Nitrogen-containing heterocyclic derivatives, pharmaceutical composition based on thereof and anticancer agent

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

 

The present invention relates to new heterocyclic compounds or their salts that can be used as a medicine.

Background of invention

It is known that as the anticancer agent can be applied heterocyclic compounds of the following formula (WO 95/027699):

where a denotes optionally substituted heteroaryl or its oxide, denotes optionally substituted ethenylene, D represents optionally substituted phenylene, G denotes optionally substituted phenyl, a R0denotes hydrogen, acetyl, optionally substituted alkyl or optionally substituted of alkenyl.

It is also known that 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine (hereinafter referred to as compound A) has potent activity aimed at inhibiting the growth of cancer cells, and that 1-oxide (E)-4-(2-(2-(N-(4-acetyl-N-(4-methoxybenzenesulfonyl) amino)phenyl)ethynyl)pyridine (hereinafter referred to as compound C) has anti-cancer activity with low toxicity. Accordingly, it was assumed that the compounds a and b are promising drugs for oral administration in the treatment of various malignant tumors, such as lung cancer, breast cancer, R. the gastrointestinal tract, prostate cancer, blood cancer, etc.

Although the compounds a and b are suitable for oral administration, it is unlikely that they can be used for intravenous injection or the like due to extremely low solubility in solutions for injection.

The absorption of anticancer agents by oral administration sometimes varies depending on the subject; and, therefore, from the point of view of reliability, accuracy and safety for the treatment of cancer is mainly used intravenously. Intravenous injection is appropriate if the patient cannot be applied oral administration. In light of the above, in the field of clinical medicine there is a need for anti-cancer agents that can be applied in the form of injection.

Description of the invention

The aim of the present invention are novel compounds with potent anticancer activity, which are water-soluble and suitable for injection.

The authors of the present invention have synthesized and investigated a different connection, in which they found that among them, the compounds of formula [I]below, are water soluble and have very high anti-cancer activity, and thus made the present invention.

The present invention relates to the following(1)-(10).

(1) Compounds is of the formula [I] or its salt

A-B-D-E [1]

where

And denotes optionally substituted heteroaryl or its oxide;

In denotes optionally substituted ethenylene;

D represents optionally substituted phenylene; and

E denotes a group of the formula

where G denotes optionally substituted phenyl; and R denotes optionally substituted heteroaryl or heteroaromatic, or a group of the formula

where n is an integer from 1 to 5; R5and R6are the same or different and independently selected from the group consisting of hydrogen, C1-C6of alkyl, hydroxyalkyl, aminoalkyl; or R5and R6taken together with the adjacent nitrogen atom, may form a 5-7-membered cyclic amino group-NR5(R6), which may be optionally substituted, and in addition to the nitrogen atom may optionally include an oxygen atom, sulfur or nitrogen as a freezing cycle of a member.

(2) the Compound of the formula [I]mentioned in the above paragraph (1)or its salt, where a denotes a 4-pyridyl or 1-oxido-4-pyridyl; In denotes ethenylene; D represents optionally substituted phenylene; and E denotes a group of the formula

where R and G are as defined in paragraph 1.

(3) the Compound of the formula [I] mentioned in the above paragraph (1), or its salt, where a denotes a 4-pyridyl or 1-oxido-4-pyridyl; In denotes ethenylene; D represents optionally substituted phenylene; and E denotes a group of the formula

where G denotes optionally substituted phenyl, and R denotes a group of the formula

where n, R5and R6are as defined in paragraph 1.

(4) the Compound mentioned in the above paragraph (3), or its salt, where R5and R6are the same or different and independently selected from the group consisting of hydrogen, C1-C6of alkyl; or R5and R6taken together with the adjacent nitrogen atom, may form an optionally substituted 5-6-membered cyclic amino group-NR5(R6).

(5) the Compound of the formula [I]mentioned in the above paragraph (1)or its salt, where a denotes a 4-pyridyl or 1-oxido-4-pyridyl; In denotes ethenylene; D is phenylene; and E denotes a group of the formula

where G denotes optionally substituted phenyl; and R denotes optionally substituted 5-6-membered heteroaryl or heteroaromatic.

