added to the reaction mixture. To remove the protective groups, a 30 20~ strength solution of ROE~ in 150 ml of methanol was then added. The reaction mixture was heated at 60 C for 0.5 h and then cooled to RT. After extraction with heptane/ethyl acetatQ, the aqueous phases were extracted several times with methylene chloride. The methylene chloride phases were then concentrated under reduced pressure. The residue was fractionated into a 1:1 mixture of the two anomers by chromatography on silica gel. This 1:1 mixture of isomers of the abovementioned product was obtained in amounts of 8.2 g (corre~ponding to 609~ of theory) with a solidification point of 56-58 C.
Example 9 Tocopheryl 9 ( Z ) -retinoate 6 g of 9(Z)-retinoic acid were dissolved in 150 ml of diisopropyl ether, and the solution was cooled to 5 C. Then 4 . 6 g of tri-f luoroacetic anhydride were added dropwise, and the reaction lo 2~9~1d mixture waa warmed to RT . A solut1on of 9 . 6 g of D, L-tocopherol in 10 ml of diisopropyl ether was then added dropwise, and the mixture was stirred at RT for 1 h. For workup, 20 ml of agueous ammonia were added to the mixture at 20 - 25 C. After phase Eieparation, the organic phase was wa3hed with water, dried and then distllled to remove the solvent. 12 g (corresponding to 84 of theory) of the abovementioned product were obtained in the form of an orange-yellow oil whose NMR data agree with the proposed structure.
Example 1 0 Ergocalciferyl 9 ( Z )-retinoate A mixture of 10 g of 9(Z)-retinoic acid, 2.9 g of pyridine and 500 ml of diethyl ether was cooled under N2 protective gas with exclusion of light to 0 C and, at 0 C, 3.5 g of thionyl chloride were added dropwise, and the reaction mixture was stirred at 0 C
for 2 h. Precipitated pyridinium hydrochloride wa~ removed. The 20 filtrate was cooled to -2S C and a solution o~ 13.2 g of ergo-calciferol in lS0 ml of diethyl ether and 4.2 g of potassium carbonate were added. The mixture was stirred at -25 C for 2 h and then warmed to 0 C over the course of 1 h. 'rhen lO~t strength aqueous KHC03 solution was added to the reaction mixture, followed by wash$ng with water. Removal of the solvent by distillation resulted in lS g of the abovementioned product in the form of a dark orange oil. The NMR spectra are consistent with the propo3ed ~ tructure .

Claims

1. Esters and amides of 9(Z)-retinoic acid for use for treating carcinomas, of the formula I
(I), where Y can be the following radicals:

, where R1 is H or C1-C20-alkyl or C1-C20-alkanoyl and R2 is C1-C4-alkyl, -CH2OH, -NR?, -CH2-O-CO-R3, , , , , or and where R3 is H or C1-C4-alkyl, X is H, F, Cl, Br, I, -OH, -OR3, -NH2, -NO2, -CN, -NHR3, -NR?, -SH, SR3, -O-CO-R3, -CO-R3, -CHO or -CO-OR3, and n is an integer from 0 to 5, or else Y is ; ;
; ;
; ;
;
; , ; ; , where R1, R3, X and n have the abovementioned meanings, and R4 is -CO-OR3, -CO-R3 or , where in the compounds which contain several R1, R2, R3 and/or R4 radicals, these can be identical or different, or else Y is one of the radicals where R3 has the abovementioned meaning, and R5 is H or C1-C4-alkyl or C1-C4-alkanoyl.

2 . Esters and amides of 9 (Z) -retinoic acid for use for treating carcinomas, of the formula I as claimed in claim 1, where Y
9 the radical where R1 is H, X is F, -OH, -OCH3, -NH2, -CN, -NHCH3 or -N(CH3)2, and n is an integer from 1 to 3.

3. Amides of 9 (Z) -retinoic acid for use for treating carcinomas, of the formula I as claimed in claim 1, where Y is one of the radicals where R5 is H, C1-C4-alkyl or C1-C4-alkanoyl and R3 is H, C1-C4-alkanoyl or C1-C4-alkyl,

4. Esters or amides of 9(Z)-retinoic acid of the formula I
, (I), where Y is ; ;
; ;
; ;
;
;

;
.
;

5. A pharmaceutical composition containing esters and amides of 9 (Z) -retinoic acid as claimed in claims 1 to 4 in addition to conventional pharmaceutical excipients or diluents and con-ventional pharmaceutical ancillary substances.