The invention relates to .novel compounds of general formula ( I ) ,

(I) and their preparation, pharmaceutical preparations containing compounds of general formula (I), and the use of these compounds in therapeutic processes.

Curcumin [1, 7-bis ( 4-hydroxy-3-methoxyphenyl ) -1, 6- heptadiene-3 , 5-dione ) ] is a yellow compound isolated from the rhizome of the plant Curcuma longa L. and used for centuries as a food colouring additive and spice, and in traditional Indian and Chinese medicine (Kuttan, R. ; Bhanumathy, P.; Nirmala, K. ; George, M. C. Cancer Lett. 1985, 29, 197-202.). A number of literature data is available about the complex pharmacological properties of curcumin having several functions. For example it induces apoptosis in different tumour cells (Jagetia, G. C; Aggarwal, B. B. J. Clin. Immunol. 2007, 27, 19-35; Potential of the dietary antioxidants resveratrol and curcumin in prevention and treatment of hematologic malignancies. Kelkel M, Jacob C, Dicato M, Diederich M. Molecules. 2010 Oct 12; 15(10) :7035- 7074), it protects cells from oxidative stress (Nutraceutical antioxidants as novel neuroprotective agents. Kelsey NA, Wilkins HM, Linseman DA. Molecules. 2010 Nov 3; 15 ( 11 ) : 7792- 7814.) A in the brain it reduces the formation of beta-amyloid plaques, it reduces the development of Alzheimer's disease (Multivalent & multifunctional ligands to beta-amyloid. Kim Y, Lee JH, Ryu J, Kim DJ. Curr Pharm Des. 2009; 15 ( 6) : 637-658. ; REVIEW: Curcumin and Alzheimer's disease. Hamaguchi T, Ono K, Yamada M. CNS Neurosci Ther. 2010 Oct; 16 (5) : 285-297.) , and it has proved to be efficient in suppressing different inflammatory processes (Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Jurenka JS . Altern Med Rev. 2009 Jun; 14 (2 ) : 141-153.) , including different inflammations of the lungs (The potential role of natural agents in treatment of airway inflammation. Sharafkhaneh A, Velamuri S, Badmaev V, Lan C, Hanania N. Ther Adv Respir Dis. 2007 Dec;l (2) : 105-120. ) .

Although curcumin is a non-toxic compound and has a broad spectrum of effects, due to its poor solubility and low bioavailability, clinical studies performed with curcumin were not concluded with favourable results. (Pan, M. H.; Huang, T. M. ; Lin, J. K. Drug Metab. Dispos. 2000, 27, 486-494.; Sharma, R. A.; Steward, W. P.; Gescher, A. J. Adv. Exp. Med. Biol. ^' 2007, 595, 453-470. ) .

On the basis of the above our aim was to prepare curcumin analogues that have more favourable solubility properties and are also efficient in low concentrations.

The above aim is reached with the new compounds of general formula ( I ) .

The invention relates to the new compounds of general formula (I) where

R ¹ is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2-4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7-membered heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups;

R ² is a hydrogen atom; or formula -SO ₂ Y or -C(0)Y, where Y is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2-4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7-membered heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups;

R ³ is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2-4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7-membered heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups; and the pharmaceutically acceptable salts of the compounds of general formula (I) .

Those compounds of general formula ( I ) according to the invention

are preferred, where

Ri is a phenyl group; which is optionally substituted with an alkyl group containing 1-4 carbon atoms, carboxyl group, acyloxy group and/or methoxy group, with 1-3 halogen atoms, where the halogen atom is preferably in meta or para position, an alkyl-halogen group,

or a heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-2 halogen atoms;

R ² is a (C(O)Y) group, where Y is an alkyl group containing 1- 4 carbon atoms or an alkenyl group containing 2-4 carbon atoms or a phenyl group, which is optionally substituted with an alkenyl group containing 2-4 carbon atoms;;

R ³ is a phenyl group substituted with 1-2 hydroxy groups, halogen atom, alkoxy group, alkoxy group and (C(O)Y) group, where Y is an alkyl group containing 1-4 carbon atoms, a phenyl group substituted with an alkyl group containing 1-4 carbon atoms and a hydroxy group,

or a heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms substituted with an alkyl- hydroxy group containing 1-4 carbon atoms or with a halogen atom;

and the pharmaceutically acceptable salts of these compounds. Those compounds of general formula (I) according to the invention

are especially preferred, where

Ri is a 4-fluoro-phenyl group or 3-bromo-phenyl group, 3- trifluoromethyl-phenyl group or 4-bromo-thiophene group; and a phenyl group, difluorophenyl group, dichlorophenyl group, chlorophenyl group, carboxy-phenyl group, butylphenyl group, acyl-oxy-methoxy-phenyl group;

R ² is an acyl group, -C(O) -methyl group or acryloyl group; and -C(0) -ethyl group, -C (0) -ethenyl group and -C (0) -ethenyl- phenyl group;

R ³ is 3-hydroxy-phenyl or 4-hydroxy-phenyl, 4-fluoro-phenyl ;

3, 4-dimethoxy-phenyl, 3-methoxy-4-hydroxy-phenyl or 3- hydroxy-4-methoxy-phenyl, 4-bromo-thiophene or 5-

(hydroxymethyl ) -furan and -C (0) -ethenyl-phenyl group, dihydroxy-phenyl ;

and the pharmaceutically acceptable salts of these compounds.

Those compounds of general formula (I) according to the invention

are especially preferred, where

Ri is a 4-fluoro-phenyl group or 3-bromo-phenyl group, 3- trifluoromethyl-phenyl group or 4-bromo-thiophene group; and a phenyl group, difluoro-phenyl group, dichloro-phenyl group, chloro-phenyl group, carboxy-phenyl group, butyl- phenyl group, acyl-oxy-methoxy-phenyl group;

R ² is an acyl group, -C (0) -methyl group or acryloyl group; and -C(0) -ethyl group, -C (0) -ethenyl group and -C (0) -ethenyl- phenyl group;

R ³ is 3-methoxy-phenyl or 4-methoxy-phenyl ;

and the pharmaceutically acceptable salts of these compounds. Brief description of the drawings : figure 1 shows the effect of certain compounds according to the invention on cell death induced by hydrogen peroxide; figure 2 illustrates the effect of compound no 12 according to the invention on the size of carrageenan-induced foot oedema; figure 3 shows the behaviour of some compounds according to the invention during the inhibition of lipopolysaccharide induced NFkB activation; figure 4 shows the inhibiting effect of some compounds according to the invention on the lesion of the intestinal mucosa in enteritis; figure 5 shows the inhibiting effect of some compounds according to the invention on intestinal myeloperoxidase activity in enteritis; figure 6 illustrates the effect of compound no 37 according to the invention on pulmonary tumour; figure 7 illustrates the effect of the nanoformulated form of compound no 37 produced according to example no 55 and its liposomal form produced according to example no 56 on leukaemia; figure 8 shows the effect of compound no 37 according to the invention and curcumin on the expression of protein GRP78; and figure 9 shows the effect of compound no 37 according to the invention and curcumin on the expression of protein GADD153.

Below we explain in what sense the individual definitions and phrases are used in the description.

The phrase "alkyl group containing 1-4 carbon atoms" means a straight-chain or branched-chain alkyl group containing 1-4 carbon atoms (e.g. methyl-, ethyl-, isopropyl group, etc.).

The phrase "alkenyl group containing 2-4 carbon atoms" means a straight-chain or branched-chain alkenyl group containing 2-4 carbon atoms (e.g. allyl- or propenyl group).

The phrase "cycloalkyl group containing 3-8 carbon atoms" means saturated or unsaturated cyclic hydrocarbons containing 3-8 carbon atoms (e.g. cyclopropyl- , cyclobutyl-, cyclohexyl-, cyclopentenyl- , cyclohexenyl group, etc.).

The phrase "aryl group containing 3-10 carbon atoms" relates to monocyclic or bicyclic aromatic hydrocarbon groups containing 3-10 carbon atoms (e.g. phenyl-, naphthyl group, etc . ) .

The phrase "aralkyl group" means a monocyclic or bicyclic aromatic hydrocarbon group containing 3-10 carbon atoms, substituted with a straight-chain or branched-chain alkyl group containing 1-4 carbon atoms (e.g. benzyl-, beta-phenyl- ethyl group, butyl-phenyl group, etc.).

The phrase "heterocyclic group" relates to 3-7-membered, preferably 5- or 6-membered aromatic groups containing one or more oxygen, nitrogen and/or sulphur atoms (e.g. pyridyl-, pyrimidyl-, pyrrolyl-, oxazolyl group, furanyl group, thiophene group, etc.).

Preferably, the phrase "electron withdrawing group" used as a substituent relates to the following substituents : halogen atom, dihaloalkyl- (that is alkyl group containing 1-4 carbon atoms substituted with a halogen atom, e.g. difluoromethyl group) , trihaloalkyl- (that is alkyl group containing 1-4 carbon atoms substituted with a halogen atom, e.g. trifluoromethyl group), nitro group, carboxyl- or cyano group .

The phrase "halogen atom" means bromine-, fluorine-, chlorine- and iodine atom, preferably fluorine or chlorine atom. Preferably, the phrase "electron donating group" relates to the following substituents: alkyl group containing 1-4 carbon atoms (e.g. methyl group), hydroxy- and methoxy group, acyl-oxy group, N-acyl group, and alkyl-hydroxy group.

Ar means an aryl group containing 3-10 carbon atoms, the meaning of which is defined above.

ArX substituent means aromatic and heterocyclic groups substituted with halogen atoms referred to with an X.

Preferably, the term "acryloyl" relates to the following substituents: alkyl-vinyl-formyl group containing 3-12 carbon atoms. The compounds of the general formula (I) can form salts with bases on their optional one or more hydroxyl groups. The "pharmaceutically (pharmacologically) acceptable salts" are prepared with the help of pharmaceutically (pharmacologically) acceptable non-toxic bases or acids. If the compound according to the present invention is acidic, obviously the appropriate salt can be produced with a pharmaceutically acceptable nontoxic base (inorganic or organic base). Among salts formed with bases, the salts formed with alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium or magnesium) or ammonia or organic amines are especially important. The latter bases can also contain other substituents (e.g. hydroxyl- or amino group), which may influence for example the solubility, manageability and other properties of the products.

Preferred representatives of the compounds of general formula (I) of the present invention are listed below: N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3, 4 - dimethoxyphenyl ) acryloyl) -3-oxo-l-phenyl-pent-4- enyl) acetamide; , 4 ' - ( ( IE, 6E) -4- (acetamido (phenyl ) methyl ) -3 , 5-dioxohepta- 1, 6-diene-l, 7-diyl) bis (2-methoxy-4 , 1-phenylene) diacetate; N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3,4- dimethoxyphenyl ) acryloyl) -1- ( 4-fluorophenyl ) -3-oxopent-4- enyl) acetamide;

N- ( (E) -1- (3-bromophenyl) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3, 4-dimethoxyphenyl) acryloyl) -3-oxo-pent-4-enyl) acetamide; N- ( (E) -5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl) acryloyl) -1- ( 2-fluorophenyl ) -3-oxo-pent-4- enyl) acetamide;

N- ( (E) -1- (3, 4-difluorophenyl) -5- ( 3 , 4-dimethoxyphenyl ) -2- ( (E) -3- (3, 4-dimethoxyphenyl) acryloyl) -3-oxopent-4- enyl) acetamide;

N- ( (E) -1- (2, 4-dichlorophenyl) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3, 4-dimethoxyphenyl) acryloyl) -3-oxopent-4- enyl ) acetamide ;

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl ) acryloyl) -3-oxo-l- (4- (trifluoromethyl) phenyl) pent-4-enyl) acetamide;

N- ( (E) -1- ( 4-bromothiophene-2-yl ) -5- (3, -dimethoxyphenyl) -

2- ( (E) -3- (3, 4-dimethoxyphenyl) acryloyl) -3-oxopent-4- enyl) acetamide;

N- ( (E) -5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl ) acryloyl) -3-oxo-l- (3- (trifluoromethyl) phenyl) pent-4-enyl) acetamide;

N- ( (E) -1- (3-bromophenyl) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy-3-methoxyphenyl) acryloyl) -3-oxopent-4- enyl) acetamide;

N- ( (E) -1- (4-klorophenyl) -5- ( 4-hydroxy-3-methoxyphenyl ) -2- ( (E) -3- ( -hydroxy-3-methoxyphenyl ) acryloyl) -3-oxopent-4- enyl) acetamide;

N- ( (E) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy-

3-methoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4- enyl) acrylamide; N- ( (E) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy- 3-methoxyphenyl) acryloyl) -3-oxo-l- (4- (trifluoromethyl) phenyl) pent-4-enyl) acetamide;

4- ( (E) -l-acetamido-5- ( 4-hydroxy-3-methoxyphenyl ) -2- ( (E) -3 ( 4-hydroxy-3-methoxyphenyl ) acryloyl) -3-oxopent-4-enyl ) benzoic acid;

N- ( (E) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy-

3-methoxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4-enyl ) acetamide;

N- ( (E) -5- (3-hydroxy-4-methoxyphenyl) -2- ( (E) -3- (3-hydroxy-

4-methoxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4-enyl ) acetamide;

N- ( (E) -1- (4-butylphenyl) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3 (3, 4-dimethoxyphenyl) acryloyl) -3-oxo-pent--4-enyl) acetamide;

4- ( (E) -l-acetamido-5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl) acryloyl) -3-oxopent-4-enyl) benzoic acid;

N- ( (E) -5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4-enyl )

acrylamide ;

4- ( (E) -l-acetamido-5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl ) acryloyl) -3-oxopent-4-enyl ) -2-methoxyphenyl acetate;

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3, 4- dimethoxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4- enyl ) propionamide ;

N- ( (E) -5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3,4- dimethoxyphenyl ) acryloyl) -1- ( 4-fluorophenyl ) -3-oxo-pent-4- enyl) acrylamide; N- ( (E) -5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, - dimethoxyphenyl) acryloyl) -3-oxo-l- (3- (trifluoromethyl) phenyl) pent-4-enyl) acrylamide;

4- ( (E) -l-acrylamido-5- (3, -dimethoxyphenyl) -2- ( (E) -3- (3, dimethoxyphenyl) acryloyl) -3-oxopent-4-enyl) benzoic acid;

N- ( (E) -1- (3, 4-difluorophenyl) -5- ( 4-hydroxy-3- methoxyphenyl) -2- ( (E) -3- (4-hydroxy-3-methoxyphenyl) acryloyl) - 3-oxopent-4-enyl) acetamide;

N- ( (E) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-enyl ) acetamide;

N- ( (E) -5- (4-bromothiophene-2-yl) -2- ( (E) -3- (4- bromothiophene-2-yl ) acryloyl) -3-oxo-l-phenylpent-4- enyl) acetamide;

N- ( (E) -1- ( 3-bromophenyl ) -5- (3, 5-dihydroxyphenyl ) -2- ( (E) -3 (3, 5-dihydroxyphenyl) acryloyl) -3-oxopent-4-enyl ) acetamide;

N- ( (E) -5- (3, 5-dihydroxyphenyl) -2- ( (E) -3- (3, 5- dihydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-enyl ) acetamide;

N- ( (E) -5- (4-hydroxyphenyl) -2- ( (E) -3- (4- hydroxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4-enyl) acetamide;

N- ( (E) -5- (5- (hydroxymethyl) furan-2-yl) -2- ( (E) -3- (5- (hydroxymethyl ) furan-2-yl) acryloyl) -3-oxo-l-phenylpent-4- enyl) acetamide;

N- ( (E) -5- (4-fluorophenyl) -2- ( (E) -3- (4- fluorophenyl ) acryloyl) -3-oxo-l-phenylpent-4-enyl ) acetamide;

4- ( (E) -l-acrylamido-5- ( 4-hydroxy-3-methoxyphenyl ) -2- ( (E) - 3- (4-hydroxy-3-methoxyphenyl) acryloyl) -3-oxopent-4- enyl) benzoic acid; 4- ( (E) -l-acrylamido-5- (3, 5-dihydroxyphenyl ) -2- ( (E) -3- (3, 5- dihydroxyphenyl) acryloyl) -3-oxopent-4-enyl ) benzoic acid;

N- ( (E) -5- (3, 5-dihydroxyphenyl) -2- ( (E) -3- (3, 5- dihydroxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4- enyl ) acrylamide;

N- ( (E) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-enyl ) acrylamide;

N- ( (E) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-enyl) cinnamamide; and the pharmaceutically acceptable salts of these compounds .

Further preferred representatives of the compounds of general formula (I) of the present invention are listed below: N- ( (E) -3-OXO-5- ( 4-oxo-4H-chromene-3-yl ) -2- ( (E) -3- (4-oxo-

4H-chromene-3-yl ) acryloyl) -l-phenylpent-4-enyl) acrylamide;

N- ( (E) -5- (3, 5-dihydroxyphenyl) -2- ( (E) -3- { 3 , 5-dihydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-enyl ) cinnamamide;

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- ( 3 , 4 -dimethoxyfe- nil) acryloyl) -3-oxo-l-phenylpent-4-enyl) cinnamamide;

N- ( (E) -1- (4-fluorophenyl) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl ) acryloyl) -3-oxopent-4-enyl) acrylamide;

4, 4 ' - ( (IE, 6E) -4- (acrylamido (phenyl ) methyl ) -3, 5-dioxohepta- 1, 6-diene-l, 7-diil) dibenzoic acid; 4, 4 ' - ( (E) -5-acetamido-4- ( (E) -3- ( 4-karboxiphenyl ) acryloyl ) -

3-oxopent-l-ene-l , 5-diil) dibenzoic acid; N- ( (E) -3-oxo-l-phenyl-5- (3, 4, 5-trimethoxyphenyl) -2- ( (E) -3- (3,4, 5-trimethoxyphenyl) acryloyl) pent-4-enyl) acrylamide;

N- ( (E) -5- (3, 4-dihydroxyphenyl) -2- ( (E) -3- (3, 4- dihydroxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4- enyl) acrylamide ;

N- ( (E) -5- (3-methoxyphenyl) -2- ( (E) -3- (3- methoxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4-enyl) acrylamide; and the pharmaceutically acceptable salts of these compounds .

Furthermore, the object of the invention is the preparation of the compounds of general formula (I), where pentanedione of general formula (II), is reacted with imine produced via a reaction between an aldehyde of general formula (III),

R.,-CHO

(III) where Ri is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2-4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7- membered heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups; and an amine of general formula (IV), R ₂ -NH ₂

(IV) where R ₂ is a hydrogen atom, or formula -S0 ₂ Y or -C(0)Y, where Y is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2- 4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7-membered heterocyclic group containing one or two oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups.

