RU2240313C2 - Medicinal agents for treatment of malignant tumors - Google Patents

Abstract

FIELD: organic chemistry, medicine, oncology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an agent used for preparing a medicinal agent for treatment of breast and prostate cancer and representing derivative of quinoline of the general formula (I)

Except for, invention relates to new compounds, pharmaceutical compositions and methods for preparing compounds of the formula (I). Agents elicit high specificity and effectiveness.

EFFECT: valuable medicinal properties of compounds.

115 cl, 2 tbl

Description

FIELD OF THE INVENTION

The present invention relates to the field of engineering and medicine and, in particular, to the use of quinoline derivatives for the production of drugs for the clinical treatment of various malignant tumors, especially solid tumors. In addition, the present invention relates to structurally new quinoline derivatives, to methods for their preparation and to compositions containing quinoline derivatives. Types of cancer that are suppressed by the quinoline derivatives of the present invention include, for example, breast cancer, colon cancer, Kaposi’s sarcoma, lung cancer, ovarian cancer, prostate cancer, and skin cancer. More specifically, the present invention relates to quinoline derivatives suitable for the treatment and prevention of prostate cancer metastases.

State of the art

Solid tumors, primary or metastases, consist of several types of cells in which the tumor cells are central type cells and are the driving force. When a certain size is reached, the need for nutrients of the micro-tumor cannot be satisfied due to the usual diffusion. New vessels penetrate the tumor, organizing a microenvironment that provides the tumor with optimal nutrition for further proliferation and growth. This tumor-induced development of blood vessels leading to the proliferation, migration, and differentiation of normal endothelial cells from neighboring small blood vessels is a prerequisite for the growth of solid tumors. Accordingly, inhibition of the development of blood vessels leads to an effective suppression of the growth of solid tumors.

Solid tumors spread by penetrating tissue boundaries and cause daughter cell colonies or metastases. Individual tumor cells or small cell aggregates spread through the circulatory or lymphatic system to distant sites. In this process, tumor cells are vulnerable and can be inhibited by natural killer cells (NK), a certain type of cytotoxic lymphocyte. An increased activity or an increased number of NK cells weakens or suppresses the formation of metastases of a solid malignant tumor. Prostate cancer is a disease with a malignant tumor that spreads over a considerable distance in the form of tumor metastases and includes tumors with a strong dependence on the formation of new vessels. Prostate cancer has long been known as the main disease of men, and it becomes more common and dangerous with an aging population. It is an adenocarcinoma, which is the second most deadly, after lung cancer. Currently, prostate cancer causes approximately 35,000 deaths annually in the United States alone. To date, there have been no effective treatments for and prevention of prostate cancer. In the early stages of a hormone-dependent cancer, treatment usually involves removal of the testicle or chemical castration. At a later stage, prostate cancer is independent of the hormone content, and metastases are widespread, usually primarily to the skeleton. Treatment of a progressive disease first involves hormonal manipulations and palliative radiotherapy or treatment with cytostatic agents. It has been shown that such a strategy gives a significant clinical effect in symptomatic sedation, but there are no effective methods that can put prostate cancer at this stage into a state of remission. The use of cytotoxic agents to suppress hormone-independent, progressive prostate cancer is currently not well understood. Few individual agents have become the objects of “conventional therapy”, despite the lack of demonstration of their effectiveness by modern standards. Thus, prostate cancer is not only relatively common, but also resistant to the effects of treatment, after the disease passes into the stage of independence from hormones.

In US patent No. 4547511 and in Europatent 59698 described some derivatives of N-aryl-1,2-dihydro-4-amino-1-alkyl-2-oxoquinoline-3-carboxamide and N-aryl-1,2-dihydro-4- hydroxy-1-alkyl-2-oxoquinoline-3-carboxamide as agents that enhance cellular immunity. It reported that Roquinimex (Merck Index, 12 ^{th Ed, №8418;. Linomide®,} N- methyl-N-phenyl-l, 2-dihydro-4-hydroxy-l-methyl-2-oxoquinoline-3-carboxamide) has antitumor activity against prostate cancer Dunning R-3327 in rats [1].

Several 5-substituted N-aryl-1,2-dihydro-4-hydroxy-1-alkyl-2-oxoquinoline-3 are known from WO 99/55678, PCT / SE / 99/01270 and PCT / SE / 99/01271 -carboxamides, which are effective in the treatment of diseases resulting from autoimmune and pathological inflammation.

A compound of Roquinimex with a known activity against the development of blood vessels and a proactivator of NK lymphocytes also causes pro-inflammatory side effects in humans, which is especially pronounced in the treatment of patients with renal cell carcinoma [2]. In this study, the Roquinimex compound is poorly tolerated: 40% of patients were excluded or the dose was reduced due to worsening conditions, mainly due to symptoms of muscle pain, joint pain and fatigue. In some cases, pericarditis and neuropathy were also observed.

The pro-inflammatory effects caused by the agent Roquinimex are effectively traced on beagle dogs. Agent Roquinimex causes pain in hounds of dogs, characterized by fever, muscle pain, joint pain, and inflammation of the arterial wall [3, 4].

SUMMARY OF THE INVENTION

The main objective of the present invention is the use of quinoline derivatives for the manufacture of a medicament for the treatment of various malignant tumors, especially solid tumors. Another objective is to provide structurally new quinoline derivatives having a pharmacological profile that is highly active in experimental models with a low level of side effects. Types of cancer that are particularly well suppressed by such quinoline derivatives include, for example, breast cancer, colon cancer, Kaposi’s sarcoma, lung cancer, ovarian cancer, prostate cancer, and skin cancer. More specifically, the present invention relates to quinoline derivatives suitable for preventing the spread of malignant tumors, especially prostate cancer. To increase the effectiveness of the treatment of metastatic malignant tumors, in particular prostate cancer, an effective therapy of malignant tumor cells, especially androgen-independent prostate cancer cells, is necessary. The approach chosen by the inventors is to inhibit the development of blood vessels caused by a tumor, and to stimulate the immune system of the host cells in order to induce / enhance the antitumor response. The present invention tested the ability of quinoline compounds to exhibit antitumor activity against androgen-independent prostate cancer Dunning R-3327 AT-1 in rats.

