Acridine derivatives, method for their preparing and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acridine of the formula (1):

wherein R, R1, R2 and R3 mean hydrogen atom; Z means oxygen or sulfur atom; X means nitrogen atom or C-R5 wherein R5 means hydrogen atom; n = 2; m = 0; R4 means (C1-C3)-alkyl residue that can be substituted with aryl, (C4-C10)-heteroaryl and other substitutes, (C6-C10)-aryl and others, and to their pharmaceutically acceptable salts. Compounds of the formula (1) possess an anti-tumor activity and can be used as an active component of the medicinal agent.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

9 cl, 1 tbl, 20 ex

 

The technical field to which the invention relates.

The invention relates to novel heteroaryl derivative, in particular a derivative of acridine General formula 1, to their preparation and use as pharmaceuticals, particularly for the treatment of neoplastic diseases.

The level of technology

Known antitumor agents based on acridine derivatives, described in Ebcid M.Y. et al. "Synthesis and antitumor activity of some derivatives 4-4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]acridine-9-ylamino-benzosulfimide" (Synthesis and antitumor activity of some 4-4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]acridin-9-ylamino-benzenesulfonamide derivatives), Bull. Fac. Pharm., 32, No. 3, 1994, str-368, and Atweel G.J. et al. "Potential antitumor agents. 50. Effects on solid tumors in vivo using derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide" (Potential antitumoragents. 50. In vivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), Journal of Medicinal Chemistry, American Chemical Society. Washington, DC, USA, t, No. 4, 1987, str-669.

The invention

The present invention is to obtain new active compounds for the treatment of tumors in mammals.

According to one object of the present invention presents new acridine derivatives of General formula 1

where R, R1, R2, R3the choice may be to recognize the ENES to carbon atoms acridine residue from C 1to C9are the same or different and independently of one another denote hydrogen, linear or branched (C1-C8)alkyl, (C3-C7)cycloalkyl, linear or branched (C1-C8)alkylsulphonyl, preferably acetyl, linear or branched (C1-C8)alkoxy, halogen, aryl(C1-C8)alkoxy, preferably benzyloxy or phenylethylene, nitro, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C8)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C8)alkyl, cyano, carboxy, (C1-C8)alkoxycarbonyl, substituted by at least one fluorine atom (C1-C4)alkyl, preferably triptorelin group, carboxy(C1-C8)alkyl or (C1-C8)alkoxycarbonyl(C1-C6)alkyl, (C2-C6)alkenyl, preferably allyl, (C2-C6)quinil, preferably ethinyl or propargyl, linear or branched cyano(C1-C6)alkyl, preferably cyanomethyl, aryl, and aryl residue is unsubstituted or substituted by one or more identical or different substituents selected from the range halogen, linear or branched (C1-C8)alkyl, (C3-C7)cycle is alkyl, carboxy, linear or branched (C1-C8)alkoxycarbonyl, preferably tertbutoxycarbonyl, trifluoromethyl, hydroxy, linear or branched (C1-C8)alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, cyano, linear or branched cyano(C1-C6)alkyl.

Z denotes oxygen or sulfur, and Deputy acridine residue of the formula

can be connected with1-C9carbon atoms acridine residue;

P, Q independently of one another denote oxygen atoms or in each case two hydrogen atoms (CH2-);

X is nitrogen or C-R5and R5means hydrogen or (C1-C6)alkyl;

n, m independently of one another denote an integer from 0 to 3, provided that when n is 0, x is the group CR5R6and R5and R6independently of one another denote hydrogen or (C1-C6)alkyl, and the Deputy of the nitrogen atom adjacent to the C=Z by the group, is a hydrogen atom or (C1-C8)alkyl,

R4means linear or branched (C1-C20)alkyl residue, which can be saturated or unsaturated and can contain from one to three double and the triple relations, and which can be unsubstituted or substituted choice on the same or different carbon atoms with one, two or more substituents, selected from a number of: aryl, heteroaryl, halogen, cyano, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, amino, mono(C1-C4)alkylamino or di(C1-C4)alkylamino; R4means (C6-C14)aryl residue, (C6-C14)aryl(C1-C4)alkyl residue or (C2-C10)heteroaryl residue or (C2-C10)heteroaryl(C1-C4)alkyl residue containing at least one heteroatom selected from N, O and S, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and (C6-C14)aryl or (C2-C10)heteroaryl residues may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: linear or branched (C1-C8)alkyl, (C3-C7)cycloalkyl, halogen, cyano, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, carboxy, (C1-C8)alkoxycarbonyl, linear or branched (C1-the 6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, hydroxy, linear or branched (C1-C8)alkoxy, preferably methoxy or ethoxy, and the neighboring oxygen atoms can be linked via (C1-C2)alkylenes group, preferably a methylene group, benzyloxy, nitro, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, aryl which in turn may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: linear or branched (C1-C8)alkyl, (C3-C7)cycloalkyl, carboxy, linear or branched (C1-C8)alkoxycarbonyl, trifluoromethyl, hydroxy, linear or branched (C1-C8)alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, cyano, linear or branched cyano(C1-C6)alkyl;

as well as their structural or stereoisomers, particularly the tautomers, the diastereomers and enantiomers and their pharmaceutically acceptable salts, especially acid additive salt.

Compounds of the present invention of General formula (1), which include at least one chiral center and form a rat who you are, can be separated by known methods on their optical isomers, as well as enantiomers or diastereoisomers. The separation can be performed on a column with a chiral phases or by recrystallisation from an optically active solvent or by using an optically active acid or base, or by modification using optically active reagents, such as optically active alcohol, followed by removal of the residue.

In addition, acridine derivatives of the present invention of General formula (1) can be converted into their salts with inorganic or organic acids, primarily with a view to their application in the pharmaceutical industry in the form of their physiologically acceptable salts. In this case, as the acid used, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, malonic acid, ambalavao acid, triperoxonane acid or maleic acid.