By entering the Mannich products formed in this way having formula (V), (VI) and (VII)

(V) (VI) (VII) where Ri is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2-4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7- membered heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups; and where R ₂ is a hydrogen atom, or formula -S0 ₂ Y or -C(0)Y, where Y is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2- 4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7-membered heterocyclic group containing one or two oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups; into a reaction with an aldehyde of general formula (VIII)

R ₃ -CHO

(VIII) where R3 is a hydrogen atom, alkyl group containing 1-4 carbon atoms, alkenyl group containing 2-4 carbon atoms, cycloalkyl group containing 3-8 carbon atoms, aryl group containing 3-10 carbon atoms, aralkyl group containing 3-10 carbon atoms, 3-7- membered heterocyclic group containing one or more oxygen, nitrogen and/or sulphur atoms, which is optionally substituted with 1-5 electron withdrawing or electron donating groups; curcuminoids of general formula (I) are obtained.

Curcuminoids of general formula (I) can occur in the reaction mixture in oxo (la) and enolic (lb) form (reaction scheme 1) .

lb

enol form

Reaction scheme 1

The obtained compound of general formula (I) optionally can be converted into its pharmaceutically acceptable salt or released from its salt .

The curcuminoid syntheses known from literature on chemistry are described on the basis of reaction schemes 2 and 3.

Several structural changes were made to the curcumin skeleton according to the prior art. J. S. Shim et al. {Bioorg. Med. Chem. 2002, 10, 2987-2992) produced type 1 pyrazole derivatives on the curcumin skeleton via cyclisations realised with N-unsubstituted and N-aryl hydrazines.

Knoevenagel condensation reactions are also known (ii), by using this method type 2 4-arylidene curcumin analogues with an antitumor effect were obtained (X. Qiu et al . , J. Med. Chem. 2010, 53, 8260-8273) .

A further general procedure is the acylation or alkylation of the phenolic hydroxyl group in position 4 and 4' (iii), as a result of which type 3 O-substituted derivatives were produced (C. Changtam et al., Eur. J. Med. Chem. 2010, 45, 941-956) .

According to the state of the art no other changes made to the curcumin skeleton are known, primarily the synthesis of the new compounds according to the invention is based on the three reaction types mentioned above ( i , ii and iii ) , illustrated in reaction scheme 2.

Reaction scheme 2

According to the prior art, the curcumin skeleton is built up starting out from pentane-2, -dione, using the Claisen- Schmidt reaction (reaction scheme 3). During the syntheses, using benzaldehydes of an optional degree of substitution and pattern, type 4 curcumin analogues can be produced. In the prior art the reactions shown in figure 3 are described by Q. Zhang et al. {Bioorg. Med. Chem. Lett. 2011, 21, 1010-1014), A. N. Nurfinal et al . , {Eur. J. Med. Chem. 1997, 32, 321-328) and S. Venkateswarlu et al . [Bioorg. Med. Chem. 2005, 13, 6374-6380) .

Reaction scheme 3

The reactions illustrated in reaction scheme 3 were first described in international patent applications no WO 6 2008/085984 Al; WO 2010/033692 Al .

The compounds of general formula ( I ) according to the invention were built up by two-step synthesis, for which we elaborated efficient and new techniques (reaction scheme 4). For elaborating our procedure we used the content of the following prior art documents: H. Mao et al., Tetrahedron 2009, 65, 1026-1033., Venkateswarlu et al . , Bioorg. Med. Chem. 2005, 13, 6374-6380. and K. Zumbansen et al., Adv. Synth. Catal. 2010, 352, 1135-1138. These procedures are illustrated in summarising figure Z.

A-method: B-method: C-method:

Argon, B ₂ 0 ₃ , B (OBu) B ₂ 0 ₃ , B (OBu) Argon , B ₂ 0 ₃ , B (OBu) tetrahydroquinoline/AcOH morpholinium- morpholinium- abs.DMF, 75°C, 3.5 hours trifluoroacetate chloroacetate

.DMF, 75°C, 16 hours abs.DMF, 75°C, 4 hours

Reaction scheme 4

In the first step according to the invention, by modifying or optimising a Mannich type reaction intermediates V), (VI) and (VII) were obtained in good yield.- By optimising the basic reaction pure intermediates were obtained, no further purification was justified, column chromatography was not necessary.

The invention also relates to Mannich intermediates of general formula (VI) not known in the prior art. Their physical-chemical characteristics and the procedure for their preparation are described through an example.

The intermediates of general formula (VI) (in which formulas the meaning of substituents Rl is defined above) were converted into derivatives with formula (VII) via a modified Heck-reaction, in the scope of which a new carbon-carbon bond was formed and an aromatic group was inserted in the compound of general formula (VI). The reaction was planned on the basis of the methods described in the following prior art documents: Beletskaya, I. P. et al., Chem. Rev. 2000, 100, 3009-3066.; Heck, R. F. ; Nolley, J. P., J. Org. Chem., 1972, 37, 2320- 2322.

The intermediates of general formula (VII) were synthesised in accordance with the following general procedure shown in reaction scheme 5.

VI VII

Reaction scheme 5 In reaction scheme 5 the meaning of Ar and ArX substituents is brominated, iodinated or chlorinated aromatic or heteroaromatic compound.

The general procedure illustrated in reaction scheme 5: to the solution of 3 mmol Af-substituted acrylamide, 10 mol% palladium(II) acetate (Pd(OAc) ₂ ) (Sigma) and 40 mol% triphenylphosphine (PPI 3) (Sigma) prepared in 15 ml toluene (Molar), 1.5 equivalent halogenated aromatic or heteroaromatic compound (ArX, where X = Br, I) (Sigma) and 2 equivalent triethylamine (TEA, Alfa Aesar) is added. ^' The reaction mixture is kept at reflux temperature while stirred intensively, conversion was checked with thin layer chromatography (TLC) (Kieselgel 60 F254; Merck, hexane isomer mixture/ethylacetate (EtOAc) = 1:1; Molar). At .the end of the reaction the solvent is distilled off, the crude product is purified with column chromatography (hexane isomer mixture: EtOAc mixture; Molar). The intermediates are converted into curcuminoid derivatives of general formula (I), using modified Claisen-Schmidt condensation .

For the conversion of Mannich intermediates (V), (VI) and (VII) into curcuminoids of general formula (I) we used three procedures, procedure A, B and C described below. In the course of preparing the compounds according to the invention the different procedures were used depending on the initial substances, typically on the R ₃ CHO (VIII) aromatic ring substituents .

Procedure C is a special one, because it can be used universally for the synthesis of curcuminoids, while in the course of using the other two procedures (procedures A and B) , in certain cases yield or conversion problems may occur. In the examples of the present patent description relating to synthesis the procedure resulting in the more favourable yield is described.

Description of the individual procedures:

Procedure A :

Under argon atmosphere, to the solution of 2 mmol Mannich intermediate of general formula (V) or (VI) prepared with 0.5 ml absolutised N, I\7-dimethylformamide (Merck), 1 equivalent boron trioxide (Sigma) and 2 equivalent tributyl borate (Sigma) are added, then the mixture is stirred at 75°C for 15 minutes. To this yellow solution 2 equivalent 3,4- dimethoxybenzaldehide (Alfa Aesar) is added at 75°C, then after 5 minutes of stirring the solution of 1 equivalent acetic acid (Molar) and 17 mol% tetrahydroquinoline (Sigma) prepared in 500 μΐ abs . N, N-dimethylformamide (Merck) is added to the system. The reaction mixture is stirred for 3 hours under inert atmosphere at 75°C (TLC: silica plate (Merck, Kieselgel 60 F254) ; 95:5 mixture of chloroform (Molar) / methanol (Molar) ) . Then the solution is cooled to room temperature, and in order to break down the formed boron complex, 25 ml of 20 m/m% aqueous acetic acid solution is added to the system. The heterogeneous mixture is stirred intensively for 1.5-2 hours at 75°C, under inert atmosphere, and then it is cooled to room temperature. The precipitated crude product is filtered under vacuum, washed with 2x20 ml water, then dried. The dry crude product is placed in a 50 ml round-bottom flask, 10 ml of ethanol (Molar) is added to it. The heterogeneous solution is boiled for 20 minutes while stirred intensively, then it is filtered during cooling, washed with 5 ml cold ethanol (Molar) and dried under vacuum.

Procedure B : Method: to the solution of 1.267 mmol Mannich intermediate prepared with 2 ml absolutised N, N-dimethylformamide (Merck), 0.7 equivalent boron trioxide (Sigma) is added, then the mixture is stirred for 30 minutes at 75°C. Then 2 equivalent aromatic aldehyde (Molar) and 2 equivalent tributyl borate (Sigma) is added to the system, and it is stirred for another 30 minutes at 75°C. After adding 2 equivalent morpholinium trifluoroacetate (preparation: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethyl ether (Molar), 0°C, lh) , the reaction mixture is stirred for 15 hours at 75°C (thin layer chromatography: silica plate (Merck, Kieselgel 60 F25 ) 95:5 mixture of chloroform (Molar) and methanol (Molar) ) , then the solution is cooled to room temperature, and in order to break down the formed boron complex, 12 ml of 5 m/m% aqueous acetic acid solution is added to the system. The heterogeneous mixture is stirred intensively for 1.5 hours at 75°C, and then it is cooled to room temperature. The precipitated crude product is filtered off, washed with 2x20 ml water, dried, crystallised (ethanol/diethyl ether (Molar) . If filtering cannot be performed because of the consistency of the raw product, in the course of processing preliminary purification is performed by extraction using 25 ml ethyl acetate (Molar) , then the organic phase is washed with 20 ml of 5 m/m% sodium hydrogen carbonate solution (Sigma) , the organic phase is dried on water-free sodium sulphate (Molar) and evaporated. The raw products were purified using column chromatography, on 50x silica gel packing (Molar, 0.063-0.200), with a mixture of chloroform and methanol (Molar) . The purified curcuminoids were crystallised from diethyl ether (Molar) and from chloroform (Molar) .

Procedure C :

Under argon atmosphere, to the solution of 3 . 86 mmol Mannich intermediate of general formula (V), (VI) or (VII) prepared with 6 ml absolutised N, N-dimethylformamide (Molar), 1 equivalent boron trioxide (Sigma) is added, then the mixture is stirred at 75°C for 30 minutes. To the yellow solution the appropriate 2 equivalent aromatic aldehyde and 2 equivalent tributyl borate is (Sigma) added at 75°C, then after 5 minutes of stirring, 25 mol% morpholinium chloroacetate (preparation: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) is added to the system. The reaction mixture is stirred for 3-4 hours, under inert atmosphere, at 75°C (TLC: silica plate (Merck, Kieselgel 60 F25 ) ; 95 : 5 mixture of chloroform (Molar) / methanol (Molar) ) . Then the solution is cooled to room temperature, and in order to break down the formed boron complex, 24 ml of 5 m/m% aqueous acetic acid solution is added to the system dropwise, and then the mixture is stirred for 5 minutes at room temperature. The heterogeneous reaction mixture is stirred intensively for 1 hour at 75°C, and then it is cooled to room temperature. The precipitated crude product is filtered under vacuum, washed with 2 x 20 ml water and dried. The dry crude product is recrystallised in a mixture of diethyl ether and ethanol (Molar) . If filtering cannot be performed because of the consistency of the raw product, in the course of processing preliminary purification is performed by extraction using 25 ml ethyl acetate (Molar) , then the organic phase is washed with 20 ml of 5 m/m% sodium hydrogen carbonate ( aHC0 ₃ ) solution (Sigma) , the organic phase is dried on water-free sodium sulphate (Na ₂ S0 ₄ ) (Molar) and evaporated. The raw products were purified using column chromatography, on 50x silica gel packing (Molar, 0.063-0.200), with a mixture of chloroform and methanol (Molar) . The purified curcuminoids were crystallised from diethyl ether (Molar) and from chloroform (Molar) .

The significance of the procedure according to the present invention is that the syntheses according to the prior art always take place in association with simple changes made to the curcumin skeleton or in association with a retrosynthetic curcumin synthesis. The preparation procedure developed by us makes it possible to create a significantly more diversified curcuminoid family.

The present invention also relates to a pharmaceutical preparation, which contains a therapeutically effective amount of the compound of general formula (I) according to the invention as its active agent, together with one or more pharmaceutically acceptable diluents, excipients and/or carriers .

The pharmaceutical preparations according to the invention can be solid (e.g. tablet, capsule), semi-solid (e.g. suppository) or liquid (e.g. injection solution) . The preparations can be administered orally, rectally or parenterally . The preparations according to the invention may contain ordinary pharmaceutically acceptable carriers and excipients (e.g. starch, cellulose or cellulose derivatives, lactose, mannitol, sodium-chloride, sodium-carbonate, sucrose, maltose, potassium-carbonate, etc.). The invention also relates to a pharmaceutical preparation with an anti-inflammatory and anti-cancerous effect, which contains the compound of general formula (I) and/or its pharmaceutically acceptable salt and inert pharmaceutical carriers and/or excipients.

The compound of general formula (I) and its pharmaceutically acceptable salts, and the pharmaceutical preparation made from it can be administered in any ordinary way. It can be used for example orally, parenterally (including subcutaneous, intramuscular and intravenous administration) , buccally, sublingually, nasally, rectally or transdermally . The pharmaceutical preparations are prepared in unit dosage form using the ordinary pharmaceutical procedures.

The orally active compound of general formula (I) and its pharmaceutically acceptable salts can be prepared in liquid or solid form. For example a syrup, suspension, emulsion, tablets, capsules or lozenges can be prepared.

If the compound of general formula (I) and its pharmaceutically acceptable salts is prepared in liquid form, for example as a suspension solution, it will contain the compound of general formula (I) or its physiologically acceptable salt in a suitable liquid carrier or carriers. Aqueous solvents (e.g. water, ethanol or glycerol) or nonaqueous solvents (e.g. polyethylene glycol or some sort of oil) can be used. The preparation may also contain suspension agents, preservatives, pH-modifying ingredients, flavouring and colouring agents.

If the solid preparation is prepared in tablet form, tablets can be formulated with any suitable carrier used in pharmaceutical routine. Solid carriers can be for example lactose, suitable silicates, sucrose, talcum, gelatine, agar, pectin, gum arabic, magnesium stearate and stearic acid, etc. Optionally a standard aqueous or non-aqueous coating technique can be applied on the tablets.

From the preparation according to the invention tablets can be prepared by pressing or moulding, using optionally one or more absorption promoting agents or adjuvants. Tablets can be manufactured for example by means of a suitable tablet press machine; the active agent can be pressed in powder or granular form, optionally mixed with excipients, lubricants, inert diluents, surface active or dispersive agents.

If the solid preparation is prepared in the form of capsules, it can be manufactured using any ordinary encapsulation method. For example pellets can be made from the active agent combined with a standard carrier, and then it can be filled in hard gelatine capsules. As an alternative solution, a dispersion or suspension can be prepared from the active agent combined with a suitable pharmaceutical carrier, and then it can be - filled in soft gelatine capsules. Suitable pharmaceutical carriers can be for example water-dispersible gums, cellulose, silicates or oils.

The typical forms of parenteral preparations are solutions or suspensions, which contain the compound of general formula (I) and its pharmaceutically acceptable salts in sterile aqueous carriers or parentally administrable non-aqueous carriers, e.g. in polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. As an alternative solution the solution can be lyophilised, and directly before administration it is transformed into a solution again with a suitable solvent. The forms of the pharmaceutical preparations according to the invention suitable for nasal administration contain the compound of general formula (I) and its pharmaceutically acceptable salts in aerosols, drops, gel or powder form. The aerosols according to the invention contain the compounds of general formula (I) typically in a solution or a fine-disperse suspension, in a physiologically acceptable aqueous or nonaqueous solvent. The sterile aerosol can be packaged in a closed container containing a single dose or several doses, which container enables administration and refilling and has a nebuliser. As an alternative, the closed container may also be suitable for the administration of unit doses; for example it can be an inhaler ensuring single doses, or an aerosol dispenser with a dispensing valve, which can be disposed when the container is empty. If administration is solved with an aerosol dispenser, a propellant, e.g. a compressed gas (compressed air) or an organic propellant (e.g. chlorinated/fluorinated hydrocarbons) can be used. The administration of the aerosol can also be solved with a nebuliser pump.

The preparations according to the invention containing the compound of general formula (I) are also suitable for buccal and sublingual administration, for example in the form of tablets, lozenges or pastilles; they contain the active agent formulated with a carrier (e.g. sugar 'and gum Arabic, tragacanth, or gelatine, glycerine, etc.). The preparation containing the compound of general formula

(I) and its pharmaceutically acceptable salts is also suitable for rectal administration. Generally suppositories are prepared, which contain the active agent in a suppository base such as cocoa butter or some other known carrier. Suppositories are prepared using the ordinary method, by mixing the components, then softening or melting the mixture and pouring the melt into a mould and cooling it. The preparation containing the compound of general formula (I) and its pharmaceutically acceptable salts is also suitable for transdermal administration, e.g. in the form of an ointment, gel or plaster.

Preferably, the preparation containing the compound of general formula (I) and its pharmaceutically acceptable salts is prepared in unit dosage form (e.g. tablets, capsules or vials) .

The preparation according to the present invention, which contains the compound of general formula (I) and its pharmaceutically acceptable salts, is prepared in oral unit dosage form, with an active agent content of 10-2000 mg.

The preparation according to the present invention, which contains the compound of general formula (I) and its pharmaceutically acceptable salts, is prepared in parenteral unit dosage form, with an active agent content of 10-1000 mg.

The invention also relates to the use of the compounds of general formula (I) and the pharmaceutically acceptable salts of the compounds of general formula (I) in the treatment of acute inflammations and tumourous diseases.

The invention also relates to a therapeutic treatment procedure, where patients with an inflammation or a tumourous disease are administered a non-toxic, pharmaceutically effective amount of one or more compounds of general formula (I) and/or their pharmaceutically acceptable salt.

The preferred characteristics of the compounds according to the present invention were demonstrated in the pharmacological examples below, in the following biological processes :

- cytotoxicity effects of tumour cells, - cytoprotective effects of heart cells,

- anti-inflammatory effect in acute inflammation models,

- effect shown in the activation of NFkB with lipopolysaccharide, and

- effect on cell proliferation in human melanoma cells.

The invention is described in detail on the basis of the examples below, without limiting the scope of protection to these examples.

The examples relating to the preferred compounds according to the invention are summarised in table 1 below.

