Indole derivatives, with stimulating apoptosis effect (alternatives), pharmaceutical compositions based on these derivatives

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of indole with general formula 1: where R is unsubstituted or substituted quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to nitrogen of the amide group; R1 is unsubstituted or substituted alkly-aryl; R2 represents hydrogen; R3-R6 represent hydrogen, R7 represents (C1-C6)-alkylcarbonyl or (C1-C6)- alkoxycarbonyl, and X, Y represent oxygen or sulphur, under the condition that, when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 have the above mentioned values, R7 is not an acetyl radical or tert-butyloxycarbonyl group. The invention also relates to physiologically tolerant salts of the indole derivatives, as well as to pharmaceutical compositions based on them and their use in obtaining medicinal preparations.

EFFECT: obtaining of medicinal preparations, used as medicines for curing tumorous diseases, especially in case of resistance to other drugs and metastasising carcinomas.

14 cl, 7 tbl, 6 dwg, 25 ex

 

The technical field to which the invention relates.

The present invention relates to the field of organic chemistry and pharmacology, specifically relates to new derivatives of indole, which have a more pronounced biological effect, better tolerated, demonstrated a higher oral bioavailability and are used as an active Foundation medicines for the treatment of cancer, especially when there is resistance to other active compounds and when the cancer spreads.

The level of technology

Cancer treatment is of great importance in medicine. Worldwide there is a need for effective methods of cancer treatment in order to achieve the treatment that is appropriate for the patient and with the aiming direction.

This can be seen in a great number of papers that have appeared recently in the field of applied Oncology and basic research related to cancer treatment.

Effects of inhibitors of cancer are due to the wide variety of mechanisms, and known only to some of them. And often find that well-known anticancer drugs with new mechanisms of action. This is also expected in relation to the compounds according to this invention. Many anticancer means to de is eliminated through such mechanisms as the locking mechanism of cell division in the cells, the barrier supply the tumor with nutrients and oxygen (antiangiogenic), prevention of metastasis, prevention of transmission and reception of cancer cell growth signals or by injecting cancer cells into the program cell death (apoptosis).

Suitable for clinical use agents are often administered in combination to achieve a synergistic therapeutic effect for the reason that they have different mechanisms of action, including the interaction with different intracellular targets.

Derivatives of indole are used in many different ways as pharmacologically active compounds and as building blocks for synthesis in pharmaceutical chemistry.

Documents WO 99/51224 A1 and WO 01/22954 A1 describe derivatives of indol-3-yl, which have antineoplastics effect and which can be substituted by a large number of groups, including 2-, 3-, 4 - and 8-quinoline radicals or 2-, 3-, 4-, 5 - and 6-pyridine radicals. 2-methyl-8-quinoline group mentioned in Example 60, as Deputy under amide group. However, there is no mention of biological properties.

WO 99/55696 A1 describes substituted oxindole as inhibitors of phosphodiesterase 4. However, there are no reports that the compounds according to this invention possess antipopes the practical activity, and no assumptions about what they can deliver that kind of activity.

WO 02/08225 A1 describes derivatives of 2-(1H-indol-3-yl)-2-oxoacetate who are antineoplastics effect against solid tumors. However, no mention was made of examples of implementation, including radicals quinoline, perioperative or indazole.

In WO 00/67802 describes indole-3-glyoxylate, which are substituted fatty acids with relatively long chains, as a potential antineoplastics funds. However, there is no mention of examples of implementation, including radicals quinoline, perioperative and indazole. Not lead any biological data regarding examples of such implementation.

Publication W.-T.Li et al. (J. Med. Chem. 2003, 46, 1706 ff.) describes N-heterocyclic intelligibility as orally active compounds with antineoplastic activity. However, do not provide any information regarding their mechanism of action.

WO 03/022280 A2 describes a 3-glycylamino and their use as medicaments for the treatment of neoplastic diseases. Their General formula also includes derivatives of 6-quinoline. In addition, mention two examples containing the radical 6-quinoline as examples of implementation and supported by biological results But there is no mention of examples of specific implementation including radicals perioperative and indazole.

US 03/0181482 A1 describes a new intelligibility. In this case, the compounds according to this invention is characterized as antineoplastics means having a cytotoxic activity and are inhibitors of angiogenesis. In addition, it is shown that the derivative of 6-quinoline may be an example implementation (compound 3; p.10), as also confirmed by the fact antiproliferative activity (see p.19; Tables 1A and 1b) and antiangiogenic properties (see p.20). However, there is no mention of examples of implementation, including radicals perioperative and indazole.

WO 02/10152 A2 describes a second class of indole derivatives for the treatment of neoplastic diseases. In this document, the active compound N-(2-methyl-6-chinolin)-[1-(4-Chlorobenzyl)indol-3-yl]glyoxylate, incidentally, was tested against antiproliferative effects on a number of lines of cancer cells.

Clinically tested compounds that either are associated with microtubules (paclitaxel and vincristine)or inhibit topoisomerase II (doxorubicin, etoposide and mitoxantrone) are currently widely used in the treatment of cancer, including breast cancer, ovarian cancer, stomach cancer and lung cancer, as well as in the case of Kaposi's sarcoma and leukemia. However, the agricultural use is limited by the emergence of drug resistance, and serious neurological, gastrointestinal, cardiovascular and hepatic side effects.

Disclosure of inventions

The purpose of this invention is to provide affordable cytotoxic substances, which have a combined mechanisms of action and are suitable for the treatment of a large number of neoplastic diseases, especially when there is drug resistance in relation to other drugs, and when carcinoma metastasize.

To reach this aim by using indole derivatives of General formula I

in which

R: it is a saturated, unsaturated or aromatic, substituted or unsubstituted (C2-C14)-heterocycle which contains one or more heteroatoms selected from the group N, O and S, and which is directly linked to the amide nitrogen, and the heterocycle is mostly

(i) unsubstituted or substituted 5-, 6-, 7-chinaillon,

(ii) unsubstituted or substituted 2-, 3-, 6-, 7 - and 8-perioperatively,

(iii) unsubstituted or substituted 3-, 4-, 5-, 6 - and 7-indazolinone,

(iv) unsubstituted or substituted 2-, 3-, 4-, 5 - and 6-pyridium,

(v) unsubstituted or substituted 3-, 4 - and 5-isoxazolyl,

(vi) unsubstituted or substituted 3-, 4 - and 5-isothiazoline,

R1: unsubstituted or substituted alkyl-aryl,

R2: (i) hydrogen,

(ii) zamesheny or substituted (C 1-C16)-alkyl,

R3-R6:

(i) hydrogen,

(ii) unsubstituted or substituted (C1-C6)-alkyl,

(iii) unsubstituted or substituted (C3-C6-cycloalkyl,

(iv) amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino,

(v) halogen,

(vi) (C1-C4)-alkyl, which is substituted by one or more fluorine atoms, mainly triptorelin group,

(vii) cyano, cyano-(C1-C6)-alkyl straight or branched chain,

(viii) (C1-C6-alkylsulphonyl,

(ix) carboxyl, (C1-C4-alkoxycarbonyl, carboxy-(C1-C6)-alkyl or (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl,

(x) hydroxyl,

(xi) -(C1-C6)-alkoxy,

(xii) aryl-(C1-C6)-alkoxy, preferably benzyl-oxy,

(xiii) (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkyl,

R7: (C1-C6-alkylsulphonyl, preferably acetyl or propionyl,

(C1-C6-alkoxycarbonyl, preferably methoxycarbonyl, etoxycarbonyl or propoxycarbonyl,

and

X, Y is oxygen or sulphur,

their tautomers and stereoisomers, including diastereomers and enantiomers, and their physiologically tolerant of salt.

When R is unsubstituted or samisen the I 2-, 3-, 4-, 5 - and 6-Peregrina group, a R1-R6 have the above meanings, R7 should not in this case be an acetyl radical or a tert-butyloxycarbonyl group.