In addition, the compounds of the present invention of formula (1)containing acidic groups such as carboxyl group, can be optionally converted into their salts with inorganic or organic basis, primarily with a view to their use of the pharmaceutical industry in the form of their physiologically acceptable salts. In this case, as the bases are used, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

According to a preferred variant embodiment of the invention receive the acridine derivatives of General formula (1), where R, R1, R2, R3, X, Z, P, Q, n and m are as defined above values and

R4means linear or branched (C1-C20)alkyl residue, which can be saturated or unsaturated and can contain from one to three double and/or triple links, and which can be unsubstituted or substituted choice on the same or different carbon atoms with one, two or more substituents, selected from a number of: aryl, heteroaryl, halogen, (C1-C6)alkoxy, amino, mono(C1-C4)alkylamino or di(C1-C4)alkylamino;

phenyl or nattily residues, which in each case are unsubstituted or substituted by one or more, same or different substituents selected from the range of: linear or branched (C1-C8)alkyl, (C3-C7)cycloalkyl, halogen, carboxy, (C1-C8)alkoxycarbonyl, linear or branched (C1-C6)alkyl, substituted with at least one fluorine atom, preferably trifter ethyl, hydroxy, linear or branched (C1-C8)alkoxy, preferably methoxy or ethoxy, and the neighboring oxygen atoms can also be linked through (C1-C2)alkylenes group, preferably a methylene group, benzyloxy, nitro, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, aryl which in turn may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: linear or branched (C1-C8)alkyl, (C3-C7)cycloalkyl, carboxy, linear or branched (C1-C8)alkoxycarbonyl, trifluoromethyl, hydroxy, linear or branched (C1-C8)alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, cyano, linear or branched cyano(C1-C6)alkyl;

2-, 4-, 5 - or 6-pyrimidinyl residual or 2-, 4-, 5 - or 6-pyrimidinyl(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 4-, 5 - or 6-pyrimidinyl residue, which may be unsubstituted or is to win one to three identical or different substituents, chosen from a number of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

3-, 4-, 5 - or 6-pyridazinyl residue or a 3-, 4-, 5 - or 6-pyridazinyl(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 3-, 4-, 5 - or 6-pyridazinyl residue, which may be unsubstituted or may contain one to three identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one fluorine atom, preferably triptime is l, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 3-, 5 - or 6-personilnya residual or 2-, 3-, 5 - or 6-pyrazinyl(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 3-, 5 - or 6-personilnya residue, which may be unsubstituted or may contain one to three identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

3-, 4-, 5-, 6-, 7 - or 8-Connolly or 3-, 4-, 5-, 6-, 7 - or 8-cinnoline(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O) -, 4-, 5-, 6-, 7 - or 8-Connolly residue, which may be unsubstituted or may contain one to five identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 4-, 5-, 6-, 7 - or 8-chinadaily residual or 2-, 4-, 5-, 6-, 7 - or 8-hintline(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen or oxo (=O), and 2-, 4-, 5-, 6-, 7 - or 8-chinadaily residue, which may be unsubstituted or may contain one to five identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)is alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 3-, 5-, 6-, 7 - or 8-khinoksalinona residual or 2-, 3-, 5-, 6-, 7 - or 8-honokalani(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 3-, 5-, 6-, 7 - or 8-khinoksalinona residue, which may be unsubstituted or may contain one to five identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 4-, 5-, 6-, 7 - or 8-phthalazinedione residue or 1-, 4-, 5-, 6-, 7 - or 8-phthalazine(C1-C4)alkyl residue, and (C1-C4)Alki the capacity residue may be unsubstituted or substituted by one or more identical or different substituents, selected from the range: (C1-C6)alkyl, halogen or oxo (=O), and 1-, 4-, 5-, 6-, 7 - or 8-phthalazinedione residue, which may be unsubstituted or may contain one to five identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 3-, 4-, 5-, 6-, 7 - or 8-ginally residual or 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 3-, 4-, 5-, 6-, 7 - or 8-ginally residue, which may be unsubstituted or may contain from one to six identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, preferably methyl, more preferably 2-methyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(the 1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 3-, 4-, 5-, 6-, 7 - or 8-ethinally residue or 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethinally residue, which may be unsubstituted or may contain from one to six identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 6-, 8 - or 9-[N]-p is rinaldy residual or 2-, 6-, 8 - or 9-[N]-purines(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O)2-, 6-, 8 - or 9-[N]-purenergy residue, which may be unsubstituted or may contain one to three identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 6-, 7 - or 8-[7H]-purenergy residual or 2-, 6-, 7 - or 8-[7H]-purines(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O)2-, 6-, 7 - or 8-[7H]-purenergy residue, which may be unsubstituted or may contain one to three same or the difference is different substituents, chosen from a number of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-criminally residue or 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-acridine(C1-C4)alkyl residue, and (C1-C4)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-criminally residue, which may be unsubstituted or may contain from one to eight identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-phenanthridinone residue or 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-phenanthridine(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen or oxo (=O), and 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 - or 9-phenanthridinone residue, which may be unsubstituted or may contain from one to eight identical or different substituents chosen from the series: (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, (C6-C10)aryl(C1-C6)alkoxy, preferably benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 3-, 4-, 5 - or 6-peredelnyj balance, and 2-, 3-, 4-, 5 - or 6-peredelnyj residue may be unsubstituted or may contain one to four identical or different substituents chosen from the series: adored, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 3-, 4-, 5 - or 6-pyridyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 3-, 4-, 5 - or 6-pyridinoline residue, which may be unsubstituted or may contain one to four identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-the 6)alkyl;

2-, 3-, 4 - or 5-thienyl residue, or 2-, 3-, 4 - or 5-thienyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 3-, 4-, or 5-thienyl residue, which may be unsubstituted or may contain one to three identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 4 - or 5-diazolidinyl residual or 2-, 4 - or 5-thiazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 4 - or 5-diazolidinyl residue, which may be unsubstituted or contain one is about up to two identical or different substituents, chosen from a number of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