Table l.a: Example compounds no 1-38

Table l.b: Example compounds no 39-47

EXAMPLES

Chemical Examples

Example 1

N- ( (E) -5- (3 , 4-dimethoxyphenyl) -2- ( (E) -3- (3,4- dimethoxyphenyl) acryloyl) -3-oxo-l-phenyl-pent-4-enyl) acetamide (Compound no 1)

The compound was prepared according to procedure A described above, in the course of which under argon atmosphere, to the solution of 500 mg (2.024 mmol) annich .intermediate (Ri = phenyl) of general formula (V) prepared with 0.5 ml absolutised (abs.) N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) and 1090 μΐ (2 equivalent) tributyl borate (Sigma) is added, then the mixture is stirred at 75°C for 15 minutes. To the yellow solution 670 mg (2 equivalent) 3 , 4-dimethoxybenzaldehide (Alfa Aesar) is added at 75°C, then after 5 minutes of stirring the solution of 120 μΐ (1 equivalent) acetic acid (Molar) and 40 μΐ (17 mol%) tetrahydroquinoline (Sigma) prepared in 500 μΐ abs. N, N- dimethylformamide (Merck) is added to the system. The reaction mixture is stirred for 3 hours under inert atmosphere (argon, Messer) at 75°C (TLC: silica plate (Merck, Kieselgel 60 F ₂₅₄ ) ; 95:5 mixture of chloroform (Molar) / methanol (Molar)). Then the solution is cooled to room temperature, and in order to break down the formed boron complex, 25 ml of 20 m/m% aqueous acetic acid solution is added to the system. The heterogeneous mixture is stirred intensively for 1.5-2 hours at 75°C, under inert atmosphere, and then it is cooled to room temperature. The precipitated crude product is filtered under vacuum, washed with 2x20 ml water, then dried. The dry crude product is placed in a 50 ml round-bottom flask, 10 ml of ethanol (Molar) is added to it. The heterogeneous solution is boiled for 20 minutes while stirred intensively, then it is filtered during cooling, washed with 5 ml cold ethanol and dried under vacuum. The product obtained: 472 mg .

C32H33NO7, M = 543.2; yield: 43% (procedure A); ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 1.70 (s, 3H, C¾C(0)), 3.78 (s, 12H, OCH ₃ ) , 5.03- 5.20 { , 1H, C (0) CHC (0) ) , 5.66-5.85 (m, 1H, NHCH) , 6.82-7.09 (m, 5H,), 7.00-7.04 (m, 13H) , 7.66 (d, 1H, J = 15.0 Hz) 8.41 (s, 1H, NHC(O)); MS (ES, neg. mode) m/z = 542.2 [M-H] ^" .

Example 2

4 , 4 ' - ( (IE, 6E) -4- (acetamido (phenyl) methyl) -3 , 5-dioxohepta-l , 6- diene-1 , 7-diyl) bis (2-methoxy-4 , 1-phenylene) diacetate

(Compound no 2)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 500 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = phenyl), 1 ml abs .

N, -dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3 , 4-dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ

1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 545 mg (yield: 45%)

C34H33NO9, M = 599.2; yield: 45%; MS (ES, neg. mode) m/z = 598.2 [M-H] ^" .

Example 3

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3 , 4- dimethoxyphenyl) acryloyl) -1- (4-fluorophenyl) -3-oxopent-4- enyl) acetamide (Compound no 3)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 536 mg (2.024 mmol) Mannich intermediate of general formula (V) (wherein the meanig of Ri is 4-fluorophenyl) , 1 ml abs. N, -dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3, 4-dimethoxybenzaldehyde (Alfa Aesar), 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 534 mg .

C32H32FNO7, M = 561.2; yield: 47% (method A); Mp. : 200-202 °C; ^X H NMR (500 MHz, CDC1 ₃ ) : δ 1.95 (s, 3H, Ci¾C(0)), 3.89 (s, 12H, OCi¾) , 4.75 (d, 1H, C(0)CflC(0) , J = 6.9 Hz), 5.97 (t, 1H, NHCH, J = 7.8 Hz), 6.70 (d, 1H, J = 13.1 Hz), 6.73 (d, 1H, J = 13.4 Hz), 6.80-6.86 (m, 2H) , 6.96 (d, 2H, J = 8.5 Hz), 7.00-7.04 (in, 2H) , 7.05-7.15 (m, 3H) , 7.34-7.40 (m, 2H) , 7.53 (d, 1H, J

= 15.6 Hz) 7.60 (d, 1H, J = 15.6 Hz); ¹³ C NMR (125.7 MHz,

CDC1 ₃ ) : δ 22.9, 51.4, 55.5, 66.8, 109.6, 109.7, 110.6, 114.9,

115.1, 121.2, 121.7, 123.5, 123.7, 126.4, 128.1, 128.2, 135.5, 145.0, 145.1, 148.9, 151.6, 160.6, 162.5, 169.0, 192.0, 194.5; MS (ES, neg. mode) m/z = 560.2 [M-H] ^~ .

Example 4

N- ( (E) -1- (3-bromophenyl) -5- (3 , 4-dimethoxyphenyl) -2- ( (E) -3- (3 , 4-dimethoxyphenyl) acryloyl) -3-oxopent-4-enyl) acetamide

(Compound no 4)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 659 mg (2.024 mmol) Mannich intermediate of general formula (V) (Ri = 3-bromophenyl), 1 ml abs . N, ΛΖ-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 mol%) (Sigma) . Product: 601 mg.

C ₃ 2H ₃ 2BrN0 ₇ , M = 603.1; yield: 48% (method A); Mp. : 215-218 °C; ¹ R NMR (500 MHz, CDCI3) : δ 1.98 (s, 3H, C¾C(0)), 3.91 (s, 12H, OCH3), 4.73 (d, 1H, C (0) C#C (0) , J = 6.5 Hz), 5.94 (t, 1H, NHCH, J = 8.0 Hz), 6.67 (d, 1H, J = 15.4 Hz), 6.74 (d, 1H, J = 15.7 Hz), 6.84 (t, 2H, J = 8.8 Hz), 7.02 (s, 1H) , 7.05 (s, 1H) , 7.06-7.12 (m, 2H) , 7.12-7.19 (jn, 2H) , 7.29-7.36 (m, 2H) , 7.51 (d, 1H, J = 15.5 Hz) 7.55 (s, 1H) 7.62 (d, 1H, J = 15.9 Hz); ¹³ C NMR (125.7 MHz,CDC13): δ 22.9, 51.5, 55.5, 66.3, 109.5,

109.6, 110.6, 110.7, 121.1, 121.8, 123.6, 123.7, 125.1, 126.3, 126.4, 129.5, 129.7, 130.3, 142.0, 145.1, 145.2, 148.8, 151.6,

151.7, 169.1, 191.8, 194.4; MS (ES, neg. mode) m/z = 620.1 [M- H] -.

Example 5

N- ( (E) -5- (3 , 4-dimethoxyphenyl) -2- ( {∑) -3- (3,4- dimethoxyphenyl) acryloyl) -1- (2-fluorophenyl) -3-oxopent-4- enyl) acetamide (Compound no 5)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 536 mg (2.024 mmol) Mannich intermediate of general formula (V) (Ri = 2-fluorophenyl ) , 1 ml abs. N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 465 mg.

C32H32FNO7, M = 561.2; yield: 41% (method A); Mp.: 209-212 °C; ¹ NMR (500 MHz, CDCI ₃ ) : δ 1.98 (s, 3H, C¾C (0) ) , 3.89 (s, 6H, OCH3), 3.92 (s, 6H, OCH3) 4.92 (d, 1H, C(0)CflC(0), J = 6.5 Hz), 6.18 (t, 1H, NHCH, J = 7.6 Hz), 6.64 (d, 1H, J = 15.7 Hz), 6.75 (d, 1H, J = 15.8 Hz), 6.82 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H J = 8.4 Hz), 6.97-7.24 (m, 8H) , 7.42-7.54 (m, 2H) , 7.68 (d, 1H, J = 15.8 Hz) ¹³ C NMR (125.7 MHz, CDC1 ₃ ) δ 22.9, 47.9, 55.5, 64.5, 109.5, 109.6, 110.5, 110.6, 115.0, 115.1, 121.6, 121.8, 123.6, 123.7, 123.9, 126.4, 128.9, 129.0, 129.2, 144.6, 145.2, 148.8, 148.9, 151.5, 151.6, 169.0, 192.3, 194.4; MS (ES, neg. mode) m/z = 560.2 [M-H] ^" .

Example 6

N- ( (E) -1- (3 , 4-difl orophenyl) -5- (3 , 4-dimethoxyphenyl) -2- ( (JE) - 3- (3 , 4-dimethoxyphenyl) acryloyl) -3-oxopent-4-enyl) acetamide (Compound no 6)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 572 mg (2.024 mmol) Mannich intermediate of general formula (V) (Ri = 3 , -difluorophenyl ) , 1 ml abs. N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 mol%) (Sigma) . Product: 598 mg.

C32H31 F2NO7 ; M = 579.2; yield: 51% (method A); Mp. : 218-220 °C; ^X H NMR (500 MHz, CDCI ₃ ) : δ 1.97 (s, 3H, C¾C (0) ) , 4.71 (s, 12H, OCH ₃ ) , 4.75 (d, 1H, C(0)CflC(0), J = 6.4 Hz), 5.91 (t, 1H, NHCH, J = 7.8 Hz), 6.68 (d, 1H, J = 15.8 Hz), 6.74 (d, 1H, J = 15.8 Hz), 6.81-6.88 {m, 2H) , 7.03 (d, 2H, J = 9.1 Hz), 7.05-7.17 (m, 5H) , 7.54 (d, 1H, J = 15.8 Hz) 7.62 (d, 1H, J = 15.8 Hz); ¹³ C NMR (125.7 MHz, CDC1 ₃ ) : δ 22.8, 51.3, 55.5, 66.4, 109.4, 109.7, 110.6, 110.7, 115.6, 115.8, 116.8, 116.9, 121.0, 121.5, 122.6, 123.6, 123.8, 126.3, 145.3, 145.4, 148.9, 151.7, 151.8, 169.2, 191.7, 194.3; MS (ES, neg, mode) m/z = 578.2 [M-H] ^" . Example 7

N- ( (£7) -1- (2 , 4-dichlorophenyl) -5- (3 , 4-dimethoxyphenyl) -2- ( - 3- (3 , 4-dimethoxyphenyl) acryloyl) -3-oxopent-4-enyl) acetamide (Compound no 7)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 637 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = 3-bromophenyl ) , 1 ml abs. N, W-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2 , 3, 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 680 mg.

C ₃ 2H31CI2NO7 , M = 611.2; yield: 55% (method A) ; Mp . : 224-226 °C; ¹ n NMR (500 MHz, CDCI ₃ ) : δ 1.99 (s, 3H, C¾C(0)), 3.87 (s, 3H, OC¾), 3.89 (s, 3H, OCH3), 3.92 (s, 6H, OC¾) , 4.99 (d, 1H, C(0)CHC(0), J = 4.74 Hz), 6.08 (dd, 1H, NHCtf, J = 8.3 Hz and 3.3 Hz), 6.51 (d, 1H, J = 15.7 Hz), 6.79-6.90 (m, 3H) , 6.97 (s, 1H) , 7.03-7.11 (in, 2H) , 7.18 (t, 2H, J = 8.3 Hz) 7.36 (s, 1H), 7.43 (s, 1H) , 7.45 (d, 1H, J = 5.8 Hz), 7.52 (d, 1H, J = 8.3 Hz); ¹³ C NMR (125.7 MHz, CDCI ₃ ) : δ 22.8, 49.9, 55.5, 62.2, 109.4, 109.8, 110.5, 110.7, 120.8, 122.6, 123.5, 123.7, 126.2, 126.4, 127.0, 129.1, 130.1, 132.3, 133.6, 135.2, 144.8, 145.3, 148.8, 148.9, 151.7, 169.1, 192.0, 194.8; MS (ES, neg. mode) m/z = 610.2 [M-H] ^~ .

Example 8 N- ( (E) -5- (3 , 4-dimethoxyphenyl) -2- ( (E) -3- (3 , 4-dimethoxy- phenyl) acryloyl) -3-oxo-l- (4- (trifluoromethyl) phenyl) pent-4- enyl) acetamide (Compound no 8)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 637 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = 4-trifluoromethyl- phenyl) , 1 ml abs. N, W-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 742 mg.

C ₃₃ H ₃₂ F ₃ N0 ₇ ; M = 611.2; yield: 60% (method A) ; Mp. : 195-196 °C; ^X H NMR (500 MHz, CDC1 ₃ ) : δ 1.98 (s, 3H, C¾C( 0 ) ) , 3.89 (s, 3H, OC¾), 3.90 (s, 6H, OCi¾), 3.91 (s, 3H, OC¾) , 4.77 (d, 1H, C(0)CHC(0), J = 6.3 Hz), 6.01 (dd, overlapped peaks, 1H, NHCH, J = 7.4 Hz), 6.68 (d, 1H, J = 15.7 Hz), 6.75 (d, 1H, J = 15.4 Hz), 6.84 (t, 2H, J = 8.4 Hz), 7.01 (s, 1H) , 7.04 (s, 1H) , 7.07-7.11 (21, 1H), 7.14 (d, 2H, J = 8.4 Hz), 7.49-7.58 (in, 4H) , 7.63 (d, 1H, J = 15.7 Hz); ¹³ C NMR (125.7 MHz, CDC1 ₃ ) : δ 22.8, 51.7, 55.5, 66.3, 109.6, 109.7, 110.6, 110.7, 121.0, 121.5, 123.6, 123.8, 125.1, 125.2, 126.2, 126.3, 126.9, 143.7, 145.3, 145.4, 148.9, 151.7, 151.8, 169.2, 191.8, 194.3; MS (ES, neg. mode) m/z = 610.2 [M-H] ^~ .

Example 9 N- ( (E) -1- (4-bromothiophen-2-yl) -5- (3 , 4-dimethoxyphenyl) -2- ( (E) -3- (3 , 4-dimethoxyphenyl) acryloyl) -3-oxopent-4- enyl) acetamide (Compound no 9)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 672 mg (2.024 mmol) Mannich intermediate of general formula (V) (Rj = 4-bromothiophen-2- yl) , 1 ml abs. N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 444 mg.

C ₃ oH ₃ oBrN0 ₇ S; M = 627.1; yield: 35% (method A) ; Mp.: 188-190 °C; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 1.72 (s, 3H, C¾C(0)), 3.76 (s, 3H, OC¾), 3.77 (s, 3H, OC¾) , 3.79 (s, 3H, OC¾) , 3.80 (s, 3H, OC¾) , 5.24 (d, 1H, C(0)CHC(0), J = 10.8 Hz), 5.90 (t, 1H, NHCH, J = 9.9 Hz), 6.95-7.04 (m, 4H) , 7.06 (d, 1H, J = 15.8 Hz), 7.25 (d, 1H, J = 8.2 Hz), 7.28-7.34 (m, 2H) , 7.35 (s, 1H) , 7.46 (s, 1H) , 7.54 (d, 1H, J = 15.8 Hz), 7.72 (d, 1H, J = 15.8 Hz), 8.51 (d, 1H, C( 0)Nff, J = 8.7 Hz); MS (ES, neg. mode) m/z = 626.1 [M-H] ^" . Example 10

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3,4- dimethoxyphenyl) acryloyl) -3-oxo-l- (3- (trifluoromethyl) - phenyl) pent-4-enyl) acetamide (Compound no 10)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 637 mg (2.024 mmol) Mannich intermediate of general formula (V) (Ri = 3- trifluoromethylphenyl ) , 1 ml abs . N, W-dimethylformamide (Merck) , 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3, 4-dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1,2,3,4- tetrahydroquinoline (17 moll) (Sigma). Product: 717 mg.

C33H32 F3NO7 ; M = 611.2; yield: 58% (method A); Mp.: 209-212 °C; H NMR (500 MHz, CDC1 ₃ ) : δ 1.98 (s, 3H, C¾C(0)), 3.89 (s, 12H, OC¾), 4.77 (d, 1H, C(0)CflC(0), J = 6.5 Hz), 6.02 (t, 1H, NHCfi, J = 7.4 Hz), 6.68 (d, 1H, J = 16.0 Hz), 6.75 (d, 1H, J = 16.0 Hz), 6.83 (t, 2H, J = 6.8 Hz), 7.00 (s, 1H) , 7.03 (s, 1H) , 7.06-7.15 (in, 2H) , 7.19 (s, 1H) , 7.37-7.44 (m, 1H) , 7.44-7.51 (in, 2H), 7.59 (d, 1H, J = 8.6 Hz), 7.67 (s, 1H) ; ¹³ C NMR (125.7 MHz, CDCI ₃ ) : δ 22.8, 51.7, 55.5, 66.3, 109.5, 109.6, 110.6, 121.0, 121.6, 122.7, 123.2, 123.6, 123.7, 124.0, 126.3, 128.6, 130.8, 145.2, 145.3, 148.8, 151.6, 169.3, 191.8, 194.3; MS (ES, neg. mode) m/z = 610.2 [M-H] ^~ .

Example 11

N- ( (E) -1- (3-bromophenyl) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (£?) - 3- (4-hydroxy-3-methoxyphenyl) acryloyl) -3-oxopent-4- enyl) ace amide (Compound no 11)

The compound was synthesized according to method B described above, in the course of that to the solution of 412 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = 3- bromophenyl) in 2 ml of abs . N, W-dimethylformamide, 60 mg (0.7 equivalent) boron trioxide (Sigma) was added, then the mixture was stirred at 75°C for 30 minutes. In next step, 385 mg (2 equivalents) 4-Hydroxy-3-methoxy-benzaldehyde (Sigma) and 684 μΐ (2 equivalents) tributyl borate were added to the mixture stirred for an additional 30 minutes. After addition of 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent of morpholine (Sigma) and 1 equivalent of trifluoroacetic acid (Sigma) , diethyl ether (Molar) , 0°C, lh) , the stirring was continued for 15 hours at 75°C (monitored by TLC: Kieselgel 60 F ₂ 5 (Merck) / eluent: chloroform (Molar) imethanol (Molar) 95:5), then the reaction was allowed to cool down to room temperature. In order to quench the generated boron complex, 12 ml of 5 m/m% aqueous acetic acid solution was added to dropwise and the heterogenous reaction mixture was stirred vigorously for 1.5h at 75°C, then reaction mixture was cooled down to room temperature again. The precipitated crude product was filtrated, washed with water (2><20mL) and dried. The crude product was purified by means of column chromatography, using 50x amount of silicagel and chloroform (Molar) : methanol (Molar) in the ratio of 95:5 as eluent. The purified product was recrystallised by diethyl ether. Product: 340 mg.