This invention further relates to an indole derivative of General formula I:

in which

R: it is directly linked to the amide nitrogen

(i) substituted 6-chinolin, substituted or unsubstituted 7-chinolin,

where 2-methyl-6-chinolin excluded, and where, when X is a sulfur atom, R can be unsubstituted 6-chinaillon,

(ii) unsubstituted or substituted 2-, 3-, 6-, 7 - and 8-perioperative,

(iii) unsubstituted or substituted 3-, 4-, 5-, 6 - and 7-indazole,

R1: unsubstituted or substituted alkyl-aryl,

R2: hydrogen,

R3-R6:

(xiv) hydrogen

(xv) unsubstituted or substituted (C1-C6)-alkyl,

(xvi) unsubstituted or substituted (C3-C7-cycloalkyl,

(xvii) amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino,

(xviii) halogen,

(xix) (C1-C4)-alkyl, which is substituted by one or more fluorine atoms, mainly triptorelin group,

(XX) cyano, cyano-(C1-C6)-alkyl straight or branched chain,

(xxi) (C1-C6-alkylsulphonyl,

(xxii) carboxyl, (C1-C4-alkoxycarbonyl, carboxy-(C1-C6)-alkiline (C 1-C6-alkoxycarbonyl-(C1-C6)-alkyl,

(xxiii) -(C1-C6)-alkoxy,

(xxiv) aryl-(C1-C6)-alkoxy, preferably benzyl-oxy,

(xxv) (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkyl,

and

R7: hydrogen,

X, Y is oxygen or sulphur,

their tautomers and stereoisomers, including diastereomers and enantiomers, and their physiologically tolerant of salt.

The present invention is a further development of the invention, which is described in WO 02/10152. It was observed that the derivatives of indole, which were obtained by replacing 2-methyl-6-chinoline group unsubstituted or substituted 2-, 3-, 6-, 7 - and 8-perioperatively or unsubstituted or substituted 3-, 4-, 5-, 6 - and 7-indazolinone demonstrate antiproliferative effect on several lines of tumor cells.

Further, it was noted that the compounds according to this invention show potent cytotoxic effect, which may be the result of a wide range of different mechanisms. One mechanism of action of the compounds according to this invention, which has been demonstrated in this invention, based on the inhibition of tubulin polymerization and inhibition of topoisomerase II. This leads to the suppression of oncogenic cells in the G2M phase. In the add is this, the compounds of this invention induce apoptosis.

Further, it was observed that the compounds according to this invention have very high solubility in water and, therefore, also high biological availability.

In addition, it was shown that the introduction of the acetyl radical as the R7 radical leads to the formation of compounds according to the invention has an extremely high activity in vivo, which is at the same time, more tolerant.

The class of compounds described in this invention, should open the possibility of obtaining antineoplastics medicines, which at lower doses has a more prolonged effect and better portable than can be achieved using conventional cytotoxic agents. In particular, it should be possible to circumvent the adverse development of resistance, which, as we know, takes place in the case of the use of many antineoplastics funds. The effect of the gain that is achieved when using indole derivatives according to this invention, should make the use of medicines more effective. In addition, it will be possible to extend the treatment to cases, which are characterized by resistance to therapy.

In a preferred embodiment, R1 is 4-Chlorobenzyl, R2-R6 - vador is d, R - heterocycle, and R7 - alkylsulphonyl or alkoxycarbonyl in a derived indole with formula I.

In another preferred embodiment, R is unsubstituted 5-chinolin, unsubstituted 6-chinolin or unsubstituted 7-chinolin, and R7 is acetyl or propionyl in a derived indole with formula I.

In another preferred embodiment, R is unsubstituted 5-chinolin, unsubstituted 6-chinolin or unsubstituted 7-chinolin, and R7 is methoxycarbonyl, etoxycarbonyl or propiolactones in a derived indole with formula I.

Brief description of drawings

Figure 1 shows a photograph of the definition cDNA.

Figure 2 presents the inhibition of "unwinding" cDNA.

Figure 3 shows a photograph of the determination of output pRYG.

4 shows the inhibition of the release of pRYG.

Figure 5 and Fig 6 shows CDDplus-nucleosomal ELISA tests with the substance 1 and substance 2.

The implementation of the invention

Some terms used in the description and in the claims, the following definitions are given.

As regards the term "heterocycle", understood as a term meaning, as hitherto in detail not mentioned, pyrrole, furan, thiophene, pyrazole, thiazole, indole, oxazole, imidazole, isothiazol, isoxazol, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazin, benzofuro is, indazole, carbazole, benzoxazole, benzimidazole, benzothiazole, quinoline, cinnoline, cinoxacin, hinzelin, phthalazine, pyridorin, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, purine, pteridine, acridine and penetratin.

In the framework of this invention, the expression "alkyl" includes acyclic saturated or unsaturated hydrocarbon which may have a straight or branched chain. In relation to the term "alkyl", the term "substituted" is understood, within the content of the present invention, but haven't given a detailed definition of how the replacement of a hydrogen radical by F, Cl, Br, I, CN, NH2, NH-alkyl, NH-cycloalkyl, HE or O-alkyl, where polyamidine radicals are to be understood as meaning those which are substituted more than once, for example two or three times, or by different atoms, or when the same atoms, for example three times on the same atom, as in the case of CF3and CH2CF3or at different sites, as in the case of-CH(OH)-CH2-CH2-CHCl2. Polyamidine can be performed using the same or different substituents.

The expression "alkyl-aryl" means (C1-C6)-alkyl-(C6-C14)-aryl and preferably (C1-C6)-alkyl-C6-aryl.

In respect to the terms "alkyl-aryl" and "cycloalkyl", "one-deputizing or substituted more than once within the scope of this invention includes, but is not specified above, the value of one or multiple, for example double, triple or four times, substitution of one or more hydrogen atoms in the ring system by F, Cl, Br, I, CN, NH2, NH-alkyl, NH-cycloalkyl, HE or O-alkyl, -CF3, alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl and/or heterocyclyl when one or, where necessary, with different atoms (that may be a Deputy, or any part thereof, which is substituted, where appropriate). In this regard, multiple substitution is done using the same or different substituents.

In respect of the terms "heterocycle", "one-deputizing or substituted more than once within the scope of this invention includes, but is not yet clarified above, the value of one or multiple, for example double, triple or four times, substitution of one or more hydrogen atoms in the ring system by F, Cl, Br, I, nitro, amino, (C1-C6)-alkyl, preferably methyl, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6-alkoxycarbonyl, (C1-C6)-alkoxycarbonyl or (C1-C6)-alkyl, which is substituted one or more times by fluorine, preferably trifluoromethyl, (C6-C10)-aryl, and/or (C6-C10)-aryl-(C1-C6 )-alkyl with one or, where necessary, with different atoms (that may be a Deputy, or any part thereof, which is substituted, where appropriate). In this regard, multiple substitution is done using the same or different substituents.

Provided that the compounds according to the invention with formula 1 have at least one center of asymmetry, they can be presented in the form of their racemates, in the form of pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. Stereoisomers may be present in a mixture in any proportions. In that case, if possible, the compounds according to this invention may be present in the form of tautomers.

Thus, methods that are known so far can be used, for example, to separate compounds according to this invention with the General formula I which have one or more chiral centers, and exist as racemates, their optical isomers, i.e. enantiomers or diastereomers. The separation can be performed by dividing by the column on chiral phases or by recrystallization from an optically active solvent or by using an optically active acid or base, or by formation of a derivative with an optically active reagent, such as optically active alcohol, followed tsalani the m residue.

If the compounds according to this invention with the General formula 1 contain an acidic group such as carboxyl, they can be converted into their physiologically tolerant of salt with inorganic and/or organic bases. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide and calcium hydroxide, while examples of suitable organic bases include ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenziletilendiaminom and lysine. In this regard, the stoichiometry of the obtained salts of the compounds according to the invention can be either integer or non-integer number multiple of one.

If they have a sufficiently basic group, such as secondary or tertiary amine, the compounds of this invention with the General formula I can be converted into salts with inorganic and organic acids. Pharmaceutically tolerated salts of the compounds according to this invention with the General structure I is preferably formed under the action of chloroethanol acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, paratoluenesulfonyl acid, carbonic acid, formic acid, acetic acid, triperoxonane acid, oxalic acid, malonic acid, maleic acid, succinic acid, vinsanity, pyruvic acid, malic acid, monowai acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. Salts which are formed, in particular, is hydrochloride, hydrobromide, sulfates, phosphates, methansulfonate, salt sulfoxyde acid, tozilaty, carbonates, bicarbonates, formats, acetates, triflate, oxalates, malonate, maleate, succinate, tartratami, malaty, embonate, mandelate, fumarate, lactates, citrates and glutaminate. In this regard, the stoichiometry of the obtained salts of the compounds according to the invention can be either integer or non-integer number multiple of one.