Unexpectedly, in this invention it was found that the compounds of general formula (I):

in which A is selected from OR ₄₁ and NR ₄₂ R ₄₃ , in which R _{41 is} selected from a hydrogen atom and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium, and organic cations, such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like like;

and a COR _A group in which R _{a is} selected from alkyl and aryl groups such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, neo-pentyl, phenyl, benzyl, phenethyl and the like;

R ₄₂ and R ₄₃ are the same or different and are selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl and cyclohexyl; or R _{42 is} selected from benzyl and phenethyl optionally mono- or disubstituted by a group selected from methyl, iso-propyl, methoxy, fluoro, chloro, bromo, dimethylamino, trifluoromethyl and nitro and R ₄₃ represents a hydrogen atom ; or

R ₄₂ and R ₄₃ together with the nitrogen atom to which they are attached form a five- or six-membered ring; or

R ₄₂ represents a COR _B group in which R _{B is} selected from alkyl and aryl groups such as C1-C4 alkyl, phenyl, benzyl and the like; or from —CH ₂ N (CH ₃ ) ₂ and –CH ₂ CH ₂ COOH; or

COR _in is a 2-acyloxymethylbenzoyl group

in which R _{C is} selected from methyl, ethyl, phenyl and benzyl and the like; or

R ₄₂ represents a COOR _D group in which R _{D is} selected from C1-C4 alkyl, phenyl and benzyl; or

R ₄₂ represents a —CH ₂ OCO-tert-butyl group; or

R ₄₂ represents CONR _F R _G , in which R _F and R _G are the same or different and are C1-C4 alkyl;

or

R ₄₂ represents a CXNHR _E group in which X is selected from an oxygen or sulfur atom and R _{E is} selected from C1-C4 alkyl, C2-C4 alkyl functionalized with a tertiary amino group, and phenyl optionally functionalized with a p-chloro group ; or

R ₄₂ represents CH ₂ NR _H R _I , in which R _H and R _I are the same or different and are C1-C4 alkyl or R _H , and R _I , together with the nitrogen atom to which they are attached, form a morpholine ring; and

R _{43 is} selected from a hydrogen atom, methyl, ethyl and cyclopropyl;

R is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and allyl; with the proviso that R is not a hydrogen atom when A is an OR ₄₁ group;

R 'is selected from a hydrogen atom, methyl, methoxy, phenyl, fluorine, chlorine, bromine, cyano, nitro, azido, trifluoromethyl, and OCH _x F _y in which

x = 0-2,

y = 1-3, provided that

x + y = 3;

and provided that R 'is not a hydrogen atom when R is methyl and A is OR ₄₁ ;

R ’’ is selected from a hydrogen, fluorine and chlorine atom, provided that R ’’ is selected from a fluorine and chlorine atom only when R ’is selected from a fluorine and chlorine atom;

R _{5 is} selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, fluorine, chlorine, bromine, trifluoromethyl, nitro , amino, dimethylamino and OCH groups _x F _y , and OCH ₂ CH _x F _y , in which

x = 0-2,

y = 1-3, provided that

x + y = 3 and

under additional conditions that R _{5 is} not a fluorine atom or an amino group when A is OR ₄₁ ; and that R ₅ represents a hydrogen atom only when A is a group NR ₄₂ R ₄₃ and R 'is trifluoromethyl;

R ₆ represents a hydrogen atom; or

R ₅ and R ₆ taken together represent a methylenedioxy group;

unexpectedly effective and specific in the treatment of patients suffering from advanced cancer.

The compounds of general formula (I) may exist in various tautomeric forms, and all such forms, if any, are included in this invention. In addition, all optical isomers and racemates of the compounds of general formula (I) are included in the invention, if such forms exist.

In a preferred embodiment, R _{5 is} selected from methyl, ethyl, methoxy, ethoxy, thiomethyl, thioethyl, chlorine and bromine, or R ₅ and R ₆ taken together are methylenedioxy, A is selected from —OR groups ₄₁ and NR ₄₂ R ₄₃ in which R _{41 is} selected from a hydrogen atom and sodium, and in which R ₄₂ and R ₄₃ are the same or different and selected from a hydrogen atom, methyl and ethyl, R is selected from a hydrogen atom, methyl, ethyl and n-propyl, especially from methyl and ethyl, and R 'is selected from a hydrogen atom, a para-methyl group, phenyl, methoxy, chloro -, trifluoromethyl and azido-, especially from methoxy, chloro, and trifluoromethyl, when R ″ represents a hydrogen atom and R ″ is selected from meta and para-fluoro, provided that R ’is ortho fluoro group.

In addition, the invention describes new compounds of General formula (I ’)

in which R ₄₂ and R ₄₃ are the same or different and are selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl and cyclohexyl; or

R _{42 is} selected from benzyl and phenethyl, optionally mono- or disubstituted, with a group selected from methyl, isopropyl, methoxy, fluoro, chloro, bromo, dimethylamino, trifluoromethyl and nitro, and R ₄₃ represents a hydrogen atom; or

R ₄₂ and R ₄₃ , together with the nitrogen atom to which they are attached, form a five- or six-membered ring; or

R ₄₂ represents a group COR _B ,

in which R _{B is} selected from alkyl and aryl groups such as C1-C4 alkyl, phenyl, benzyl and the like; or from the groups —CH ₂ N (CH ₃ ) ₂ and —CH ₂ CH ₂ COOH; or COR _B is a 2-acyloxymethylbenzoyl group

in which R _{C is} selected from methyl, ethyl, phenyl and benzyl and the like; or R ₄₂ represents a COOR _D group in which R _{D is} selected from C1-C4 alkyl, phenyl and benzyl; or R ₄₂ represents –CH ₂ OCO-tert-butyl; or

R ₄₂ represents CONR _F R _G , in which R _F and R _G are the same or different and are C1-C4 alkyl;

or

R ₄₂ represents a CXNHR _E group in which X is selected from an oxygen or sulfur atom and R _{E is} selected from C1-C4 alkyl, C2-C4 alkyl functionalized with a tertiary amino group, and phenyl optionally functionalized with a p-chloro group ; or

R ₄₂ represents CH ₂ NR _H R _I in which R _H and R _I are the same or different and are C1-C4 alkyl or R _H and R _I, together with the nitrogen atom to which they are attached, form a morpholine ring; and R _{43 is} selected from a hydrogen, methyl, ethyl, and cyclopropyl atom;

R is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl;

