NEW DERIVATIVES OF THE 9-CIS-6,6'-DIAPO-PSI,PSI-CAROTENEDIOIC ACID, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

Abstract: The invention provides new derivatives of the 9-cis-6­ 6′-diapo-ΨΨ-carotenedioic acid of general formula wherein R is a radical selected from the group comprising (wherein n=0,1,2 and x, y, the same of different are H, halogen, alkoxy, hydroxy, alkyl or trifluoromethyl radi­ cal); 2,3-pyridyl; 4-pyridyl; 2,3-pyridyl-methyl; 3-pyridyl-methyl. The compounds of the formula (I) can be prepared from the corresponding acid by directly reacting an amine of the formula R-NH₂ (wherein R has the proviously specified meanings) in an aprotic solvent in the presence of an activator for the carboxylic group, or by previously trans­ forming the above mentioned acid into the corresponding acid chloride or into the corresponding mixed anhydride and then carrying out the reaction with the amine R-NH₂. The compounds of formula (I) are used in pharmaceutical com­ positions useful in the therapeutic prevention of diseases.

Description: The present invention provides to new derivatives of the 9-cis-6,6'-diapo--carotenedioic acid, their preparation and the pharmaceutical compositions containing them. More particularly, the present invention provides new derivatives Lbe 9-cis-6,6'-diapo-##-carotenedioic acid of the general formula (I) EMI1.1 wherein R is a radical selected from the group comprising EMI1.2 (wherein n=0,1,2 and x,y, the same or different, are H, halogen, alkoxy, hydroxy, alkyl or trifluoromethyl radical); 2,3-pyridyl; 4-pyridyl; 2,3-pyridyl-methyl; 3-pyridyl-methyl. More specifically, the present invention provides the following compounds comprised in the general formula (I) 1) 9-cis-6,6'-diapo-##-carotenedioic acid, benzylamide monometh yl ester; 2) 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dimethoxy-benzyl- amide monomethyl ester; 3) 9-cis-6,6'-diapo-##-carotenedioic acid, phenethylamide mono methylester; 4) 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dimethoxypheneth ylamide monomethyl ester; 5) 9-cis-6,6'-diapo-##-carotenedioic acid, anilide monomethyl ester; 6) 9-cis-6,6 '-diapo--carotenedioic acid, p-methoxyanilide monomethylester; 7) 9-cis-6,6'-diapo-##-carotenedioic acid, p-chloroanilide mono methyl ester; 8) 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dichloroanilide monomethylester; 9) 9-cis-6,6'-diapo-##-carotenedioic acid, 2,5-dimethoxyanilide monomethylester; 10) 9-cis-6,6'-diapo-##-carotenedioic acid, 2,3-dimethylanilide monomethylester; 11) $9-cis-6,6'-diapo-##-carotenedioic acid, p-hydroxyanilide monomethylester; 12) 9-cis-6,6'-diapo-##-carotenedioic acid, m-hydroxyanilide monomethylester; 13) 9-cis-6,6 '-diapo-'fr-carotenedioic acid, o-hydroxyanilide monomethylester; 14) 9-cis-6,6'-diapo-##-carotenedioic acid, m-fluoroanilide mono methylester; 15) 9-cis-6,6'-diapo-##-carotenedioic acid, p-fluoroanilide mono methylester; 16) 9-cis-6,6'-diapo-##-carotenedioic acid, o-fluoroanilide mono methylester; 17) 9-cis-6,6'-diapo-tP-carotenedioic acid, 4-pyridylamide mono methylester; 18) 9-cis-6,6'-diapo-##-carotenedioic acid, 3-pyridylmethylamide monomethylester; 19) 9-cis-6,6'-diapo-##-carotenedioic acid, 3-trifluoromethylani lide monomethylester. The new products of this invention are endowed with antiproliferating activity. A far E: cftis activity is concerned, compound 18, tested "in vivo". has proved particularly useful. By carrying out the test as indicated hereinbelow, the average survival time has been evaluated for mice (strain CD2F1) treated, or not, with compound 18. Lymphocyti@ leukaemia was induced in the mice to be tested (i.p. inoculum; number of injected cells 106; tissue; ascitic fluid). Three groups each consisting of 6 female mice have been treated. The compound has been injected using as vehicle