2-[(3,4,5-triphenyl)phenyl]acetic acid, derivatives, and production thereof

Abstract

A first aspect of the invention relates to a synthesis of 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives thereof. Another aspect relates to the synthesis thereof and precursor molecules. Finally, the invention relates to pharmaceutical compositions which comprise compounds according to the invention.

Description

[0001] 2-[(3,4,5-Triphenyl)phenyl]acetic acid and derivatives and their preparation

[0002] In a first aspect, the present application relates to the synthesis of 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives thereof. In a further aspect, the synthesis of these compounds and of precursor molecules is described. Finally, the present application relates to pharmaceutical compositions containing the compounds according to the invention and their use.

[0003] State of the art

[0004] Phenyleacetic acid and its derivatives represent a versatile class of substances with a wide range of properties, particularly biological activities. Phenyleacetic acid is described as a plant auxin that also exhibits antimicrobial activity. It occurs very frequently in nature, and its role in plants, fungi, and bacteria has been extensively studied.

[0005] Phenyleacetic acid and its derivatives play an important role as metabolites. Figure 1 shows an example of a metabolite, namely 3,4-dihydroxyphenylacetic acid. This figure also shows examples of phenyleacetic acid and its derivatives as components of various active pharmaceutical ingredients. 3,4-Dihydroxyphenylacetic acid is attributed with anticancer properties. It is known as a metabolite of the neurotransmitter dopamine, but has also been identified as a metabolite of other compounds such as rutin, a flavonoid with a very broad pharmacological spectrum.

[0006] Phenyleacetic acid also possesses an ammonium ion-binding effect and is used as an adjuvant, for example, in the treatment of acute hyperammonemia and the associated encephalopathy in patients with enzyme deficiency in the urea cycle. One salt, sodium phenyl acetate, can inhibit the growth of tumor cells. Other derivatives, such as 4'-carboxymethyl-4-nonyloxy-[1,T-biphenyl]-3-carboxylic acid (BPDA2) and 2-[(1,1'-biphenyl)-4-yl]- / (3-fluorobenzyl)acetamide, shown in Figure 1b, have been attributed with antiproliferative and antitumor properties against various types of cancer.

[0007] Furthermore, phenylacetic acid and its derivatives are a building block of many well-known drugs. Figure 1c shows examples of ibuprofen, diclofenac, and flurbiprofen. Ester and amide derivatives of phenylacetic acid are also used as drugs; well-known examples are shown in Figure 1d with cyclopentolate, atenolol, and penicillin G.

[0008] The above-mentioned drugs are used in a variety of ways, e.g. as non-steroidal anti-inflammatory drugs, analgesics, cancer drugs, mydriatics and cycloplegics.

[0009] Furthermore, 2-[(3,5-Diphenyl)phenyl]acetic acid has been proposed as a candidate for the treatment of Alzheimer's disease.

[0010] Accordingly, phenylacetic acid and its derivatives are starting materials for the synthesis of a large number of pharmaceuticals. Examples include penicillin, but also bendazole, camylofine, triafungine, phenacenide, lorcainide, phenindione, and cyclopentolate.

[0011] Furthermore, phenylacetic acid is also a starting material in the synthesis of amphetamine.

[0012] Due to the diverse properties of phenylacetic acid derivatives and the possibilities of their wide application, both the development of new synthetic routes and the synthesis of new derivatives with corresponding properties are of interest.

[0013] There are already numerous proposals for synthesizing corresponding derivatives.

[0014] The object of the present invention is to provide new phenylacetic acid derivatives with corresponding biological activity and new synthetic routes for their preparation. These should be stable and exhibit desired properties, such as antitumor properties.

[0015] Description of the invention

[0016] In a first aspect, new compounds of the general structural formula are:

[0017] a, b, c are independently of each other an integer from 1 to 5;

[0018] R 1 Each is independently hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen;

[0019] R 2 Each is independently hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen;

[0020] R 3 Each is independently hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-Ü4-alkoxy, OH, halogen;

[0021] R 4 , R 5 are the same or different hydrogen or Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen;

[0022] X is selected from OH, OR 6 , ON, NH2, NHR 6 , N(R 6 )2, where R 6 a residue comprising a functional group; or salts, solvates or hydrates thereof.