C ₃ oH28BrN0 ₇ ; M = 593.1; yield: 45% (method B) ; Mp. : 146-148. °C; ^X H NMR (500 MHz, CDC1 ₃ ) : δ 1.98 (s, 3H, C¾C (0) ) , 3.90 (s, broading, 6H, 0C¾) , 4.72 (d, 1H, C(0)CHC(0), J = 6.3 Hz), 5.94 (t, 1H, CflNH, J = 7.6 Hz), 6.17 (s, overlapped peaks, 2H, 2xOH) , 6.65 (d, 1H, J = 15.9 Hz), 6.72 (d, 1H, J = 15.9 Hz), 6.88 (t, 3H, J = 8.4 Hz), 6.97-7.06 (m, 3H) , 7.06-7.18 (m, 2H) , 7.31 (d, 1H, J = 7.9 Hz), 7.50 (d, 1H, J = 15.9 Hz), 7.55 (s, 1H), 7.60 (d, 1H, J = 15.9 Hz); ¹³ C NMR (125.7 MHz, CDC1 ₃ ) : δ 22.9, 51.5, 55.6, 66.3, 109.3, 109.5, 114.4, 114.5, 120.8, 121.4, 122.3, 123.9, 124.2, 125.1, 125.9, 129.5, 129.7, 130.3, 142.0, 145.3, 145.4, 146.4, 148.6, 148.7, 169.3, 191.8, 194.4; MS (ES, neg. mode) m/z = 592.1 [M-H] ^~ .

Example 12

N- ( (£ -1- (4-chlorophenyl) -5- (4-hydroxy-3-methoxyphenyl)

( <JE7> -3- (4-hydroxy-3-methoxypheny1) acryloyl) -3-oxopent-4

yl) acetamide (Compound no 12)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 356 mg (1.267 mmol) Mannich intermediate of general formula (V) (R _x = 4-chlorophenyl), 2 ml abs . N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 4-hydroxy-3-methoxy- benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethylether (Molar), 0°C, lh) . Product: 326 mg

C30H28C I O7 , M = 549.2; yield: 47% (Method B ) ; ¹ NMR (500 MHz DMSO-d ₆ ) : δ 1.70 (s, 3H, C¾C(0)), 3.77 (s, 3H, 0Ci¾) , 3.81 (s 3H, OCH3), 5.07 (d, 1H, C (0) CHC (Ό) , J = 10.6 Hz), 5.71 (t, 1H NHCH, J = 9.9 Hz), 6.76 (d, 1H, J = 8.2 Hz), 6.81 (d, 1H, J = 8.0 Hz), 6.86 (d, 1H, J = 15.7 Hz), 6.94 (d, 1H, J = 15.7 Hz), 7.09 (d, 1H, J = 8.0 Hz), 7.19 (d, 1H, J = 8.0 Hz), 7.22 (jbs, 1H), 7.29-7.43 (m, 6H) , 7.64 (d, 1H, J = 15.7 Hz), 8.42 (d, 1H, C(0)Nff, J = 8.9 Hz), 9.73 (2xs, overlapped peaks, 2H, 2x0H) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 21.7, 51.3, 55.7, 67.0, 111.6, 115.6, 115.7, 122.0, 122.5, 123.7, 124.1, 125.4, 125.7, 128.1, 129.4, 131.6, 140.5, 144.6, 144.7, 147.9, 148.0, 150.0, 150.1, 168.3, 191.7, 192.0; MS (ES, neg. mode) m/z = 548.1 [M- ΗΓ.

Example 13

N- ( (E) -5- ( -hydroxy-3-methoxyphenyl) -2- ( (E) -3-

inethoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) acrylamide (Com ound no 13)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 383 mg (1.267 mmol) Mannich intermediate of general formula (VI) (Ri = 4-carboxyphenyl) , 2 ml abs . N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 4-hydroxy-3-methoxy- benzaldehyde (Sigma), 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethylether (Molar), 0°C, lh) . Product: 478 mg.

C34H33NO9; M = 599.22; yield: 63% (Method B) ; Mp.: 218-220 °C; ² H NMR (500 MHz, DMSO-d ₆ ) : δ 3.76 (s, 3H, OCi¾) , 3.78 (s, 3H, 0C¾), 3.80 (s, 3H, OC¾), 3.81 (s, 3H, OC¾) , 5.27 (d, 1H, C(0)CHC(0), J = 10.6 Hz), 5.54 (dd, overlapped peaks, 1H, CHH=CH, J = 10.2 Hz), 5.88 (t, 1H, CHNH, J = 9.5 Hz), 6.01 (dd, overlapped peaks, 1H, CHH=CH, J = 17.0 Hz), 6.16 (dd, 1H, CHH=CH, J = 6.8 and 17.0 Hz), 6.93-6.99 (m, 2H) , 6.99-7.06 (m, 2H) , 7.21 (d, 1H, J = 8.3 Hz), 7.24 (s, 1H) , 7.31 (d, 1H, J = 8.3 Hz), 7.35 (s, 1H) , 7.43 (d, 1H, J = 15.9 Hz), 7.53 (d, 2H, J = 8.3 Hz), 7.71 (d, 1H, J = 15.9 Hz), 7.86 (d, 1H, J = 7.8 Hz), 8.71 (d, 1H, C(0)NH, J = 8.9 Hz) 12.8 (bs, 1H, C(O)OH) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.7, 55.5, 66.5, 110.6, 111.5, 111.6, 122.9, 123.4, 123.6, 123.9, 125.8, 126.6, 126.9, 127.7, 129.2, 129.6, 131.3, 144.2, 144.4, 145.9, 148.9, 149.0, 151.5, 151.6, 163.7 ,166.9, 191.5, 191.8; MS (ES, neg. mode) m/z = 598.2 [Μ-Η -

Example 14

N- ( (E) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy-3- methoxyphenyl) acryloyl) -3-oxo-l- (4- (trifluoromethyl) phenyl) pent-4-en-l-yl) acetamide Compound no 14)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 400 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = 4-trifluoromethylphenyl) , 2 ml abs. N, N-dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 4-hydroxy-3-methoxy- benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 310 mg.

C31H28 F3 O ₇ ; M = 583.2; yield: 42% (Method B ) ; Mp. : 144-147 °C; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 1.74 (s, 3H, Ci¾C(0)), 3.74 (s, 3H, OC¾), 3.82 (s, 3H, OCH ₃ ) , 5.15 (d, 1H, C(0)CJiC(0), J = 10.9 Hz), 5.79 (t, 1H, NHCH, J = 9.7 Hz), 6.77 (d, 1H, J = 8.0 Hz), 6.83 (d, 1H, J = 7.6 Hz), 6.88 (d, 1H, J = 15.2 Hz), 6.96 (d, 1H, J = 17.3 Hz), 7.10 (d, 1H, J = 8.0 Hz ) , ,1.17-7.27 (jn, 2H), 7.33 (s, 1H) , 7.39 (d, 1H, J = 15.2 Hz), 7.57-7.71 (m, 5H), 8.50 (d, 1H, C ( 0 ) NH, J = 8.8 Hz), 9.74 (j s, 2H, 2x0H) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.6, 51.5, 55.6, 55.7, 66.6, 111.6, 115.6, 115.7, 121.9, 122.4, 123.7, 124.0, 124.9, 125.0, 125.3, 125.6, 128.3, 144.6, 144.7, 146.1, 147.8, 147.9, 149.9, 150.0, 168.3, 191.5, 191.8; (ES, neg. mode) m/z = 582.2 [ - H ] ^" .

Example 15

4- ( (E) -1-acetamido-5- (4-hydroxy-3-me hoxyphenyl) -2- ( (E) -3- (4- hydroxy-3-me hoxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) benzoic acid (Compound no 15)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 368 mg (1.267 mmol) Mannich intermediate of general formula (V) ( Ri = 4-carboxyphenyl ) , 2 ml abs . N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma), 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 4-hydroxy-3-methoxy- benzaldehyde (Sigma), 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 340 mg.

C ₃₁ H29N0 ₉ , M = 559.2; Yield: 48% (Method B) ; Mp. : 199-201 °C; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 1.72 (s, 3H, C¾C ( 0 ) ) , 3.77 ( s , 3H, 0C¾), 3.82 (s, 3H, OCi¾) , 5.14 (d, 1H, C(0)CHC(0), J = 10.6 Hz), 5.78 (t, 1H, NHCH, J = 10.0 Hz), 6.78 (d, 1H, J = 8.2 Hz), 6.81-6.89 (m, 2H) , 6.97 (d, 1H, J = 16.0 Hz), 7.09 (dd, overlapped peaks, 1H, J = 8.2 Hz), 7.18-7.24 {m, 2H) , 7.33 ( s, 1H) , 7.38 (d, 1H, J = 15.7 Hz), 7.50 (d, 2H, J = 8.2 Hz), 7.65 (d, 1H, J = 16.0 Hz), 7.84 (d, 2H, J = 8.2 Hz), 8.50 ( d, 1H, C(0)NH, J = 9.0 Hz), 9.80 (s, broading, 2H, 2x0H) ; ¹³ C NMR (125.7 MHz, DMSO-de) : δ 22.6, 51.6, 55.6, 55.7, 66.7, 111.5, 111.6, 115.6, 115.7, 122.0, 122.5, 123.7, 124.0, 125.3, 125.7, 127.6, 129.1, 144.5, 144.6, 146.1, 147.9, 148.0, 150.0, 150.1, 167.1, 168.3, 191.6, 191.9; (ES, neg. mode) m/z = 558.2 [M-H] ^~ .

Examle 16

N- ( (E) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy-3- me hoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l-yl) acetamide (Compound no 16)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = phenyl), 2 ml abs. N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 385 mg (2 equivalents) 4-hydroxy-3-methoxy benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 261 mg.

C30H29NO7; M = 515.2; yield: 40% (Method B) ; Mp. : 145-147 °C; ¹ R NMR (500 MHz, CDC1 ₃ ) : δ 1.97 (s, 3H, C¾C(0)), 3.89 {bs, 6H, OC¾) , 4.78 (d, 1H, C(0)CHC(0), J = 6.5 Hz), 6.02 ( t, 1H, CflNH, J = 8.2 Hz), 6.22 (s, 1H, OH), 6.30 (s, 1H, Off) , 6.70 (t, 2H, J = 16.9 Hz), 6.87 (t, 2H, J = 8.9 Hz), 6.97-7.04 (m, 3H) , 7.06 (d, 1H, J = 8.4 Hz), 7.10 (d, 1H, J = 9.1 Hz), 7.18-7.24 (jn, 1H) , 7.29 (t, 2H, J = 7.3 Hz), 7.35-7.41 (m, 1H) , 7.50 (d, 1H, J = 15.7 Hz), 7.59 (d, 1H, <J = 15.7 Hz); ¹³ C NMR (125.7 MHz , CDCI ₃ ) : δ 22.9, 51.9, 55.5, 66.6, 109.3, 109.5, 114.4,

114.5, 121.0, 121.5, 123.9, 124.2, 126.0, 126.3, 127.2, 128.2,

139.6, 145.0, 145.1, 146.5, 148.6, 169.2, 192.2, 194.7; (ES, neg. mode) m/z = 514.2 [M-H] ^~ .

Example 17

AT- ( (£) -5- (3-hydroxy- -methoxyphenyl) -2- ( (E) -3- (3-hydroxy-4- methoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l-yl) acetamide (Compound no 17)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (R _x = phenyl), 2 ml abs . N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 3-hydroxy-4-methoxy- benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethylether (Molar), 0°C, lh) . Product: 294 mg.

C30H29NO7; M = 515.2; yield: 45% (Method B ) ; Mp. : 182-185 °C; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 1.65 (s, 3H, C¾C(0)), 3.78 (s, 3H, OC¾) , 3.80 (s, 3H, OCH ₃ ) , 5.40 (d, 1H, C(0)CHC(0), J = 10.8 Hz), 5.74 (t, 1H, NHCH, J = 10.1 Hz), 6.72 (d, 1H, J = 15.7 Hz), 6.86 (d, 1H, J = 15.7 Hz), 6.94-6.99 (m, 1H) , 7.02-7.08 (m, 2H) , 7.02-7.08 (m, 2H) , 7.09-7.18 (m, 2H) , 7.25 (t, 2H, J = 7.5 Hz), 7.30 (d, 2H, J = 10.4 Hz), 7.36 (d, 1H, J = 7.5 Hz), 7.55 (d, 1H, <J = 15.7 Hz), 8.39 (d, 1H, C(0)NH, J = 9.0 Hz), 9.19 (s, 1H, OH); 9.24 (s, 1H, OH); ¹³ C NMR (125.7 MHz, DMSO-de) : δ 22.6, 51.8, 55.6, 67.6, 112.0, 112.1, 114.1, 114.2, 114.3, 122.2, 122.3, 122.6, 126.7, 127.1, 127.5, 128.1, 140.4, 141.3, 144.0, 146.7, 146.0, 150.6, 168.1, 192.0, 192.3; (ES, neg. mode) m/z = 514.1 [M-H] ^~ .

Example 18

N- ( (E) -1- (4-butylphenyl) -5- (3 , 4-dime hoxyphenyl) -2- ( (E) -3- (3, 4-dimethoxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) acetamide (Compound no 18)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 613 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = 4-butylphenyl) , 1 ml abs . N, I\7-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 mol%) (Sigma) . Product: 364 mg .

C ₃₆ H ₄ iN0 ₇ ; M = 599.3; Yield: 30% (Method A) ; Mp.: 182-183°C; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 0.80 (t, 3H, C¾CH ₂ , J = 7.3 Hz), 1.16-1.24 (m, 2H, C¾CH ₂ ) , 1.38-1.47 (m, 2H, CH ₂ C¾) , 1.69 (s, 3H, Ci¾C(0)), 2.45 (t, 2H, CH ₃ C¾Ph, J = 7.5 Hz), 3.76 (s, 3H, OCi¾) , 3.77 (s, 3H, OC¾) , 3.79 (s, 3H, OC¾) , 3.80 (s, 3H, 0C¾), 5.08 (d, 1H, C(0)CfiC(0), J = 10.7 Hz), 5.72 (t, 1H, NHCfi, J = 9.9 Hz), 6.89 (d, 1H, J = 15.9 Hz), 6.95 (d, 1H, J = 8.2 Hz), 6.97-7.03 (m, 2H) , 7.06 (d, 2H, J = 7.9 Hz), 7.18 (d, 1H, J = 8.4 Hz), 7.21-7.32 (m, 4H) , 7.33 (s, 1H) , 7.37 (d, 1H, J = 15.9 Hz), 7.65 (d, 1H, J = 15.9 Hz), 8.37 (d, 1H, C(0)Nff, J = 8.9 Hz) ; MS (ES, neg. mode) m/z = 598.2 [M-H] ^~ .

Example 19

4- ( (E) -l-acetamido-5- (3 , 4-dimethoxyphenyl) -2- ( (E) -3- (3,

dimethoxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) benzoic

(Compound no 19)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 588 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = 4-carboxyphenyl ) , 1 ml abs. IV, IV-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma) . Product: 735 mg. C33H33NO9; M = 587.2; yield: 62% (Method A) ; ^X H NMR (500 MHz , DMSO-d ₆ ) : δ 1.72 (s, 3H, C¾C(0)), 3.76 (s, 3H, OCH ₃ ) , 3.77 (s, 3H, OC¾), 3.80 (s, 3H, OC¾) , 3.81 (s, 3H, OC¾) , 5.19 (d, 1H, C(0)CiiC(0), J = 10.5 Hz), 5.80 (t, 1H, NHCJi, J = 10.2 Hz), 6.90-6.99 (m, 3H) , 7.00-7.06 (m, 2H) , 7.21 (d, 1H, J = 8.4 Hz), 7.24 (s, 1H) , 7.32 (d, 1H, J = 8.4 Hz), 7.35 (s, 1H) , 7.42 (d, 1H, J = 15.9 Hz), 7.50 (d, 2H, J = 8.2 Hz), 7.70 (d, 1H, J = 15.9 Hz), 7.85 (d, 2H, <J = 8.2 Hz), 8.49 (d, 1H, C(0)NH, J = 8.9 Hz); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.6, 51.6, 55.5, 66.7, 110.61, 110.64, 111.5, 111.6, 122.9, 123.5, 123.6, 123.8, 126.6, 126.9, 127.7, 129.1, 144.1, 144.2, 146.2, 148.9, 149.0, 151.4, 151.5, 167.0, 168.3, 191.7, 192.0. MS (ES, neg. mode) m/z = 586.2 [M-H] ^~ .

Example 20

N- ( (£?) -5- (3 , 4-dimethoxyphenyl) -2- ( (E) -3- (3,4

dimethoxyphenyl) acryloyl) -3-oxo-l-phenylpent

yl) acrylamide (Compound no 20)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 613 mg (2.024 mmol) Mannich intermediate of general formula (VI) (R _x = phenyl), 1 ml abs . N, JV-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3 , 4-dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 640 mg . C ₃₃ H ₃₃ NO ₇ ; M = 555.2; yield: 57% (Method A) ; Mp. : 186-189 °C; ¹ R NMR (500 MHz, CDC1 ₃ ) : δ 3.88 (s, broading, 12H, 4xOC¾) , 4.86 (d, 1H, C(0)CHC(0), J = 6.3 Hz), 7.06-7.16 (m, 2H) 6.21 (d, 1H, J = 17.1 Hz), 6.74 (t, 2H, J = 15.8 Hz), 6.79-6.87 (m, 2H) 6.99-7.04 (m, 2H) 7.07 (d, 1H, J = 8.2 Hz), 7.10 (d, 1H, J = 8.2 Hz), 7.16-7.23 (m, 1H) 7.28 (t, 2H, J = 7.6 Hz) 7.36 (d, 1H, J = 9.0 Hz), 7.41 (d, 2H, J = 7.5 Hz), 7.52 (d, 1H, J = 15.8 Hz), 7.61 (d, 1H, J = 15.8 Hz); ¹³ C NMR (125.7 MHz , CDCI ₃ ) : δ 52.1, 55.5, 66.6, 109.6, 109.7, 110.5, 110.6, 121.3, 121.9, 123.5, 123.7, 126.40, 126.48, 126.52, 127.2, 128.2, 130.3, 139.5, 144.9, 145.0, 148.8, 151.54, 151.56, 164.5, 192.1, 194.7; MS (ES, neg. mode) m/z = 554.2 [M-H] ^" .