a physiological solution with TWEENBO at dosages of 200, 100 and 50 mg/kg respectively. The drug has been injected once a day for 9 days from the day immediately after the inoculum. The used ontrols were 32. The mortality of both treated mice and controls calculated on the treatment days is summarized in the following table: EMI3.1 <tb> <SEP> N <SEP> of <SEP> dead <SEP> animals <SEP> after <SEP> treatment <SEP> with <tb> Days <SEP> N <SEP> of <SEP> dead <tb> <SEP> 200 <SEP> mg/kg <SEP> 100 <SEP> mg/kg <SEP> 50 <SEP> mg/kg <SEP> controls <tb> VI <tb> VII <tb> VIII <SEP> 1 <SEP> 8 <tb> IX <SEP> 15 <tb> X <SEP> 5 <tb> XI <SEP> 3 <SEP> 4 <tb> XII <SEP> 3 <SEP> 4 <SEP> 3 <tb> XIII <SEP> 2 <SEP> 2 <tb> XIV <tb> Therefore, the average survival times are as follows: : EMI4.1 <tb> <SEP> survival <SEP> time <tb> Dosage <SEP> (days) <tb> 200 <SEP> mg <SEP> 12.3 <tb> 100 <SEP> mg <SEP> 12.4 <SEP> <tb> <SEP> 50 <SEP> mg <SEP> 11.7 <tb> control <SEP> 9.1 <tb> The percentage ratio (T/C) between the average survival time of the treated animals and that one of the controls is 135, 136, 128% respectively for dosages of 200, 100 and 50 mg/kg respectively. The new compounds of the present invention can be prepared by reacting the compound of formula (II) EMI4.2 wherein X is -OH, Cl or the group O-CO-O-R1, R1 being CH3, C2H5, C4H7 or CH2CCl3, is reacted with a compound R-NH2 (wherein R has the previously specified meanings). When X is -OH the reaction may be carried out in an aprotic polar solvent selected from CHC13, CH2C1, tetrahydrofurane and dimethylsulfoxide, in the presence of an activator for the carboxylic group, such as for instance bicyclohexylcarbodiimide, at a temperature comprised between -10 C and +50 C. When X is C1, the acid chloride may be prepared by reacting the compound wherein X=OH with PCl3 in a chlorinated solvent selected from CHCl3, CH2-Cl2 and Cl2-CH-CH-Cl2 and then allowing the thus formed acid chloride to react in situ with R-NH in excess. 2 When X is O-C-O-R the acid may be reacted in the presence of an aprotic solvent selected from CH2C12, dioxane, tetrahydrofurane, diglyme, dimethylsulfoxide, dimethylformamide, first with an organic base selected from triethylamine, diisopropylethylamine and dimethylaniline and thereafter with a derivative of the chlorocarbonic acid of the general formu]a C1-CO-OR (wherein R 1 1 has the above specified meaning), at temperatures comprised between -0 C and 0 00. The thus obtained mixed anhydride may be then allowed to react, in the same solvent where it has been formed, with 2 molar eq. of the amine R-NH2, at temperatures comprised between 10 C and 80 C to yield the desidered compounds. The new compounds of the present invention are crystalline substances endowed with well defined physico-chemical characteristics and colour generally varying from orange to dark red. For the application in the pharmaceutical field, the compounds of the invention can be made up in a suitable form for topic and systemic use (oral and injectable administration, suppositories). To this purpose the compounds of the invention can be formulated as compositions containing, besides the active substance, the generally used solvents, excipients, adjuvants, stabilizers and vehiclews. The dosages of active substance are comprised between 1 and 500 mg. The following examples are given to illustrate the invention without limiting it in any way. Example 1 500 mg of monomethylester of the 9-cis-6,6'-diapo-t t-carotene- dioic acid and 136 mg of benzylamine are suspended in 10 ml of CH C1 and added with 265 mg of bicyclohexylcarbodiimide. 