3-, 4 - or 5-isothiazolinones residue or a 3-, 4 - or 5-isothiazolin(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 3-, 4-, or 5-isothiazolinones residue, which may be unsubstituted or contain one or two identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C 6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 4-, 5-, 6 - or 7-benzothiazolyl residual or 2-, 4-, 5-, 6 - or 7-benzothiazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 4-, 5-, 6 - or 7-benzothiazolyl residue, which may be unsubstituted or may contain one to four identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 2-, 4 - or 5-imidazolidinyl residue or 1-, 2-, 4 - or 5-imidazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogenide oxo (=O), and 1-, 2-, 4 - or 5-imidazolidinyl residue, which may be unsubstituted or may contain one to three identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 3-, 4 - or 5-personilnya residue or 1-, 3-, 4 - or 5-pyrazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 1-, 3-, 4 - or 5-personilnya residue, which may be unsubstituted or may contain one to three identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1- 6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 2-, 3-, 4 - or 5-pyrrolidinyl residue or 1-, 2-, 3-, 4 - or 5-pyrrolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 1-, 2-, 3-, 4-, or 5-pyrrolidinyl residue, which may be unsubstituted or may contain one to four identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 3 - or 5-[1.2.4]diazolidinyl residue or 1-, 3 - or 5-[1.2.4]triazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be nezametnymi substituted by one or more identical or different substituents, chosen from a number of: hydrogen, (C1-C6)alkyl, halogen or oxo (=O), and 1-, 3 - or 5-[1.2.4]diazolidinyl residue, which may be unsubstituted or contain one or two identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 4 - or 5-[1.2.3]diazolidinyl residue or 1-, 4 - or 5-[1.2.3]-triazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 1-, 4 - or 5-[1.2.3]diazolidinyl residue, which may be unsubstituted or contain one or two identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1 - or 5-[1H]-tetrazolyl residue or 1 - or 5-[1H]-tetrazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 1 - or 5-[1H]-tetrazolyl residue, which may be unsubstituted or may contain a Deputy from a number of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2 - or 5-[2H]-tetrazolyl residual or 2 - or 5-[2H]-tetrazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be illegal is emenim or substituted by one or more identical or different substituents, selected from the range: (C1-C6)alkyl, halogen or oxo (=O)2 - or 5-[2H]-tetrazolyl residue, which may be unsubstituted or may contain a Deputy from a number of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 4 -, or 6-[1.3.5]-creasingly residual or 2-, 4 -, or 6-[1.3.5]-triazinyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen or oxo (=O), and 2-, 4 -, or 6-[1.3.5]teasingly residue, which may be unsubstituted or contain one or two identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)ALCO is dicarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

2-, 4 - or 5-oxazolidinyl residual or 2-, 4 - or 5-oxazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen or oxo (=O), and 2-, 4 - or 5-oxazolidinyl residue, which may be unsubstituted or contain one or two identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

3-, 4 - or 5-isoxazolyl residue or a 3-, 4 - or 5-isoxazolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted and the and substituted by one or more identical or different substituents, selected from the range: (C1-C6)alkyl, halogen or oxo (=O), and 3-, 4 - or 5-isoxazolyl residue, which may be unsubstituted or contain one or two identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

1-, 2-, 3-, 4-, 5-, 6 - or 7-indolinyl residue or 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl(C1-C6)alkyl residue, and (C1-C6)alkyl residue may be unsubstituted or substituted by one or more identical or different substituents chosen from the series: (C1-C6)alkyl, halogen and oxo (=O), and 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolinyl residue, which may be unsubstituted or may contain from one to six identical or different substituents selected from the range of: hydrogen, (C1-C6)alkyl, halogen, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)al is hydroxy, benzyloxy, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkyl, substituted with at least one atom of fluorine, preferably trifluoromethyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;

as well as their isomers, especially the tautomers, the diastereomers and enantiomers and their pharmaceutically acceptable salts, especially acid additive salt.

According to other variant embodiments of the present invention presents acridine derivatives of General formula (1), where R, R1, R2, R3, X, Z, P, Q, n and m have the above values, a R4means phenyl, which is unsubstituted or contains as substituents of one to five identical or different (C1-C6)alkoxygroup, and the neighboring oxygen atoms can also be linked through (C1-C6)alkylenes group.

According to the following variant of the embodiment of the present invention presents acridine derivatives of General formula (1), where R, R1, R2, R3, X, Z, P, Q, n and m have the above values, a R4means 3,5-acid.

According to other variant embodiments of the present invention presents acridine derivatives of General formula (1), where R4has the above significance, and R Rsub> 1, R2, R3in each case mean a hydrogen atom, Z means oxygen atom, and X denotes a nitrogen atom, P and Q in each case denote two hydrogen atoms (CH2-), m is zero and n is an integer 2.

According to another variant embodiment of the present invention presents acridine derivatives of General formula (1), where the substituents R, R1, R2, R3in each case mean a hydrogen atom, Z means oxygen atom, X denotes a nitrogen atom, P and Q in each case denote two hydrogen atoms (CH2-), m is zero, n is an integer 2, and R4means 3,5-acid.

According to another object of the present invention presents a method of obtaining derivatives of acridine General formula (1), namely, that greencarbon acid of General formula (2),

where R, R1, R2, R3have the above values, Z means oxygen atom or sulfur, a Y means delete the group, such as halogen, hydroxy, (C1-C6)alkoxy, preferably methoxy or ethoxy, -O-tosyl, -O-mesyl or imidazolyl lead in the interaction with the amine of General formula (3)

where R4, P, Q, X, m and n have the aforementioned meanings, with the formation of the desired derivative of acridine, if necessary, and the use of diluents or excipients.

The scheme for synthesis of:

Compounds of General formula 1 are according to the following synthesis scheme 1:

Synthesis of 1

Starting compound (2) and (3) can be obtained from the manufacturers or can be obtained by known methods of synthesis.

Selected derivatives (2) and (3) are valuable intermediate compounds to obtain the acridine derivatives of the present invention of formula (1).

Required used solvents and excipients, as well as the reaction parameters, such as temperature and duration of reaction, well-known specialists in this field of technology.

Derivatives of acridine according to the present invention of General formula (1) are suitable as pharmaceuticals, particularly as anticancer agents for the treatment of mammals, especially humans, and domestic animals such as horses, cows, dogs, cats, rabbits, sheep, poultry, etc.