(6) Salt mentioned in the above paragraph (1), where salt is the hydrochloride.

(7) a Pharmaceutical composition comprising as active ingredient the compounds is of the formula [I], mentioned in paragraph (1)or its salt.

(8) the Pharmaceutical composition according to the above item (7), which is in injectable form.

(9) an Anticancer agent comprising as an active ingredient a compound of the formula [I]mentioned above in paragraph (1)or its salt.

(10) an anti-Cancer agent according to the above item (9), which is in injectable form.

Structural feature of the compounds of the present invention is that the phenyl in stilbazolium the core carries aminoacylating, or heteroaromatic, or heteroaromatic group containing a nitrogen atom.

Connection with the above-mentioned structural feature, is a novel compound not previously described. The compound of the present invention has an excellent antitumor activity and low toxicity.

Hereinafter the present invention will be described in detail.

Terms used in this description to denote different substituents, defined below.

Examples of "phenylenebis" groups include 1,2-phenylene, 1,3-phenylene and 1,4-phenylene. Fenelonov group can have one or two substituent in arbitrary positions, examples of which include hydroxy, halogen, amino, C1-C6alkyl and C1-C6alkoxy. Among others, a preferable one is camping optionally substituted 1,2-phenylene, especially unsubstituted 1,2-phenylene.

Actilingua group may have a substituent(s) at each carbon atom, examples of which include cyano, bromine and C1-C6alkyl. Among others, preferred is optionally substituted ethenylene, especially the unsubstituted ethenylene.

The term "heteroaryl" refers to a 5-6-membered heteroaryl group having one or two nitrogen atoms as forming the loop members. Heteroaryl group optionally has one or two Deputy in arbitrary positions, examples of which include halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy and C1-C6aminoalkyl. Heteroaryl for And includes a 6-membered heteroaryl, for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl and pyrazinyl. Among others, preferred is an unsubstituted 4-pyridyl. Heteroaryl for R includes 5-6-membered heteroaryl, for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-imidazolyl, 2-imidazolyl and 4-imidazolyl.

The term "alkyl" refers to linear or branched alkyl group of 1-6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isoge the forces etc. Among others, preferred is a C1-C3alkyl, especially methyl.

The alkyl fragment "hydroxyalkyl" and "aminoalkyl" is the same as defined above.

Examples of the "cyclic amino group" include, for example, pyrrolidin-1-yl, piperidino, hexamethyleneimino, tetrahydropyridine-1-yl, octahydrate-1-yl, piperazine-1-yl, homopiperazin-1-yl, morpholino, thiomorpholine. The cyclic amino group may have one or two substituent selected from the group consisting of alkyl, alkenyl, quinil, aryl, aralkyl and heterocyclic groups having a nitrogen atom in any position. Among others, preferred are an unsubstituted pyrrolidin-1-yl, piperidino, morpholine, and piperazine-1-yl, substituted by pyridium.

Examples of "halogen" includes fluorine, chlorine, bromine, iodine.

"Phenyl" group may have one or two substituent, such as hydroxy or C1-C6alkoxy. Among others, preferred is a phenyl, substituted alkoxy, especially 4-methoxyphenyl.

Alkylen, presents "-(CH2)n-"may have a Deputy selected from the group consisting of amino or C1-C6the alkyl in any position.

The term "alkoxy" refers to a linear or branched CNS group of 1-6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, the-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, n-hexyloxy, etexilate etc. Among others, preferred is a C1-C3alkoxy, especially methoxy.

The term "alkenyl" refers to linear or branched alkenylphenol group of 2-6 carbon atoms and includes, for example, vinyl, 1-propenyl, 2-propenyl, Isopropenyl, 2-butenyl, 3-butenyl, Isobutanol, Metall, prenyl, isoprenyl, 1,1-dimethylallyl and the like, Especially preferred is a2-C4alkenyl.