[0023] According to the invention, new phenylacetic acid derivatives can be provided; the common denominator of these new compounds are the phenyl substituents present in meta and para positions (3,4,5 position) on the benzene ring of the phenylacetic acid.

[0024] It was shown that 2-[(3,4,5-triphenyl)phenyl]acetic acid and its derivatives exhibit biological activity, e.g., antitumor activity. Cytotoxicity against various tumor cells, such as solid tumors, was demonstrated.

[0025] The compounds according to the invention can exist as such or as corresponding salts, e.g., alkali salts, alkaline earth salts, or metal salts in general. Furthermore, the compounds according to the invention can exist as solvates or hydrates.

[0026] According to the invention, the three phenyl substituents on the benzene ring of phenylacetic acid can be unsubstituted or substituted, i.e., the substituents R 1 , R 2 , R 3 can occur independently of each other. If R 1 , R 2 , R 3 Since hydrogen is present, the phenyls are unsubstituted. Other suitable substituents include, in particular, a C1-C4 alkyl group, a hydroxy-Ci-C4 alkyl group, a Ci-C4 alkoxy group, OH, and halogen.

[0027] The term "halogen" here refers to substituents of F, CI, Br, I. Br and / or CI are preferred.

[0028] As mentioned, these substituents can R 1 , R 2 and R 3 a, b, c are independent of each other, that is, a, b, c are independently integers from 1 to 5. In one embodiment, a, b, c are equal to 1, 2, or 3. In particular, it is preferred that a, b, c are equal to 1 and hydrogen. Correspondingly, in one embodiment, the phenyl substituents are unsubstituted.

[0029] Furthermore, in addition to the three phenyl substituents, the central benzene ring can also contain the substituents R 4 and / or R 5 exhibit R 4 and / or R 5 can be the same or different, where these substituents can be hydrogen or represent a Ci-C4 alkyl group, hydroxy-Ci-C4 alkyl group, Ci-C4 alkoxy group, OH or halogen.

[0030] The substituent X is selected from OH, OR 6 , CN, NH2, NHR 6 , or N(R 62. That is, this residue exists as a carboxylic acid group, a nitrile group, or an amide group. Further products with other functional groups, such as esters, can be formed via these groups.

[0031] In this context, a functional group is understood to mean that an organic substituent is present, such as in penicillin G or acyl or aryl groups.

[0032] In one embodiment, X is selected from OH, CN or NH2.

[0033] Corresponding salts can be formed via the substituent X, such as alkali salts, alkaline earth salts, or metal salts in general. Such possibilities are known to those skilled in the art.

[0034] In one embodiment of the present compound according to the invention, X is OH or NH₂ or a salt thereof, such that a corresponding phenylacetic acid or a phenylacetic acid amide is formed. In a corresponding embodiment, a phenylacetic acid nitrile with X = CN is present as an intermediate. In one embodiment, in the compounds a, b, c according to the invention, 1 or 2 and R are independently 1 , R 2 and / or R 3 , hydrogen, halogen or OH.

[0035] In one embodiment, the substituents R 1 , R 2 and / or R 3 at the para position of the respective phenyl substituents. That is, a, b, and c are each 1 and R 1 , R 2 and / or R 3 are located at the para position.

[0036] In a preferred embodiment, the compounds according to the invention are those in which X is OH or NH2, R 4 and R 5are hydrogen, a, b, and c are 1 where R 1 , R 2 and R 3 Hydrogen are involved. Some of these compounds (X = OH) can also exist as salts, such as alkali salts, e.g., Na. + - or K + -Salts are present.

[0037] According to the invention, the aforementioned compounds can also be used as solvates or hydrates.