Example 21

4- ( (E) -l-acetamido-5- (3 , 4-dimethoxyphenyl) -2- ( {E) -3- (3,4- dimethoxyphenyl) aciryloyl) -3-oxopent-4-en-l-yl) -2-methoxyphenyl acetate (Compound no 21)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 702 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = 4-acetoxy-3-methoxy- phenyl) , 1 ml abs . N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, -tetrahydroquinoline (17 mol%) (Sigma). Product: 625 mg. C35H37NO10; M = 631.2; yield: 49% (Method A) ; Mp.: 180-182 °C; ^X H NMR (500 MHz , CDC1 ₃ ) : δ 1.94 (s, 3H, C¾C(0) ), 2.26 (s, 3H, C¾C(0)0-Ar), 3.79 (s, 3H, OC¾) , 3.89 (jbs, overlapped peaks, 12H, OC¾), 4.76 (d, 1H, C(0)C#C(0), J = 7.0 Hz), 5.99 (t, 1H, NHCH, J = 7.7 Hz), 6.72 (d, 1H, J = 10.5 Hz), 6.75 (d, 1H, J = 10.5 Hz), 6 , 8 0 - 6 . 8 6 (m, 2H) , 6.93 (bs, 2H) , 7.04 (jbs, overlapped peaks, 4H) , 7.08-7.15 {m, 2H) , 7.56 (d, 1H, J = 15.7 Hz), 7.60 (d, 1H, J = 15.7 Hz); ¹³ C NMR (125.7 MHz, CDCI ₃ ) : δ 20.2, 22.9, 51.8, 55.5, 66.9, 109.6, 110.6, 111.5, 118.3, 121.4, 121.6, 122.4, 123.5, 123.7, 126.4, 138.7, 144.9, 145.0, 148.8, 151.5, 168.4, 169.0, 192.0, 194.5; MS (ES, neg. mode) m/z = 630.2 [M-H] ^" .

Example 22

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3,4- dimethoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl)propionamide (Compound no 22)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 665 mg (2.024 mmol) Mannich intermediate of general formula (V) (R _x = phenyl), 1 ml abs . N, ΛΓ-dimethyIformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3 , 4-dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 625 mg. "C33H35NO7; M = 557.2; yield: 59% (Method A) ; ^X H NMR (500 MHz , DMSO-d ₆ ) : δ 0.85 (t, 3H, J = 7.6 Hz, C(0)CH ₂ C¾), 1.98 (q, 2H, J = 7.6 Hz, C(0)C¾CH ₃ ), 3.77 (s, 3H, OC¾) , 3.78 (s, 3H, OC¾) , 3.80 (s, 3H, OC¾), 3.82 (s, 3H, OC¾) _/ 5.11 (d, 1H, C(0)CHC(0), J = 10.7 Hz), 5.80 (t, 1H, NHCH, J = 10.0 Hz), 6.90 (d, 1H, J = 15.9 Hz), 6.97 (d, 1H, J = 8.3 Hz), 6.99-7.05 (m, 2H) , 7.15-7.23 (m, 2H) , 7.24-7.32 (m, 4H) , 7.34 (bs, 1H) , 7.37-7.45 (ffl, 3H) , 7.65 (d, 1H, J = 15.9 Hz), 8.34 (d, 1H, C(0)NH, J = 9.1 Hz); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 9.7, 28.5, 51.5, 55.5, 67.2, 110.5, 111.5, 111.6, 123.1, 123.2, 123.5,

123.8, 126.6, 126.9, 127.0, 127.4, 128.0, 141.4, 143.8, 143.9,

148.9, 149.0, 151.4, 151.5, 171.8, 192.0, 192.4; MS (ES, neg . mode) m/z = 556.2 [M-H] ^~ . Example 23

N- ( (E) -5- (3 , 4-dimethoxyphenyl) -2- ( {E) -3- (3,4- dimethoxyphenyl) acryloyl) -1- (4-fluorophenyl) -3-oxopent-4-en-l- yl) aer 1amide (Com ound no 23)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 560 mg (2.024 mmol) Mannich intermediate of general formula (VI) (Rx = 4-fluorophenyl ) , 1 ml abs. N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma), 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 mol%) (Sigma). Product: 637 mg. C33H32FNO7; M = 573.2; yield: 55% (Method A) ; Mp. : 184-187 °C; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 3.76 (s, 6H, 2xOC¾) , 3.79 (s, 3H, OC¾), 3.80 (s, 3H, OC¾), 5.20 (d, 1H, C(0)CflC(0), J = 10.9 Hz), 5.52 (d, 1H, CHH=CH, J = 10.2 Hz), 5.82 (t, 1H, CHNH, J = 9.3 Hz), 5.99 (d, 1H, CHH=CH, J = 16.8 Hz), 6.13 (dd, 1H, CHH=CH, J = 10.2 Hz), 6.90-6.98 (m, 2H) , 6.98-7.05 (m, 2H) , 7.11 (s, broading, 3H) , 7.17-7.27 (m, 2H) , 7.27-7.37 (m, 2H) , 7.38-7.49 ( ffl , 2H) , 7.69 (d, 1H, J = 16.1 Hz), 8.66 (d, 1H, C(0)NH, J = 8.6 Hz; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.3, 55.6, 67.0, 110.6, 111.6, 111.7, 114.8, 115.0, 123.0, 123.4, 123.7, 123.9, 125.7, 126.7, 126.9, 129.5, 129.6, 131.5, 137.4, 144.3, 144.4, 148.9, 149.0, 151.5, 151.6, 163.7, 191.7, 192.0; MS (ES, neg. mode) m/z = 572.2 [M-H] ^~ . Example 24

N- ( (£) -5- (3 , 4-dimethoxyphenyl) -2- ( (JET) -3- (3,4- dimethoxyphenyl) acryloyl) -3-oxo-l- (3-

(trifluoromethyl) phenyl) pent-4-en-l-yl) acrylamide (Compound no 24)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 661 mg (2.024 mmol) Mannich intermediate of general formula (VI) (R _x = 3-trifluorophenyl ) , 1 ml abs. N, N-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1, 2, 3, 4-tetrahydroquinoline (17 mol%) (Sigma) . Product: 680 mg.

C34H32 F3NO ₇ ; M = 623.2; yield: 54% (Method A); ^λ Η NMR (500 MHz, DMSO-d ₆ ) : δ 3.75 (s, 3H, OC¾) , 3.76 (s, 3H, OCi¾) , 3.79 (s, 3H, OC¾), 3.80 (s, 3H, OC¾) , 5.28 (d, 1H, C(0)CflC(0), J = 10.8 Hz), 5.54 (d, 1H, CflH=CH, J = 10.2 Hz), 5.88 (dd, overlapped peaks, 1H, CflNH, J = 9.5 Hz), 6.01 (d, 1H, CHff=CH, J = 17.2 Hz), 6.16 (dd, 1H, CHH=CH, J = 10.2 Hz), 6.92-7.09 (in, 5H) , 7.20 (d, 1H, J = 8.3 Hz), 7.24 (s, 1H) , 7.31 (d, 1H, J = 8.3 Hz), 7.35 (s, 1H) , 7.43 (d, 1H, J = 15.7 Hz), 7.51- 7.57 (m, 2H) 7.69 (s, 1H) 7.78 (s, 1H) , 8.74 (d, 1H, C(0)NH, J = 8.5 Hz; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.7, 55.6, 66.6, 110.6, 110.7, 111.6, 111.7, 122.8, 123.5, 123.8, 124.0, 124.1, 126.0, 126.6, 126.9, 129.3, 131.3, 131.9, 142.5, 144.4, 144.6, 148.9, 149.0, 151.6, 151.7, 163.9, 191.6, 191.8; MS (ES, neg. mode) m/z = 622.2 [M-H] ^~ .

Example 25

4- ( (E) -l-acrylamido-5- (3 , 4-dimethoxyphenyl) -2- ( {E) -3- (3,4- dimethoxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) benzoic acid (Compound no 25)

The compound was synthesized according to the method A described in Example 1, except that for the synthesis we used the following reagents: 613 mg (2.024 mmol) Mannich intermediate of general formula (VI) (R _x = 4-carboxyphenyl ) , 1 ml abs. N, W-dimethylformamide (Merck), 140 mg (1 equivalent) boron trioxide (Sigma) , 1090 μΐ (2 equivalents) tributyl borate (Sigma), 670 mg (2 equivalents) 3,4- dimethoxybenzaldehyde (Alfa Aesar) , 120 μΐ (1 equivalent) acetic acid (Molar), 40 μΐ 1 , 2 , 3 , 4-tetrahydroquinoline (17 moll) (Sigma) . Product: 763 mg.

C34H33NO9; M = 599.2; yield: 63% (Method A) ; Mp . : 218-220 °C; H NMR (500 MHz , DMSO-d ₆ ) : δ 3.76 (s, 3H, OC¾) , 3.78 (s, 3H, OC¾), 3.80 (s, 3H, OC¾), 3.81 (s, 3H, OC¾) , 5.27 (d, 1H, C(0)CHC(0), J = 10.6 Hz), 5.54 (dd, ^■ overlapped peaks, 1H, C#H=CH, J = 10.2 Hz), 5.88 ( t, 1H, CHNH, J = 9.5 Hz), 6.01 (dd, overlapped peaks, 1H, CHH=CH, J = 17.0 Hz), 6.16 (dd, 1H, CHH=CH, J = 6.8 and 17.0 Hz), 6.93-6.99 {m, 2H) , 6.99-7.06 {m, 2H) , 7.21 (d, 1H, J = 8.3 Hz), 7.24 (s, 1H) , 7.31 (d, 1H, J = 8.3 Hz), 7.35 (s, 1H) , 7.43 (d, 1H, J = 15.9 Hz), 7.53 (d, 2H, J = 8.3 Hz), 7.71 (d, 1H, J = 15.9 Hz), 7.86 (d, 1H, J = 7.8 Hz), 8.71 (d, 1H, C(0)NH, J = 8.9 Hz) 12.8 (bs, 1H, C(O)Ofi) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.7, 55.5, 66.5, 110.6, 111.5, 111.6, 122.9, 123.4, 123.6, 123.9, 125.8, 126.6, 126.9, 127.7, 129.2, 129.6, 131.3, 144.2, 144.4, 145.9, 148.9, 149.0, 151.5, 151.6, 163.7 ,166.9, 191.5, 191.8; MS (ES, neg. mode) m/z = 598.2 [M-H] ^~ .

Example 26

N- ( (E) -1- (3 , 4-difluorophenyl) -5- (4-hydroxy-3-methoxypheny1) -2- ( (J?) -3- (4-hydroxy-3-methoxypheny1) acryloyl) -3-oxopent-4-en-l- yl) acetamide (Compound no 26)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 335 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = 3, 4-difluorophenyl) , 2 ml abs . N _f N-dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate

(Sigma), 385 mg (2 equivalents) 4-hydroxy-3-methoxy- benzaldehyde (Sigma), 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethylether

(Molar), 0°C, lh) . Product: 279 mg.

C30H27 F2NO7 ; M = 551.2; Yield: 40% (Method B ) ; Mp. : 163-166 °C; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 1.73 ,(s, 3H, C¾C(0)), 3.78 (s, 3H, OC¾), 3.82 (s, 3H, OCi¾) , 5.09 (d, 1H, C(0)CHG(0), J = 10.4 Hz), 5.71 (t, 1H, NHCH, J = 9.5 Hz), 6.78 (d, 1H, J = 7.6 Hz), 6.83 (d, 1H, J = 8.0 Hz), 6.90 (dd, overlapped peaks, 2H, J = 16.5 Hz), 7.11 (d, 1H, J = 7.6 Hz), 7.17-7.27 (m, 3H) , 7.32 (s, broading, 2H) , 7.40 (d, 1H, J = 16.1 Hz), 7.67 (d, 1H, J = 15.8 Hz), 8.41 (d, 1H, C(0)NH, J = 8.2 Hz), 9.71 (s, broading, 2H, 2xOH) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.6, 51.0, 55.6, 55.7, 66.7, 111.6, 115.6, 115.7, 116.3, 116.4, 116.9, 117.1, 121.9, 122.5, 123.7, 124.0, 125.3, 125.6, 139.2, 144.6, 144.8, 147.9, 148.0, 149.9, 150.1, 168.3, 191.6, 191.8; (ES, neg. mode) m/z = 550.2 [M-H] ^" .

Example 27

N- ( (£) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l-yl) ace amide (Compound no 27)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = phenyl), 2 ml abs . N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 3-hydroxy-benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) .

Product: 294 mg.

C28H25NO5; 455.2; yield: 51% (Method B) ; Mp.: 200-202 °C; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 1.70 (s, 3H, C(0)C¾), 5.14 (d, 1H, C(0)CHC(0), J = 10.7 Hz), 5.77 (t, 1H, NHCH, J = 10.1 Hz), 6.77-6.93 (m, 3H) , 7.00 (d, 1H, J = 9.7 Hz), 7.05 (d, 1H, J = 10.6 Hz), 7.08 (broad s, 1H) , 7.13-7.21 (m, 4H) , 7.22-7.30 (in, 3H) , 7.32 (s, 1H), 7.37 (t, 2H, J = 5.3 and 7.6 Hz), 7.60 (d, 1H, J = 15.9 Hz), 8.42 (d, 1H, J = 9.4 Hz), 9.61 (s, 1H, OH), 9.66 (s, 1H, OH), ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.7, 51.9, 67.4, 114.8, 114.9, 118.2, 118.3, 119.9, 125.1, 125.2, 127.2, 127.5, 128.2, 130.0, 130.1, 135.2, 135.5, 141.1, 143.9, 157.7, 157.8, 168.2, 192.4 and 192.7; MS (ES, neg. mode) m/z = 454.2 [M-H] ^~ .

Example 28

N- ( (E) -5- (4-bromo hiophen-2-yl) -2- ( (E) -3- (4-bromothiophen-2- yl) acryloyl) -3-oxo-l-phenylpent-4-en-l-yl) acetamide (Compound no 28)

The compound was synthesized according to the method B described above,, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (R _x = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma), 684 μΐ (2 equivalents) tributyl borate (Sigma) , 478 mg (2 equivalents) 4-bromo-thiophene-2- carboxaldehyde (Alfa Aesar) , 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 291 mg.

C ₂ 4H ₁₉ Br ₂ N0 ₃ S ₂ ; M = 590.9; yield: 39% (Method B) ; Mp. : 148-150°C; XH NMR (500 MHz, DMSO-d ₆ ) : δ 1.71 (s, 3H, C(0)C¾), 5.07 (d, 1H, C(0)C#C(0), J = 10.7 Hz), 5.69 (t, 1H, NHCH, J = 10.3 Hz), 6.75 (d, 1H, J = 15.7 Hz), 6.89 (d, 1H, J = 15.8 Hz), 7.16- 7.22 (m, 1H) , 7.27 (t, 2H, J = 7.5 Hz), 7.36 (d, 2H, J = 7.5 Hz), 7.52 (d, 1H, J = 15.4 Hz), 7.59 (s, 1H) , 7.64 (s, 1H) , 7.80 (d, 1H, J = 5.8 Hz), 7.84 (s, 1H) , 7.88 (s, 1H) , 8.41 (d, 1H, J = 8.8 Hz) . MS (ES, neg. mode) m/z = 589.9 [M-H] ^~

Example 29

N- ( (E) -1- (3-bromophenyl) -5- (3 , 5-dihydroxyphenyl) -2- ( (JB) -3- (3 , 5-dihydroxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) ace amide (Compound no 29)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 411 mg (1.267 mmol) Mannich intermediate of general formula (V) (R _x = phenyl), 2 ml abs . N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 350 mg (2 equivalents) 3 , 5-dihydroxybenzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 265 mg.

C ₂ 8H ₂₄ BrN0 ₇ ; M = 565.07; yield: 37% (Method B ) ; Mp . : 125-127 °C; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 1.71 (s, 3H, C(0)C¾), 5.16 (d, 1H, C(0)CHC(0), J = 11.3 Hz), 5.69 ( t, 1H, NHCH, J = 8.7 Hz), 6.32 (d, 2H, J = 16.5 Hz), 6.47 (s, 2H) , 6.56 (s, 2H) , 6.80 (d, 1H, J = 15.6 Hz), 6.89 (d, 1H, J = 15.6 Hz), 7.21-7.31 (m, 2H), 7.39 (t, 2H, J = 8.5 Hz), 7.51 (d, 1H, J = 16.2 Hz), 7.59 (s, 1H) , 8.42 (d, 1H, J = 8.8 Hz), 9.45 (2H, 2<Otf) and 9.49 (2H 2*OH) , ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.3, 51.5, 62.8, 105.4, 105.5, 106.6, 106.7, 121.5, 124.7, 124.9, 126.7, 130.0, 130.1, 130.3, 135.5, 135.8, 143.8, 144.4, 144.5, 158.6, 158.7, 168.3, 192.2 and 192.4; MS (ES, neg. mode) m/z = 564.2 [M-H] ^" . Example 30

N- ( (E) -5- (3 , 5-dihydroxyphenyl) -2- ( (E) -3- (3 , 5- dihydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) cetamide (compound no 30)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 350 mg (2 equivalents) 3, 5-dihydroxybenzaldehyde (Sigma), 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product :216' mg. C ₂₈ H ₂₅ N0 ₇ ; M = 487.16; yield: 35% (Method B ) ; Mp.: 145-148 °C; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 1.71 (s, 3H, C(0)C¾), 5.09 (d, 1H, C(0)CflC(0), J = 11.3 Hz), 5.75 (t, 1H, NHCif, J = 9.1 Hz), 6.31 (d, 2H, J = 16.9 Hz), 6.45 (s, 2H) , 6.55 (s, 2H) , 6.74 (d, 1H, J = 15.9 Hz), 6.91 (d, 1H, J = 15.9 Hz), 7.18 (t, 1H, J = 7.5 Hz), 7.24-7.30 (m, 3H) , 7.37 (d, 2H, J = 7.9 Hz), 7.47 (d, 1H, J = 15.8 Hz), 8.40 (d, 1H, J = 8.9 Hz), 9.45 (2H, 2*OH) and 9.49 (2H 2*OH) , ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.9, 51.8, 64.9, 105.4, 105.5, 106.6, 124.7, 124.8, 127.2, 127.5, 128.1, 135.5, 135.8, 141.0, 144.1, 144.2, 158.7, 158.8, 168.1, 192.3 and 192.6; MS (ES, neg. mode) m/z = 486.2 [M-H] ^~ .

Example 31

N- ( (E) -5- (4-hydroxyphenyl) -2- ( (E) -3- (4- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l-yl) acetamide (Compound no 31)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (R _x = phenyl), 2 ml abs. N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma), 684 μΐ (2 equivalents) tributyl borate (Sigma), 350 mg (2 equivalents) 4-hydroxybenzaldehyde (Sigma), 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 270 mg.

C ₂₈ H ₂₅ NO ₅ ; M = 455.17; yield: 47% (Method B ) ; ¹ H NMR (500 MHz,

DMSO-d ₆ ) : δ 1.70 (s, 3H, C(0)C¾), 5.01 (d, 1H, C(0)CflC(0), 10.2 Hz), 5.76 (t, 1H, NHCH, J = 9.3 Hz), 6.74-6.80 (m, 3H) , 6.83 (d, 2H, J = 8.6 Hz), 6.91 (d, 1H, J = 15.7 Hz), 7.16 (t, 1H, J = 7.3 Hz), 7.27 (t, 2H, J = 7.6 Hz), 7.33-7.40 (m, 3H) , 7.50 (d, 2H, J = 8.6 Hz), 7.58 (d, 2H, J = 8.6 Hz), 7.62 (s, 1H) , 8.39 (d, 1H, J = 9.1 Hz), 10.11 (s, 2H, 2><OH) , ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.6, 51.8, 67.6, 115.8, 115.9, 121.9, 124.9, 125.2, 127.0, 127.5, 128.0, 130.8, 130.9, 141.3, 143.8, 143.9, 160.3, 160.4, 168.1, 191.9 and 192.2; MS (ES, neg. mode) m/z = 454.2 [M-H] ^" .