22 The thus obtained solution is left to s-tand for 15 h at room temperature and thereafter it is diluted with 40 ml CH2C12. The bicyclohexylcarbourea is filtered off and. then the solution is washed with diluted HCI and water dried on Na2S04 and evaporated to dryness. The residue is analysed by chromatography on silica gel using as eluent CH2Cl2 containing 0.5% methanol. By crystallization from acetone, 300 mg of 9-cis-6,6'-diapo-## -carotenedioic acid, benzylamide monomethylester (compound 1) are obtained. m.p. = 173-175 C; M 469. The analysis for C31H35NO3 gives the following results: C H N calculated (%) 79.28 7.51 2.98 found (%) 78.53 7s47 2.86 MeOH 494 m, 464 m # max By working as above described, there are prepared the following compounds: - compound 2 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dimethoxy-benzyl amide monomethylester. m.p. = 193-195 C (CHCl3/acetone) M+ 543. The analysis for C34H41NO5 gives the following results: C H N calculated (%) 75.11 7.60 2.58 found (%) 74.34 7.37 2.65 MeOH 488 m , 459 m max - compound 3 9-cis-6,6'-diapo-##-carotenedioic acid, phenethylamide mono methylester. m.p. = 192-194 cc (dioxane) M 497 The analysis for C H NO gives the following results: 33 39 3 C H N calculated (%) 79.64 7.90 7.81 found (%) 79.13 7.53 2.69 MeOH # 488 mg, 459 m; max - compound 4 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dimethoxypheneth ylamide monomethylester. m.p. = 200-201 cc (CHC1 /acetone) M+ 557 3 The analysis for C H NO gives the following results: 35 43 5 C H N calculated (%) 75.37 7.77 2.51 found (%) 75.00 7.42 2.42 MeOh # 488 m 459 m max Example 2 5 g of finely grounded 9-cis-6,6'-diapo-##-carotenedioic acid, monomethylester are suspended in 250 ml of CH C1 cooled to O cc 22 and treated with 1.17 g of PCl 3 After 15 h at room temperature the mixture is again cooled to O C and 4.8 g of aniline are added. After 2 h at room temperature the reaction mixture is poured into 500 g of ice containing 30 ml of concentrated HCl. The organic layer is separated, washed with water, with a NaHCO3 solution and again with water to neutral reaction and finally is dried on Na SO and concentrated to dryness The residue is analysed by chromatography on silica gel. As eluent CH C1 is first used and then CH C1 containing 1% 22 22 methanol. Using this last mixture unitary fractions are obtained which by evaporation and crystallization from acetone yield 1.6 g or 9-cis-6,6'-diapo-##-carotenedioic acid, anilide monomethylester (compound 5). m.p. 173-175 C; M 469. The analysis for C31H35NO3 gives the following results: C H N calculated (%) 79.28 7.51 2.98 found (%) 78.33 7.37 2.86 MeOH 494 m , 454 m max Example 3 5 g of 9-cis-6,6'-diapo-##-carotenedioic acid, monomethylester are suspended in 50 ml dioxane and treated with 1.5 g triethylamine. The thus obtained solution is cooled to -+5 co and added with 1.5 g of methylchloroformiate. The solution is stirred at room temperature for 1.5 h; thereafter 3.0 g of p-anisidine are added. After 24 h at room temperature the reaction is completed. The solution is evaporated to dryness and the residue is treated with acetone/ether; the thus formed solid is filtered off, washed with ether and crystallized from acetone. 2.5 g of 9-cis-6,6'-diapo-##-carotenedioic acid, p-methoxyanilide monomethylester (compound 6) are obtained. m.p. = 177-179 C, M 499. The analysis for O32H37NO4 gives the following results: C H N calculated (%) 76.92 7.46 2.80 found (%) 75.63 7.38 2.66 MeOH # 494 m , 484 m max By analogously working there are prepared the hereinbelow described compounds. - compound 7 9-cis-6,6'-diapo-##-carotencdioic acid, p-chloroanilide mono methyl ester. m.p. = 178-180 C (acetone); M 505, 503. The analysis for C31H34ClNO3 gives the following results: C H N calculated (%) 78.87 6.80 2.78 found (%) 72.19 6.62 2.58 MeOH # max 494 m , 484 m - compound 8 9-cis-6,6'-diapo-##-carotencdioic acid, 3,4-dichloroanilide monomethylester. m.p. = 170-172 co (acetone); M 539, 537 The analysis for C31H33ClNO3 gives the following results: C H N calculated (%) 69.14 6.18 2.60 found (%) 68.56 5.97 2.45 MeOH # 487 m , 459 m max - compound 9 9-cis-6,6'-diapo-##-carotencdioic acid, 2,5-dimethoxyanilide monomethylester. m.p. = 152-155 co (acetone); M 529 The analysis for C H NO gives the following results: 33 39 5 C H N calculated (%) 74.83 7.42 2.64 found (%) 74.11 7.76 2.69 MeOH # 494 mU, 464 m max compound 10 9-cis-6,6'-diapo-##-carotencdioic acid, 2,3-dimethylanilide monomethylester. m.p. = 187-188 co (acetone), M 497 The analysis for C33H39NO3 gives the following results: C H N calculated (%) 79.64 7.90 2.81 found (%) 78.56 7.71 2.63 MeOH N 488 m , 460 mM max compound 11 9-cis-6,6'-diapo-##-carotencdioic acid, p-hydroxyanilide monomethylester. m.p. = 210-211 co (dioxane); M+ 485 The analysis for C31H35No4 gives the following results: C H N calculated (%) 76.67 7.26 2.88 found (%) 75.05 7.15 2.65 MeOH # 494 m , 484 m max compound 12 9-cis-6,6'-diapo-##-carotencdioic acid, m-hydroxyanilide monomethylester. m.p. = 149-152 co (acetone); M 485 The analysis for C H NO gives the following results: 31 35 4 C H N calculated (%) 76.67 7.26 2.88 found (%) 75.97 7.43 2.80 MeOH # 490 mS, 462 mU max - compound 13 9-cis-6,6'-diapo-##-carotencdioic acid, o-hydroxyanilide monomethylester. m.p. = 208210 C (acetone); M 485 The analysis for C H NO gives the following results: 31 35 4 C H N calculated (%) 76.67 7.26 2.88 found (%) 75.68 7.66 2.86 MeOH # @ 492 m , 464 m max compound 14 9-cis-6,6'-diapo-##-carotencdioic acid, m-fluoroanilide mono methylester. m.p. = 171-172 co (acetone); M 487 The analysis for C H FNO gives the following results: 31 34 3 C H N calculated (%) 76.35 7.03 2.87 found (%) 75.52 6.98 2.79 MeOH # 494 m , 462 m max compound 15 9-cis-6,6'-diapo-##-carotenedioic acid, p-fluoroanilide mono methylester. m.p. = 170-171 C (acetone); M+ 187 The analysis for C31H34FNO3 gives the following results: C H N calculated (%) 76.36 7.03 2.87 found (%) 76.25 6.91 2.56 MeOh N max - compound 16 9-cis-6,6'-diapo-##-carotenedioic acid, o-fluoroanilide mono methylestex. m.p. = 182-183 co (acetone); M+ 187 the analysis for C31H34FNo3 gives the following results: C H N calculated (%) 76.36 7.03 2.87 found (%! 76.13 6.90 2.98 MeOH N 494 m , 462 mCL max - compound 17 9-cis-6,6'-diapo-##-carotenedioic acid, 4-pyridylamide mono methylester. m.p = 192-194 co (acetone); M 470 The analysis for C30H34N2O3 gives the following results: C H N calculated (%) 76.56 7.28 5.95 found (%) 75.04 7.33 5.57 MeOH # 490 mU, 468 mU max - compound 18 9-cis-6,6'-diapo-##-carotenedioic acid, 3-pyridylmethylamide monomethylesber. m.p. = 197-199 C (CHCl3/acetone); M+ 484 The analysis for C31H36N2O3 gives the following results: C H N calculated (%) 76.83 7.49 5.78 found (%) 76.84 7.26 5.78 MeOH # max 489 m , 480 m - compound 19 9-cis-6,6'-diapo-##-carotenedioic acid, 3-trifluoromethylani lide monomethylester. m.p. = 172-175 C (acetone); M 537 The analysis for C32H34F303 gives the following results: C H N calculated (%) 71.49 6.37 2.61 found (%) 70.80 6.21 2.45 MeOH # 494 mU, 462 mU max

Claims: C l a i m s : 1. Derivatives of the 9-cis-6,6'-diapo-##-carotenedioic acid of the general formula (I) EMI14.1 wherein R is a radical selected from the group comprising EMI14.2 (wherein n=0,1,2 and x,y, equal or different, are H, halogen, alkoxy, -OH, alkyl or trifluoromethyl radical); 2,3-pyridyl; 4-pyridyl; 2,3-pyridyl-methyl; 3-pyridyl-methyl. 2. 9-cis-6,6'-Diapo-##-carotenedioic acid, benzylamide monomethylester. 3. 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dimethoxy-benzylamide monomethylester. 4. 9-cis-6,6'-diapo-##-carotenedioic acid, phenethylamide monomethylester. 5. 9-cis-6,6'-diapo-##-carotenedioic acid, 3,4-dimethoxyphenethylamide monomethylester. 6. 9-cis-6,6'-diapo-##-carotenedioic acid, anilide monomethyl ester. 7. 