[0038] In a further aspect, the present invention relates to a method for producing a compound according to the invention. This method is illustrated by way of example in Scheme 1. That is, the method according to the invention is one for producing a compound according to the invention and comprises the bromination of a compound of general formula II. - Nitrile synthesis using the compound of general formula III to obtain a compound of general formula IV i) Hydrolysis of the compound of general formula IV to obtain a compound of general formula I with X = NH2 followed by acid-catalyzed hydrolysis to obtain the compound of general formula I with X = OH. ii) alkaline hydrolysis of the compound according to general formula IV

[0039] to obtain a compound according to general formula I with X equal to OH

[0040] That is, in a first step, a triphenyltoluene is brominated according to known methods to obtain a corresponding bromine derivative. As shown in the example, this can be done, for example, using μV-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) (Dötz, F. et al., J. Am. Chem. Soc. 2000, 122, 7707-7717).

[0041] Following the bromination step to obtain a compound with general structural formula III, the nitrile synthesis is carried out starting from this compound. For this purpose, a Kolbe nitrile synthesis is performed (US 2003 / 212094), involving the replacement of the halogen with a CN group. The corresponding process steps for carrying out the Kolbe nitrile synthesis are known to those skilled in the art. The nitrile synthesis yields a compound with general formula IV. When carrying out the reaction, e.g., with potassium cyanide in the presence of 18-crown-6 in acetonitrile, as detailed in the examples, it was found that a comparatively large amount of 18-crown-6 had to be used, e.g., in ratios of 3 to 4 equivalents of starting material per equivalent of crown ether.

[0042] The compound of general formula IV is subsequently hydrolyzed, either under alkaline or acidic conditions. In one embodiment, the hydrolysis of the compound of general formula IV is preferably carried out under acidic conditions to obtain a compound of general formula I with X = NH₂. For example, this can be achieved by using hydrogen bromide in acetic acid. Suitable methods for acidic hydrolysis are known to those skilled in the art. As mentioned, acidic hydrolysis yields a compound of general formula I with X = NH₂. Acidic hydrolysis, for example, gave a yield of 71% of the corresponding acetamide.

[0043] To obtain the corresponding acid, an acid-catalytic hydrolysis of the compound of general formula I with X = NH2 is necessary, e.g. by treatment with aqueous HCl and a catalytic amount of TiCk. The corresponding phenylacetic acid derivative with X = OH can then be obtained in a high yield of 85%.

[0044] Alternatively, the compound of general formula IV can be subjected to alkaline hydrolysis. This allows the direct preparation of a compound of general formula I with X = OH, i.e., the corresponding acetic acid derivative. However, it was found that alkaline hydrolysis resulted in lower yields of the phenylacetic acid derivative.

[0045] If necessary, the formation of corresponding salts, e.g., of a corresponding

[0046] Potassium acetate derivatives can be obtained by treatment with KOH.

[0047] Scheme 1 illustrates the synthesis pathway once again.

[0048] Scheme 1. Syntheses of the phenylacetic acid derivatives 1a, 1b, and 2. Reagents and conditions: (a) NBS, AIBN, CCI4, 20 min, reflux (73% of 6); (b) KCN, 18-crown-6, MeCN, 72 h, reflux (64% of 7); (c) HBr in AcOH (33%), 6 h, reflux (71% of 2); (d) TiCU, HCl, dioxane, water, 2 h, reflux (85% of 1a); (e) KOH, MeOH, water, 2 h, reflux (80% of 1b); (f) KOH, MeOH, 72 h, reflux; conc. H2SO4, room temperature (27% of 1a). The respective product yield is given in percent. In Scheme 1, a, b, and c are equal to 1 and R. 1 , R 2 and R 3 are hydrogen, R 4 and R 5 are hydrogen in relation to the general formulas.

[0049] In one embodiment of the process according to the invention, esterification of the corresponding acid derivative or the amide derivative can further be carried out under known conditions. In another embodiment, the process allows the provision of corresponding alkali salts of the compounds of the general structural formula I.

[0050] In another aspect, a method for producing a compound of general formula II is provided.

[0051] Formula II represents the starting material for the inventive process described above.