Preference is also given to solvate, especially a hydrate, compounds with the formula I according to the invention, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this regard, one, two, three, or any arbitrary number of molecules of solvent or water may be associated with the compounds according to this invention with the formation of the solvate or hydrate.

It is known that the chemical substance form solid particles that exist in a state of varying degrees of order and are called polymorphic forms or modifications. Different polymorphic modifications of a substance can vary widely in their physical properties. is soedineniya according to this invention with the General formula I may be present in different polymorphic forms, with the opportunity for special modifications, being metastable.

Compounds according to formula I and their salts are biologically active. Compounds according to formula I can be used in free form and in the form of salts with physiologically tolerant of acids or bases.

Compounds with the General formula I can be used orally, rectally, transbukkalno (e.g., sublingual), parenteral (e.g., subcutaneously, intramuscularly, intradermally or intravenously), topically, or transdermally.

This invention further relates to pharmaceutical preparations that contain at least one of the compounds with the formula I or their salts with physiologically tolerant of inorganic or organic acids and where should pharmaceutically applicable carriers and/or diluents or additives.

These medicines are used for the treatment of neoplastic diseases, especially for the treatment of neoplastic diseases that are complicated by drug resistance in relation to other active compounds and/or neoplastic diseases, including metastatic carcinoma.

Examples of easy to use forms are tablets, pills with sugar coating, capsules, solutions for infusion or capsules, suppositories, plasters, medicines in the form of powders that can be used for inhalation, suspense and, creams and ointments.

Compounds according to the invention can also be dispersed in the composition containing microparticles, such as nanoparticles.

In detail, therapeutically useful properties that have been set are associated with the following advantages:

connection according to the invention are characterized by a strong antiproliferative properties;

connection according to the invention inhibit the polymerization of tubulin;

connection according to the invention inhibit the topoisomerase II;

connection according to the invention inhibit dividing cells in the G2M phase;

connection according to the invention induce apoptosis;

connection according to the invention are characterized by extremely high antineoplastic activity in vivo, while at the same time, more tolerant;

connection according to the invention with formula I active in vitro on mdr-resistant cell lines, in contrast to paclitaxel, vincristine, doxorubicin or etoposide.

The most preferred compounds according to this invention with the General formula I, which are included in the following set:

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-pyrido[2,3-b]pyrazin-7-ylacetamide (1)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-(1H-indazol-5-yl)-2-oxoacetate (4)

N-{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}-N-quinoline-6-ylacetamide (2)

methyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl} quinoline-6-carbamate (3)

ethyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (5)

propyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (6)

N-{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}-N-quinoline-6-ylpropionic (7)

ethyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl} pyridine-4-ylcarbamate (8)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-quinoline-6-yl-2-dioxazine (11)

Compounds (1), (4) and (11) are compounds in which the radical R7 is hydrogen. Connection(2), (3), (5) and (6)-(8) contain alkylcarboxylic group or alkoxycarbonyl group as a group R7.

The following connections(9), (10), (12), (13), (14) and (15) are compounds that have been studied for comparison. Connection(9), (10), (14) and (15) are known from previous achievements. Compound (9) described in WO 02/10152 of the Applicant, the compound (10) is described in WO 03/022280, compound (13) exhaustively covered in the claims in WO 02/08225 A1 and compound (12), (14) and (15) are presented in the claims in WO 99/51224 A1 and WO 01/22954.

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-(2-methylinosine-6-yl)-2-oxoacetate (9)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinoline-6-ylacetamide (10)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinoline-8-ylacetamide (12)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-isoquinoline-5-yl-2-oxoacetate (13)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-pyridin-4-ylacetamide (14)

2-[1-(4-Chlorobenzyl)-1H-indol-3-and the]-N-(2-methylinosine-8-yl)-2-oxoacetate (15)

Compounds with the General formulas 1A and 1b on the scheme can be obtained in accordance with the following scheme:

Compounds with the General formula 1C, in which X=S, can be obtained according to Scheme 2:

Compounds with the General formula 1C where Y=S, can be obtained by using methods known in the literature (W.-D. Malberg et al. Liebigs Ann. Chem. 10, 1983; 1649-1711).

Starting compound II, III and IV can be purchased commercially or produced using known methods. Starting compound II, III and IV are valuable intermediates to produce indole derivatives according to this invention with formula I.

To obtain the source compounds and target compounds can be recommended, for example, the following exemplary works on organic synthesis, the contents of which, therefore, intend to include in the description of this application:

- Houben-Weyl, vol E 7a (Part 1) SC-492, SS-740

- Houben-Weyl, vol E 7a (Part 2) SS-156, s-686, SS-204

- Monograph "Heterocyclic Compounds" (Elderfield),

Volume 1, SS-207, s-616

Volume 3, SS-274

Volume 6, s-135, s-323

- Monograph "Comprehensive Organic Chemistry" (S.D.Barton, W.D.Ollis)

Volume 4, s-204, s-232, s-564

A qualified technician familiar because of their expertise with solvents and auxiliary means, when the parameters of the reaction, such as the reaction temperature and duration of reaction, which is used where necessary.

The following compounds, the inclusion of which in the subsequent discussion it is clear, based on their characteristic chemical structure, were synthesized in accordance with these General directions for stages 1, 2 and 3, as shown in the synthesis Schemes 1 and 2. The compounds of this invention were characterized analytically by determining their melting points and/or using 1H NMR spectroscopy and/or mass spectroscopy.

Used chemicals and solvents were either purchased commercially from the conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc)or were synthesized.

The invention will be explained in more detail using the following examples, without being limited to them.

Examples

Example 1 (Reaction according to Scheme 1, stage 1):

Obtaining 1-(4-Chlorobenzyl)indole

The solution 5,86 g (0.05 mol) of indole in 25 ml of dimethyl sulfoxide (DMSO) are added to a mixture of 1.32 g of sodium hydride (by 0.055 mol, suspension in mineral oil) in 50 ml of dimethylsulfoxide. The resulting mixture is heated at 60°for 1,3 hours; then allow to cool down and added dropwise to 17.7 g (0.11 mol) of 4-Chlorobenzyl chloride. The solution is heated to 60°and leave for the night; then it is poured into 200 ml of water with stirring. This is mesh extracted with a total volume of 75 ml of CH 2Cl2, after which the organic phase is removed by drying using anhydrous sodium sulfate and filtered, and the filtrate is evaporated in vacuum.

Yield: 11.5 g (95% of theoretical).

Example 2 (Reaction according to Scheme 1, stage 2):

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-pyrido[2,3-b]pyrazin-7-ylacetamide (1)

A solution of 10.2 g (of 10.7 mmol) of 1-(4-Chlorobenzyl)indole in 200 ml of ether at 0°and in nitrogen atmosphere are added dropwise to a solution of 1.12 ml oxalyl chloride in 50 ml of ether. The mixture is heated under reflux for 2 hours and the solvent then evaporated. 30 ml of DMF were then added to the precipitate, after this type of 1.93 g (a 13.9 mmol) of potassium carbonate, and the suspension is cooled to 0°; then added dropwise a solution of 1.57 g (of 10.7 mmol) of the amino component in 10 ml of DMF. The reaction mixture is left under stirring overnight at room temperature. In the end it is stirred into ice water and the precipitate is filtered with suction. The crude product chromatografic on 100 g of silica gel using n-heptane/ethyl acetate = 4:1.

Output: 3,23 g (68,0%)

Melting point: 250°

1H-NMR (DMSO-D6) δ=to 11.56 (s, 1H), at 9.53 (d, 1H), 9,12 (s, 1H), which is 9.09 (d, 1H), 9,04 (s, 1H), 8,32 (d, 1H), and 7.6 (d, 1H), 7,40 (d, 2H), 7,35 (m, 3H), 7,32 (m, 2H), 5,64 (s, 2H) ppm

Example 3 (Reaction according to Scheme 1, 3rd stage):

N-{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}-N-quinoline-6-ylacetamide (2)

0,833 g 6,82 mmol) DMAP, 1,38 g (to 13.6 mmol) of triethylamine and 13.9 g (136 mmol) of acetic anhydride is added in nitrogen atmosphere to a stirred solution of 6.0 g (to 13.6 mmol) of 2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-M-quinoline-6-ylacetamide in 60 ml DMF. The reaction mixture was stirred at room temperature for 10 minutes and then poured into 200 ml of ethyl acetate. Then add 300 ml of water, the mixture is shaken in a separating funnel, after which the two phases are separated. Precipitation begins after 20 minutes. Pale-yellow crystals are filtered and dried in vacuum at 60°C.