The term "quinil" refers to linear or branched alkenylphenol group of 2-6 carbon atoms and includes, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 2-butynyl, 3-butynyl, 3-methyl-2-butenyl and the like, Especially preferred is a2-C4quinil.

The term "aryl" refers to aryl of 6-10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl.

The term "aralkyl" refers to aralkyl of 7-8 carbon atoms, such as benzyl and penetro.

The term "heterocycle with the nitrogen atom"refers to the above-mentioned cyclic amino group or heteroaryl. Such a heterocycle may have one or two substituent selected from the group consisting of alkyl, amino, hydroxy and oxo.

Salts of the compounds [1], which fall within the scope of the present invention include pharmaceutically acceptable salts formed reorgan the ical acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and Hydrobromic acid; organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, naphthalenesulfonate acid and camphorsulfonic acid.

The compound of the present invention can exist in CIS- (Z) and TRANS (E) form. Related isomers and mixtures thereof also fall within the scope of the present invention. Among others, preferred is an E-form.

Among the compounds of this invention of the formula [I] preferred are compounds in which a represents optionally substituted pyridyl or 1-oxidability, especially unsubstituted 4-pyridyl or 1-oxido-4-pyridyl; In denotes attilan in the TRANS-form, especially the unsubstituted ethenylene in the TRANS-form; D denotes unsubstituted 1,2-phenylene; and E denotes a 4-substituted phenyl, and preference is given to 4-alkoxyphenyl, especially 4-alkoxyphenyl.

For the present invention are preferred hydrochloride 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-piperidineacetate)phenyl)ethynyl)the feast of the Dina (the compound of example 5), hydrochloride of 1-oxide (E)-4-(2-(2-(N-(N,N-dimethylphenyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine (compound of example 8), the dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-(4-(2-pyridyl)piperazine derivatives)acetylamino)phenyl)ethynyl)pyridine (compound of example 9), 1 hydrochloride-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-morpholinoethyl)phenyl)-ethynyl)pyridine (compound of example 13) and the hydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-pyrrolidinecarboxamido)phenyl)ethynyl)pyridine (compound of example 14).

The compound of the present invention can be synthesized in accordance with the methods illustrated below.

Method 1

where a, b, D, G and R such as defined above.

Connection [3] and carboxylic acid, [4] is subjected to the direct reaction of condensation, using a condensing agent in accordance with the known per se method, receiving the connection [1]. The reaction can be carried out in the presence of such a condensing agent as N,N-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole or diphenylphosphoryl (DPPA), in a suitable solvent (e.g. halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; acetonitrile; N,N-dimethylformamide (DMF) or the like)at a temperature of priblisitelno -30 to 180° C. If necessary, the catalyst can be used 4-dimethylaminopyridine (DMAP) or 4-pyrrolidinone (4-PPY). When using 1 mol of compound [3] can be used equimolar amount or a slight excess of compound [4] and condensing agent (e.g., DCC). When using the catalyst, its amount may be from 0.1 to 1 mol for one mol of compound [3]. The reaction time depends on the nature of substances, solvent, reaction temperature, etc. used in the reaction, but is usually from about 5 minutes to 70 hours.

Alternatively, the compound [1] can be obtained by the interaction of the compound [3] with a reactive derivative of carboxylic acid [4] in an appropriate solvent. The solvent used for the reaction may be any solvent that does not hinder the reaction, for example ethers, such as tetrahydrofuran, dioxane and diethyl ether; hydrocarbons, such as benzene and toluene; halogenated hydrocarbons, such as methylene chloride and chloroform; ketones, such as acetone and methyl ethyl ketone; aprotic solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, pyridine or acetonitrile, or various mixtures of such solvents. Reactive carboxylic acid derivative includes traditionally used proizvodnye, such as acylhomoserine, anhydrides of carboxylic acids, activated amides and activated esters. Mostly preferred are acylhomoserine. Such acylhomoserine include acylchlorides and Allbreed. Anhydrides of acids include mixed anhydrides derived from monoalkylammonium acids and mixed anhydrides derived from aliphatic carboxylic acids (e.g. acetic acid, tert-butylcarbamoyl, trimethylhexanoic acid, valerianic acid, isovalerianic acid, triperoxonane acid and others), as well as symmetric anhydrides.