[0052] The preparation of this is schematically illustrated by example in Scheme 2. Here, Rf is a substituent R, which replaces R. 1 , R 2 or R 3 where f stands for a, b or c, as defined above.

[0053] Synthesis scheme according to the example:

[0054] Scheme 2. General synthetic route and synthesis of 3,4,5-triphenyltoluene derivatives (5) according to the example of the invention. The following information is for compounds in which R 4 and R 5 Hydrogen are, and Rf (with f equal to 1) is hydrogen. Reagents and conditions for the first step [CuBr2, tert-butyl nitrite, MeCN, 1 h, 60 °C (76% of 4)] and the second step [argon-atm., Pd(PPh3)4 (5 mol% solution), Na2COa, toluene, EtOH, water, 72 h, reflux (68% of 5)]. The respective product yield is given in percent.

[0055] The process according to the invention comprises the diazotization of a compound of the general formula V and reaction with copper bromide.

[0056] By appropriate diazotization and reaction with copper bromide (Sandmeyer reaction), a corresponding 3,4,5-trihalotoluene, 3,4,5-tribromotoluene (4) is obtained according to Scheme 2. This brominated toluene is then reacted with a compound of general formula VII, a phenylboronic acid derivative, to obtain a compound of general formula II.

[0057] Furthermore, a process for the preparation of a compound of general formula I is presented, which, in addition to the process steps according to Scheme 1, also includes the preparation of the triphenyltoluene derivative of general structural formula II.

[0058] Scheme 3 shows an alternative synthesis route for the preparation of the compounds according to the invention:

[0059] Scheme 3. General synthesis route of 3,4,5-triph-phenylacetic acid derivatives according to the invention. R represents the corresponding substituents. 1 , R 2 and / or R3 The first step involves an electrophilic aromatic substitution in which 4-hydroxyphenylacetic acid methyl ester is doubly brominated. The product of this reaction is reacted with trifluoromethanesulfonic acid to form the starting material for the subsequent Suzuki-Miyaura coupling reaction. The coupling is carried out with various phenylboronic acids according to the process described above. The resulting 1,3,5-triphenylphenylacetic acid methyl ester is then saponified and can be used as a salt of the corresponding acid or, after neutralization, as the acid itself.

[0060] Finally, pharmaceutical compositions comprising a compound according to the invention are provided.

[0061] The compounds according to the invention can be in the form of pharmaceutically acceptable salts or solvates. That is to say, the pharmaceutical composition contains a compound according to the invention.

[0062] Pharmaceutically acceptable salts are primarily acid addition salts, which are formed accordingly at amine groups. Base addition salts or corresponding zwitterion addition salts are also possible.

[0063] The term "pharmaceutically acceptable solvates" refers to the association of one or more solvent molecules and a compound according to the invention. Examples of such solvent molecules that form pharmaceutically acceptable solvates include: water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, and acetic acid.

[0064] The present invention comprises pharmaceutical compositions which, in addition to the usual carriers or diluents, contain the compounds according to the invention. The preparation of the pharmaceutical preparations listed above is carried out in the usual manner according to known processes, e.g., by mixing the active ingredient(s) or carrier(s).

[0065] In general, the compounds according to the invention can be administered in total amounts determined using suitable methods, optionally in the form of several individual doses, to achieve the desired results. The methods for determining the dose are well known to those skilled in the art. This can be done depending on the patient's age, body weight, the type and severity of the disease, the method of preparation and administration of the drug, as well as the period or interval of administration. The compounds according to the invention exhibited, in particular, cytotoxic activities and are suitable for use in the treatment of cancer, such as non-solid and solid tumors.

[0066] In another exemplary embodiment, the human cancer cell lines used were derived from ovarian, lung, breast, and colon carcinomas, as well as melanomas. Treatment with compound 2 showed the strongest effect in cell line A549 (lung carcinoma), followed by cell lines A2780 (ovarian carcinoma) and MCF7 (breast carcinoma). A clear, though somewhat weaker, effect was observed in cell line HT29 (human colorectal adenocarcinoma). Compound 2 proved to be more effective than compound 1a and its salt 1b.