Output: Android 4.04 g (61,5%)

Melting point: 122,9°

1H-NMR (600 MHz, DMSO-d6) δ=9,02 (d, 1H), 8,54 (s, 1H), 8,44 (d, 1H), 8,21 (d, 1H), 8,17 (d, 1H), 8,10 (m, 1H), 7,88 (m, 1H), 7,65 (m, 1H), 7,58 (m, 1H), 7,44 (d, 2H), 7,33 (d, 2H), 7,28 (m, 2H), the ceiling of 5.60 (s, 2H), of 2.15 (s, 3H).

MS(ESI) m/z 482,1 (MH+), (tiora. 481,94)

Example 4 (Reaction according to Scheme 1, stage 3. I (a)):

Methyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (3)

930,2 mg cases (27.3 mmol) of NaH (60% dispersion in mineral oil) are added under nitrogen atmosphere to a cooled stirred solution of 10.0 g (22.7 mmol) of 2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinoline-6-ylacetamide in 500 ml of dry THF. The solution was stirred at 0°that is highlighted yellow precipitate, and then stirred for another 15 minutes. Then added dropwise 2.58 g (27,3 mmol) methylcarbamate at temperatures below +5°C. the Reaction control the display using thin-layer chromatography (eluent: n-heptane/ethyl acetate 1/1 RF=0,11). The reaction mixture was poured into water and the resulting mixture extracted with ethyl acetate; the organic phase is washed with a saturated solution of sodium chloride and dried over anhydrous MgSO4. Evaporation of the solvent gives the crude product, which was purified by column chromatography (n-heptane/acetone 2/1) to obtain 3. Thin layer chromatography shows that 3 still contains minor impurities that can be removed by stirring the crude 3 with acetone for 1 hour. Filtering allows you to get 3 in the form of pale yellow crystals.

Yield: 3.0 g (26.5 per cent)

Melting point: 178,5°

1H-NMR (600 MHz, DMSO-d6) δ=9,02 (d, 1H), 8,58 (s, 1H), of 8.47 (d, 1H), 8,17 (m, 3H), to 7.84 (m, 1H), 7,63 (m, 2H), 7,44 (d, 2H), 7,34 (m, 4H), ceiling of 5.60 (s, 2H), the 3.65 (s, 3H).

MS(ESI) m/z 498,2 (MN+), (tiora. 497,94)

Example 5 (Reaction according to Scheme 2, 3-stage I (b)):

Getting 2-[1-(4-chlorbenzyl)-1 H-indol-3-yl]-N-quinoline-6-yl-2-dioxooleana (11)

3,68 g (9.1 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide added under nitrogen atmosphere to a suspension of 4.00 g (9.1 mmol) of 2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinoline-6-ylacetamide in 200 ml of toluene, after which the mixture is heated at 75°C for 3 hours. The formed precipitate is filtered hot from the reaction solution and then washed with 100 ml of methylene chloride. The filtrate was concentrated in vacuo and chromatograph the residue is display on flash silica gel (eluent: methylene chloride/methanol 99:1). Fractions of product were filtered on a flash silica gel (eluent: n-heptane/ethyl acetate 1/1) after the solvent was removed again.

Output: 0,46 g (11% of theoretical)

ESI-MS: m/e=456,1 (MN+), (tiora. 455,97)

1H-MP (DMSO-D6) δ=10,89 (s, 1H), and 8.8 (s, 1H), up 8.75 (s, 1H), 8,55 (s, 1H), 8,12 (d, 1H), 8,35 (d, 1H), 8.0 a (d, 1H), to 7.93 (d, 1H), 7,63 (d, 1H), 7,50 (m, 1H), and 7.4 (m, 3H), and 7.3 (m, 3H), 5,6 (s, 2H) ppm.

The following compounds of formula I have been simplified by analogy with the method of synthesis in Scheme 1 and in accordance with Examples 2 and 3.

Example 6:

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-(1H-indazol-5-yl)-2-oxoacetate (4)

Melting point: 203°

1H-NMR (DMSO-D6) δ=13,02 (s, 1H)and 10.7 (s, 1H), 9,04 (s, 1H), 8,48 (s, 1H), 8,42 (d, 1H), of 8.06 (s, 1H), 7,73 (d, 1H), and 7.6 (d, 1H), 7,55 (d, 1H), 7,40 (d, 2H), 7,28-7,35 (m, 4H), 5,63 (s, 2H) ppm.

Example 7:

Ethyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (5)

Melting point: 199°

1H-NMR (600 MHz, DMSO-d6) δ=9,02 (m, 1H), at 8.60 (s, 1H), 8,48 (d, 1H), 8,15 (m, 3H), 7,83 (m, 1H), 7,63 (m, 2H), 7,43 (d, 2H), 7,32 (m, 4H), ceiling of 5.60 (s, 2H), 4,15 (q, 2H), of 0.95 (t, 3H).

MS(ESI) m/z 514,2, 512,1 (MN+), (tiora. 511,97).

Example 8:

Propyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (6)

The melting point of 164°

1H-NMR (600 MHz, DMSO-d6) δ=9,02 (m, 1H), at 8.60 (s, 1H), 8,48 (d, 1H), 8,17 (m, 3H), to 7.84 (m, 1H), 7,63 (m, 2H), 7,43 (d, 2H), 7,33 (m, 4H), 5,61 (s, 2H), a 4.03 (t, 2H), 1,32 (m, 2H),0,56 (t, 3H).

Example 9:

N-{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}-N-quinoline-6-ylpropionic (7)

1H-NMR (600 MHz, DMSO-d6) δ=9,03 (m, 1H), charged 8.52 (s, 1H) to 8.45 (d, 1H), 8,23 (d, 2H), 8,18 (d, 1H), 8,13 (m, 1H), 7,88 (m, 1H), 7,65 (m, 1H), 7,58 (m, 1H), 7,45 (d, 2H), 7,30 (m, 4H), 5,59 (s, 2H), 2,61 (q, 3H), from 0.88 (t, 3H).

Example 10:

Ethyl{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}pyridine-4-ylcarbamate (8)

Melting point: 62°

1H-NMR (600 MHz, DMSO-d6) δ=total of 8.74 (m, 2H), charged 8.52 (s, 1H), 8,12 (m, 1H), 7,60 (m, 1H), 7,55 (m, 2H), 7,40 (m, 2H), 7,30 (m, 4H), to 5.57 (s, 2H), 4,10 (q, 2H), of 0.95 (t, 3H).

Example 11 (Substance comparison):

Getting 2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-(2-methylinosine-6-yl)-2-oxoacetate (9)

Yield: 14.8 g (77,3% of theoretical)

Melting point: 182-185°

1H-NMR(COCl3) δ=9,58 (s, 1H), 9,12 (s, 1H), 8,5 (s, 1H), to 8.41 (s, 1H), 8,05 (t, 2H), 7,78 (d, 1H), and 7.4 (dd, 1H), 7,32 (m, 4H), 7,26 (s, 1H), 7,15 (d, 1H), 5,38 (s, 2H), by 2.73 (s, 3H) ppm.

Example 12 (Substance comparison):

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinoline-6-ylacetamide (10)

Melting point: 200°

1H-NMR(OMSO-D6) δ=11,5 (s, 1H), 9,05 (s, 1H), cent to 8.85 (s, 1H), 8,66 (s, 1H), 8,32 (d, 2H), 8,12 (d, 1H), 8,03 (d, 1H), 7,63 (d, 1H), 7,53 (dd, 1H), 7,42 (d, 2H), 7,3-7,38 (m, 4H), 5,63 (s, 2H) ppm.