Example 32

N- ( (E) -5- (5- (hydroxymethyl) furan-2-yl) -2- ( (E) -3- (5- (hydroxymethyl) furan-2-yl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) acetamide (Compound no 32)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 319 mg (2 equivalents) 5- (hydroxymethyl) -furan-2- carbaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethylether (Molar), 0°C, lh) . Product: 223 mg.

C26H25 O7; M = 463.16; yield: 38% (Method B) ; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 1.70 (s, 3H, C(0)C¾), 4.45 (d, 4H, J = 16.8 Hz), 4.96 (d, 1H, C(0)CffC(0), J = 10.7 Hz), 5.41 (broad s, 2H, 2xOH), 5.78 (t, 1H, NHCH, J = 10.0 Hz), 6.45 (d, 1H, J = 2,2 Hz), 6.49 (d, 1H, J = 2.2 Hz), 6.58 (d, 1H, J = 15.8 Hz), 6.74 (d, 1H, J = 15.7 Hz), 6.92 (d, 1H, J = 2.2 Hz), 6.99 (d, 1H, J = 2.2 Hz), 7.15-7.30 (m, 4H) , 7.35 (d, 2H, J = 7.2 Hz), 7.45 (d, 1H, J = 15.7 Hz), 8.39 ( (d, 1H, J = 9.1 Hz); ¹³ C N R (125.7 MHz, CDC1 ₃ ) : δ 22.9, 51.9, 55.7, 55.8, 68.2, 110.2, 110.3, 119.3, 119.5, 120.5, 120.8, 127.1, 127.4 (2*CH _Ar ) , 128.1 (2xCH _Ar ), 129.9, 130.1, 140.1, 149.5, 149.8, 159.4, 159.6, 168.1, 191.4 and 191.9; MS (ES, neg. mode) m/z = 462.2 [M-H] ^~ . Example 33

N- ( (E) -5- (4-fluorophenyl) -2- ( (£?) -3- (4-fluorophenyl) acryloyl) - 3-oxo-l-phenylpent-4-en-l-yl) acetamide (Compound no 33)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 312 mg (1.267 mmol) Mannich intermediate of general formula (V) (Ri = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 314 mg (2 equivalents) 4-fluorobenzaldehyde (Sigma), 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 325 mg.

C28H23 F2NO3 ; M = 459.16; yield: 56% (Method B ) ; ^L R NMR (500 MHz, DMSO-d ₆ ) : δ 1.70 (s, 3H, C(0)C¾), 5.14 (d, 1H, C (0) CBC (0) , J = 10.8 Hz), 5.78 (t, 1H, NHCH, J = 9.5 Hz), 6.98 (d, 1H, J = 16.2 Hz), 7.10 (d, 1H, J = 15.8 Hz), 7.17 ^' (t, 1H, , J = 7.1 Hz), 7.21-7.34 (m, 6H) , 7.39 (d, 2H, J = 8.1Hz), 7.44 (d, 1H, J = 16.2 Hz), 7.69 (s, 1H) , 7.71-7.76 (m, 2H) , 7.82 (t, 2H, , J = 8.1 Hz), 8.42 (d, 1H, J = 8.6 Hz), ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.6, 51.8, 67.3, 115.9 (d) , 116.1 (d) , 125.1, 125.3, 127.2, 127.4 (2*CH _Ar ) , 128.1 (2*CH _Ar ) , 130.6 (m) , 130.9, 131.0 (d), 131.1 (d), 141.0, .142.4 (2*CH _ftr ), 162.5, 164.5, 168.1, 192.2 and 192.5; MS (ES, neg. mode) m/z = 458.2 [M-H] ^~ .

Example 34

4- ( (E) -l-acrylamido-5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4- hydroxy-3-me hoxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) benzoic acid (Compound no 34)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 383 mg (1.267 mmol) Mannich intermediate of general formula (VI) (Ri = 4-carboxyphenyl) , 2 ml abs . N,N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma) , 385 mg (2 equivalents) 3-methoxy-4-hydroxy- benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium- trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma) , diethylether (Molar), 0°C, lh) . Product: 354 mg.

C32H29NO9, M = 571.18; yield: 49% (Method B ) ; MS (ES, neg. mode) m/z = 570.2 [M-H] ^~ .

Example 35

4- ( (E) -l-acrylamido-5- (3 , 5-dihydroxyphenyl) -2- ( (E) -3- (3,5- dihydroxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) benzoic acid (Compound no 35)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 383 mg (1.267 mmol) Mannich intermediate of general formula (VI) (R _x = 4-carboxyphenyl ) , 2 ml abs. N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 350 mg (2 equivalents) 3, 5-dihydroxy-benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 233 mg.

C ₃₀ H ₂₅ NO ₉ , M = 543.15; yield: 34% (Method B) ; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 5.27 (d, 1H, C(0)CHC(0), J = 11.0 Hz), 5.54 (dd, 1H, , J - 10.8 and 1.7 Hz), 5.85 (t, 1H, NHCH, J = 9.5 Hz), 6.00 (d, 1H, J = 17.1 Hz), 6.15 (dd, 1H, J = 10.2 and 10.5 Hz), 6.20-6.27 (m, 1H) , 6.30 (broad s, 1H) , 6.33 (broad s, 1H), 6.37 (t, 1H, J = 8.1 Hz), 6.41-6.45 (m, 1H) , 6.47 (d, 2H, J = 2.2 Hz), 6.55 (d, 2H, J = 2.2 Hz), 6.79 (d, 1H, J = 15.9 Hz), 6.91 (d, 1H, J = 15.9 Hz), 7.28 (d, 1H, J = 15.9 Hz), 7.35-7.45 (m, 1H) , 7.47-7.54 (m, 3H) , 7.85 (d, 2H, J = 8.5 Hz), 8.69 (d, 1H, J = 8.9 Hz), 9.53 (broad s, 1H, COOH) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 52.0, 67.5, 105.5, 105.6, 106.6, 106.8 (2xCH _Ar ), 124.7, 124.8, 127.3, 127.6 (2*CH _Ar ) , 128.2 (2xCH _Ar ), 135.6, 135.9, 141.1, 144.3, 144.4, 158.6, 158.7, 158.8, 168.2, 192.4 and 192.8; MS (ES, neg. mode) m/z = 542.2 [M-H] ^~ .

Example 36 N- ( (E) -5- (3 , 5-dihydroxyphenyl) -2-((£)-3-(3,5

dihydroxyphenyl) acryloyl) -3-oxo-l-phenylpent

yl) acrylamide (Compound no 36)

The compound was synthesized according to the method B described above, except that for the synthesis we used the following reagents: 328 mg (1.267 mmol) Mannich intermediate of general formula (VI) (Ri = phenyl), 2 ml abs. N, N- dimethylformamide (Merck), 60 mg (0.7 equivalent) boron trioxide (Sigma) , 684 μΐ (2 equivalents) tributyl borate (Sigma), 350 mg (2 equivalents) 3 , 5-dihydroxy-benzaldehyde (Sigma) , 508 mg (2 equivalents) morpholinium-trifluoroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent trifluoroacetic acid (Sigma), diethylether (Molar), 0°C, lh) . Product: 196 mg.

C29H25NO7; M = 499.16; yield: 31% (method B) ; ^X H NMR (500 MHz, DMS0-d ₆ ) : δ 5.19 (d, 1H, C(0)CHC(0), J = 10.1 Hz), 5.53 (d, 1H, , J = 9.0 Hz), 5.81 (t, 1H, NHCfl, J = 10.1 Hz), 6.00 (d, 1H, J = 15.8 Hz), 6.14 (dd, 1H, J = 10.1 and 9.0 Hz), 6.20-6.61 {m, 5H) , 6.77 (d, 1H, J = 15.8 Hz), 6.91 (d, 1H, J = 16.3 Hz), 7.10-7.54 (m, 6H) , 8.62 (d, 1H, J = 7.9 Hz), 9.34-9.55 (4H, 4*OH); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.9, 67.1, 105.5, 106.7 (2xCH _ftr ), 124.7, 124.8, 125.8, 127.3, 127.5 (2*CH _Ar ) , 128.3 (2*CH _Ar ), 131.4, 135.5, 135.8, 140.8, 144.4, 144.5, 158.6, 158.7, 163.6, 192.2 and 192.4; MS (ES, neg. mode) m/z = 498.2 [M-H] ^" .

Example 37 I ϋΐ/ι lucu I <_./ υ u u u 3 «j

N- ( (E) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) acrylamide (Compound no 37)

The compound was synthesized according to method C described above, in the course of that to the solution of lg (3.86 mmol) Mannich intermediate of general formula (VI) (where Ri = phenyl) in 6 ml of abs . DMF (Merck), 268 mg (1 equivalent) boron trioxide (Sigma) was added under argon athmosphere. To the yellow solution, 942 mg (2 equivalents) 3-methoxy-4- hydroxybenzaldehyde (Sigma) and 2 ml (2 equivalents) tributyl borate (Sigma) were added at 75°C and stirred further for 5 minutes. After addition of 175 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent (Sigma) of morpholine and 1 equivalent (Sigma) of chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) , the stirring was continued for 3-4 hours under inert athmosphere at 75°C (monitored by TLC: Kieselgel 60 F254 (Merck) / eluent: chloroform (Molar) rmethanol (Molar) 95:5), then the reaction was allowed to cool down to room temperature. In order to quench the generated boron complex, 24 ml of 5 m/m% aqueous acetic acid solution was added dropwise and the mixture was stirred for 5 minutes at ambient temperature. Afterwards, the heterogenous reaction mixture was heated to 75°C and stirred vigorously for further 1 hour then cooled down to room temperature. The precipitated product was filtrated on vacuo, washed with water (2x20mL) and dried. The dried product was recrystallised in the mixture of diethyl ether (Molar) and ethanol (Molar) . Product: 860 mg. C29H ₂₅ 0 ₅ ; M = 467.17; yield: 50% (method C) ; Mp. : 194-196°C; ^X H NMR (500 MHz , DMSO-d ₆ ) : δ 5.22 (d, 1H, C (0) CtfC (0) , J = 10.6 Hz), 5.52 (d, 1H, J = 11.1 Hz), 5.82 (t, 1H, NHCH, J = 10.3 Hz), 5.99 (d, 1H, J = 16.6 Hz), 6.13 (dd, 1H, J = 10.3 Hz), 6.83 (dd, 2H, J = 7.54 and 8.04 Hz), 6.91 (d, 1H, J = 16.3 Hz), 6.96-7.44 (m, 13H) , 7.60 (d, 1H, J = 16.3 Hz), 8.64 (d, 1H, J = 9.1 Hz), 9.61 (s, 1H, OH), 9.65 (s, 1H, OH); ¹³ C NMR (125.7 MHz, DMSO-dg) : δ 51.9, 67.1, 114.8, 114.9, 118.3 (2xCH _ar ), 119.9 (2*CH _Ar ), 125.1 (2><CH _Ar ) , 125.8, 127.3, 127.6 (2*CH _Ar ), 128.3 (2*CH _Ar ) , 130.0, 130.1, 131.5, 135.2, 135.5, 140.9, 144.0, 144.1, 157.7, 157.8, 163.7, 192.3 and 192.5; MS (ES, neg. mode) m/z = 466.2 [M-H] ^" .

Example 38

N- ( (E) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) cinnamamide (Compound no 38)

The compound was synthesized according to the method C described in Example 37.

424 mg (1.267 mmol) Mannich intermediate of general formula (VII) (Ri = phenyl), 2 ml abs. N, W-dimethylformamide (Molar), 88 mg (1 equivalent) boron trioxide (Sigma), 684 μΐ (2 equivalents) tributyl borate (Sigma), 309 mg (2 equivalents) 3-hydroxy-benzaldehyde (Sigma), 57 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma) , diethyl ether (Molar), 0°C, lh) . Product: 323 mg. C35H29NO5; M = 543.20; yield: 47% (method C) ; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 5.27 (d, 1H, C(0)CHC(0), J = 10.2 Hz), 5.90 (t, 1H, J = 9.4 Hz), 6.56 (d, 1H, J = 15.5 Hz), 6.77-7.50 (m, 22H) , 7.61 (d, 1H, J = 15.5 Hz), 8.68 (d, 1H, J = 9.0 Hz), 9.62 (s, 1H, OH), 9.68 (s, 1H, OH); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 52.0, 67.1, 114.8, 114.9, 118.2, 118.3, 119.9, 121.9, 125.1, 125.2, 127.3, 127.5, 127.6, 128.2, 128.8, 129.5, 130.0, 130.1, 134.7, 135.2, 135.4, 139.3, 140.9, 144.0, 144.1, 157.7, 157.8, 164.0, 192.3, 192.6. Example 39

N- ( (E) -3-OXO-5- (4-oxo-4H-chromen-3-yl) -2- ( (E) -3- (4-oxo-4H- chromen-3-yl) acryloyl) -l-phenylpent-4-en-l-yl) acrylamide

(Compound no 39)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 250 mg (0.96 mmol) Mannich intermediate of general formula (VI) (Ri = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 67 mg (1 equivalent) boron trioxide (Sigma), 530 μΐ (2 equivalents) tributyl borate (Sigma), 309 mg (2 equivalents) aldehyde, 44 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma) , diethyl ether (Molar), 0°C, lh) . Product: 350 mg. (Method C)

C ₃₅ H ₂₅ N0 ₇ ; ¹ tt NMR (500 MHz, DMSO-d ₆ ) : δ 5.05 (d, 1H, J = 11.2 Hz), 5.52 (d, 1H, J = 10.2 Hz), 5.81 (t, 1H, J = 10.2 Hz), 5.99 (d, 1H, J = 17.1 Hz), 6.12 (dd, 1H, J = 10.0 and 16.9 Hz), 7.17 (t, 1H, J = 7.4 Hz), 7.24-7.30 (m, 2H) , 7.39 (d, 2H, J = 7.4 Hz), 7.48 (d, 1H, J = 15.6 Hz), 7.53 (dd, 3H, J = 13.5 and 6.9 Hz), 7.60 (d, 1H, J = 15.8 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.69 (d, 1H, J = 8.4 Hz), 7.76-7.85 (m, 3H) , 8.1 (d, 1H, J = 8.4 Hz), 8.12 (d, 1H, J = 7.4 Hz), 8.67 (d, 1H, J = 8.9 Hz), 8.83 (s, 1H) , 8.90 (s, 1H) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 52.0, 68.6, 117.8, 118.1, 118.5, 123.4, 123.5, 125.4, 125.5, 125.7, 126.2, 126.8, 127.3, 127.6, 128.2, 131.5, 134.7, 136.1, 136.3, 140.8 155.0, 163.5, 175.1, 175.2, 192.3, 192.6; MS (ES, neg. mode) m/z = 570.2 [M-H] ^~ .

Example 40

N- ( (£?) -5- (3, 5-dihydroxyphenyl) -2- ( (E) -3- (3,5- dihydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) cinnamamide (Compound no 40)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 265 mg (0.96 mmol) Mannich intermediate of general formula (VII) (Rx = phenyl), 2 ml abs. N, N- dimethylformamide (Merck), 55 mg (1 equivalent) boron trioxide (Sigma), 427 μΐ (2 equivalents) tributyl borate (Sigma), 218 mg (2 equivalents) 3 , 5-dihydroxy-benzaldehyde (Sigma), 36 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 180 mg. (Method C)

C35H29NO7; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 5.23 (d, 1H, J = 10.8 Hz), 5.87 (t,lH, J = 9.7Hz), 6.31 (d, 2H, J = 8.2 Hz), 6.47 (s, 2H), 6.54 (s, 2H) , 6.81 (d, 1H, J = 16.1 Hz), 6.93 (d, 1H, J = 16.1 Hz), 7.18 (t, 1H, J = 7.1 Hz), 7.24-7.38 (m, 8H) , 7.42 (d, 2H, J = 6.4 Hz), 7.45-7.52 (ffl, 3H) , 8.66 (d, 1H, J = 8.9 Hz), 9.46 (s, 2H) , 9.48 (s, 2H) ); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 52.0, 67.1, 105.4, 105.5, 106.7, 121.9, 124.8, 124.9, 127.3, 127.5, 127.6, 128.2, 128. 9 , 129.5, 134.7, 135.5, 135.8, 139.3, 140.9, 144.4, 144.5, 158.7, 158.8, 164.0, 192.3, 192.6; MS (ES, neg. mode) m/z = 574.2 [M-H] ^~ .

Example 41

N- ( (E) -5- (3, 4-dimethoxyphenyl) -2- ( (E) -3- (3,4- dime hoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) cinnamamide (Compound no 41)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 265 mg (0.96 mmol) Mannich intermediate of general formula (VII) (R _x = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 55 mg (1 equivalent) boron trioxide (Sigma) , 427 μΐ (2 equivalents) tributyl borate (Sigma) , 263 mg (2 equivalents) veratraldehyde (Sigma), 36 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 200 mg. (Method C)

C39H37NO7; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 3.73-3.82 (m, 12H) , 5.24 (d, 1H, J = 10.5 Hz), 5.90 (t, 1H, J = 9.5 Hz), 6.56 (d, 1H, J = 15.2 Hz), 6.90-7.08 (m, 4H) , 7.14-7.39 (m, 11H) , 7.39-7.52 (m, 5H) , 7.68 (d, 1H, J = 16.2 Hz), 8.67 (d, 1H, J = 9.5 Hz) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 52.0, 55.6, 66.9, 110.6, 111.6, 111.7, 122.0, 123.1, 123.5, 123.6, 123.9, 126.7, 127.0, 127.2, 127.5, 127.6, 128.2, 128.9, 129.5, 134.7, 139.2, 141.2, 144.1, 144.2, 148.9, 149.0, 151.5, 151.6, 163.2, ^' 191.9, 192.3; MS (ES, neg. mode) m/z = 630.2 [M-H] ^~ .