[0067] Furthermore, compound 2 exhibits higher efficacy against human tumor cell lines (sample) than against non-malignant cell lines (control). The selectivity index values ​​[SI = IC50 (control) / ICso(sample)] range from 1.61 to 3.64.

[0068] In another exemplary embodiment, the ability of compound 2 to overcome chemoresistance was investigated. A chemoresistant variant of the aforementioned cell line A2780, namely A2780cis, was tested, and a resistance index (RI = IC50 A2780cis / IC50 A2780) of 1.01 was determined.

[0069] One application and corresponding treatment method is therefore aimed at the treatment of, for example, carcinomas and hematological cancers.

[0070] Finally, a method for treating tumors in individuals is further disclosed, comprising administering a therapeutically effective amount of a compound according to the invention or a pharmaceutical composition containing it. The administration can be carried out in the usual manner.

[0071] The invention will be explained in more detail below using examples:

[0072] Examples

[0073] 3,4,5-Triphenyltoluene (5)

[0074] Compound 4 (3.00 g, 9.12 mmol) was dissolved in toluene (50 mL) and treated with 2 M Na₂COa solution (15 mL), EtOH (50 mL), and phenylboronic acid (3.34 g, 27.37 mmol). After adding a Pd(PPh₃)₄ solution (5 mol%, 0.527 g, 0.456 mmol), the reaction mixture was refluxed for 3 days, then cooled to room temperature and filtered. The organic phase was separated, and the aqueous phase was extracted twice with EtOAc (15 mL). The combined organic phases were washed once with water, dried over MgSC>4, and the solvent was removed under reduced pressure. The resulting oily-yellow residue was stored at room temperature and treated with a small amount of CHCh, causing the crude product to solidify. The resulting solid was filtered off and recrystallized from MeOH. Yield 68% of 5 (1.98 g, 6.18 mmol); Mp 118-119 °C. 1H NMR (500 MHz, CDCI3): ö = 2.46 - 2.47 (m, 3H), 6.80 - 6.83 (m, 2H), 6.93 - 6.98 (m, 3H), 7.06 - 7.09 (m, 4H), 7.11 - 7.16 (m, 6H), 7.26 - 7.27 (m, 2H) ppm. 13 C-NMR (125 MHz, CDCI3): ö = 21.2, 125.8, 126.2, 127.3, 127.6, 130.0, 130.5, 131.9, 136.5, 137.0, 139.6, 142.0, 142.1 ppm. IR (KBr): ü = 3053, 3020, 2915, 2854, 1951 , 1888, 1807, 1770, 1602, 1575, 1494, 1459, 1442, 1427, 1280, 1180, 1153, 1072, 1029, 1006, 921 , 910, 871 , 842, 788, 763, 750, 698, 628, 617, 601 , 578, 565, 505, 406 cm’ 1 . HRMS-ESI: berechnet für C25H21 [M + H] + : 321.1637, bestimmt: 321.1622.

[0075] 3,4,5-Triphenylbenzylbromid (6)

[0076] Compound 5 (1.00 g, 3.12 mmol) and / V-bromsuccinimide (0.28 g, 1.56 mmol) were dissolved in carbon tetrachloride (20 mL) and a spatula tip of AIBN was added. The mixture was heated under reflux for 20 minutes, cooled to room temperature, and the solvent was removed under vacuum. The residue was dissolved in chloroform (30 mL), washed with salt solution and water, and then dried over MgSC. The solvent was removed, and the residue was recrystallized from n-hexane. Yield 73% of 6 (0.90 g, 2.25 mmol); Mp 164–165 °C. 1 H NMR (500 MHz, CDCI3): ö = 4.60 (s, 2H), 6.79 - 6.83 (m, 2H), 6.94 - 7.00 (m, 3H), 7.05 - 7.09 (m, 4H), 7.13 - 7.17 (m, 6H), 7.46 (s, 2H) ppm. 13C-NMR (125 MHz, CDCI3): ö = 33.3, 126.2, 126.5, 127.4, 127.7, 129.9, 130.3, 131.6, 136.8, 139.0, 139.4, 141.4, 142.6 ppm. IR (KBr): ü = 3108, 3083, 3056, 3035, 3022, 2923, 2852, 2736, 1951, 1880, 1805, 1758, 1600, 1575, 1560, 1492, 1457, 1446, 1434, 1425, 1415, 1390, 1334, 1311, 1280, 1268, 1259, 1243, 1211, 1182, 1153, 1137, 1106, 1072, 1031, 1006, 989, 970, 923, 910, 889, 877, 842, 823, 792, 763, 752, 696, 667, 653, 626, 597, 576, 543, 511, 491, 406 cm' 1 HRMS-ESI: calculated for C 25 Hi9BrNa [M + Na] + : 423.0545, determined: 423.0571.