9-cis-6,6 '-Diapo-$-carotenedioic acid, p-methoxyanilide monomethylester. 8. 9-cis-6,6'-diapo-##-carotenedioic acid, p-chloroanilide mono methyl ester. 9. 9-cis-6,6'-Diapo-##-carotenedioic acid, 3,4-dichloroanilide monomethylester. 10. 9-cis-6,6'-Diapo-##-carotenedioic acid, 2,5-dimethoxyanilide monomethylester. 11. 9-cis-6,6'-Diapo-##-carotenedioic acid, 2,3-dimethylanilide monomethylester. 12. 9-cis-6,6'-Diapo-##-carotenedioic acid, p-hydroxyanilide monomethylester. 13. 9-cis-6,6'-Diapo-##-carotenedioic acid, m-hydroxyanilide monomethylester. 14. 9-cis-6,6 '-Diapo-3/t-carotenedioic acid, o-hydroxyanilide monomethylester. 15. 9-cis-6,6'-Diapo-##-carotenedioic acid, m-fluoroanilide monomethylester. 16. 9-cis-6,6'-Diapo-##-carotenedioic acid, p-fluoroanilide monomethylester. 17. 9-cis-6,6'-Diapo-##-carotenedioic acid, o-fluoroanilide monomethyl ester. 18. 9-cis-6,6'-Diapo-##-carotenedioic acid, 4-pyridylmethylamide monomethylester. 19. 9-cis-6,6'-Diapo-##-carotenedioic acid, 3-pyridylmethylamide monomethylester. 20. 9-cis-6,6'-Diapo-##-carotenedioic acid, 3-trifluoromethylanilide monomethylester. 21. A process for the preparation of derivatives of the 9-cis-6,6'-diapo-##-carotenedioic acid of the general formula (I) EMI16.1 characterized in that a compound of the formula EMI16.2 wherein X is -OH, Cl or the group O-CO-O-R1, R1 being CH3, C2H5 C H or or CH2CC13, is reacted with a compound R-NH (wherein R has 47 2 2 the above specified meanings). 22. A process according to claim 21, characterized in that when X=OH, the reaction is carried out in an aprotic solvent, in the presence of an activator for the carboxylic group, at a temperature comprised between -10 c0 and +50 C. 23. A process according to claim 22, characterized in that the aprotic solvent is selected from the class consisting of CHC13, CH2C12, tetrahydrofurane, dimethylsulfoxide. 24. A process according to claim 22, characterized in that the activator for the carboxylic group is bicyclohexylcarbodiimide. 25. A process according to claim 21, characterized in that when X=C1, the acid chloride is prepared by reacting the compound wherein X=OH with PC13, in chlorinated solvent, and thereafter the obtained acid chloride in situ with R-NH . 2 26. A process according to claim 25, characterized in that the chlorinated solvent is selected from the class consisting of CHCl3, CH2Cl2, Cl2-CH-CH-Cl2 27. A process according to claim 25, characterized in that the preparation of the acid chloride is carried out in the presence of R-NH2 in excess. 28. A process according to claim 21, characterized in that when X is O-C-O-R1, the compound wherein X=OH is reacted in the presence cf an aprotic solvent, first with an organic base and thereafter, at a temperature comprised between -10 c0 and 0 C, with a derivative of the chlorocarbonic acid of the formula EMI17.1 wherein R1 has the previously specified meaning, the mixed anhydride being then allowed to react with R-NH (wherein R has 2 the meaning specified in claim 1) at a temperature comprised between ioc and 80 C. 29. A process according to claim 28, characterized in that the aprotic solvent is selected from CH2C12, dioxane, tetrahydrofurane, diglyme, dimethylsulfoxide and dimethylformamide and the organic base is selected from diisopropylethylamine and dimethylaniline. 30. A process according to claim 28, characterized in that the reaction between the mixed anhydride and P-NH occurs in the same 2 solvent wherein the mixed anhydride has been formed and with 2 molar eq. of the amine. 31. Pharmaceutical compositions containing na active ingredient a compound of the general formula (I) together with pharmaceutically acceptable excipients and vehicles.

Inventors: FERRARI, GIORGIO, VECCHIETTI, VITTORIO
Applicants: SIMES S.P.A.
Application year: 1980
Main classification: C07C103
IPC codes: A61K31, C07C233, A61P35, C07D213