Example 42

N- ( (E) -1- (4-fluorophenyl) -5- (3-hydroxyphenyl) -2- ( (E) -3- (3- hydroxyphenyl) acryloyl) -3-oxopent-4-en-l-yl) acrylamide

(Compound no 42)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 219 mg (0.79 mmol) Mannich intermediate of general formula (VI) ( Ri = 4-fluorophenyl ) , 2 ml abs . N,N- dimethylformamide (Merck), 55 mg (1 equivalent) boron trioxide (Sigma) , 427 μΐ (2 equivalents) tributyl borate (Sigma) , 193 mg (2 equivalents) 3-hydroxybenzaldehyde (Sigma) , 36 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 100 mg. (Method C)

C29H24F O7; ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 5.22 (d, 1H, J = 10.9 Hz), 5.52 (d, 1H, J = 11.6 Hz), 5.81 (t, 1H, J = 9.7 Hz), 5.99 (d, 1H, J = 17.4 Hz), 6.13 (dd, 1H, J = 9.7 and, 16.8 Hz), 6.84 (t, 2H, J = 10.3 Hz), 6.92 (d, 1H, J = 15.5 Hz), 7.00 (s, 2H) , 7.02-7.26 (m, 7H) , 7.37 (d, 1H, J = 16.1 Hz), 7.40-7.47 (m, 2H) , 7.62 (d, 1H, J = 16.1 Hz), 8.65 (d, 1H, J = 9.0 Hz), 9.62 (s, 1H), 9.66 (s, 1H) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.3, 67.1, 114.9, 115.0, 115.1, 118.2, 118.3, 119.9, ^' 120.0, 125.0, 125.1, 125,9, 129.5, 129.6, 130.0, 130.1, 131.4, 135.1, 135.4, 137.1, 144.1, 144.2, 157.7, 157.8, 163.7, 192.1, 192.3; MS (ES, neg. mode) m/z = 484.2 [M-H] ^~

Example 43

, ¹ - ( (IE, 6E) -4- (acrylamido (phenyl) methyl) -3 , 5-dioxohepta-l , 6- diene-1 , 7-diyl) dibenzoic acid (Compound no 43)

The compound was synthesized according to. the method C described above, except that for the synthesis we used the following reagents: 250 mg (0.97 mmol) Mannich intermediate of general formula (VI) (Rl = 4-carboxyphenyl) , 2 ml abs . N,N- dimethylformamide (Merck), 67 mg (1 equivalent) boron trioxide (Sigma) , 530 μΐ (2 equivalents) tributyl borate (Sigma) , 290 mg (2 equivalents) 4-formylbenzoic acid (Sigma) , 44 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 235 mg. (Method C)

C ₃ iH ₂₅ N0 ₇ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) : δ 5.32 (d, 1H, J = 11.3 Hz), 5.50 (d, 1H, J = 11.2 Hz), 5.85 (t, 1H, J = 9.9 Hz), 5.99 (d, 1H, J = 16.5 Hz), 6.14 (dd, 1H, J = 9.9 and 16.5 Hz), 7.10-7.24 (m, 3H) , 7.25-7.33 (m, 3H) , 7.42 (d, 2H, J = 7.24 Hz), 7.50 (d, 1H, J = 15.8 Hz), 7.72-7.80 (m, 2H) , 7.84 (d, 2H, J = 7.9 Hz), 7.92 (d, 2H, J = 8.1 Hz), 7.98 (d, 2H, J = 8.2 Hz), 8.69 (d, 1H, J = 8.9 Hz); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 52.0, 67.1, 125.9, 127.2, 127.4, 127.5, 127.6, 128.3, 128.8, 128.9, 129.7, 129.8, 131.4, 132.4, 138.0, 138.2, 140.7, 142.3, 142.4, 163.7, 166.7, 166.8, 192.3, 192.6; MS (ES, neg. mode) m/z = 522.2 [M-H] ^~

Example 44

4 , 4 ' - ( (E) -5-acetamido-4- ( (JE) -3- (4-carboxyphenyl) acryloyl) -3- oxopent-l-ene-1 , 5-diyl) dibenzoic acid (Compound no 44)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 280 mg (0.97 mmol) Mannich intermediate of general formula (V) (Ri = 4-carboxyphenyl), 2 ml abs . N, N- dimethylformamide (Merck), 67 mg (1 equivalent) boron trioxide (Sigma) , 530 μΐ (2 equivalents) tributyl borate (Sigma) , 290 mg (2 equivalents) 4-formylbenzoic acid (Sigma), 44 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 190 mg. (Method C)

C31H25NO9,. ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 1.71 (s, 3H) , 5.29 (d, 1H, J = 10.7 Hz), 5.80 (t, 1H, J = 9.7 Hz), 7.14 (d, 1H, J = 15.7 Hz), 7.24 (d, 1H, J = 16.8 Hz), 7.45-7.55 (m, 3H) , 7.60 (d, 1H, J = 8.1 Hz), 7.72-7.80 (m, 3H) , 7.82-7.88 (m, 3H) , 7.91 (d, 2H, J = 7.7 Hz), 7.98 (d, 2H, J = 8.2 Hz), 8.52 (d, 1H, J = 9.0 Hz); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 22.6, 51.7, 66.8, 127.1, 127.6, 127.7, 128.8, 128.9, 129.3, 129.7, 129.8, 132.4, 137.9, 138.3, 142.4, 142.5, 145.8, 166.7, 166.8, 167.0, 168.4, 192.3, 192.6; MS (ES, neg. mode) m/z = 554.2 [M-H] ^~

Example 45 N- ( (E) -3-oxo-l-phenyl-5- (3,4, 5-trimethoxyphenyl) -2- ( (E) -3- (3,4, 5-trimethoxyphenyl) acryloyl) pent-4-en-1-yl) acrylamide

(Compound no 45)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 205 mg (0.97 mmol) Mannich intermediate of general formula (VI) (R _x = phenyl), 2 ml abs . N, N- dimethylformamide (Merck), 55 mg (1 equivalent) boron trioxide (Sigma) , 427 μΐ (2 equivalents) tributyl borate (Sigma) , 380 mg (2 equivalents) 3, 4 , 5-trimethoxybenzaldehyde (Sigma), 36 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 160 mg . (method C)

C35H37B2NO9 ,. ^X H NMR (500 MHz, DMSO-d ₆ ) : δ 3.66 (s, 3H) , 3.69 (s, 3H) , 3.76 (s, 6H) , 3.81 (s, 6H) , 5.27 (d, 1H, J = 11.0 Hz), 5.53 (d, 1H, J = 10.0 Hz), 5.84 (t, 1H, J = 9.6 Hz), 6.00 (d, 1H, J = 16.9 Hz), 6.16 (dd, 1H, J = 10.5 and 17.4 Hz), 6.98 (s, 2H), 7.02 (d, 1H, J = 16.0 Hz), 7.09 (t, 3H, J = 7.3 Hz), 7.19 (t, 1H, J = 8.2 Hz), 7.29 (t, 2H, J = 7.8 Hz), 7.39-7.46 {m, 3H),7.70 ( t, 1H, J = 15.5 Hz), 8.67 (d, 1H, J = 9.1 Hz) ; ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.8, 56.0, 60.1, 66.8, 106.3, 106.5, 124.6, 125.1, 125.7, 127.3, 127.6, 128.2, 129.4, 129.8, 131.5, 140.0, 140.1, 141.1, 144.1, 144.3, 153.0, 153.1, 163.7, 191.8, 192.2; MS (ES, neg. mode) m/z = 614.2 [M-H] ^"

Example 46 N- ( (£) -5- (3, 4-dihydroxyphenyl) -2- ( (E) -3- (3,4- dihydroxyphenyl) acryloyl) -3-oxo-l-phenylpent-4- yl) acrylamide (Compound no 46)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 205 mg (0.97 mmol) Mannich intermediate of general formula (VI) (R _x = phenyl), 2 ml abs . N, N- dimethylformamide (Merck) , 55 mg (1 equivalent) boron trioxide (Sigma) , 427 μΐ (2 equivalents) tributyl borate (Sigma) , 268 mg (2 equivalents) 3 , 4-dihydroxybenzaldehyde (Sigma), 36 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 165 mg. (Method C)

C29H25NO7,. MS (ES, neg. mode) m/z = 498.1 [Μ-Η

Example 47

N- ( (E) -5- (3-methoxyphenyl) -2- ( (£) -3- (3- methoxyphenyl) acryloyl) -3-oxo-l-phenylpent-4-en-l- yl) acrylamide (Compound no 47)

The compound was synthesized according to the method C described above, except that for the synthesis we used the following reagents: 265 mg (0.97 mmol) Mannich intermediate of general formula ((VI) R _x = phenyl), 2 ml abs. N, N- dimethylformamide (Merck), 55 mg (1 equivalent) boron trioxide (Sigma), 427 μΐ (2 equivalents) tributyl borate (Sigma), 262 mg (2 equivalents) 3-methoxybenzaldehyde (Sigma), 36 mg (0.25 equivalent) morpholinium-chloroacetate (synthesis: 1 equivalent morpholine (Sigma) and 1 equivalent chloroacetic acid (Sigma), diethyl ether (Molar), 0°C, lh) . Product: 196 mg. (Method C)

C ₃ iH ₂₉ 0 ₅ ; ^X H NMR (500 MHz, DMS0-d ₆ ) : δ 3.75 (s, 3H) , 3.78 (s, 3H) , 5.28 (d, 1H, J = 10.3 Hz), 5.51 (d, 1H, J = 10.3 Hz), 5.85 (t, 1H, J = 9.7 Hz), 5.99 (d, 1H, J = 18.2 Hz), 6.15 (dd, 1H, J = 10.3 and 17.0 Hz), 6.94-7.03 (in, 2H) , 7.06 (d, 2H, J = 15.8 Hz), 7.11-7.24 (m, 4H) , 7.27-7.38 (m, 6H) , 7.39-7.48 (m, 2H), 7.70 (d, 1H, J = 16.4 Hz), 8.67 (d, 1H, J = 8.5 Hz); ¹³ C NMR (125.7 MHz, DMSO-d ₆ ) : δ 51.9, 55.2, 67.0, 113.4, 116.9, 117.0, 121.3, 121.4, 125.6, 125.7, 125.9, 127.3, 127.6, 128.2, 130.0, 130.1, 131.5, 135.3, 135.6, 140.9, 143.7, 143.9, 159.6, 159.7, 163.7, 192.2, 192.4; MS (ES, neg. mode) m/z = 494.2 [M- ΗΓ Example 48

N- (2-acetyl-3-oxo-l-phenylbutyl) acrylamide

To the solution of 710 mg (10 mmol) acrylamide (Sigma), 1.06 g (1 eq.) benzaldehyde (Alfa Aesar) and 1 g (1 eq. ) acetylacetone (Sigma) prepared in 20 ml diethyl ether (Molar), 1.26 ml (1.2 eq. ) TMSC1 is added, then the reaction mixture is stirred at room temperature for 1 day. Then 2.5 ml ethanol (Molar) is added to the heterogeneous mixture, and it is stirred for another hour. The precipitated crude product is filtered, and dried under vacuum. The crude product is filtered on silica gel, washed with ethyl acetate (Molar) , the combined organic fractions are evaporated. 10 ml diethyl ether (Molar) is poured on the obtained product and it is left alone for an hour at room temperature, then it is filtered, and dried on vacuum.

C15H17 O3; M = 259.12; Yield: 1.9 g (73%); Op.: 136-138 °C; ^λ Η NMR (500 MHz, DMSO-d ₆ ) : δ 1.93 (s, 3H, C¾) , 2.17 (s, 3H, C¾) , 4.54 (d, 1H, C(0)CflC(0), J = 10.9 Hz), 5.54-5.61 (m, 2H) , 6.03 (dd, overlapping peaks, 1H, CHH=CH, J = 17.1 Hz), 6.16 (dd, 1H, CHH=CH, J = 17.1 Hz), 7.20-7.25 (m, 1H) , 7.27-7.39 (m, 4H) , 8.59 (d, 1H, C(0)NH, J = 9.3 Hz); MS (ES, neg. mode) m/z = 258.1 [Μ-ΗΓ.

Pharmacological examples Example 49

The cytotoxic effect of the compounds according to the invention on different tumour cell lines

The cell lines in the example were grown in the following liquid culture media: U373MG (human glioblastoma-astrocytoma) , HeLa (human cervical carcinoma): Dulbecco's Modified Eagle Medium (D-MEM) (high glucose) (Gibco BRL, Carlsbad, CA, USA), penicillin (50 IU/ml -streptomycin (50 mg/ml) , 10% foetal bovine serum. Hep3B (human hepatocellular carcinoma) , A549 (human pulmonary carcinoma), MCF-7 (human mammary carcinoma): Dulbecco's Modified Eagle Medium (D-MEM) (high glucose) (Gibco BRL, Carlsbad, CA, USA) and Nutrient Mixture F-12 Ham (Sigma, St. Louis, MO, USA) 1:1 mixture, penicillin (50 IU/ml)- streptomycin (50 mg/ml) , 10% foetal bovine serum.

K562 (human erythroblastic leukaemia) , HT168 (human melanoma) , HT199 (human melanoma) , HT29 (human colon carcinoma) , LNCaP (human prostate carcinoma) , MDA-MB-231 (human mammary carcinoma), DU4475 (human mammary carcinoma), PC3 (human prostate carcinoma) , U266 (human myeloma) : RPMI Media 1640 (Gibco BRL, Carlsbad, CA, USA) , penicillin (50 IU/ml - streptomycin (50 mg/ml), 10% foetal bovine serum.

The cells were placed in 96-well microtxtre plates (10,000 cells/well) , and after 24 hours the cells were incubated with different substances for 48 hours. After incubation an MTS test (3- (4, 5- dimethylthiazole . -2-yl) - 5 - ( 3 - carboximethoxyphenyl ) -2- ( -sulphophenyl ) -2H-tetrazolium)

(Promega, Madison, Wi, USA)) was performed by adding it to the cells in a final concentration of 0.5 mg/ml, and then the cells were incubated for 1 hour at 37°C. The cells were washed with PBS and the formazan dye was dissolved in isopropanol. The amount of the transformed . formazan dye was measured on Powerwave reader (Biotek, Winooski, VT) at 570 nm; background measurement: 690 nm. The calibration curved was drawn by measuring the MTS transforming capacity of the serial dilutions of the cells, and the number of viable cells was calculated using Gen5 software.

The results of the experiment performed with the different cells are shown in table 2. In this table the EC50 values of the individual substances are shown. The EC50 value means the concentration where on the basis of the results received from the MTS test half of the cells dies. It can be seen here that the compounds according to the present invention exerted a cytotoxic effect on the different tumour cell lines.

Table 2 : The cytotoxic effect of different curcumin derivatives on different human cell lines

28 >20 >20 >20 >20 >20

30 >20 >20

31 >20 1.80

37 1.97 0.85 1.63 5.94 0.94

Example 50

Preventing cell death caused by hydrogen peroxide on in vitro heart cells

H9c2 rat embryonic myocardial cells (ATCC, Rockville, MD, USA) were grown in Dulbecco ' s modified Eagle medium containing 10% bovine serum, 4 mM L-glutamine ( Sigma-Aldrich, Hungary) , 100 units/ml penicillin and 100 ug/ml streptomycin. The cells were kept in 100 mm TC dishes (Orange Scientific, Belgium) in an incubator at 37 °C, in a space containing humidified air and 5% C0 ₂ .

The cells were placed on 96-well E-plate (Roche) microtitre plates (10,000 cells/well) preliminarily treated with gelatine, and then they were grown for 16 hours. 30 minutes after treatment different compounds of general formula (I) in different concentrations were placed on them, and the viability of the cells was measured continuously, every 2 minutes on an Excelligence device, using the RT-CES method (Roche) , by determining the Cell Index. In this experiment the following compounds of general formula (I) were tested (also stating which curve in figure 1 shows the effect of the given compound on the normalised cell index) :

4- ( (E) -l-acetamido-5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) -3- (4-hydroxy-3-methoxyphenyl) acryloyl) -3-oxopent-4-enyl) benzoic acid used in a concentration of 1 μΜ (figure 1, curve "B", compound 15) , N- ( (E) -5- (3, 5-dihydroxyphenyl) -2- ( (E) -3- (3, 5- dihydroxyphenyl ) acryloyl) -3-oxo-l-phenylpent-4 -enyl ) acetamide used in a concentration of 1 μΜ (figure 1, curve "C", compound 30) ,

N- ( (E) -5- (5- (hydroxymethyl) furan-2-yl ) -2- ( (E) -3- (5-

(hydroxymethyl ) furan-2-yl) acryloyl) -3-oxo-l-phenylpent-4- enyl) acetamide used in a concentration of 1 μΜ (figure 1, curve "E", compound 32).

The tests were performed in order to determine the cytoprotective effect on H9c2 rat embryonic myocardial cells, 30 minutes before treatment with H ₂ 0 ₂ . In these cells 250 u hydrogen peroxide was used. Cell growth before the use of hydrogen peroxide was linear. In the case of different compounds of general formula (I) according to the invention, 30 minutes after treatment the slopes of the cell index curves changed significantly because of hydrogen peroxide, as a result of which different cytoprotective effects of the compounds according to the invention could be determined.

The results are shown in figure 1. Curve "A" represents untreated control, curve "D" represents curcumin used in a concentration of 20 μΜ, as a reference substance, and curve "F" represents control treated with peroxide.

Example 51

Effect on acute inflammation in mice

Twenty-four laboratory-bred mice (Balb/C) were divided into five groups at random. The groups containing eight mice each were the following: control group (it only received the carrier), group "A", group "B" (example 12, active agent, N- ( (E) -1- (4-chlorophenyl) -5- (4-hydroxy-3-methoxyphenyl) -2- ( (E) - 3- (4-hydroxy-3-methoxyphenyl) acryloyl) -3-oxopent-4- enyl ) acetamide , 10 mg/kg, intraperitoneal administration), and group "C": dexamethasone group (reference active agent, 0.4 mg/kg) . Through the caudal vein each mouse was administered the same amount (0.1 ml) of physiological salt solution or active agent. At the same time inflammation was induced by subplantar injection of 30 μΐ of 2% suspension of carrageenan (Sigma-Aldrich) prepared with 0.9% physiological salt solution, which was injected into the aponeurosis of the right paw of the mouse (Winter, C.A., Risley, E.A., Nuss, G.W., 1962. Carrageenan-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proceedings of the Society for Experimental Biology and Medicine 111, 544-547.).

The volume of the paws was measured before treatment and 6 hours following treatment. In the case of all animals the carrageenan injection induced paw oedema.

As it can be seen in figure 2, compound 12 reduced the size of the paw oedema induced by carrageenan, although it resulted in inflammation reduction of a lower extent than dexamethasone in a concentration of 0.4 mg/kg.