According to another object of the present invention presents a way of dealing with neoplastic diseases of mammals, especially humans, namely, that at least one derivative of acridine General formula (1) is administered to the mammal in an effective treatment for tumors of the number. Input therapeutically effective dose derived by acridine infusion is his invention depends among other things, on the type and stage of tumor, age and sex of the patient, the type of injection drugs and duration of treatment. The introduction can be performed oral, rectal, buccal (e.g., sublingual), parenteral (e.g. subcutaneous, intramuscular, subcutaneous injection or intravenous), local or percutaneous methods.

According to another object of the present invention presents a drug for the treatment of neoplastic diseases, comprising as active ingredient at least one derivative of acridine described above, or its pharmaceutically acceptable salt, optionally in a mixture with standard pharmaceutically acceptable auxiliary substances, additives and carriers. This may be received solid, semi-solid, liquid or aerosol products. Suitable solid preparations include, for example, capsules, powders, granules, tablets. Suitable semi-solid preparations include, for example, ointments, creams, gels, pastes, suspensions, emulsions of the type oil-in-water" and "water in oil". Suitable liquid preparations include, for example, sterile aqueous preparations for parenteral administration, which is isotonic to the blood of the patient.

The present invention is described in more detail in follow the examples, do not limit the claims of the invention.

Information confirming the possibility of carrying out the invention

Example 1

1-(3,5-Acid)-4-(9-akademikerne)piperazine (D-43411)

8 g (35,84 mmol) acridine-9-carboxylic acid are stirred in 300 ml of DMF. Then to this mixture with stirring consistently add 5,79 g (57,34 mmol) N-methylmorpholine, and then the solution 24,24 g (46,59 mmol) of Ru-THEFT (hexaphosphate 1-benzotriazolyl-triprolidine) and of 7.96 g (35,81 mmol) of 1-(3,5-acid)piperazine in 50 ml of DMF. The mixture is stirred for 12 h at room temperature, the DMF is removed in vacuo and the residue purified on a column of kieselgel (kieselgel 60, Merck AG, Darmstadt) using as eluent a mixture of dichloro methane/methanol (95:5 vol./vol.).

The output is of 12.9 g (84.2% of theory), TPL 172-175°C.

MS: m/e=428 (M+H)

1H-NMR (DMSO-d6) δ=8,23 (d,2H), 7,98 (d,2H), to 7.93 (dd,2H), of 7.70 (dd,2H), 6,07 (s,2H), 6,01 (s,1H), 4,07-of 4.12 (t,2H), 3,69 (s,6H), 3,42-3,47 (m,2H), 3,06-3,10 (m,2H), 2,92-2,95 (m,2H) ppm

TPL 168°

Example 2

2-[4-(Acridine-9-carbonyl)-piperazine-1-yl]-nicotinate (D-82266)

MS: m/e=394 (M+H)

1H-NMR (DMSO-d6) δ=8,43 (d,1H), 8,32 (d,2H), 8,06-8,16 (m,5H), 7,81 (dd,2H), 6,98 (dd,1H), 4,13-4,18 (m,2H), 3,92-of 3.97 (m,2H), 3,40-of 3.46 (m,2H), 3,19-3,24 (m,2H) ppm

TPL 122°

Example 3

Acridine-9-yl[4-(3,5-dichlorophenyl)-piperazine-1-yl]-methanon (D-81694)

MS: m/e=437 (M+H)/p>

1H-NMR (DMSO-d6) δ=8,23 (d,2H), 7,98 (d,2H), 7,92 (dd,2H), 7,71 (dd,2H), 6,98 (s,2H), 6.87 in (s,1H), 4,06-4,10 (m,2H), 3,57-of 3.60 (m,2H), 3,03-3,10 (m,4H) ppm

TPL 241 to 243°

Example 4

Acridine-9-yl-[4-(2,3-dimetilfenil)-piperazine-1-yl]metano (D-81745)

MS: m/e=396 (M+H)

1H-NMR (DMSO-d6) δ=8,23 (d,2H), to 7.99 (d,2H), to $ 7.91 (dd,2H), 7,72 (dd,2H), 7,02 (dd,1H), 7,85-7,89 (m,2H), 4,10-4,16 (m,2H), 3,12-and 3.16 (m,2H), 3.04 from-is 3.08 (m,2H), 2,56-2,60 (t,2H), 2,19 (s,3H), of 2.15 (s,3H) ppm

TPL 122-124°

Example 5

Acridine-9-yl-(4-naphthalene-1-ylmethyl-piperazine-1-yl)-methanon (D-81803)

MS: m/e=432 (M+H)

1H-NMR (DMSO-d6) δ=compared to 8.26 (d,1H), they were 8.22 (d,2H), 7,86-of 7.96 (m,5H), of 7.82 (d,1H), 7,71 (dd,2H), 7,47-7,52 (m,2H), 7,41-7,44 (m,2H), 4,8-4,96 (m,4H), 2,94 are 2.98 (m,2H), 2,68-of 2.72 (m,2H), 2,23-of 2.27 (m,2H) ppm

Example 6

Acridine-9-yl-(4-econsultancy-piperazine-1-yl)-methanon (D-81804)

MS: m/e=384 (M+H)

1H-NMR (DMSO-d6) δ=8,32 (d,1H), 8,12 (m,4H), 7,78-a 7.85 (m,2H), of 4.05 (m,2H), 3,52 (m,2H), 3,1-3,17 (m,4H), 2,97 was 3.05 (m,2H), 1.26 in (t,3H) ppm

TPL 126-128°

Example 7

Acridine-9-yl-[4-(1-phenyl-ethyl)-piperazine-1-yl]-methanon (D-81805)

MS: m/e=396 (M+H)

1H-NMR (DMSO-d6) δ=by 8.22 (d,2H), 7,88 (d,2H), 7,78 (dd,2H), 7,56 (dd,2H), 7.18 in-7,28 (m,5H), 4,13-was 4.02 (m,2H), 3.43 points (q,1H), 3,01-of 3.07 (m,2H), 2,63-2,89 (m,2H), 2,12-of 2.27 (m,2H), 1,33 (d,3H) ppm