R 'is selected from a hydrogen atom, methyl, methoxy, fluorine, chlorine, bromine, cyano, nitro, azido, trifluoromethyl, and OCH _x F _y , in which

x = 0-2,

y = 1-3, provided that

x + y = 3;

R ’’ is selected from a hydrogen, fluorine and chlorine atom, provided that R ’’ is selected from a fluorine and chlorine atom only when R ’is selected from fluorine and chlorine;

R _{5 is} selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, fluorine, chlorine, bromine, trifluoromethyl, nitro , amino, dimethylamino and OCH _x F _y groups, and OCH ₂ CH _x F _y , in which

x = 0-2,

y = 1-3, provided that

x + y = 3 and

with the proviso that R ₅ represents a hydrogen atom only when R 'represents trifluoromethyl; R ₆ represents a hydrogen atom; or R ₅ and R ₆ taken together represent a methylenedioxy group;

or any tautomeric form thereof, optical isomer or racemate;

as well as new compounds of the general formula (I ’’)

in which R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl;

R _{41 is} selected from a hydrogen atom and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium, and organic cations, such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like; and COR _A groups in which R _{A is} selected from alkyl and aryl groups such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl, neo-pentyl, phenyl, benzyl, phenethyl and the like;

R ’is selected from a hydrogen atom and phenyl;

R ’’ represents a hydrogen atom;

R ₅ represents methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, a chlorine atom, bromine, trifluoromethyl, dimethylamino and the group OCH _x F _y , and OCH ₂ CH _x F _y , in which

x = 0-2,

y = 1-3, provided that

x + y = 3 and

under the additional condition that R 'represents only a hydrogen atom when R ₅ is a dimethylamino group and R is different from methyl;

or any tautomeric form thereof, optical isomer or racemate.

Among the most preferred compounds are: N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1- methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide or its sodium salt, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-1,2- dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide, N- tyl-N-phenyl-1,2-dihydro-4-hydroxy-5-dimethylamino-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N- (3-fluoro-phenyl) -1, 2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chlorophenyl) -1,2-dihydro-4-hydroxy-5- chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-methyl-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2- oxo-quinoline-3-carboxamide, N-methyl-N- (4-phenyl-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,5-difluoro-phenyl) -1,2-dihydride o-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N- (3-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5- ethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl- 2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,5-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline- 3-carboxamide, N-methyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl- N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro phenyl) -1,2-dig dro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5- ethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-n-propyl-N-phenyl-1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline- 3-carboxamide, N-methyl-N- (4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl- N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro -phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,5-difluoro-phenyl) -1, 2-dihydro-4-hydro si-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-methoxy-phenyl) -1,2-dihydro-5-dimethylamino-4-hydroxy-1- methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N-phenyl-4-amino-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide, N-methyl- N-phenyl-4-amino-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N-phenyl-5-chloro-1,2-dihydro 4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N-phenyl-1,2-dihydro-1,5-dimethyl-4- (N-methylamino) - 2-oxo-quinoline-3-carboxamide, N-methyl-N-phenyl-1,2-dihydro-5-methoxy-4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4- riftorometil-phenyl) -4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide.

The high energy of the crystal lattice of the solid compound leads to poor solubility of the compound, for example, in water. Therefore, an approach to reduce this energy will lead to improved solubility in water. The drug precursor itself is an inactive compound. The main condition when searching for a drug precursor is the reverse conversion of the drug precursor to the parent drug in the body. Conversion of the precursor into a drug can take place before, during, or after absorption. The necessary conversion of the drug precursors to the molecules of the starting drug substance in the body can proceed through a variety of reactions. The most common drug precursors are those that require hydrolytic cleavage with intermediate enzymatic hydrolysis. In other cases, drug molecules are regenerated from their precursors using biochemical reduction or oxidation processes.

The esters of drug compounds containing a hydroxyl group were considered as a precursor of drugs, mainly on the basis that there are many enzymes in the body that can hydrolyze esters. The compounds of the present invention contain an enolized carbonyl group as a known functional group. Under appropriate conditions, the enol form can be fixed by acylation of the enol group. Steric and electronic effects within the acyl group have a significant effect on the rate of hydrolysis both in water and under the action of the enzyme. In addition, physicochemical properties such as water solubility, lipophilicity and dissolution rate can be modified for the starting compound. The compounds of the present invention contain an amine function at position-4. Acylation of amines on nitrogen, with the formation of activated amides, can be a promising way to obtain forms of the drug precursor. 2-Hydroxymethylbenzamides undergo cyclization (lactonization) in an aqueous solution with the formation of phthalide and a free amine. Substitution of two hydrogen atoms in the methylene group of 2-hydroxymethylbenzamide, for example, methyl and phenyl groups, strongly affects the rate of lactonization. In addition, blocking the lactonization process by acylating 2-hydroxymethylbenzamides to form 2-acyl-hydroxymethylbenzamides inhibits lactonization, which should be preceded by hydrolysis of the ester group. Moreover, acylation allows you to adjust the ratio of lipophilicity / hydrophilicity in the drug precursor due to the appropriate choice of the acyl group. The use of various carbamate derivatives, as well as Mannich N bases, can also be considered as a method of forming a drug precursor.

The compounds of general formula (I) are tested for their ability to inhibit the growth of prostate cancer in rats Dunning R-3327 AT-1. As a positive control of treatment, Roquinimex was used, which gives 30% inhibition at a dose of 4 mg / kg.

Compounds of general formula (I) in which A represents a group NR ₄₂ N ₄₃ are prepared as follows:

Method A

The compounds of formula (I ′) can be prepared by known methods, for example, by reacting a 4-chloro-1,2-dihydro-2-oxo-quinoline-3-carboxamide derivative (X = Cl; II) known from US Pat. No. 4,547,511 , with an amine compound in a suitable solvent, such as an alcohol, for example ethyl alcohol. All compounds had satisfactory ¹ H-NMR spectra and mass spectra, although the NMR spectra were complex because of the presence of E and Z amide isomers. Only the main isomer of the shifts in the NMR spectrum is described below.

Method B.

Compounds of general formula (I ’’) can be prepared according to methods known from US Pat. No. 6,077,851, and, for example, as shown above, by reacting the ester derivative of quinoline carboxylic acid with aniline in a suitable solvent, such as toluene, xylene and the like. General methods for preparing ester derivatives of a quinoline carboxylic acid of formula (III) are known from US Pat. No. 4,547,511. N-Alkylated anilines of formula (IV) are commercially available from the literature, for example, from Johnstone et al., J. Chem. Soc. 1969, 2223-2224. Compounds within the scope of formula (IV) can be prepared by methods that are substantially similar to those cited in the literature.