Example 13 (Substance comparison):

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinoline-8-ylacetamide (12)

Melting point: 178°

Example 14 (Substance comparison):

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-isoquinoline-5-yl-2-oxoacetate (13)

Melting point: 239-241°

Example 15 (Substance comparison):

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-pyridin-4-ylacetamide (14)

Melting point: 264°

Example 16 (Substance comparison):

2-[1-(4-Chlorobenzyl)-1H-indole--yl]-N-(2-methylinosine-8-yl)-2-oxoacetate (15)

Melting point: 200-202°

The biological effects of the compounds according to this invention

Conducting in vitro and in vivo tests on selected tumor models showed the presence of the following pharmacological activities.

Example 17: Antiproliferative effect on cancer cells

Investigated the antiproliferative activity of substances 1, 2, 4, 9, 11, 12, 13 and 15 in the test on the proliferation of lines resistant cancer cells (D.A.Scuderio et al. Cancer Res. 1988, 48, 4827-4833). Used test characterizes the activity of cellular dehydrogenase and allows you to determine cell viability, as well as to indirectly determine the number of cells. We used the following cell lines: cell line cervical carcinoma KB/HeLa (ATCC CCL17), cell line of ovarian adenocarcinoma SKOV-3 (ATCC HTB77), cell line human glioblastoma SF-268 (NCI 503138) and cell line lung carcinoma NCI-H460 (NCI 503473).

Table 1:

The ability of compounds according to the invention to inhibit proliferation in HTT cytotoxic test conducted on cell lines human cancer.
Analysis of HTT-proliferation, AS in mcg/ml
ExampleKB/HeLaSKOV-3SF-268NCI-H460
1 0.0450.0290.042
20.2020.1230.166
40.3350.144>3.16
110.0360.0290.036
9 (C)0.1830.1740.261
12 (C)>3.16>3.16>3.16>3.16
13 (C)>3.16>3.16>3.16>3.16
15 (C)>3.16the concentration is>3.16the concentration is
C = the Substance of the comparison; concentration: not defined

The results show that the embodiments 1, 2, 4, and 11 are very potent inhibitors of proliferation of selected lines of tumor cells.

Example 18: Antiproliferative effect on the lines of MDR cancer cells

To further characteristics of the substances 1, 2, 4 and 11 were studied in relation to their impact on multi-drug resistant cell lines compared to not to be resistant lines of wild-type cells.

Were studied the following cell lines: murine cell line L1210, cell line OST the CSOs myeloid leukemia L12 and resistant lines L1210/mdr and LT12/mdr. Murine cell lines R (methylcholantrene-induced lymphoid neoplasma) and doxorubicin-resistant line R were also included as test systems.

The results are summarized in Table 2 below:

Table 2:

The inhibitory effect of substances cancer cell line human in the test for XTT-proliferation.
Analysis of HTT-proliferation, AS in mcg/ml
ExampleLT12LT12/mdrL1210L1210VCRRP388ADR
10.0150.0170.0180.0210.0120.019
20.2250.2720.2060.5580.2240.215
40.0840.0930.2460.2410.1750.231
110.0230.0540.0520.0670.0180.051
Paclitaxel (C)0.0050.340.048>3.160.035>3.16
VI is Christine (C) 0.0020.1340.015>3.160,0040.93
Doxorubicin (C)0.029>3.60.269>3.160.204>3.16
Mitoxantrone (C)0.0063.10.092.10.0530.608
Etoposide (C)0.094>3.60.269>3.160.202>3.16
= Example to compare

Substances 1, 2, 4, and 11 show very high inhibitory effect on all tested cell lines, while the classic substances are those that have a tubulin-inhibiting effect, such as paclitaxel or vincristine, and topoisomerase II inhibitors (doxorubicin, mitoxantrone and etoposide), as you can see, affect MDR1-resistant cell lines the effect that, at least much less.

Example 19: Inhibition of polymerization of tubulin

Substances 1, 4, 9, 11, 12, 13 and 15 were studied for their ability to inhibit the polymerization of bovine tubulin in the test in vitro (D.M.Bollag et al. Cancer Res. 1955, 55, 2325-2333). This test is performed using Abolina, which was cleared in the process of polymerization - depolymerization and which is polymerized by adding GTP and heating. Table 3 gives the values of EC50where is the inhibition of polymerization of tubulin containing 30% associated proteins (the maximum number).

Table 3:

Inhibition of tubulin polymerization. The average values of two independent experiments
ExampleInhibition of polymerization of tubulin, EU50in mcg/ml
10.71
41.26
110.97
9 (C)1.16
12 (C)>10 microns
13 (C)>10 microns
15 (C)>10 microns
Vincristine0.35
C - example to compare

The results show that the substances 1, 4, 9 and 11 have a strong inhibitory effect on the polymerization of tubulin at that time, as compounds 12, 13, and 15 have no effect.

Example 20: Inhibition of topoisomerase II

The ability of a substance to inhibit the topoisomerase II was studied in two in vitro tests.

Analysis of cDNA for determining the activity of topoi operasi II

In this quantitative analysis, which was described P.Arimondo (Anti-Cancer Drug Design 2000, 15 (6), 413-421), "DNA treated with DNA-topoisomerase II person in the absence and in the presence of compound components analysis. In this system connection 1 according to this invention was tested at three different concentrations (100, 31,6, and 10 μm). Were used for comparison, the positive control and standard connections m-amsacrine (m-amsa), paclitaxel (Taxol and vincristine, in each case, the concentration was 100 μm.

Analysis:

2 μl of 10x standard buffer for analysis, 1 µl of cDNA (200 ng)and 0.5 μl of topoisomerase II (1 unit) and 15.5 μl of N2About add by pipette 1 ál of previously entered analyte (concentrated 20-fold in 100% DMSO) and mixed reagents. Samples from the reaction mixture is placed in a thermostat, which is pre-heated to 37°and incubated at 37°C for 10 minutes. The incubation is stopped after adding 4 ál of 5x stop buffer and the substance further extracted with CIA. After that, 20 μl of the supernatant applied to 1% agarose gel containing 0.25 μg of ethidium-bromide in 1 ml, and subjected to separation at 100 V for 1 h In the end of the gel photographed in UV light (see Figure 1). Inhibition of decatenation (untwisting) cDNA assess quantitatively, using the Software Analysis of the Torah GelPRO ®(see Figure 2).

Analysis of the release of pRYG for determining the activity of topoisomerase II

This analytical system was used to further identify the inhibitory properties of the compounds of this invention against topoisomerase II. In this system connection 1 according to this invention was tested at three different concentrations (100, 31,6, and 10 μm). For comparison used the standard connection m-amsacrine (m-amsa), paclitaxel (Taxol) and vincristine concentrations 316 and 100 microns.

The analysis was carried out as follows.

2 μl of 10x standard buffer for analysis, 0,5 µl pRYG cDNA (125 ng)and 0.5 μl of topoisomerase II (1 unit) and 16 μl of H2O add by pipette 1 ál of previously entered analyte (concentrated 20-fold in 100% DMSO) and mixed reagents. Samples from the reaction mixture is placed in a thermostat, which is pre-heated to 37°and incubated at 37°C for 30 minutes. The incubation is stopped after adding 4 ál of 5x stop buffer. Then 10 μl of the sample put on a 1.2% agarose gel containing 0.25 μg of ethidium-bromide in 1 ml, and subjected to separation at 100 V for 2.5 h In the end of the gel photographed in UV light (see figure 3). Inhibition of release of pRYG assess quantitatively using Software GelPRO Analyzer® (see Figure 2).

Taking all the facts into consideration, we can conclude that it has been shown that compound 1 according to this invention significantly inhibits topoisomerase II in both analytical systems. The results obtained with compound 1, comparable with the values of inhibition obtained with the topoisomerase II inhibitor m-amsacrine. As expected, neither paclitaxel or vincristine showed no inhibitory effect in two conducted definitions.

Example 21: Analysis of the cell cycle

The cell cycle comprises the development of cells from one cell generation to another. During the rest phase (GO) and phase presentata (G1), the cell has a diploid set of chromosomes (2). In phase synthesis (S), the amount of DNA increases by replication. The phase ends when prebiotically phase (G2M), in which the cell has a double set of chromosomes (4) and double DNA content. In the next phase of mitosis (M), which is short in duration, regulirovanie chromosomes are equally distributed between the two daughter cells, each of which again has a diploid DNA content and is in phase G01, which means that the cell cycle can begin again.