[0077] 2-[(3, 4, 5-triphenyl)phenyl]acetonitrile (7)

[0078] Compound 6 (300 mg, 0.75 mmol), KCN (54 mg, 0.83 mmol), and 18-crown-6 (60 mg, 0.23 mmol) were placed in a round-bottom flask and mixed with 10 mL of absoluted acetonitrile. The mixture was refluxed for 3 days, and the solvent was then removed. The crude product was purified by flash chromatography [eluent CHCh: hexane 3:1 (v / v)] and recrystallized from a cyclohexane / dioxane mixture. Yield 64% of 7 (165 mg, 0.47 mmol); Mp 152–153 °C. 1 H NMR (500 MHz, CDCI3): ö = 3.85 (s, 2H), 6.79 - 6.82 (m, 2H), 6.95 - 7.01 (m, 3H), 7.04 - 7.08 (m, 4H), 7.14 - 7.18 (m, 6H), 7.39 (s, 2H) ppm. 13C-NMR (125 MHz, CDCI3): ö = 23.4, 117.8, 126.1, 126.6, 127.3, 127.7, 128.9, 129.0, 129.7, 131.5, 138.7, 139.1, 141.0, 142.9 ppm. IR (KBr): 0 = 3108, 3083, 3054, 3037, 2958, 2921, 2858, 2250, 1959, 1897, 1820, 1805, 1762, 1695, 1600, 1565, 1492, 1463, 1446, 1417, 1361, 1328 1313, 1297, 1278, 1253, 1234, 1187, 1182, 1162, 1120, 1082, 1029, 1008, 997, 981, 971, 939, 925, 916, 896, 889, 865, 854, 844, 811, 792, 763, 746, 728, 696, 676, 630, 617, 607, 595, 568, 524, 514, 493, 455, 416 cm' 1 HRMS-ESI: calculated for C2eHigNNa [M + Na] + : 368.1410, determined: 368.1418.

[0079] 2-(3,4,5-Triphenyl)phenyl]acetamide (2) Compound 7 (300 mg, 0.87 mmol) was refluxed for 6 h in a solution of HBr in acetic acid (33% HBr, 75 mL). The cooled reaction mixture was poured onto a small amount of water and the resulting white precipitate was extracted with diethyl ether. The combined organic phases were washed with water and then dried over Na₂SC>4. The solvent was removed and the oily yellow-brown crude product was recrystallized from cyclohexane / dioxane. Yield 71% of 2 (224 mg, 0.61 mmol); Mp 171–173 °C. 1 H NMR (500 MHz, CDCI3): ö = 3.68 (s, 2H), 5.68 (s, 1H), 6.08 (s, 1H), 6.79 - 6.83 (m, 2H), 6.93 - 7.00 (m, 3H), 7.04 - 7.08 (m, 4H), 7.12 - 7.16 (m, 6H), 7.35 (s, 2H) ppm. 13C-NMR (125 MHz, CDCI3): ö = 43.0, 126.1, 126.5, 127.4, 127.7, 129.9, 130.6, 131.7, 133.9, 138.4, 139.1, 141.5, 142.7, 173.7 ppm. IR (KBr): ü = 3346, 3319, 3155, 3058, 3053, 3049, 2964, 2910, 2856, 1683, 1658, 1598, 1573, 1490, 1446, 1390, 1382, 1268, 1253, 1213, 1180, 1157, 1112, 1074, 1027, 1010, 993, 900, 890, 865, 848, 815, 790, 763, 744, 698, 651, 600, 515, 499, 430cm' 1 HRMS-ESI: calculated for C26H22NO [M + H] + : 364.1696, determined: 364.1710.