Information confirming the possibility of carrying out the invention

The scope of the invention is defined by the claims below. The following examples are intended to illustrate the invention without limiting its scope.

Example 1. N-Methyl-N-phenyl-4-chloro-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide

N-Methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide (3.5 g) is heated in phosphorus oxytrichloride (7 ml) at 100 ° C for 2 hours. The mixture was concentrated, dissolved in dichloromethane and washed with water. The organic phase is dried (Na ₂ SO ₄ ) and concentrated. The residue was triturated with ethyl acetate and filtered to give the title compound (2.3 g).

¹ H NMR (CDCl ₃ ): δ 7.50-7.00 (8H, aromatic protons), 3.60 (N-Methyl, s), 3.48 (N-Methyl, s), 2.80 (Phenylmethyl , from).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 341.

In almost the same way, the following compounds are prepared from the corresponding starting materials:

N-methyl-N-phenyl-4,5-dichloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.55-7.15 (8H, aromatic protons), 3.60 (N-methyl, s), 3.47 (N-methyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 361.

N-methyl-N- (4-trifluoromethylphenyl) -4-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ ): δ 8.10-7.22 (8H, aromatic protons), 3.60 (N-methyl, s), 3.47 (N-methyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 395.

Example 2. N-methyl-N-phenyl-1,2-dihydro-4- (N, N-dimethylamino) -1,5-dimethyl-2-oxo-quinoline-3-carboxamide.

N-Methyl-N-phenyl-4-chloro-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide (0.52 g) in a mixture of dimethylamine and ethanol is heated in a thick-walled glass flask, closed lid on the thread. The progress of the reaction is monitored by thin layer chromatography (TLC) using dichloromethane / methanol mixtures as eluents.

After 8 hours of heating, the flask was cooled, opened and diluted with water.

The precipitate formed was filtered, washed with water and dried in vacuo to give the title compound (0.39 g).

¹ H NMR (CDCl ₃ + TFA): δ 7.50-6.70 (8H, aromatic protons), 3.70 (N-Methyl, s), 3.58 (N-Methyl, s), 3.50 (N-methyl, s); 3.43 (N-methyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : found 350, calculated 350.

In practice, the following compounds are prepared in the same way from the corresponding starting materials:

N-methyl-N-phenyl-1,2-dihydro-1,5-dimethyl-4- (N-methylamino) -2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.80-6.80 (8H, aromatic protons), 3.82 (N-methyl, s), 3.59 (N-methyl, s), 3.10 (N-Methyl, s); 1.85 (phenylmethyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 336.

N-methyl-N-phenyl-4-amino-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.80-6.40 (8H, aromatic protons), 3.80 (N-methyl, s), 3.57 (N-methyl, s), 2.28 (Phenylmethyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 322.

N-methyl-N-phenyl-5-chloro-1,2-dihydro-4- (N, N-dimethylamino) -1-methyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.70-7.00 (8H, aromatic protons), 3.68 (N-methyl, s), 3.50 (N-methyl, s), 3.18 (N-dimethyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 370.

N-methyl-N-phenyl-5-chloro1,2-dihydro-4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.60-7.00 (8H, aromatic protons). 3.73 (N-methyl, s). 3.57 (N-methyl, s); 3.15 (N-methyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 356.

N-methyl-N-phenyl-4-amino-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.62-7.23 (8H, aromatic protons), 3.63 (N-Methyl, s), 3.50 (N-Methyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 342.

N-ethyl-N-phenyl-5-bromo-1,2-dihydro-4- (N-ethylamino) -1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethyl-N-phenyl-5-chloro-4- (N-cyclopentylamino) -1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethyl-N-phenyl-1,2-dihydro-5-ethyl-4- (N-ethylamino) -1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethyl-N-phenyl-1,2-dihydro-4- (N, N-dimethylamino) -5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethyl-N-phenyl-4- (N, N-diethylamino) -1,2-dihydro-1-methyl-5-trifluoromethyl-2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-1,2-dihydro-5-fluoro-1-methyl-4- (1-pyrrolidinyl) -2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-1,2-dihydro-5-ethyl-1-methyl-4- (1-piperidinyl) -2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-1,2-dihydro-1,5-dimethyl-4- (N-ethylamino) -2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-1,2-dihydro-4- (N, N-dimethylamino) -5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-4- (N-benzylamino) -1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-1,2-dihydro-5-methoxy-1-methyl-4- (N-methylamino) -2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-1,2-dihydro-4- (N, N-dimethylamino) -1-methyl-5-trifluoromethyl-2-oxo-quinoline-3-carboxamide,

N-methyl-N-phenyl-4 - [(4-chlorophenyl) amino] -1,2-dihydro-1-methyl-5-trifluoromethyl-2-oxo-quinoline-3-carboxamide,

N- (n-propyl) -N-phenyl-5-chloro-1,2-dihydro-4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide,

N-isopropyl-N-phenyl-1,2-dihydro-5-ethyl-4- (N-ethylamino) -1-methyl-2-oxo-quinoline-3-carboxamide.

The following two 4-amino derivatives are obtained by slightly modifying the process described above. After cooling, the reaction mixture was concentrated and dissolved in dichloromethane. The organic phase is extracted with water, dried and concentrated to obtain a product.

N-methyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-1-methyl-4- (N-methylamino) -2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.82-7.24 (8H, aromatic protons), 3.85 (N-methyl, s), 3.52 (N-methyl, s), 3.18 (M-Methyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 390.

N-methyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4- (N, N-dimethylamino) -1-methyl-2-oxo-quinoline-3-carboxamide

¹ H NMR (CDCl ₃ + TFA): δ 7.80-6.87 (8H, aromatic protons), 3.78 (N-methyl, s), 3.58 (N-methyl, s), 3.25 (N-dimethyl, s).

Mass spectrum (ESI, m / z) [M + H] ⁺ : 404.