Example 8

Acridine-9-yl(2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)-methanon (D-81851)

MS: m/e=370 (M+H)

1H-NMR (DMSO-d6) δ=8,31 (s,1H), 8,24 (d,2H), 8,08 (d,1H), of 7.96 (d,2H), 7,88 (dd,2H), 7,86 (d,1H), to 7.67-7,71 (dd,2H), 4,1 (m,2H), 3,90-of 3.96 (m,2H), 3,38-of 3.42 (m,2H), 3,10-3,15 (m,2H) ppm

So is L. 210-212°

Example 9

Acridine-9-yl-[4-(2-morpholine-4-yl-ethyl)-piperazine-1-yl]-methanon (D-81854)

MS: m/e=405 (M+H)

1H-NMR (DMSO-d6) δ=8,18 (d,2H), 7,88-to 7.95 (m,4H), 7.68 per-7,76 (dd,2H), 3,92-of 3.96 (m,2H), 3,53-to 3.58 (m,4H), 2.95 and (t,2H), 2,69 (t,2H), 2,41 of $ 2.53 (m,8H), 2,20-of 2.25 (m,2H) ppm

Example 10

Acridine-9-yl-[4-(2,4-differenl)-piperazine-1-yl]-methanon (D-81439)

MS: m/e=404 (M+H)

1H-NMR (DMSO-d6) δ=of 8.25 (d,2H), and 8.0 (d,2H), 7,95 (dd,2H), of 7.75 (dd,2H), 7,2 (m,1H), and 7.1 (m,1H), 7,0 (m,1H), 4,1 (m,2H), 3,25 (m,2H), 3.15 in (m,2H), 2,85 (m,2H) ppm

TPL 193-196°

Example 11

Acridine-9-yl-(4-phenyl-piperidine-1-yl)-methanon (D-81806)

MS: m/e=367 (M+N)

1H-NMR (DMSO-d6) δ=8,32 (d,2H), 8,07 (d,1H), 7,89 (d,1H), 7,78-a 7.85 (m,2H), EUR 7.57-to 7.68 (m,2H), 7.18 in-7,35 (m,5H), 5,31 (dd,1H), 2,78 of 3.28 (m,4H), 1,48-2,22 (m,4H) ppm

TPL 217-219°

Example 12

Acridine-9-yl-[4-(3,5-acid)-piperazine-1-yl]-methanon hydrochloride (D-81852)

MS: m/e=428 (M+H)

1H-NMR (DMSO-d6) δ=8,65 (d,2H), by 8.22-8,29 (m,4H), 7,92 (t,2H), 6,18 (s,2H), 6,07 (s,1H), 4,12-4,18 (m,2H), 3,68 (s,6H), 3,53-to 3.58 (m,2H), 3,24-of 3.27 (m,2H), 2,97 to 3.0 (m,2H) ppm

TPL 158-159°

Example 13

Acridine-9-yl-[4-(6-methyl-pyridine-2-yl)-piperazine-1-yl]-methanon (D-82316)

MS: m/e=383 (M+N)

1H-NMR (DMSO-d6) δ=8,2 (d,2H), 7,95 (d,2H), 7,9 (dd,2H), 7,65 (dd,2H), and 7.4 (dd,1H), 6,55 (d,1H), 6,5 (d,1H), 4,1 (m,2H, in), 3.75 (m,2H), 3,25 (m,2H), 3,05 (m,2H, in), 2.25 (s,3H) ppm

TPL 172°

Example 14

Acridine-9-yl-[4-(3, 5dimethylphenyl)-piperazine-1-yl]-methanon (D-82317)

MS: m/e=396 (M+H)

1H-NMR (DMSO-d6 ) δ=of 8.25 (d,2H), 7,95 (d,2H), 7,9 (dd,2H), and 7.7 (dd,2H), 6,55 (s,2H), 6,45 (s,1H), 4,1 (m,2H), 3,4 (m,2H), 3,1 (m,2H), 2.95 and (m,2H), 2,2 (s,6H) ppm

TPL 126-128°

Example 15

Acridine-9-yl-[4-(3-methoxyphenyl)-piperazine-1-yl]-methanon (D-82318)

MS: m/e=398 (M+H)

1H-NMR (DMSO-d6) δ=of 8.25 (d,2H), 7,95 (d,2H), 7,9 (dd,2H), and 7.7 (dd,2H), and 7.1 (dd,2H), and 6.5 (d,1H), 6,45 (s,1H), 6,4 (d, 1H), 4,1 (m,2H), and 3.7 (s,3H), of 3.45 (m,2H), 3,1 (m,2H), 2.95 and (m,2H) ppm

TPL 188-189°

Example 16

4-[4-(Acridine-9-carbonyl)-piperazine-1-yl]-butyronitrile (D-82673)

MS: m/e=359 (M+H)

1H-NMR (DMSO-d6) δ=of 8.25 (d,2H), 7,95 (m,4H), and 7.7 (m,2H), and 3.7 (m,2H), 3,6 (m,4H), 3,5 (m,2H), 3,2 (m,2H), and 2.6 (m,2H), 1,95 (m,2H) ppm

TPL 201-204°

Example 17

Acridine-9-yl-[4-(3,5-dihydroxyphenyl)-piperazine-1-yl]-methanon (D-82747)

MS: m/e=400 (M+H)

1H-NMR (DMSO-d6) δ=8,4 (d,2H), and 8.2 (m,4H), 7,9 (m,2H), to 5.85 (s,2H), and 5.8 (s,1H), 4,1 (m,2H), 3,5 (m,2H), 3,2 (m,2H), 2,85 (m,2H) ppm

TPL 260°

Example 18

Acridine-9-yl-[4-(3-methoxyphenyl)-piperazine-1-yl]-retention (D-87088)

1H-NMR (DMSO-d6) δ=8,16 (d,2H), of 7.97 (d,2H), 7,86 (dd,2H), to 7.64 (dd,2H), to 7.09 (dd,1H), 6.48 in (dd,1H), gold 6.43 (s,1H), 6,38 (dd,1H), 4,70-4,72 (m,2H), to 3.67 (s,3H), to 3.67 (s,3H), 3,57-of 3.60 (m,2H), 3.33 and-to 3.36 (m,2H), 2,98-a 3.01 (m,2H) ppm

TPL 218°

1. Antiproliferative effect on various tumor cell lines

For compounds of examples 1, 3, 4, 8, 12-15, 18 determine the antiproliferative activity with the use of resistant tumor cell lines and method of analysis of proliferation. In this analysis, we define the act shall want to make cellular dehydrogenase as a measure of cell viability and indirectly the number of cells. Used cell lines are cell line carcinoma human cervical KB/HeLa (ATCC CCL17), lymphocytic leukemia mouse L1210 (ATCC CCL-219), adenocarcinoma of human breast MCF7 (ATCC HTB22) and adenocarcinoma ovarian SKOV-3 (ATCC HTB77), and lung carcinoma NCI-H460 (NCI 503473). Using well-characterized stable cell line obtained in the ATCC, and cultured them.