[0080] 2-[(3,4,5-Triphenyl)phenyl]acetic acid (1 a)

[0081] Compound 2 (100 mg, 0.28 mmol) was dissolved in a 9:1 (v / v) mixture of dioxane / water (2 mL) and titanium chloride (5.2 mg, 0.03 mmol) and concentrated HCl (28 mg, 0.28 mmol) were added. The reaction was refluxed for 2 hours. After cooling, the mixture was poured into water (2 mL) and the aqueous phase was extracted with EtOAc (3 x 3 mL). The combined organic phases were dried over Na₂SC>4 and the solvent was removed under vacuum. The resulting solid was recrystallized from toluene and acetonitrile. Yield: 85% of 1a (85 mg, 0.23 mmol).

[0082] Compound 7 (200 mg, 0.58 mmol) and KOH (162 mg, 2.89 mmol) were refluxed in methanol (ag) (10 mL) for 2 days. The solvent was removed, and the residue was dissolved in warm water (20 mL). Concentrated sulfuric acid was then added dropwise until no further precipitate formed. The precipitate was filtered and dried under vacuum. The crude product was recrystallized first from toluene and then from MeCN. Yield 27% of 1a (56 mg, 0.15 mmol). Mp 198 °C. 1 H NMR (500 MHz, DMSO-cfe) ö = 3.72 (s, 2H), 6.80 - 6.84 (m, 2H), 6.97 - 7.00 (m, 4H), 7.02 - 7.04 (m, 4H), 7.13 -7.18 (m, 6H), 7.30 (s, 2H) ppm. 13C-NMR (125 MHz, DMSO-cfe): ö = 40.2 126.1, 126.4, 127.3, 127.7, 129.6, 130.5, 131.3, 134.3, 137.1, 139.1, 141.4, 172.8 ppm. IR (KBr): ü = 3434, 3081, 3054, 3023, 2964, 2912, 2846, 2630, 2536, 1699, 1600, 1575, 1492, 1459, 1446, 1417, 1403, 1346, 1311, 1305, 1234, 1182, 1157, 1153, 1126, 1074, 1027, 1008, 943, 914, 871, 848, 792, 763, 744, 696, 661, 628, 607, 599, 553, 518, 501, 439 cm -1 HRMS-ESI: calculated for C26H2oC>2Na [M + Na] + : 387.1356, determined: 387.1334.

[0083] Potassium 2-[(3,4,5-triphenyl)phenyl]acetate (1 b)

[0084] Compound 1a (50 mg, 0.14 mmol) was suspended in 1 mL of MeOH and a 7.5 N KOH solution (4 mL) was added. The mixture was refluxed for 2 h and then stirred at room temperature. The resulting solid was filtered and washed with a small amount of water. Yield 80% of 1b (44 mg, 0.11 mmol); Mp >360 °C. 1H NMR (500 MHz, CD3OD) ö = 3.60 (s, 2H), 6.76 - 6.80 (m, 2H), 6.90 - 6.97 (m, 3H), 7.03 - 7.07 (m, 4H), 7.08 - 7.13 (m, 6H), 7.08 - 7.13 (m, 6H), p.m. 13 C-NMR (125 MHz, CD3OD): ö = 46.1 , 126.7, 127.0, 128.1 , 128.5, 131.0, 131.4, 132.9, 138.0, 138.4, 141.2, 13.0, 18.5. ppm. IR (KBr): ü = 3592, 3320 (H2O), 3201 , 3083, 3060, 3050, 3035, 2944, 2923, 2858, 1556, 1492, 1444, 1421, 12376, 1180, 1159, 1151 , 1072, 1029, 1008, 931 , 916, 869, 850, 813, 790, 746, 698, 667, 597, 547, 518, 518, 41 cm 1 . HRMS-ESI: calculated for C26H20KO2 [M + H]+: 403.1095, determined: 403.1092.