For cell cycle analysis cells KB/HeLa was treated with the studied substances in different concentrations(0.1 to 1000 nm) at 37° With in 24 hours.

The percentage of cells that are stopped at the G2/M-phase of the cell cycle, after they were treated with standard substances or selected test substances shown in the following Table 4. The results were analyzed using custom software (ModFit™).

Table 4:

The concentration required for inhibition of 50% of the cells in phase G2/m
ExampleIS in nm (50% of cells in G2/M)
125.2
2125.3
4252
1141.8
14 (C)>1000
Paclitaxel26.9
Mitoxantrone25.3

Substances 1, 2, 4, and 11 according to this invention exhibit activity comparable with the activity of standard compounds of paclitaxel and mitoxantrone.

Example 22: a Demonstration of apoptosis CDDplus-nucleosomal ELISA test

Fragmentation of nuclei is a late consequence of apoptosis. Changes that can be observed in this connection may be a characteristic sign that the DNA strands are split endonucleases, and the result is crushing on nucleosomal particles.

CDDplus-nucleosomal the ELISA test described Roche Molecular Biochemicals, was used to demonstrate nucleosomal particles.

For this purpose, we studied the effects of compounds 1 and 2 on the cell line U-937 at various concentrations (1 nm-10 μm; 24 hour processing). (See Figure 5 and 6).

In this test it was possible to observe dependent on the concentration of the increase in the content of nucleosomes in the cell lysates for compounds 1 and 2. It was not possible to demonstrate any significant increase in the supernatant of cell culture, which is a fact in favor of the death apoptotic cells occurred after exposure to compounds 1 and 2.

Example 23: a Demonstration of the water solubility of the compounds according to the invention under conditions of saturation

Determined the solubility of substances 1, 2, 10, and 14 in the water under saturated conditions, as described below. Added a maximum of 1% DMSO, with the aim of dissolving substances, and in order to achieve wetting of the samples. Used method HPLC-UV to check the contents. The results are summarized in Table 5 below.

Table 5:

Values of solubility at saturation substances 1, 2, 10, 14
Connection nameSolubility in water at saturation [mg/ml]
125.0
228.5
10 (C)0.038
14 (C)0.35

1) the number of dead animals is compared with the total number of

Example 24: Activity in vivo

In xenograft models of human (melanoma MEXF-462) studied the activity and tolerability in vivo compound 2 according to the invention in comparison with the same indicators of substances 10 and 14. The results are collected in table 6 below.

The activity of compounds 2, 10, and 14 in vivo (melanoma MEXF-462).

Table 6:

The activity of compounds 2, 10, and 14 in vivo (melanoma MEXF-462)
SubstanceDose, mg/kgApplicationDeath, n1The optimum T/S % (day)
280inside0/6 mice0,0% (18), complete remission in all 6 animals
10 (C)70inside5/6 mice dead2,3% (7)
10 (C)55inside2/6 mice dead0,8% (14)
14 (C)32inside3/5 mice dead14.6% (7)
14 (C)16inside3/5 mice dead/td> 0.7% (18)

1) the Number of dead animals in comparison with the total number of

In this xenograft models was observed that compound 2 causes complete remission of neoplastic diseases in animals treated at the same time, it is well tolerated. Comparable antineoplastics effect was observed also in the case of compounds 10 and 14, but these substances were worse portable.

Example 25: Activity in vivo

In other xenograft models of human (breast, MAXF857) studied the activity and tolerability in vivo compound 2 according to the invention in comparison with the same indicators in substance 10. The results are shown in the table below.

The effect of compounds 2 and 10 on breast cancer MAXF857.

Table 7:

The activity in vivo of compounds 2 and 10 (mammary gland, MAXF857)
SubstanceDose [mg/kg]ApplicationDeath, n1The optimum T/S % (day)
280inside0/6 mice9,6% (10)
10 (C)40inside2/6 mice dead6,5% (10)

1) the Number of dead animals in comparison with the total number of

While it was found, chesedonia 2 and 10 are comparable antineoplastics effect matter 10 was significantly worse portable (2,6 mice dead)than agent 2.

1. Derivatives of indole of General formula I

where R is unsubstituted or substituted by chinaillon, perioperatively, indazolin or pyridium and which is directly linked to the amide nitrogen group

R1: unsubstituted or substituted alkyl-aryl,

R2: hydrogen,

R3-R6: hydrogen,

R7: (C1-C6-alkylsulphonyl or (C1-C6-alkoxycarbonyl,

and

X, Y is oxygen or sulphur,

with the proviso that when R is unsubstituted or substituted 2-, 3-, 4-, 5 - and 6-Peregrina group and R1-R6 have the above meanings, R7 not be an acetyl radical or a tert-butyloxycarbonyl group; and their physiologically tolerant of salt.

2. Derivatives of indole according to claim 1, wherein R is unsubstituted or substituted 5-, 6-, 7-chinaillon, unsubstituted or substituted 2-, 3-, 6-, 7 - and 8-perioperatively, unsubstituted or substituted 3-, 4-, 5-, 6 - and 7-indazolinone, unsubstituted or substituted 2-, 3-, 4-, 5 - and 6-pyridium.

3. Derivatives of indole according to claim 1 or 2, characterized in that R7 is methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, acetyl or propionyl.

4. Derivatives of indole according to claim 1, characterized in that they are chosen from the following the groups:

N-{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}-N-quinoline-6-ylacetamide (2)

methyl {2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (3)

ethyl {2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (5)

propyl {2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}quinoline-6-ylcarbamate (6)

N-{2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}-N-quinoline-6-ylpropionic (7)

ethyl {2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxoacyl}pyridine-4-ylcarbamate (8).

5. Derivatives of indole according to claim 1, characterized in that R1 represents a 4-Chlorobenzyl, R2-R6 is hydrogen, and X and Y are oxygen or sulfur.

6. Derivatives of indole of General formula I,

where R: is directly related to the nitrogen of amide substituted 6-chinolin, substituted or unsubstituted 7-chinolin, where 2-methyl-6-chinolin excluded, and where, when X is a sulfur atom, R can be unsubstituted 6-chinaillon;

unsubstituted or substituted 2-, 3-, 6-, 7 - and 8-perioperative, unsubstituted or substituted 3-, 4-, 5-, 6 - and 7-indazole,

R1: unsubstituted or substituted alkyl-aryl,

R2: hydrogen,

R3-R6: hydrogen, and

R7: hydrogen,

X, Y is oxygen or sulphur,

and their physiologically tolerant of salt.

7. Derivatives of indole according to claim 6, characterized in that they are chosen from the following groups:

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-quinoline-6-yl-dioxazine (11)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-pyrido[2,3-b]pyrazin-7-ylacetamide (1)

2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-(1H-indazol-5-yl)-2-oxoacetate (4).

8. Derivatives of indole on PP-7, characterized in that R1 represents a 4-Chlorobenzyl, R2-R6 is hydrogen, and X and Y are oxygen or sulfur.

9. Pharmaceutical composition having inducing apoptosis effect, characterized in that it contains an effective amount of at least one indole derivatives described in claims 1 to 8.

10. The composition according to claim 9, characterized in that a derivative of indole is composed of microparticles or nanoparticles.

11. The composition according to claim 9 or 10, characterized in that it further comprises a pharmaceutically suitable carrier and/or excipient and is in the form of pills, tablets, sugar coating, capsules, solutions for infusion or capsules, suppositories, plasters, medicines in the form of powders that can be used for inhalation, suspensions, creams and ointments.

12. Use of derivatives of indole, characterized in claims 1 to 8, to obtain a pharmaceutical composition for treatment of tumor diseases.

13. Use 12 for the treatment of neoplastic diseases in the case of drug resistance in relation to other active compounds.

14. Use 12 for the treatment of opuholizabolevaniya in the case of metastatic carcinoma.



 

Same patents:

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compounds of and formula: I II those developing antiviral activity allowing application in pharmaceutical formulations and for antiviral medicines production.

EFFECT: new compounds have useful biological properties.

5 cl, 3 dwg, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.

EFFECT: compounds possess inhibiting activity.

13 cl, 1 tbl, 8 ex

FIELD: CHEMISTRY.