Table 1 shows the results indicate extremely high antiproliferative activity of these compounds against cell lines SKOV-3, L-1210 and HeLa/KB. In connection with the special slow growth lines MCF7 observed only a small effect connection D-43411 in the period of the experiment (48 h): suppression is 18% at a concentration of 3.16 mg/ml, the amount of cytotoxicity is >3,16).

Table 1.

Activity in vitro of the compounds of examples 1, 3, 4, 8, 12-15, 18.
Analysis using XTT, ES, ug/ml
ExampleKB/HelaSKOV3SF-268NC1-H460RKOP27
1(D-43411)0,0060,0050,0050,0110,016
3(D-81694)0,0610,061 0,0370,080,058
4(D-81745)to 0.0320,0290,0400,0490,020
8(D-81851)0,1940,1280,1520,1890,077
12 (D-81852)0,0060,0140,0070,0190,015
13 (D-82316)0,0110,0090,0150,0110,011
14 (D-82317)0,0130,0170,0150,019to 0.032
15 (D-82318)0,0040,0080,0040,0060,005
18 (D-87088)0,0130,0130,0130,0160,016

2. Methods

The determination of the activity of cellular dehydrogenase using XTT

The growing line of adhesive cell lines HeLa/KB, SKOV-3 and MCF7, and the suspension is growing leukaemia cell line L1210 cultivated under standard conditions in an incubator at 37°C, 5% CO2and 95% humidity. On the first day of the test cells are removed by treatment with trypsin/EDTU and precipitated by centrifugation. Then the cellular precipitate, containing the appropriate number of cells, resuspended the t in culture medium RPMI and contribute in a 96-well microplate. Tablets cultivated in an incubator overnight. Prepare the original solutions of the investigated compounds in DMSO and on day 2 was diluted to the appropriate concentration of the culture medium. Then join in the culture medium was added to cells and incubated in the incubator for 45 hours as a control using cells not treated with the investigational compound.

For analysis using the XTT solution prepared XTT (sodium salt of 3'-[1-(phenylenecarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzosulfimide acid) with a concentration of 1 mg/ml in medium RPMI-1640 without finalmessage. In addition, prepare a solution of PMS (methyl sulfate N-methyldibenzothiophene) with a concentration 0,383 mg/ml in saline phosphate buffer solution (PBS). On the 4th day tablets with cells treated with the investigational compounds for 45 h, with a pipette and make a mixture Templ/PMS 75 ál into the hole. To do this, before using the XTT solution briefly stirred with a solution of PMS in the ratio of 50:1 (vol./vol.). Then the tablets with the cells are again incubated in the incubator for a further 3 h and determine the optical density in a spectrophotometer (ODNm).

Then using specific values OD490 nmcalculate the percentage of inhibition compared with the control cells. Antiproliferative effect estimate using regression what about the analysis.

Example 19. Tablets containing 50 mg of active substance

Composition:

(1) Active substance50.0 mg
(2) Milk sugar98,0 mg
(3) Corn starch50.0 mg
(4) Polyvinylpyrrolidone15,0 mg
(5) magnesium Stearate2.0 mg
Total:215,0 mg

Method of delivery:

Components (1), (2) and (3) are mixed and granularit mixed with an aqueous solution of the component (4). To the dried granules are added during the mixing of the component (5). The resulting mixture is pressed to tablets.

Example 20. Capsules containing 50 mg of active connections

Composition:

(1) Active substance50.0 mg
(2) Dried corn
starch58.0 m g
(3) Powdered milk
sugar50.0 mg
(4) magnesium Stearate2.0 mg
Total:160,0 mg

Method of delivery:

Component (1) pound of component (3). The resulting mixture was added to the mixture of components (2) and (4) when intensive paramesh the processes. This powder mixture is filled hard gelatin stamped capsules of size 3 using the apparatus for filling capsules.

1. Derivatives of acridine General formula 1

where

R, R1, R2, R3mean hydrogen;

Z denotes oxygen or sulfur, and Deputy acridine residue of the formula

can be connected with9atom acridine residue;

P, Q denote two hydrogen atoms (CH2-);

X is nitrogen or C-R5and R5means hydrogen;

n=2, m-0,

R4means linear or branched (C1-C3)alkyl residue, which can be substituted by the same or different carbon atoms with one, two or more substituents, selected from a number of: aryl, C4-10heteroaryl containing 1 or 2 heteroatoms selected from O or N; cyano; R4means (C6-C10)aryl residue, (C6-C10)aryl(C1-C3) alkyl residue or (C2-C10)heteroaryl residue or (C2-C10) heteroaryl(C1-C3)alkyl residue containing at least one heteroatom selected from N, O, and (C6-C10)aryl or (C -C10) heteroaryl residues may be unsubstituted or substituted by one or more identical or different substituents selected from the range of: linear or branched (C1-C8)alkyl, halogen, cyano, (C1-C6) alkoxy, hydroxy;

and their pharmaceutically acceptable salts, especially acid additive salt.