Example 3. 1,2-Dihydro-4-hydroxy-5-dimethylamino-1-methyl-2-oxo-quinoline-3-carboxylic acid, ethyl ether

A solution of 2,6-difluorobenzonitrile (35.7 g, 0.26 mol) and dimethylamine (17.5 g, 0.39 mol) in 100 ml of anhydrous isopropanol is heated at 110 ° C for 18 hours in an autoclave. After cooling, the solvent was evaporated, and the residue was treated with water and diethyl ether to obtain a yellowish oil of 2-dimethylamino-6-fluoro-benzonitrile (41 g), with an admixture of 2-4% 2,6-di (dimethylamino) benzonitrile. This crude mixture was dissolved in 40% aqueous methylamine (130 ml, 1.5 mol) and ethyl alcohol (100 ml) and heated at 110 ° C. for 18 hours in an autoclave. The product is treated as described above to obtain 44 g of 2-dimethylamino-6-methylaminobenzonitrile (purity> 95%). This compound is hydrolyzed in concentrated sulfuric acid (170 ml) and water (34 ml) at 120 ° C. for 3 hours. The brown solution is cooled and neutralized with a 5 molar NaOH solution.

The resulting cloudy mixture was filtered through celite and washed with 30 ml of diethyl ether. The aqueous solution was extracted with dichloromethane (3 × 50 ml), the extracts were washed with water and evaporated to give 6-dimethylamino-N-methyl-anthranilic acid. Anthranilic acid (21.5 g, 0.11 mol) was dissolved in 250 ml of 1,4-dioxane. Phosgene (25 ml, 0.45 mol) is slowly added while cooling in an ice bath. The mixture was heated at 40 ° C for 1 h, cooled to 15 ° C, and the product was collected by filtration. The product is treated with an aqueous solution of sodium bicarbonate and dichloromethane, the organic phase is dried thoroughly and evaporated, yielding pure 5-dimethylamino-N-methyl-isatoic anhydride. This anhydride (22 g, 0.10 mol) was dissolved in anhydrous methyl alcohol (150 ml) and sodium methoxide (5.4 g, 0.10 mol) was added. After stirring at 50 ° C. for 3 hours, the solvent was removed and the residue was taken up in water and ether to give a yellow oil (15 g). This oil, 6-dimethylamino-N-methyl-anthranilic acid methyl ester (10.4 g, 0.05 mol) was dissolved in dichloromethane (100 ml) and cooled in an ice bath. Ethyl malonic acid chloride (10 g, 0.07 mol) was added. After stirring for 1 h at room temperature, the turbid mixture was washed with an aqueous solution of sodium bicarbonate. The organic phase is dried thoroughly and concentrated in vacuo. The residue was dissolved in dried ethanol (100 ml) and sodium methoxide (9 g, 0.16 mol) was added. The mixture was stirred for 1 h and neutralized with hydrochloric acid. The solvent was removed and the residue was treated with water and dichloromethane. The organic phase was dried and the solvent was removed to give the title compound as pure, grayish crystals (11 g).

¹ H NMR (CDCl ₃ ) δ 1.36 (3H, t), 2.78 (6H, s), 3.59 (3H, s), 4.39 (2H, q), 7.17 (1H, d) 7.21 (1H, d), 7.54 (1H, t), 17.1 (1H, s).

Example 4. N-Ethyl-N-phenyl-1,2-dihydro-5-dimethylamino-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (Method B).

N-Ethylaniline (4.4 g, 0.036 mol) was dissolved in 80 ml of toluene. About 30 ml of solvent is distilled off to obtain a dry solution. 1,2-Dihydro-4-hydroxy-dimethylamino-1-methyl-oxo-quinoline-3-carboxylic acid ethyl ester (3.5 g, 0.012 mol) was added to the boiling solution. Ethyl alcohol formed during the reaction was distilled off with a small amount of toluene for about 10 hours. The mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane, and dried to obtain the title compound (3.1 g), 71% yield.

¹ H NMR (CDCl ₃ ) δ 1.25 (3H, s), 2.63 (3H, s), 2.78 (3H, s), 3.51 (3H, s), 3.87-4, 07 (2H, m), 7.07-7.19 (5H, m), 7.39-7.48 (3H, m).

¹³ C NMR (CDCl ₃ ) δ 13.2 (CH ₃ ), 29.4 (CH ₃ ), 43.7 (CH ₂ ), 45.2 (CH ₃ ), 46.5 (CH ₃ ), 109, 6 (C), 110.4 (C), 113.0 (CH), 114.0 (CH), 127.3 (CH), 127.5 + 127.5 (CH), 128.3 + 128, 3 (CH), 130.8 (CH), 140.7 (C), 142.3 (C), 150.6 (C), 159.7 (C), 160.6 (C = O), 165 , 0 (C = O).

Mass spectrum (ESI m / z) [M + H] ⁺ 366, fragment 245.

Example 5. N-Methyl-4-aminodiphenyl

Trifluoroacetic anhydride (3.4 ml, 0.024 mol) is slowly added to a cooled solution of 4-bromoaniline (3.4 g, 0.02 mol) and triethylamine (5.5 ml, 0.04 mol) in dichloromethane (50 ml). . After stirring for 1 h, the mixture was treated with aqueous hydrochloric acid (0.5 M) and an aqueous solution of sodium bicarbonate. The organic phase is dried and evaporated to dryness. The resulting crystals (5.2 g) were dissolved in dried tetrahydrofuran (40 ml), cooled and treated with potassium t-butoxide (3.4 g, 0.03 mol). After 1 h of stirring, methyl iodide (3.8 ml, 0.06 mol) was added and the mixture was allowed to stand overnight. The mixture was treated in the usual manner with aqueous hydrochloric acid (0.5 M), aqueous sodium bicarbonate, dried and evaporated to dryness to obtain 4.6 g of the intermediate, N- (4-bromophenyl) -2,2,2-trifluoro-N- methyl acetamide. When carrying out the Suzuki cross-coupling reaction, this material (4.6 g, 0.016 mol) is charged into a reactor thoroughly purged with nitrogen, together with 40 ml of toluene, 5.4 g of sodium bicarbonate (0.064 mol), tetrakis (triphenylphosphine) palladium (0) (0.6 g, 0.048 mol) and water (15 ml). Benzeneboronic acid (2.2 g, 0.017 mol) dissolved in ethanol (8 ml) was added to the reactor, and the dark mixture was heated to boiling (reflux) and stirred vigorously for 10 hours. The mixture was cooled, filtered through celite and the organic phase is evaporated to dryness. The residue was recrystallized from ethanol to give beige crystals (2.4 g, 54% yield). These crystals are hydrolyzed in a mixture (50 ml) of methyl alcohol / ammonia (1: 1) with rapid heating (1 h). The solvents were evaporated, and the residue was dissolved in dichloromethane (25 ml), dried and evaporated to dryness to give the title compound (1.3 g) as a syrup.