SUBSTANCE: invention relates to novel method for preparation of compounds of formula IX or IXа, which implies reaction of compound of formula Va, in solvent, with compound of formula VII or formula VIIa, in the presence of palladium catalyst and phospho ligand, in the presence of amine base, resulting in compound of formula VIII or VIIIa. The method also implies reaction of compound of formula VIII or VIIIa, in solvent, with cyclopropylamine, not necessarily in the presence of catalyst. Also, invention relates to method for purification of compound of formula IX or IXa.

Va - R1 may be either С1-8alkyl, aryl or heteroaryl, not necessarily aryl- and/or С1-8alkyl-substituted; and

.

EFFECT: method for preparation of biologically useful compounds is described.

17 cl, 3 tbl, 77 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically suitable salt or solvate thereof, where dashed line stands for additional bond, а is a number from 0 to 2, b is a number from 0 to 2, n is 2, p is 2, r is 1, М1 stands for nitrogen, М2 stands for С(R3), X stands for either a bond or alkylene group with number of carbon atoms from 1 to 6, Y stands for -С(О)- group, Z stands for a bond, or alkylene group with number of carbon atoms from 1 to 6, or alkenylene group with number of carbon atoms from 1 to 6, or -С(O)-, -CH(CN)-, -SO2- or СН2С(O)NR4- group, R1 stands for groups, R2 stands for six-membered heteroaryl ring with one or two heteroatoms chosen independently of each other from either nitrogen atom or N-O group, other atoms of the cycle being carbon, five-membered heteroaryl ring with one, two, three or four heteroatoms chosen independently of each other from nitrogen, oxygen or sulphur, other atoms of the cycle being carbon, R32 stands for substituded quinoline group, R32 stands for substituted aryl group, heterocycloalkyl group, cycloalkyl group with number of carbon atoms from 3 to 6, alkyl group with number of carbon atoms from 1 to 6, group, where the said six-membered heteroaryl ring or the said five-membered heteroaryl ring may be R6-substituted, R12 independently of others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group or fluorine atom, provided in case R12 stands for hydroxyl or fluorine the rest of R12 cannot be bonded to a nitrogen-bonded carbon atom, or two R12 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjaicent carbon atoms of the ring, R13 independently of the others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group, alcoxy group with number of carbon atoms from 1 to 6, or fluorine atom, provided in case R13 stands for hydroxyl or fluorine the rest of R13 cannot be bonded to a nitrogen-bonded carbon atom, or two R13 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjacent carbon atoms of the ring. See description for meaning of the other structural elements. Invention relates also to pharmaceutical compositions, as well as to application of compounds of formula I.

EFFECT: preparation of novel biologically active substances and pharmaceutical compositions.

20 cl, 659 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method (variants) for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone and its (+)-enantiomer. The first variant of method for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone involves step (e) and another variant involves steps (b)-(e). Method for synthesis of (+)-enantiomer involves the following steps (a)-(f): (a) interaction of 2,6-diaminopyridine with malic and sulfuric acids to form 2-amino-7-hydroxy-1,8-naphthyridine hydrosulfate that (b) is treated with phthalyl reagent in a solvent medium to form phthalimidylnaphthyridine of the formula (2): that (c) is chlorinated to form chloride of the formula (3): that (d) is reduced to hydroxyindolinone of the formula (4): that (e) is treated with 5-methyl-2-oxohexyltriphenylphosphonium halide to yield racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone that (f) is separated and final (+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone is prepared. Invention provides improving method for synthesis of 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone from 2-(7-chloro-1,8-naphthyridine-2-yl)-3-hydroxyisoindolinone-1-one based on using 5-methyl-2-oxohexyltriphenylphosphonium halide.

EFFECT: improved methods of synthesis.

13 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): that are antagonists of CRF receptors and wherein Ar means optionally substituted phenyl or monocyclic 6-membered heteroaryl comprising one heteroatom chosen from nitrogen, oxygen or sulfur atoms; R1-R4 have values given in the invention claim, or to their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of indicated compounds and to pharmaceutical compositions containing these compounds that are useful for administration to a patient suffering from diseases that are relived in therapy using antagonists of CRF receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 tbl, 17 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one isethionate salt and to its crystalline forms. These substances show properties of selective inhibitor of cyclin-dependent kinase 4 (CDK4) and can be used in treatment, for example, of inflammatory and cellular proliferative diseases. Crystalline forms of salt show powdery roentgenogram in values 2θ about 8.7, 13.5 and 17.6 (form A); 5.1, 11.8, 12.1, 12.8, 13.1 and 14.7 (form B), and 8.4, 8.9 and 21.9 (form D). Also, invention relates to methods for preparing crystalline 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one isethionate salt, to medicinal agent and its using for preparing a medicinal agent.

EFFECT: valuable medicinal and biochemical properties of compound.

23 cl, 5 tbl, 18 dwg, 12 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to 4-pyperazinyl-benzen-sulfanylindols with the general formula I , where: R1 and R2 each independently means hydrogen, halogen, alcoxy, R3 and R4 each independently means hydrogen, halogen, alkyl, n is equal to 0 to 4, R6 in each particular case means hydrogen or halogen, R7 and R8 each means hydrogen, R9 means hydrogen, alkyl, or individual isomer, racemic or non-racemic mixture of isomers or their pharmaceutically acceptable salt or solvate. The pharmaceutical compositions are described based on compound I.

EFFECT: compounds can be efficiently used in treatment of certain diseases of central nervous system.

14 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the general formula (I): and their pharmaceutically acceptable salts and in vivo hydrolyzed esters as aurorakinase inhibitors and their using, to a method for inhibition and pharmaceutical composition based on thereof, and to a method for their synthesis. In compound of the general formula (I) X represents -NR6 wherein R6 represents hydrogen atom or (C1-C6)-alkyl; R5 represents group of the formula (a): or (b): wherein * means a point for adding to group X in compound of the formula (I); R1, R2, R3 and R4 are chosen independently from hydrogen atom or -X1R9 wherein X1 represents -O-, and R9 is chosen from one of the following groups: (1) hydrogen atom or (C1-C5)-alkyl; (3) (C1-C5)-alkyl-X3R20 wherein X3 represents -O- or -NR25 wherein R25 represents hydrogen atom, (C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl, and R20 represents hydrogen atom, (C1-C3)-alkyl, cyclopentyl, cyclohexyl or 5- or 6-membered saturated heterocyclic group with 1 or 2 heteroatoms that are chosen independently from nitrogen atom (N) wherein (C1-C3)-alkyl group can carry 1 or 2 substitutes that are chosen from oxo, hydroxy group, halogen atom and (C1-C4)-alkoxy group, and wherein cyclic group can carry 1 or 2 substitutes that are chosen from (C1-C4)-alkyl; (4) (C1-C5)-alkyl-X4-(C1-C5)-alkyl-X5R26 wherein X4 and X5 can be similar or different, and each means -O- or -NR31- wherein R31 represents hydrogen atom, (C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl, and R26 represents hydrogen atom or (C1-C3)-alkyl; (5) R32 wherein R32 represents 5- or 6-membered saturated heterocyclic group added through carbon atom or nitrogen atom with 1 or 2 heteroatoms that are chosen independently from oxygen (O), sulfur (S) and N atoms wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from hydroxy, (C1-C4)-alkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkyl; (6) (C1-C5)-alkyl-R32 wherein R32 is given above; (18) (C1-C5)-alkyl optionally substituted with 1, 2 or 3 halogen atoms; (19) (C1-C5)-alkyl-X10-(C1-C5)-alkyl-X11R90 wherein X10 and X11 that can be similar or different each means -O- or -NR95- wherein R95 represents (C1-C5)-alkyl, (C1-C3)-alkyl substituted with 1, 2 or 3 halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy groups, (and wherein 2 (C1-C4)-alkoxy groups by (C1-C4)-alkyl groups alkoxy can form in common 5- or 6-membered saturated heterocyclic group that comprises 2 oxygen atoms), (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl; R90 represents hydrogen atom or (C1-C3)-alkyl; (22) (C1-C5)-alkyl-R96 wherein R96 represents 5- or 6-membered heterocyclic group that can be saturated or unsaturated (added through carbon or nitrogen atom) with 1 or 2 heteroatoms that are chosen independently from N wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from (C1-C4)-hydroxyalkyl, (C1-C4)-alkyl, hydroxy and (C1-C4)-alkoxy-(C1-C4)-alkyl, and wherein R60 represents hydrogen atom; R61 represents group of the subformula (k): wherein p represents 0 or 1; q represents 1; R'1 and R''1 represent independently hydrogen atom or (C1-C10)-alkyl; T represents C=O; V represents -N(R63)R64 wherein R63 represents -(CH2)q'R70 or phenyl optionally substituted with 1 or 2 groups chosen independently from halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy, trifluoromethyl, trifluoromethoxy, nitro, difluoromethyl, difluoromethoxy and cyano group; R64 represents hydrogen atom or (C1-C3)-alkyl; q' = 0; R70 represents -K-J wherein K represents a bond, and J represents phenyl optionally substituted with 1, 2 or 3 groups that are chosen from halogen atom, (C1-C3)-alkyl, cyano, (C1-C3)-alkoxy, and R62 represents hydrogen atom. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by aurorakinase activity, for example, proliferative diseases, such as cancer.