[0085] Conclusion:

[0086] A multi-step synthesis for the preparation of 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives with valuable biological activities was developed. Based on this multi-step synthesis, five compounds not previously described in the literature were synthesized (compounds 1a, 1b, 2, 6, and 7); compound 5 was prepared for the first time using this method. The described synthetic route is also suitable for the preparation of a wide range of new members of this class of compounds. Furthermore, the prepared compounds are valuable starting materials for various functionalization reactions.

[0087] To determine the cytotoxicity of these compounds according to established procedures, several human tumor cell lines were used, including melanoma, ovarian cancer, colorectal adenocarcinoma, oropharyngeal carcinoma, lung cancer, and breast cancer. Compound 2, for example, showed the best cytotoxic activity in the case of lung cancer, ovarian cancer, and breast cancer. The selectivity index values ​​ranged from 1.61 to 3.64. A resistance index of 1.01 was also determined.

Claims

Patent claims:

1. Combination of the general structural formula I: where a, b, c are independent integers from 1 to 5; R 1 Each is independently hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen; R 2 Each is independently hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen; R 3 Each is independently hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen; R 4 , R 5 are the same or different hydrogen or Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy, OH, halogen; X is selected from OH, OR 6 , ON, NH2, NHR 6 , N(R 6 )2, where R 6 a residue comprising a functional group; or salts, solvates or hydrates thereof.

2. Compound according to claim 1, wherein X is OH, CN or NH2 or a salt, in particular an alkali salt thereof.

3. Compound according to one of the preceding claims, wherein R 4 and R 5 hydrogen.

4. Compound according to any of the preceding claims, wherein a, b and c are independently 1 or 2 and R 1 , R 2 and / or R 3 are hydrogen, halogen, or OH.

5. Combination according to one of the preceding claims, wherein X OH or NH2 is; R 4 and R 5 are hydrogen; a, b, c are 1 and R 1 , R 2 and R 3 Hydrogen, or solvates, hydrates or salts thereof.

6. Method for producing a compound according to any one of claims 1 to 5, comprising - Bromination of a compound of general formula II to obtain a compound of general formula III - Nitrile synthesis using the compound of general formula III to obtain a compound of general formula IV i) Hydrolysis of the compound of general formula IV to obtain a compound of general formula I with X = NH2 followed by acid-catalytic hydrolysis to obtain the compound of general formula I with X = OH. ii) alkaline hydrolysis of the compound according to general formula IV to obtain a compound according to general formula I with X equal to OH 7. Method according to claim 6, wherein compounds of the general structural formula I with X = NH2, NHR 6 or N(R 6)2 are produced, wherein the process according to alternative i) is carried out without the step of acid-catalytic hydrolysis to a compound of general formula I with X equal to OH, and optionally further reaction of the compound of general formula I with X = NH2 to obtain an amide compound with NHR 6 or N(R 6 )2.

8. Method according to claim 6 or 7 comprising a reaction with a metal salt, in particular an alkali salt, to obtain a salt of a compound of the general structural formula I, in particular an alkali salt.

9. Method for the preparation of a compound of general formula II comprehensive the diazotization of a compound of the general formula V and reaction with copper bromide to obtain a compound of general formula VI; then the reaction of the compound of general formula VI with a Combination of the general formula VII Where Rf is one of the substituents R 1 , R 2 or R 3 and f is a, b, or c, as defined in claim 1, to obtain a compound of general formula II.

10. Method for producing a compound according to any one of claims 6 to 8, further comprising the method for producing the compound according to general formula II according to claim 9.

11. Pharmaceutical composition comprising a compound according to any one of claims 1 to 5.

12. Pharmaceutical composition according to claim 11 for use in the treatment of tumors.

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