¹ H NMR (CDCl ₃ ) δ 2.88 (3H, s), 6.70 (2H, d), 7.27 (1H, t), 7.41 (2H, t), 7.48 (2H, d) 7.57 (2H, d).

Example 6. N- (4-phenyl-phenyl) -N-methyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

In an ice-cooled solution of 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylic acid (1.6 g, 6.5 mmol), triethylamine (3 ml, 22.7 mmol), N-methyl-4-aminodiphenyl (1.3 g, 7 mmol) in methylene chloride (25 ml), a solution of thionyl chloride (1.0 g, 8.4 mmol) in methylene chloride (10 ml) is added dropwise over 10 minutes ) Stirring was continued at 4 ° C for 4 hours. The solution was diluted with methylene chloride (10 ml), washed with cold unipolar (1 M) sulfuric acid and then extracted with 1 M sodium hydroxide solution. The pH of the aqueous phase is set to 8-8.5, it is purified by filtration and then further acidified with a hydrochloric acid solution to pH 4. Upon standing, a crystalline precipitate forms, which is filtered off, washed with water and dried to obtain the title compound (1.9 g )

¹ H NMR (CDCl ₃ ) δ 63.33 (3H, s), 3.52 (3H, s), 7.13 (1H, d), 7.20-7.35 (4H, m), 7, 36-7.56 (7H, m).

All embodiments of the invention that are disclosed in the claims are included in the description of the invention.

Pharmacological methods. Primary screening

Human prostate cancer R-3327 AT-1 is a solid tumor of the angiogenic type. Dunning R-3327 AT-1 is a rat prostate cancer and is a good experimental animal model for this disease. The AT-1 tumor is sequentially transplanted under the skin (sc) of syngenetic rats of the Copenhagen strain. Small pieces of the tumor are transplanted under the skin of the recipient rats, and treatment of rats with the transplanted tumor begins when the tumor becomes easily visible, approximately on the 10th day after the transplantation. The required doses of the compounds are administered either orally or parenterally 5 days a week for four weeks. Throughout the entire experiment, tumor growth and body weight gain are monitored.

Tests for evaluating pro-inflammatory activity

Beagle Dog Pain Syndrome

Hound dogs pain syndrome (BSH) is reflected in clinical and laboratory manifestations, for example, fever, increased erythrocyte sedimentation rate (ROE), alkaline phosphate (ALP), the induction of acute dysproteinosis and vasculitis, which justifies the use of BSH as a model for a syndrome similar to influenza caused by human action of Roquinimex. By its nature, BSH is an acute inflammatory disease. There are some changes in hematology and clinical chemistry. Substances are administered to beagle dogs intravenously. Dosage is given for five consecutive days. The pro-inflammatory response of dogs, i.e. increased ROE and alkaline phosphatase. The percentage change in laboratory values between the eighth day and the background level is determined.

Neutrophilic inflammation

Neutrophilic inflammation (HB) is caused by subcutaneous injection of carrageenin or zymosan. The accumulation of neutrophils is estimated by the change in the activity of a neutrophilic enzyme - myeloperoxidase from a provocative skin test.

Tumor formation

Tumor formation is caused by subcutaneous injection of carrageenin. The degree of tumor formation is evaluated by measuring the penetration of plasma from the vessels of a provocative skin sample upon intravenous injection of Evans blue dye.

Slow allergic reaction

Slow-type allergic reactions (AZTs) are transmitted by T cells and are inflammatory reactions specific to the antigen, which are used for research in the field of modulation of immunological and inflammatory events. Mice are sensitized by the administration of oxazolone into the skin. A provocative test is taken locally on the ears, and the inflammatory response is quantified by the change in ear thickness.

The following examples are intended to illustrate the invention without limiting its scope.

Among the preferred compounds are N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro -phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluorophenyl) -1,2- dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide and N-methyl-N-phenyl-4-amino-1,2-dihydro-1,5-dimethyl-2- oxo-quinoline-3-carboxamide, which are hereinafter referred to respectively as compounds A, B, C and D. As a standard compound, Roquinimex is used, which is hereinafter called the compound E. In addition, the antineoplasia agents vinblastine (Merck Index 12 ^th Ed., No. 10119) and doxorubicin (Merck Index 12 ^th Ed., No. 3495) were used as standard compounds (see Tables 1, 2).

The administration of the compounds of formula (I) for the practical implementation of the proposed methods of therapy is carried out by administering an effective amount of the selected compound to patients in need of such treatment or prevention. The effective amount of an individual compound is determined by the attending physician, and it depends on factors such as the exact nature of the disease to be treated, the severity of the disease and the presence of other diseases or conditions that the patient suffers from, and other factors that are the responsibility of the attending physician. It can be noted that these compounds are active at a low dose concentration, as a result of which effective treatment or prophylaxis is ensured with little chance of side effects or cross-reactions with other treatment methods or with other drugs. It is believed that a suitable daily dosage of the compounds used in the treatment may vary between approximately 0.002 and 100 mg / kg body weight, in particular between 0.02 and 10 mg / kg body weight, depending on the specific conditions, for example, prostate cancer being treated the gland, age and weight of the particular patient and the patient's specific response to the drug. The exact individual dosage, as well as the daily dosage, will be determined in accordance with the usual principles of medicine and under the supervision of a physician.

Effective amounts of the compounds of formula (I) are preferably administered to patients in need of such treatment in accordance with conventional methods of administration, and their formulation is in accordance with conventional pharmaceutical compositions containing an effective amount of the active ingredient and a suitable pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with other components of the formulation and is not harmful to its recipient. Such compositions may take various forms, for example, solutions, suspensions, emulsions, tablets, capsules and powders prepared for oral administration, sterile solutions for parenteral administration, suppositories for rectal administration or suitable local formulations. In preparing the composition of the present invention, the active ingredient is usually mixed with a carrier or diluted with a carrier, or encapsulated inside a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a carrier, excipient, or medium for the active component. Various additives are considered to increase stability or facilitate administration of a drug. Thus, the compositions may take the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in liquid medium), soft and hard gelatin capsules, suppositories, sterile solutions for injection, sterile powder packs, etc. Traditional techniques for selecting and preparing suitable pharmaceutical compositions are described, for example, in the book Pharmaceuticals - The Science of Dosage Form Design, M.B. Aulton, Churchill Livingstone, 1988. The pharmaceutical composition may also contain additional, therapeutically useful compounds other than the compounds of formula (I).