Activated amides include amides of the acids, as imidazole, pyrazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole and benzothiazole. Activated esters include such esters as methyl ether, methoxymethyl ether, propargilovyh ether, 4-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, methansulfonate ether, N-hydroxysuccinimide and N-hydroxyphthalimide.

If the method of the present invention use allalone, preferably the reaction is carried out in the presence of a suitable base. Examples of such bases include compounds of alkali metals such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and sodium methylate, and organic tertiary amines, that is s, as pyridine, triethylamine, triethylenediamine. In many cases, the reaction may proceed at room temperature, but if necessary it can be carried out with cooling or heating, in the temperature range from -78 to 150°C, preferably from 0 to 120°C. the Number of connections [4] on 1 mol of compound [3] is preferably from 1 to 10 molar equivalents and more preferably from 1 to 3 molar equivalents. The reaction time depends on starting compounds, solvent, reaction temperature and the like, but it usually takes approximately 5 minutes to 70 hours. The compound [1] can also be obtained by the reaction Mitsunobu (Mitsunobu) (see Synthesis 981,1).

Method 2

where a, b, D, R and G are such as defined above, and X represents halogen.

The compound [1] of the present invention can be obtained by the interaction of the compound [5] with the compound [6] in an appropriate solvent. The reaction can be carried out essentially by the method used for the reaction between the reactive derivative of carboxylic acid and the compound [3] in method 1, described above.

Thus obtained compound [1] can be isolated and purified known per se techniques, such as concentration, pH regulation, redistribution, extraction dissolve elem, crystallization, recrystallization, fractional distillation and chromatography.

The original compound [3] can be obtained in accordance with the known method (WO 95/27699).

The original compound of the formula [4], in which R represents -(CH2)n-NR5R6(compound [4A]), among others, can be obtained by the reaction scheme below, as described later in this document in the reference example.

where R5, R6, n and X are such as defined above, a Radenotes a protective group for hydroxyl group.

As for the starting compounds of the formula [4], in which R denotes heteroaryl or heteroaromatic, among other commercially available can be heteroaryl carboxylic acid or heteroaryl acetic acids, or their derivatives, or those that can be obtained from existing compounds in accordance with the known per se method.

The parent compound [5] can be obtained in accordance with the following reaction scheme.

where b, D and R such as defined above; A0denotes heteroaryl corresponding to A; A1denotes the oxide And0; and Rbdenotes a leaving group.

Examples of leaving groups include chlorine, bromine, iodine, hydroxyl group, alkoxycarbonyl auxillou group, etc.

Connection [10A] interacts with the compound [4b] in an appropriate solvent to obtain the compound [5A], corresponding to the compound of formula [5], where And denotes heteroaryl. Essentially, the reaction can be carried out by the method used in the above-described method 1. Connection [10A] can be converted into the oxide [10b] the interaction with the organic peroxide method, known from the literature (Jikken Called Koza 21, Yukikagobutsu-no-Gosei III (Part 2), p.295, 1958), after which it is subjected to interaction with the compound [4b], the result is a connection [5b], corresponding to the compound of formula [5], where And denotes the oxide or heteroaryl.

Compounds in which R represents -(CH2)n-NR5R6can also be obtained in accordance with the following reaction scheme:

where A0, A1, V, D, R5, R6, n, X and R13such as defined above.

The compound [12A] can be obtained by the interaction of the compounds [10A] with the compound [11] in an appropriate solvent method 1; however, if the connection [11] is a reactive derivative of carboxylic acid requires the presence of a base. The compound [12A] interacts with the amine [8] in an appropriate solvent, optionally in the presence of a base, at a temperature of from 0 to 160°With, before occhialino from 10 to 120° With connection [5C], corresponding to the compound of formula [5], in which R represents -(CH2)n-NR5R6and means heteroaryl. If desired, the compound [12A] can be subjected to interaction with the organic peroxide by the method described in the literature (Jikken Called Koza 21, Yukikagobutsu-no-Gosei III (Part 2), p.295, 1958), with oxide [12b], which in turn interacts with the compound [8] the method used for the reaction between the compound [8] and the compound [12A] connection [5d], corresponding to the compound of formula [5], in which R represents -(CH2)n-NR5R6and And denotes the oxide heteroaryl.