EFFECT: valuable medicinal properties of compounds.

32 cl, 7 tbl, 2 sch, 147 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-[(4-phenyl-1-piperazinyl)alkyl]-substituted heteroarene carboxamide of the general formula (I): and structurally similar 2-ferrocenyl compounds of the general formula (II): showing activity with respect to neuroreceptors and wherein R means hydrogen atom, (C1-C6)-alkyl, halogen atom; R1, R2 and R3 are chosen independently from hydrogen atom, hydroxy group, (C1-C6)-alkyl, (C1-C4)-alkoxy group, halogen atom, trifluoromethyl and cyano group; X can represent sulfur atom (S), oxygen atom (O), -NH or Te. Proposed compounds can be used in treatment of the central nervous system diseases. Also, invention describes methods for synthesis of these compounds, a pharmaceutical composition based on thereof and using for preparing a drug used in treatment of the central nervous system diseases.

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

26 cl, 2 tbl, 25 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of tetrahydrocarbazole of the formula (I): wherein n = 0, 1 or 2; X represents -NH or oxygen atom (O); each R is a similar or different radical and chosen independently from group consisting of halogen atom, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group; each R1 is a similar or different radical and chosen independently from group consisting of halogen, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group and wherein each m means 2 independently; each R10 is a similar or different radical and chosen independently from alkylene; each p and q is chosen independently from 0, 1, 2, 3, 4 or 5; each R2 is a similar or different radical and chosen independently from group consisting of hydrogen atom (H), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl and -R10OH; ring A represents phenyl, naphthyl or heteroaryl wherein heteroaryl represents monocyclic 5-7-membered aromatic ring or condensed bicyclic aromatic ring system consisting of two such aromatic rings that comprise one or two nitrogen atoms and/or sulfur atoms, and to their pharmaceutically acceptable salts, solvates, esters and amides. Compounds of the formula (I) possess effect against disorders caused by HPV-infection and useful in treatment of human papilloma. Also, invention relates to a pharmaceutical composition based on compounds of the formula (I) and its using in preparing drugs for their using in treatment and prophylactic of states or disorders caused by HPV-infection.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) or their pharmaceutically acceptable salts or solvates possessing properties of modulator of activity of insulin-like growth factor-1 (IGF-1) receptors, their synthesis and using. These compounds can be used in cancer treatment also. In the general formula (I) R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom chosen from nitrogen, oxygen or sulfur atom and wherein this ring is optionally substituted with at least a substitute chosen from (C1-C6)-alkyl, (C1-C6)-alkoxy-group (each can be optionally substituted with at least one substitute chosen from halogen atom, hydroxyl and trifluoromethyl group), halogen atom, cyano-group, hydroxyl, (C1-C6)-alkoxycarbonyl, -C(O)NR7N8, and unsaturated 5-6-membered ring that can comprise at least one heteroatom chosen from nitrogen atom, and wherein this ring is optionally substituted with at least one substitute chosen from (C1-C6)-alkyl, (C1-C6)-alkoxy-group (each can be optionally substituted with at least one substitute chosen from halogen atom, hydroxyl and trifluoromethyl group), halogen atom and cyano-group; R2 represents (C1-C4)-alkyl group; R3 represents hydrogen atom or halogen atom; R4 represents 5-membered heteroaromatic ring comprising at least one ring heteroatom chosen from nitrogen atom, and wherein this ring is optionally substituted with at least one substitute chosen from (C1-C6)-alkyl, (C1-C6)-alkoxy-group (each can be optionally substituted with at least one substitute chosen from halogen atom, hydroxyl and trifluoromethyl group),(C3-C6)-cycloalkyl; each R7 and R8 represents independently hydrogen atom, or R7 and R8 in common with nitrogen atom to which they are bound form 4-6-membered saturated heterocycle.

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

24 cl, 102 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes cyclic-substituted diphenylazethidinones of the formula (I): wherein each radical among R1, R2, R3, R4, R5 and R6 means independently of one another (C1-C30)-alkylene-(LAG)n wherein n = 1-2; one or two carbon atoms in alkylene residue are replaced with phenyl or piperazinyl residues or (C3-C10)-cycloalkyl residue; one or some carbon atoms in alkylene residue can be replaced with -S(O)n wherein n = 2; -O-, -(C=O)- or -NH-; hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J), O-(C1-C6)-alkyl; (LAG)n means mono- or tricyclic trialkyl ammoniumalkyl residue, -(CH2)0-SO3H, -(CH2)0-COOH, -(CH2)0-C(=NH)(NH2), and pharmaceutically acceptable salts also. Proposed compounds decrease the serum cholesterol content. Also, invention describes using these compounds for preparing a medicinal agent used in treatment of lipid metabolism disorders.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of azethedine of the formula (I): in free form or as a salt wherein Ar means phenyl optionally substituted with one or some substitutes chosen from halogen atom, (C1-C8)-alkyl, cyano-group; R1 means hydrogen atom (H), (C1-C8)-alkyl optionally substituted with hydroxy-, (C1-C8)-alkoxy-, (C1-C8)-alkylcarbonyloxy-group, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl; R2 means H, (C1-C8)-alkyl, (C3-C10)-cycloalkyl; R3 means (C1-C8)-alkyl substituted with phenyl, phenoxy-, (C1-C8)-alkylcarbonyloxy-group, naphthyl; or R2 represents (C3-C10)-cyclalkyl optionally comprising benzo-group, condensed benzo-group, 5-6-membered heterocyclic group comprising 1-3 different heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S), or up to 4 N atoms, or it means 5-6-membered heterocyclic group comprising 1 or 2 ring O or N atoms and optionally substituted with substitutes enumerated in the formula; or R3 means phenyl or naphthyl wherein indicated phenyl, phenoxy- or naphthyl group is substituted optionally with one or some substitutes chosen from halogen atom, cyano-, hydroxy-group, (C1-C8)-alkylcarbonyl, -SO2NH2, (C1-C8)-alkyl, optionally substituted (C1-C8)-alkoxy-, (C1-C8)-alkylthio-group, -SO2-(C1-C8)-alkyl, (C1-C8)-alkoxycarbonyl, (C1-C8)-acylamino-group substituted optionally with (C1-C8)-alkyl by nitrogen atom, (C1-C8)-alkylamino-group, aminocarbonyl, (C1-C8)-alkylaminocarbonyl, di-(C1-C8-alkyl)amino-group, di-(C1-C8-alkyl)aminocarbonyl, di-(C1-C8-alkyl)aminocarbonylmethoxy-group; X means -C(=O)-, -O-, -CH2- or -CH(OH); Y means O, S; m means 1, 2, 3 or 4; each n, p and q means 0 or 1, n + p + q = 1, n + q = 1 and p+ q = 1 and when n means 0 then p means 0. Compounds of the formula (I) inhibit binding eotaxine with CCR-3 receptor that allows their using as component of pharmaceutical composition and for preparing a medicinal agent used in inflammatory or allergic state.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 201 ex

FIELD: organic chemistry.

SUBSTANCE: description is given of compounds with formula (I) and their pharmaceutical salts, in which n, X, Y, R1, R2, R3, R4 and R5 are defined in this invention. The obtained compounds have modulating action relative to "5-НТ6" receptors. Description is also given of a pharmaceutical composition based on compounds with formula (I), used as "5-НТ6" modulators for treating damages to the central nervous system.

EFFECT: obtaining of new compounds, with useful biological properties.

10 cl, 1 tbl, 5 ex

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