Sources of information

1. Ichikawa, T. et al. Antitumor effect of Linomide quinoline-3-carboxamide on rat prostate cancer Dunning R-3327. Cancer Research 52: 3022-3028, 1992.

2. de Wit R., et al., EORTC phase II study of daily oral linomide in metastatic renal cell carcinoma patients with good prognostic factors. Eur. J. Cancer 33: 493-495, 1997.

3. Kelly D.F., Grimsell C.S. and Kenyon, C. J., Polyarteritis in the dog: A case report. Vet Record 92: 363-366, 1973.

4. Harcourt R.A., Polyarterites in a colony of beagles. Vet Record 102: 519-522, 1978.

Claims (62)

1. An agent for the treatment of breast and prostate cancer, which is a quinoline derivative of the general formula (I)

in which A is selected from OR ₄₁ and NR ₄₂ R ₄₃ , where R _{41 is} selected from a hydrogen atom and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium, and organic cations, such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and like them; and COR _A groups, where r _{A is} selected from alkyl and aryl groups such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl, neo-pentyl, phenyl, benzyl, phenethyl and the like; R ₄₂ and R ₄₃ are the same and different and are selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; or R ₄₂ is a COR _B group in which r _{b is} selected from C1-C4 alkyl, or COR _B is a 2-acyloxymethylbenzoyl group of the formula

in which R _{C is} selected from methyl, ethyl, phenyl and benzyl and the like; R is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and allyl, provided that R is not a hydrogen atom when A is an OR ₄₁ group; R 'is selected from a hydrogen atom, methyl, methoxy, fluorine, chlorine, bromine, cyano, trifluoromethyl and OCH _x F _y groups in which x = 0-2, y = 1-3, provided that x + y = 3, and provided that R 'is not hydrogen when R is methyl and A is OR ₄₁ ; R "is selected from an atom of hydrogen, fluorine and chlorine, provided that R" is selected only from a fluorine atom and chlorine, when R 'is selected from a fluorine atom and chlorine; R _{5 is} selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino and OCH _x F _y and OCH ₂ CH _x F _y groups, in which x = 0-2, y = 1-3, provided that x + y = 3 and under additional conditions that R _{5 is} not a fluorine atom when A is OR ₄₁ and that R ₅ is only a hydrogen atom, when A is a group NR ₄₂ R ₄₃ and R 'is trifluoromethyl; R ₆ represents a hydrogen atom, or the radicals R ₅ and R ₆ taken together represent a methylenedioxy group, or their any tautomer. 2. The tool according to claim 1, in which a represents a group OR ₄₁ . 3. The tool according to claim 1, in which a represents a group NR ₄₂ R ₄₃ . 4. The tool according to claim 1 or 2, in which R ₅ represents a methyl, ethyl, methoxy, chlorine, bromine atom and R ₅ and R ₆ taken together represent a methylenedioxy group. 5. The tool according to any one of claims 1, 2 or 4, in which R is methyl and ethyl. 6. The tool according to claims 1, 2 or 5, in which R is ethyl and R 'is a hydrogen atom. 7. The tool according to any one of claims 1, 2 or 4, in which R 'is selected from para-methyl, methoxy, chlorine atom, trifluoromethyl. 8. The tool according to any one of claims 1, 2 or 4, in which R "is selected from meta'- and parafluoro, provided that R 'is orthofluoro. 9. The tool according to claim 2, in which R _{41 is} selected from a hydrogen atom and sodium. 10. The tool according to claim 2, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide. 11. The tool according to claim 2, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide. 12. The tool according to claim 2, in which the compound is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide. 13. The tool according to claim 2, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide or its sodium salt. 14. The tool according to claim 2, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxamide. 15. The tool according to claim 2, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide. 16. The tool according to claim 2, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-dimethylamino-1-methyl-2-oxo-quinoline-3-carboxamide. 17. The tool according to claim 2, which is a compound, N-ethyl-N- (3-fluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline- 3-carboxamide. 18. The tool according to claim 2, which is N-methyl-N- (4-chlorophenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide. 19. The tool according to claim 2, which is N-methyl-N- (4-methylphenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide. 20. The tool according to claim 2, which is N-methyl-N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinolin-3- carboxamide. 21. The tool according to claim 2, which is N-methyl-N- (2,5-difluorophenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinolin-3- carboxamide. 22. The tool according to claim 2, which is N-ethyl-N- (3-methoxyphenyl) -1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide. 23. The tool according to claim 2, which is N-ethyl-N- (4-chlorophenyl) -1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide. 24. The tool according to claim 2, which is N-methyl-N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3- carboxamide. 25. The tool according to claim 2, which is N-methyl-N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinolin-3- carboxamide. 26. The tool according to claim 2, which is N-methyl-N- (2,5-difluorophenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinolin-3- carboxamide. 27. The tool according to claim 2, which is N-methyl-N- (4-trifluoromethylphenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide. 28. The tool according to claim 2, which is N-methyl-N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline- 3-carboxamide. 29. The tool according to claim 2, which is N-methyl-N- (4-methoxyphenyl) -1,2-dihydro-5-dimethylamino-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide. 30. The tool according to claim 1 or 3, in which R ₅ selected from methyl, ethyl, methoxy, ethoxy, chlorine and bromine atoms, or R ₅ and R ₆ taken together are methylenedioxy. 31. The tool according to any one of claims 1, 3 and 30, in which R is selected from methyl, ethyl, n-propyl. 32. The tool according to any one of claims 1, 3 and 30, in which R is a hydrogen atom. 33. The tool according to claims 1, 3 and 30, in which R is methyl and R 'is a hydrogen atom. 34. The tool according to any one of claims 1, 3 and 30, in which R ₄₂ and R ₄₃ represent a hydrogen atom. 35. The tool according to any one of claims 1, 3 and 30, in which R 'is selected from a hydrogen atom, a parameter, methoxy, chloro and trifluoromethyl. 36. The tool according to any one of claims 1, 3 and 30, in which R "is selected from meta'- and para-fluoro - provided that R 'is orthofluoro. 37. The tool according to claim 3, which is N-methyl-N-phenyl-4-amino-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide. 38. The tool according to claim 3, which is N-methyl-N-phenyl-4-amino-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide. 39. The tool according to claim 3, which is N-methyl-N-phenyl-1,2-dihydro-1,5-dimethyl-4- (N-methylamino) -2-oxo-quinoline-3-carboxamide. 40. The tool according to claim 3, which is N-methyl-N-phenyl-1,2-dihydro-5-methoxy-4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide. 41. The tool according to claim 3, which is N-methyl-N- (4-trifluoromethyl) phenyl-4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide. 42. A compound representing a quinoline derivative of the general formula (I ′)