2. Derivatives of acridine according to claim 1, characterized in that R, R1, R2, R3, X, Z, P, Q, n and m are defined in claim 1 values and R4means linear or branched (C1-C3)alkyl residue, which can be unsubstituted or substituted choice on the same or different carbon atoms with one, two or more substituents, selected from a number of: aryl, C4-10heteroaryl containing 1 or 2 heteroatoms selected from O and N; phenyl or nattily residues, which in each case are unsubstituted or substituted by one or more, same or different substituents selected from the range of: linear or branched (C1-C8)alkyl, halogen, hydroxy, linear or branched (C1-C8)alkoxy, preferably methoxy or ethoxy; 6-personilnya balance; 6-peredelnyj residue, which may be unsubstituted or may contain one to four identical or different substituents chosen from the series hydrogen, (C1-C6)alkyl, cyano; 6-pyridyl(C1-C6)alkyl residue.

3. Derivatives of acridine according to claim 1 or 2, characterized in that R, R1, R2, R3, X, Z, P, Q, n and m are defined in claim 1 values, a R4means phenyl, which is unsubstituted or contains as substituents of one to five identical or different (C1-C6)-alkoxygroup.

4. Derivatives of acridine one of claims 1 to 3, characterized in that R, R1, R2, R3, X, Z, P, Q, n and m are defined in claim 1 values, a R4means 3,5-acid.

5. Derivatives of acridine according to one of claims 1 to 4, characterized in that R4is defined in claim 1 values, a R, R1, R2, R3in each case mean a hydrogen atom, Z means oxygen atom, X denotes a nitrogen atom, P and Q in each case denote two hydrogen atoms (CH2-), m is zero and n is an integer 2.

6. Derivatives of acridine according to one of claims 1 to 5, characterized in that R, R1, R2, R3in each case mean a hydrogen atom, Z means oxygen atom, X denotes a nitrogen atom, P and Q in each case denote two hydrogen atoms (CH3-), m is zero, n is an integer 2, a R4means 3,5-acid.

7. Derivatives of acridine according to one of claims 1 to 6, characterized in that they are used in ka is este active component of the medicinal product, with antitumor activity.

8. The method of obtaining the derivative of acridine according to one of claims 1 to 6, characterized in that greencarbon acid of General formula (2),

where R, R1, R2, R3have defined in claim 1 values, Z means oxygen atom or sulfur, a Y means delete the group, such as halogen, hydroxy, (C1-C6)alkoxy, preferably methoxy or ethoxy, -O-tosyl, -O-mesyl or imidazolyl lead in the interaction with the amine of General formula (3)

where R4, X, P, Q, m, and n are defined in claim 1 values, with the formation of the desired derivative of acridine if necessary with the use of diluents or excipients.

9. Pharmaceutical composition having antitumor activity and containing at least one derivative of acridine according to one of claims 1 to 6 as an active ingredient in an effective amount, in a mixture with standard pharmaceutically acceptable auxiliary substances, additives or carriers in required quantities.



 

Same patents:

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to substituted derivatives of N-benzylindol-3-yl-glyoxylic acid of the formula (1): wherein groups R, R1, R2, R3, R4 and Z have the following values: R means -NO2, -NH2, (C1-C6)-acylamino-, aroylamino-, nicotinoyl or isonicotinoyl, arylsulfonylamino-, succinimido- wherein this residue R can be substituted with (C1-C6)-group by choosing by carbon atom at positions 2, 3 and 4 of phenyl ring; R1 means hydrogen atom (H), (C1-C6)-alkyl that can be replaced with at least one phenyl group; R2 means pyridyl; R3 and R4 mean H; Z means oxygen (O), sulfur (S) atom. Compounds of the formula (1) possess an antitumor effect that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

6 cl, 2 dwg, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new heteroaryl derivatives, in particular, derivatives of quinoline of he general formula (I): wherein R, R1, R2 and R3 are similar or different and mean independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl, halogen atom, aryl-(C1-C8)-alkoxy-group, aryl. Except for, R and R1 or R2 and R3 can form six-membered aromatic ring condensed with quinoline residue; X means oxygen atom; p, Q mean in each case -CH2-; X means nitrogen atom; n = 2; m = 0; R4 means phenyl or pyridyl. Also, invention relates to their pharmaceutically acceptable salts, in particular, acid-additive salts. Compounds are useful as antitumor agents. Also, invention describes a method for preparing compounds and medicinal agent based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

11 cl, 2 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: medicine.

SUBSTANCE: method involves combining vaccine prepared from 107 cells of autologic tumor lysate with 60 mg of betaleukine and introducing it strictly in intracutaneous paravertebral mode in three points arranged 3 cm far from each other. The introduction takes place every 3 weeks so that the first two vaccinations are combined with 470 mg of betaleukine introduced into anterior abdominal wall. Vaccination treatment is continued on receiving positive retarded type hypersensitivity response to injection after every vaccination with tumor lysate without betaleukine.

EFFECT: enhanced effectiveness in inducing and supporting antitumor immune response.

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to method for malignant tumor treatment (including cancer, sarcoma, melanocytoma) in human by ectasceine ET743 intravenous infusion in dose of 500-1650 mug/m2 of surface are; to similar treatment by combination of ET743 with antiemetic agent; as well as to relative composite preparation. Method of present invention provides clinical amelioration in subject suffering from progressive or metastasing cancer and improves treatment effectiveness of diseases being progressed after known chemotherapy.

EFFECT: new effective method for cancer treatment; drug with good acceptability.

31 cl, 3 ex, 1 tbl

FIELD: medicine, oncology, gastroenterology, immunobiotechnology.

SUBSTANCE: invention describes an antibody or its derivative, or its fragment showing the structure able to bind the target structure. Antibody is located inside and on surface of human gastroenteric tract epithelial tumor cells and in subpopulation of normal gastroenteric tract epithelial cells. Indicated binding structures comprise sequences determining the complementarity of the region (CDR) in light chain comprising in main amino acids at number 23-33 (CDR 1), 49-55 (CDR 2), 88-98 (CDR 3) of amino acid sequence represented in SEQ ID NO:2, and CDR sequence in heavy chains comprising in main amino acids at number 158-162 (CDR 1), 177-193 (CDR 2), 226-238 (CDR 3) of amino acid sequence represented in SEQ ID NO:2, or other binding structures with similar unique binding properties. Also, invention describes the target-structure located inside or on surface of tumor cells: vaccine composition designated for treatment of malignant disease in human and comprising abovementioned antibody. Also, invention describes methods for treatment and diagnosis of malignant disease. Using this invention provides preparing antibodies that relieve identification of new phenotype-specific tumor-associated antigens, to predict and treat metastatic human diseases. Invention can be used in medicinal practice.