Connection [5d] can also be obtained in accordance with the following reaction scheme.

where A0, A1, V, D, R5, R6n and R13such as defined above.

Connection [13A] make the connection [13b] the method used for the conversion of compound [12A] connection [12b]. Then the connection [13b] restore method, known from the literature (Shin-Jikken Called Koza 14, Yukikagobutsu-no-Gosei (Part 3), p.1333, 1978), receiving the connection [10b]. Connection [10b] and the compound [14] interact method used for the reaction between the compound [10b] and [4b], connection [5d].

The parent compound [4b] and [11] whether the about are commercially available, either get them by way of reference.

The parent compound [6], [7] and [8] are commercially available.

The original connection [10a] can be obtained by the method described in WO 95/27699.

In the above-described methods before joining compounds in the reaction of the amino group or hydroxyl group may be optionally protected by conventional protecting group. The removal of the protective group can be carried out at an appropriate stage by known per se methods, such as acid treatment, alkali treatment or catalytic reduction.

Examples aminosidine groups include benzyl, benzyloxycarbonyl and TRIFLUOROACETYL. Examples hydroxyamine groups include methoxymethyl. 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl and tert-butyldimethylsilyl.

Salts of the compounds [1] of the present invention can be obtained in known per se manner. For example, hydrochloride compounds [1] of the present invention can be obtained by treating compound [1] with a solution of hydrogen chloride in alcohol or ethyl ether and the allocation of crystalline precipitates by filtration. In the case of a small number of crystal precipitation or no solution can be concentrated and the precipitated crystals to filter.

If the connection of this image is the shadow administered as a drug, it can be directly introduced mammals, including humans, or in the form of a pharmaceutical composition containing the compound in a pharmaceutically acceptable non-toxic and inert medium at a concentration of, component of, for example, 0.1 to 99.5%, preferably from 0.5 to 90%.

The examples used carriers include solid, semi-solid or liquid diluents, fillers and other auxiliary means for compositions, and uses at least one of them. The pharmaceutical composition is preferably administered in a dosage form. The compound of the present invention is water-soluble and can be used in the form of solutions (for example, solution for injection for intravenous or oral administration of the bladder, or syrup for oral administration), as well as in solid form. The pharmaceutical composition of the present invention can be introduced into the tissue (hereinafter in this description referred to as "injecting"), orally, topically (e.g., percutaneous) or rectally. Of course, the applied dosage form suitable for each route of administration. For example, intravenous administration is particularly preferred.

The dose of the compounds as anticancer means preferably should be determined depending on such pairs is TRS patient, as age, body weight, nature and severity of the disease, but also on the method of administration; however, the daily dose of the compounds of the present invention as the active ingredient when administered intravenously to adults, as a rule, can be 0.1 - 1000 mg, preferably 1 to 500 mg. of the above interval dose is not required, and in some cases it may be sufficient to lower the dose, whereas in other cases, you may need a dose exceeding the upper limit of the specified interval. Daily dose, usually, is preferably introduced at once. The composition of the present invention can also be entered continuously or periodically.

Parenteral administration can be accomplished with the use of liquid dosage forms, such as a solution for subcutaneous, intramuscular or intravenous injection. Such dosage form can be obtained by dissolving a predetermined amount of non-toxic compounds in liquid medium for injection, such as water or an oil medium, and sterilizing solution. Alternatively, it can be obtained by placing a predetermined number of connections in each bottle, sterilization of the bottle and the contents and sealing the bottle. For dissolving or mixing for immediate admission p is roccabruna or liofilizirovannoe active compound may be supplied with extra bottle and environment. For isotonic solution for injection may be added non-toxic salt or salt solution. In addition, together with the connection can also be used stabilizers, preservatives, emulsifiers and other additives.