in which R ₄₂ and R ₄₃ are the same and different and are selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl and cyclopropyl, or R ₄₂ is a COR _B group in which r _{b is} selected from C1-C4 alkyl, or COR _B is a 2-acyloxymethylbenzoyl group of the formula

in which R _{C is} selected from methyl, ethyl, phenyl and benzyl and the like; R is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R ^{1 is} selected from a hydrogen atom, methyl, methoxy, fluorine, chlorine, bromine, cyano, trifluoromethyl and OCH _x F _y , in which x = 0-2, y = 1-3, provided that x + y = 3; R "is selected from an atom of hydrogen, fluorine and chlorine, provided that R" is selected from a fluorine atom and chlorine only when R 'is selected from fluorine and chlorine; R ₅ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, dimethylamino groups and OCH _x F _y and och ₂ CH _x F _y, wherein x = 0-2, y = 1-3, provided that x + y = 3, and provided that R ₅ represents only a hydrogen atom, when R 'represents trifluoromethyl; R ₆ represents a hydrogen atom, or r ₅ and R ₆ taken together represent a methylenedioxy group, or any tautomeric form thereof. 43. The compound of claim 42, wherein R _{5 is} selected from methyl, ethyl, methoxy, ethoxy, and R ₅ and R ₆ , taken together, are methylenedioxy. 44. The compound of claim 42 or 43, wherein R is selected from methyl, ethyl, n-propyl. 45. The compound according to § 42 or 43, in which R represents a hydrogen atom. 46. The compound of claims 42 and 43, wherein R is methyl and R ′ is a hydrogen atom. 47. The compound of claim 42 or 43, wherein R ₄₂ and R ₄₃ represent a hydrogen atom. 48. The compound of claim 42 or 43, wherein R 'is selected from a hydrogen atom and trifluoromethyl. 49. The compound of claim 42, which is N-methyl-N-phenyl-4-amino-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide. 50. The compound of claim 42, which is N-methyl-N-phenyl-4-amino-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide. 51. The compound of claim 42, which is N-methyl-N-phenyl-1,2-dihydro-1,5-dimethyl-4- (N-methylamino) -2-oxo-quinoline-3-carboxamide. 52. The compound of claim 42, which is N-methyl-N-phenyl-1,2-dihydro-5-methoxy-4- (N-methylamino) -1-methyl-2-oxo-quinoline-3-carboxamide. 53. The compound of claim 42, which is N-methyl-N- (4-trifluoromethyl) phenyl-4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide. 54. A compound representing a quinoline derivative of the general formula (I)

in which A is OR ₄₁ , where R ₄₁ is a COR _A group in which R _{A is} selected from alkyl and aryl groups, such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, neopentyl, phenyl, benzyl phenethyl and the like; R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R 'is selected from a hydrogen atom, methyl, methoxy, fluorine, chlorine, bromine, cyano, trifluoromethyl and OCH _x F _y groups in which x = 0-2, y = 1-3, provided that x + y = 3, and provided that R 'is not a hydrogen atom when R is methyl; R "is selected from a hydrogen, fluorine and chlorine atom, provided that R" is selected from a fluorine and chlorine atom, only when R 'is selected from a fluorine and chlorine atom; r _{5 is} selected from methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, trifluoromethyl, dimethylamino and OCH _x F _y and OCH ₂ CH _x F _y groups in which x = 0-2 , y = 1-3, provided that x + y = 3 and R ₆ represents a hydrogen atom or r ₅ and R ₆ taken together represent a methylenedioxy group. 55. A compound representing a quinoline derivative of the general formula (I ")

in which R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R _{41 is} selected from a hydrogen atom and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium, and organic cations, such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like, and COR _A group in which r _{a is} selected from alkyl and aryl groups such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl, neo-pentyl, phenyl, benzyl, phenethyl and the like; R 'is selected from a hydrogen atom, methyl, methoxy, fluorine, chlorine, bromine, cyano, trifluoromethyl and OCH _x F _y groups in which x = 0-2, y = 1-3, provided that x + y = 3, and provided that R 'is not a hydrogen atom when R is methyl; R "is selected from a hydrogen, fluorine and chlorine atom, provided that R" is selected from a fluorine and chlorine atom, only when R 'is selected from a fluorine and chlorine atom; r ₅ represents a dimethylamino group; or any tautomeric form thereof. 56. The compound of claim 55, which is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-dimethylamino-1-methyl-2-oxo-quinoline-3-carboxamide. 57. The compound according to any one of paragraphs.54-56 as a therapeutic agent. 58. A pharmaceutical composition for treating breast and prostate cancer, comprising, as an active ingredient, an agent according to any one of claims 1 to 41 or a compound according to any one of claims 42 to 57 and a pharmaceutically acceptable carrier. 59. The pharmaceutical composition according to p. 58, containing as an active ingredient the compound according to p. 42, the compound according to p. 54 or the compound according to p. 55. 60. The pharmaceutical composition according to § 59 in a dosage form that is sufficient to provide a daily dose of the active substance from about 0.002 to 100 mg / kg body weight, preferably from 0.02 to 10 mg / kg body weight. 61. A method of producing a compound according to any one of claims 42-53 by reacting a 4-chloro-1,2-dihydro-2-oxo-quinoline-3-carboxamide derivative of the formula (II)

with an amino compound in a suitable solvent, such as an alcohol, for example ethanol. 62. A method of producing compounds according to any one of claims 54-56 by reacting an ester derivative of a quinoline carboxylic acid having the formula III

with aniline of formula IV

in a suitable solvent such as toluene, xylene and the like.