EFFECT: valuable medicinal properties of antibodies.

37 cl, 21 dwg, 4 tbl, 8 ex

Chalcone coumarins // 2266291

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): or their pharmaceutically acceptable salts or solvates wherein Ar represents a substituted or unsubstituted (preferably aromatic one) carbocyclic or heterocyclic group wherein abovementioned carbocyclic or heterocyclic group comprises 5 or 6 atoms in cyclic structure wherein a heteroatom is taken among the group consisting of nitrogen (N) and sulfur (S) atom and any substitutes at Ar group are taken independently of one another of the group consisting of Cl, Br, F atoms and OR10 wherein R10 represents saturated or unsaturated lower hydrocarbon (C1-C6)-radical of normal or branched structure; R represents OR10 wherein R10 corresponds to above given value; R1 represents lower hydrocarbon (C1-C6)-radical of normal or branched structure under condition that if R1 represents -CH3 and R means -OCH3 or -OH then Ar group can't represent 4-methoxyphenyl or 3,4-dimethoxyphenyl. Also, invention proposes a component of medicinal agent used in treatment or prophylaxis of neoplasms. Also, invention proposes a pharmaceutical composition possessing with an anti-proliferative activity and comprising the effective amount of one or some compounds of the formula (I) in combination with one or some pharmaceutically acceptable additives. Invention provides the development of chalcone coumarins possessing with the enhanced anti-proliferative effect with respect to sensitive tumor cells, cells with resistance to conventional chemotherapeutic agents, among them, to anti-tumor medicinal agents of the last generation represented by paclitaxel and docetaxel.

EFFECT: valuable medicinal properties of compounds and compositions.

1 tbl, 21 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to substituted derivatives of N-benzylindol-3-yl-glyoxylic acid of the formula (1): wherein groups R, R1, R2, R3, R4 and Z have the following values: R means -NO2, -NH2, (C1-C6)-acylamino-, aroylamino-, nicotinoyl or isonicotinoyl, arylsulfonylamino-, succinimido- wherein this residue R can be substituted with (C1-C6)-group by choosing by carbon atom at positions 2, 3 and 4 of phenyl ring; R1 means hydrogen atom (H), (C1-C6)-alkyl that can be replaced with at least one phenyl group; R2 means pyridyl; R3 and R4 mean H; Z means oxygen (O), sulfur (S) atom. Compounds of the formula (1) possess an antitumor effect that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

6 cl, 2 dwg, 3 tbl, 9 ex

FIELD: pharmaceutical and cosmetic industries, biological aromatic vitamin D analogs.

SUBSTANCE: invention relates to compounds selected from group containing (E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-in-2-ol, (3E,5E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, (E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]phenyl}-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-in-2-ol; and (3E,5E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]phenyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, as well as from abovementioned compounds wherein one or more hydroxyl groups have protective group of formula -(C=O)-R, wherein R represents linear or branched C1-C6-alkyl, or C6-C10-aryl, or C7-C11-aralkyl; and aryl and aralkyl radicals may be substituted with one or two hydroxyl groups, C1-C3-alkoxy groups, halogen atoms, nitro or amino groups. Also disclosed are methods for application of said analogs in pharmaceutical composition with cell proliferation and differentiation activity useful in therapy and veterinary (i.e. dermatology, oncology, autoimmune diseases, organ and tissue transplantation), as well as in cosmetic composition.

EFFECT: vitamin D analogs with value pharmaceutical and cosmetic properties.

12 cl, 5 tbl, 6 dwg, 10 ex

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a spontaneously dispersing composition comprising N-benzoylstaurosporin, a hydrophilic component, a lipophilic component and a surface-active substance taken in the definite ratio of components. Also, invention relates to a method for treatment of the patient needing administration of N-benzoylstautosporin as a component of the spontaneously dispersing composition. The composition possesses the enhanced level of biological availability or diminished variability of the biological availability levels and effectiveness.

EFFECT: improved and valuable properties of composition.

13 cl, 3 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new heteroaryl derivatives, in particular, derivatives of quinoline of he general formula (I): wherein R, R1, R2 and R3 are similar or different and mean independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl, halogen atom, aryl-(C1-C8)-alkoxy-group, aryl. Except for, R and R1 or R2 and R3 can form six-membered aromatic ring condensed with quinoline residue; X means oxygen atom; p, Q mean in each case -CH2-; X means nitrogen atom; n = 2; m = 0; R4 means phenyl or pyridyl. Also, invention relates to their pharmaceutically acceptable salts, in particular, acid-additive salts. Compounds are useful as antitumor agents. Also, invention describes a method for preparing compounds and medicinal agent based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

11 cl, 2 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: pharmaceutical technology.

SUBSTANCE: method involves extraction of the above-ground part of yellow poppy (Glaucium flavum Crantz.) with an organic solvent, the following filtration, alkalization of an aqueous-acid solution, extraction of alkaloids with an organic solvent, removing an organic solvent under vacuum, treatment of prepared glaucine base with hydrochloric acid and purifying the product. Extraction of vegetable raw is carried out with 60% aqueous alcohol solution in the presence or tribasic mineral acid, for example, phosphoric acid. Organic solvent is removed under vacuum, an aqueous vat residue is neutralized with mixture of calcium carbonate and calcium chloride, or calcium carbonate and aluminum chloride followed by filtration. Filtrate is alkalinized to obtain alkaloid bases that are extracted from an aqueous phase with an organic solvent, preferably, with aromatic solvent, for example, with benzene or toluene. Organic phase is evaporated under vacuum, residue is treated with hydrochloric acid and product is subjected for purification, or after filtration alkaloid hydrochlorides formed are extracted with chloroform. Organic phase is evaporated under vacuum and product is subjected for purification. Invention provides simplifying the process.

EFFECT: improved preparing method.

2 cl, 5 ex

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