Oral administration can be performed using solid or liquid dosage forms, such as bulk powders, powders, tablets, coated tablets, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, candles and other forms. Bulk powders obtained by grinding the active substance to obtain particles of a suitable size. The powders obtained by grinding the active substance to obtain particles of a suitable size and mixing the obtained powder with a similarly comminuted pharmaceutical carrier, such as food carbohydrates, such as starch, mannitol and the like, and with other substances, if required their presence. If necessary, can be added flavors, preservatives, dispersing funds, dyes, odorants and other

Capsules get in the industry by signing crushed bulk particles, powders or granules obtained by the method described below for tablets, gelatin or other capsule shell. To powdery substances before kapsulirovaniem can the be added lubricant or loosening agent, for example, colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, etc. Medical effectiveness of the capsules after swallowing can be improved by adding dezintegriruetsja or solubilizing means, for example carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropylcellulose with a low degree of substitution, sodium salt croscarmellose, sodium salt carboxysome, calcium carbonate and sodium carbonate.

Finely ground powder can be suspended and dispersing in vegetable oil, polyethylene glycol, glycerin or a surface-active substance and the packaging in the gelatinous shell to obtain soft capsules. Tablets can be obtained by granulating and molding powder composition by adding thereto dezintegriruetsja or lubricating agent and compressing the mixture. The powdered composition may be obtained by mixing a suitable image of the crushed substance with a diluent or base, mentioned above, which can optionally contain, if necessary, the binder (for example, sodium carboxymethyl cellulose, hydroxypropylcellulose, methylcellulose, hypromellose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol and others), the moderator of dissolution (e.g. the measures paraffin, wax, gidrirovannoe castor oil and others), the stimulator reabsorption (e.g., Quaternary salts) and the adsorbent (for example, bentonite, kaolin, dicalcium phosphate and others). The powdered composition can be pelletized moistening substance binding agent, such as syrup, starch paste, a solution of gum Arabic or cellulose, or a polymer solution, and then passing the wet mass through a sieve under pressure. Ungranulated powder can be pressed using the device for tableting with getting lumps of rough shape, which are then crushed, receiving granules.

Thus obtained granules can be protected from adhesion by adding a lubricating agent, such as stearic acid, a salt of stearic acid, talc or mineral oil. The lubricated granules are then pressed into tablets.

Received uncoated tablets can be coated or sugar.

The drug is not subjected to the above process of granulation or molding, you can directly extrude after mixing with granular inert carrier. May also be transparent or translucent protective coating comprising a sealed shellac film, sugar or polymeric coating or a coating of wax glaze.

Other dosage forms for the pen the actual application, such as solutions, syrups and elixirs can also be formulated in dosage forms, each of which contains a predetermined quantity of a drug. The syrup can be obtained by dissolving the compound in a suitable aqueous medium with a pleasant aroma, while the elixir can be obtained by using non-toxic alcohol environment.

If necessary, single dose compositions for oral administration may be enclosed in a microcapsule. This dose can also be covered with a polymer, wax or the like, or immersed in a polymer, wax or the like to provide prolonged action or slow release of the active ingredient.

Rectal administration can be carried out with the use of candles, which can be obtained by mixing the compounds with water-soluble or water-insoluble solid with a low melting point such as polyethylene glycol, cacao butter or higher esters (for example, ministervalletta), or their mixture.

The best way of carrying out the invention

The following examples of the preparation of the parent compounds (reference examples) and compounds of the present invention (examples)and examples of formulations and examples of analyses are presented for a more detailed additional illustrations of this izaberete the Oia and are in no way limit the present invention. The specific rotation was measured at 20°C.

Reference example 1

Synthesis of 4-methylpiperazin-1-luxusni acid

[Method 1]

Synthesis of benzyl 4-methylpiperazin-1-ilaclama

N-Methylpiperazine (to 2.29 g) was dissolved in DMF (20 ml). To the solution was added potassium carbonate (2.76 g) and benzyl bromoacetate (1.20 g) and the mixture is heated at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue is combined with water with ice and extracted with chloroform. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent: CH2CL2/CH3HE/NH3(28% aq.) = 90/10/1)to give the target compound (2.0 g, colorless oil).