Example 52

Effects on TNBS (trinitrobenzene sulfonic acid) induced mucositis in the case of using compounds 30 and 37

In an enteritis model, in TNBS (2 , 4 , 6-trinitrobenzene sulfonic acid) induced mucositis, under TNBS induction, intravenously administered compounds F05, F07, F08 inhibited inflammation. In the experiment 10 mg TNBS was dissolved in 0.5% CMC (carboxymethylcellulose) , and generally a dose was administered on one or two occasions during the experiments. Six groups participated in the test, which were administered the following compounds:

Group 1 : absolute control, that is the untreated group; Group 2 : the animals were administered 10 mg TNBS orally, on one occasion;

Group 3 : the animals were administered compound 30

TNBS + compound 30, treated group, 40 mg/kg/day oral treatment (0.5 ml 0.5% carboxymethylcellulose 0.9% NaCl/rat) The treatment was performed twice a day, the administered dose was divided into two parts;

Group : the animals were administered compound 37

TNBS + compound 37, treated group, 40 mg/kg/day oral treatment (0.5 ml 0.5% carboxymethylcellulose 0.9% NaCl/rat) The treatment was performed twice a day, the administered dose was divided into two parts;

Group 5: the animals were administered infliximab

TNBS + Infliximab 3.0 mg/kg, 0.4 ml/day i.v.;

Group 6: the animals were administered sulfasalazine

SASP 50 CMC = TNBS + sulfasalazine, treated group, 50 mg/kg/day (25 mg/kg/ p.o. b.i.d.; 0.5 ml 0.5% carboxymethylcellulose 0.9% NaCl/rat).

The rats were treated for 3 days, the first treatment took place 1 hour following the administration of TNBS. On the 4 ^th day the animals were euthanised, and the small intestine was resected .

The small intestine was cut longitudinally into four parallel sections, from which the normal myeloperoxidase level in units per gram of wet tissue was determined as well as the extent of the inflammation.

Figure 4 shows the effect of compounds 30 and 37 out of the compounds of general formula (I) on the extent of TNBS-induced mucosal lesions. The efficacy was observed in the reduction of the size of the mucosal lesions.

Figure 5 shows the effect of compounds 30 and 37 out of the compounds of general formula (I) on the increase of TNBS- induced myeloperoxidase (MPO) activity. The efficacy was observed in the reduction of the myeloperoxidase activity.

Above the columns of the diagrams the P values are marked with a star. The P value determines the size of all inflamed areas as compared to the size of not inflamed areas, in percentage. The P values were calculated in relation to the group treated with TNBS, and they are shown in the figure as below:

* P < 0.05,

**P < 0.01,

Results ± S.E.M.; n = 8-12.

It is pointed out here that the initial number of animals dropped in certain groups because of deaths caused by enteritis .

Example 53

The behaviour of the compounds according to the invention in the course of inhibiting the activation of NFkappaB with lipopolysaccharide NFkappaB (hereinafter: NFkB) was identified in 1986 as a nuclear factor bound to the kappa light chain of B cells and plays a role in the immune response (Sen, R. ; Baltimore, D. (1986) Cell, 46, 705-716.). In inflammatory processes and during tumour growth the induction of the activation of NFkB and the expression of the genes regulating it plays an important role. The inhibition of NFkB induction by the new compounds according to the present invention was examined under in vitro conditions, on recombinant human macrophage cells. The experiment was carried out as described below:

Raw264.7 /NF-kB-Luc cells were placed on a Luminoplate

(Corning-Costar ; Cat. No. 3903; Zenon Biotechnology Ltd., Szeged, Hungary) in a concentration of 6*104 cells/well, and then they were incubated in a C0 ₂ incubator at 37 °C for 16 hours. They were grown in 200 μΐ MIX MEM culture medium (Invitrogen, Hungary) in the presence of 10% foetal bovine serum (Invitrogen) . After 16 hours of incubation the cells were induced with 100 ng/ml LPS (Sigma; Cat. no. L6529) , and immediately after this different compounds according to the present invention were used in several concentrations. After six hours of incubation the supernatant was removed from the cells, and after washing they were lysed with the help of a Cell Culture Lysis Reagent (20 μΐ/well; Promega Bio-Science Hungary; Part No. E153A) at room temperature for 10 minutes. After adding a substrate (20 μΐ/well; Promega; Cat. No. E2620) the luciferase activity was measured with a Luminoskan Ascent (Thermo Electron Corporation, altham, MA) scanning luminometer.

During the experiment curcumin was used as a reference compound. In addition to this, five of the new compounds according to the invention were tested (compounds no 1, 20, 27, 31 and 37) . The results can be seen in figure 3.

In figure 3 the IC50 values of the individual compounds are also shown. It can be seen that the new compounds inhibited NFkB induction in a much lower concentration than curcumin used as reference. Each of the compounds in the example had an inhibiting effect below 10 μΜ, while curcumin could have the same effect only in a concentration of 66 μΜ.

Example 54

Examining the effect of curcumin derivatives on cell proliferation on human melanoma cells

The curcumin derivatives according to the invention were tested on HT-168 human melanoma cells with a chemiluminescent cell proliferation kit (Cell Proliferation ELISA, BrdU; Roche; kit catalogue number: 11 669 915 001). This chemiluminescent immunoassay determines the extent of cell division by detecting the proportion of BrdU incorporation during DNA synthesis. Its process: the cells are spread onto a media plate, treated on the following day and terminated after 16 hours, the extent of proliferation is measured with the help of a chemiluminescent kit.

A subconfluently growing HT-168 human melanoma cell culture was streaked on a sterile 96-well medium plate. For the treatment different curcumin derivatives were freshly dissolved in DMSO solvent (dimethyl sulfoxide, Sigma-Aldrich) . The stock-solutions were further diluted in a serous medium used for the cells. After treatment the 96-well medium plate was returned to the incubator and incubated for 16 hours.

When terminating the experiment, in order to determine the extent of proliferation, with a BrdU labelling reagent the cells were incubated, fixed, and treated with an anti-BrdU antibody (Roche) . After washing the wells of the medium plate a chemiluminescent substrate was added to the wells. Then the plates were measured with a luminescent imaging device (IVIS 100, Xenogen) . Measurement: 1-minute luminescent detection, with 15 cm focus distance, the aperture is in position 4 (lower adjustment), set to record a high-resolution image. Table 3: summarised results on the proliferation effect of the treatments (x < 1.0 increasing cell division inhibition)

50 μΜ 25 μΜ 10 μΜ

Curcumin 0.07 0.62 0.81

5 μΜ 2.5 μΜ 1 μΜ 0.5 μΜ 0.25 μΜ

Compound no 1 0.13 0.17 0.33 0.65 0.87

Compound no 20 0.03 0.16 0.19 0.46 0.61

Compound no 27 0.00 0.08 0.26 0.59 0.68

Compound no 37 0.01 0.11 0.20 0.47 0.64 In the case of curcumin as a reference compound the lowest proliferation value could be observed in a 50 μΜ dose. In the case of the analogues according to the invention a similar effect was detected in the case of the ten times lower concentration (5 μΜ dose) of certain materials (compound 1, compound 20, compound 27 and compound 37). As compared to treatment with 25 μΜ curcumin, in the case of 100 times lower concentration (250 nM) a similar reduction in cell division could be detected in the case of compound 20, compound 27 and compound 37.

Example 55 :

Producing nanodispersion formulated preparation of curcumin derivatives

Polyvinyl alcohol (Mw: 40000), NaCl and Polysorbate 80 was obtained from Sigma company (St. Louis, MO, United State).

Nanoparticles were produced with high-pressure homogenisation technique. Short description of the method: 0.13 M NaCl and 0.25 mM polyvinyl alcohol was dissolved in 100 ml ultrafiltered water. Compound 37 was pulverised at 200 rpm for 60 minutes with a Retsch PM100 Planetary Ball Mill device (Retsch AG, Germany) . To pulverised compound 37, 13 mM polysorbate 80 was added in water, until the powder formed a soluble dispersion. This solubilised compound 37 was dispersed in the solution of 0.13 M NaCl and 0.25 mM polyvinyl alcohol with the help of a homogeniser (Heidolph Diax 900, Heidolph GmbH, Schwabach, Germany) at 21000 1/minute (600W) for 10 minutes until a dispersion was obtained. This dispersion was homogenised under a pressure of 17400 psi (1200 bar) through nine cycles (Emulsiflex-C3 device, Avestin Inc. , Canada) , finally it was filtered with a Millipore PVDF membrane filter until it was sterile (pore size: 0.45 μπι) . The average grain size and the polydispersity index was measured using laser diffractometry (Malvern Mastersizer 2000, Malvern Instruments Ltd, United Kingdom) (n=5) . The concentration of the nanodispersion was 2 mg/ml.

The values of the nanodispersion form of compound 37 in the example were the following: surface weighted mean: D[3.2] (nm) : 351 ± 11; volume weighted mean: D[4.3] (nm) : 648 ± 9; Specific surface size: 17.1 m2/g; polydispersity index: 0.964 ± 0.040.

Example 56:

Producing the liposome formulation preparation of compound 37 DSPE-mPEG (2000) (polyethylene glycol) 2000- phosphatidyl ethanolamine conjugate) was obtained from Avanti Polar Lipids Inc. (United States); cholesterol, L-a-phosphatidyl choline and ethanol was purchased from Sigma company (St. Louis, MO, United States). Ultrafiltered water (0.2 μπι) was used for the aqueous phase (TKA Smart2Pure, TKA Gmbh, Niederelbert , Germany) .

Liposomes containing compound 37 were prepared on the BUCHI R- 210 Rotavapor system (BUCHI AG., Flawil, Switzerland). Cholesterol/L-a-phosphatidylcholine/DSPE-mPEG (2000) lipid powder mixture (62/28/0.6 mol%) and compound 37 was dissolved in (9.2 mol%) in alcohol. The solution was dried overnight under vacuum. The formed lipid film was hydrated in PBS solution (0.1 M, pH 6.8) and redispersed to reach the final concentration of compound 37 of 0.5 mM. This process was continued for 25 minutes above the phase transition temperature of organic components. The dispersion was subjected to size exclusion with the help of a Millipore PVDF membrane filter of a pore size of 0.45 μιτι, then it was filtered until sterile on Millipore PVDF membrane filter of a pore size of 0.22 μιι. The liposome size, the specific surface area and the polydispersity index was measured using laser diffractometry (Malvern Mastersizer 2000, Malvern Instruments 5 Ltd, United Kingdom) (n=5) .

The liposome form of compound 37 in the example had the following values : d ( 0.1 ) , d(0.5) mean value: 75 ± 19 nm; d(0.9) liposome size (nm) : 114 ± 20; specific surface area: 54.5 m2/g; polydispersity index: 0.901 ± 0.20.

L0

Example 57 :

The anticancerous effect of compound 37 in live animals : I . pulmonary carcinoma

The effect on pulmonary carcinoma was studied on NSG immune- deficient mouse model inoculated subcutaneously with A549 human cells (ATCC) (3 million cells/animal) . Two groups were formed from randomly selected mice, with 8 animals in both groups. Group 1: control group, it was only administered a carrier (0.1 mL, 0.9% NaCl solution) intravenously; group 2: group treated with compound 37, it was administered 3 mg/kg of compound 37 in a nanoformulated form described in example 55 (in 0.1 mL, 0.9% NaCl suspension).

The treatments were performed from the seventh day, three times a week (Monday, Wednesday, Friday) , for 4 weeks, on a total of 12 occasions. Starting from the 20 ^th day on every second day the size of the increasing tumours was determined in the case of each animal, and the group average was represented per group (figure 6) . The standard deviation was determined in SEM. It can be seen that the treatment with compound 37 reduced the size of the increasing pulmonary tumour . Example 58 :

The anticancerous effect of compound 37 in live animals : II . leukaemia

5 The effect on leukaemia was studied on SCID immune-deficient mouse model inoculated intravenously with HL60 human acute myeloid leukaemia cells (ATCC) (1 million cells/animal). Three groups were formed from randomly selected mice, with 10 animals in each group. Group 1: control group, it was only

L0 administered a carrier (0.1 mL, 0.9% NaCl solution) intravenously; group 2: group treated with compound 37, it was administered 3 mg/kg of compound 37 in a nanoformulated form described in example 55 (in 0.1 mL, 0.9% NaCl suspension), intravenously; group 3: group treated with compound 37, it was

L5 administered 1.5 mg/kg of compound 37 in a liposome form described in example 56 (in 0.1 mL, 0.9% NaCl suspension), intravenously .

The treatments were performed from the third day, on five consecutive occasions per week, for 2 weeks, on a total of 10

!O occasions. As time went on, every day we determined the number of surviving animals and represented it in percentage per group as compared to the total initial number of animals (figure 7) . It can be seen that both the 3 mg/kg dose administered in a nanoformulated form and the 1.5 mg/kg dose

!5 administered in a liposome form were effective, the treatment with compound 37 increased the survival rate of the animals.

Example 59:

Activation of the expression of GRP78 and GADD153 proteins 10 induced by compound 37

The process referred to English special literature as "unfolded protein response or UPR belongs to the defence system of cells. Oxidative stress or stress in the endoplasmic reticulum may result in the apoptosis of tumour cells, which is realised through the UPR system (From acute ER stress to physiological roles of the unfolded protein response. Wu J, Kaufman RJ. Cell Death Differ 2006; 13: 374-384; Integrated endoplasmic reticulum stress responses in cancer. Moenner M, Pluquet 0, Bouchecareilh M, Chevet E. Cancer Res 2007; 67: 10631-10634.). During the UPR process several proteins are activated, such as the GRP78 protein referred to in English special literature as "glucose-regulated protein 78", and the CCAAT/enhancer binding protein also called CHOP/GADD153 transcription factor. The activation of the latter one results in the apoptosis of tumour cells, that is cell death.

In our example we describe that compound 37 increased the amount of both GRP78 and GADD153 protein in glioma tumour cells 6 hours following treatment. While in the cells after 6 hours of treatment the level of GRP78 was activated in concentrations of 0.5 μΜ and 2.5 μΜ with the Western-blot protein detection method, the chemically unmodified original curcumin could have the same effect only in a much lower concentration, 25 μΜ. The result is shown in figure 8.

We experienced the same in the case of GADD153 protein activation, which could be detected 3 and 6 hours after treatment with compound 37. While compound 37 was activated already in concentrations 0.5 μΜ and 2.5 μΜ with the Western- blot protein detection method, the chemically unmodified original curcumin could induce the same in a much lower concentration, 25 μ . The result is shown in figure 9. The Western blot technique was performed as described below:

U87 human glioblastoma cells were grown until 80% confluency in cell growing dishes of a diameter of 100 mm, and then they were treated with curcumin (in a concentration of 25 μΜ) , with compound 37 (in concentrations of 0.5 and 2.5 μ ) and with 0.2% DMSO for control. The cells treated for 3 and 6 hours were washed with cold PBS, and then protein extraction was

5 performed with 400 ml RIPA buffer (50 mM Tris, 150 mM NaCl, 0,5% Na- deoxycholate, 1% NP-40, protease inhibitor cocktail) per dish. With a Nanodrop ND-1000 instrument, on the basis of the absorption measured at 280 nm we determined the protein concentration of the samples. 200 μς protein per sample was

L0 boiled with 2x Laemmli buffer (Sigma-Aldrich) of the same volume for 5 minutes. The samples treated in this way were separated SDS-polyacrylamide gel electrophoresis: 30-30 μg of protein was applied to the gradient gel (4-15% Mini-PROTEAN® TGX™ Precast Gel, Bio-Rad) , then the samples were run in Mini-

L5 Protean Tetra Cell system (Bio-Rad) at 200 V for about 30 minutes. Then the proteins separated in the gel were electroblotted on a nitrocellulose membrane at 80 V for an hour in ice cold Towbin buffer (25 mM Tris, 192 mM glycine, 10% methanol) . The efficacy of the blot was tested with

10 Ponceau staining, and then it was blocked for 2 hours in the membrane blocking buffer (5% nonfat milk powder, 50 mM Tris, 150 mM NaCl, 0.1% Tween 20, pH 7.4) . The blocked membrane was incubated for 1 hour in a blocking buffer containing anti- beta-actin or anti-GADD153 or anti-GRP78 (Santa Cruz

15 Biotechnology) primary antibody, where the ratio of the antibody was 1:200 in each case. Then the membrane was washed for 5x5 minutes in TBST buffer (50 mM Tris, 150 mM NaCl, 0.05% Tween 20, pH 7.4), and then it was soaked for 1 hour in a blocking buffer containing HRP-conj ugated secondary antibody

50 (Santa Cruz Biotechnology) , where the ratio of the antibody was 1:500. After washing it again for 5x5 minutes the membrane was developed with the help of the chemiluminescent method (ECL Western Blotting Substrate, Pierce) and autoradiography. Example 60

Producing pharmaceutical preparations : a) Tablets :

0.01-50% active agent of general formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinylpyrrolidone, 1- 5% talcum, 0.01-3% magnesium-stearate, 1-3% colloid silicon dioxide and 2-7% ultraamylopectin is mixed together and then granulated using the wet granulation method and compressed into tablets. b) Dragees, film-coated tablets:

The tablets produced according to the previous example are coated with a layer containing entero- or gastrosolvent film or sugar and with talcum. The dragees are given a lacquer coating, which consists of the mixture of beeswax and carnauba wax . c) Capsules :

0.01-50% active agent of general formula (I), 1-5% sodium- lauryl-sulfate, 15-50% starch, 15-50% lactose, 1-3% colloid silicon dioxide and 0.01-3% magnesium-stearate is mixed together thoroughly, the mixture is pressed through a sieve and filled in hard gelatine capsules. d) Suspensions :

Constituents: 0.01-15% active agent of general formula (I), 0.1-2% sodium-hydroxide, 0.1-3% citric acid, 0.05-0.2% Nipagin (Sodium Methyl 4-hydroxybenzoate) , 0.005-0.02% Nipazol, 0.01-0.5% Carbopol (polyacrylic acid), 0.1-5% 96% ethanol, 0.1-1% flavouring agent, 20-70% sorbitol (70% aqueous solution) and 30-50% distilled water. To the solution of Nipagin and citric acid prepared in 20 ml distilled water Carbopol is added in small amounts while stirring intensively, the solution obtained is put aside and left alone for 10-12 hours. Then during intensive stirring sodium hydroxide in 1 ml distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavour is added to it. To this carrier the active agent is added in small amounts and suspended with an immersing homogeniser. Finally the suspension is filled up to the desired final volume with distilled water and the suspension syrup is passed through a colloid mill. e) Suppositories :

0.01-15% active agent of general formula (I) and 1-20% lactose is thoroughly mixed, then this mixture is added to 50- 95% melted fatty substance suitable for making suppositories, cooled down to 35°C (e.g. Witepsol 4), the mixture obtained is homogenised and poured in cooled moulds. f) Lyophilized powder ampoule composi'bions :

A 5% solution of mannitol or lactose is made with bidistilled water for injection use, and the solution is filtered until its sterile. In the same way, a 0.01-5% sterile solution is made from active agent of general formula (I). The two solutions are mixed under aseptic conditions, filled in 1 ml ampoules, the content of the ampoules is lyophilised and the ampoules are sealed under nitrogen. The content of the ampoules is dissolved in sterile water or sterile physiological salt solution (0.9% sodium chloride solution) directly before administration.