The following connections get in the way described above.

Benzyl 4-piperidineacetate

Benzyl 4-(3-pyridyl)piperazine-1-ylacetic

Benzyl 4-(2-pyridyl)piperazine-1-ylacetic

Benzyl 4-pyrrolidinedithiocarbamate

Benzylpiperidine

Ethyl 4-(4-piperidinylidene)butyrate

Ethyl 3-(4-piperidinylidene)propionate

Benzylmorphine

Benzylpyrrolidine

Ethyl 2-piperidinophenyl

[Method 2]

Synthesis of 4-methylpiperazin-1-luxusni acid

Benzyl-4-methylpiperazin-1-ylacetic (1.98 g)obtained in the above-described SP is the FDS 1, dissolved in methanol (20 ml) and subjected to hydrogenolysis at room temperature under normal pressure for 4 hours in the presence of 10% palladium on coal. The reaction solution is filtered and the filtrate concentrated under reduced pressure, obtaining the target compound (1,11 g, colorless crystals).

The following connections get in the way described above.

4-Piperidinecarboxylate acid

4-(3-Pyridyl)piperazine-1-ilocana acid

4-(2-Pyridyl)piperazine-1-ilocana acid

4-Pyrrolidinedione acid

Piperidinyloxy acid

Morpholinoethoxy acid

Pyrrolidinone acid

Reference example 2

Synthesis of the hydrochloride of 4-(4-piperidinylidene)butyric acid

Ethyl-4-(4-piperidinylidene)butyrate (2.20 g)obtained by the method of reference example 1 (method 1), dissolved in ethanol (20 ml). After adding 1N aqueous solution of sodium hydroxide (11.7 ml) and the mixture refluxed for 4 hours under stirring. The reaction mixture is concentrated to dryness. The residue is precipitated by dilution with ethanol followed by the addition of 1N hydrochloric acid under ice cooling. The crystalline precipitate is filtered off and used as the starting material without further purification.

The following connections will receive the above method.

Hydrochloride 3-(4-piperidinylidene)propionic acid

Hydrochloride 3-piperidinemethanol acid

Example 1

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-glycyl-N-(4-methoxy-benzazolyl)amino)phenyl)ethynyl)pyridine

1-Oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine (1,15 g) dissolved in methylene chloride (25 ml) and add N-(tert-butoxycarbonyl)glycine (1.31 g) and 4-pyrrolidinedione (44 mg). To the mixture is added dropwise N,N'-dicyclohexylcarbodiimide (1.55 g), dissolved in methylene chloride (15 ml), and the mixture is stirred over night at room temperature. The reaction solution is filtered and the filtrate concentrated. The resulting residue is dissolved in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (eluent: l3/CH3HE=30/1)to give colorless powdery compound (2.10 g). The obtained product is dissolved in ethanol (20 ml) and refluxed overnight after adding 1N hydrochloric acid (20 ml). The reaction solution is concentrated and the precipitated crystals are washed with a warm mixture of chloroform and methanol, obtaining the target compound (0,70 g, colorless powder). TPL 235-237°C.

Elemental analysis for C22 21N3O5S·Hcl·2,5H2About:

Calculated (%): C, 50,67; N, With 4.64; N, 8,06;

Found (Percent): C, 50,69; N, To 4.62; N, 8,01.

Example 2

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methylpiperazin-1-yl)acetyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)-pyridine

1-Oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine (0.96 g) was dissolved in methylene chloride (25 ml) and add 4-methylpiperazin-1-luksusowe acid (0,99 g)obtained in reference example 1 and 4-pyrrolidinedione (37 mg). To the mixture is added dropwise N,N'-dicyclohexylcarbodiimide (1.29 g)dissolved in methylene chloride (13 ml), and the mixture is stirred over night at room temperature. The reaction solution is filtered and the filtrate concentrated. The resulting residue is subjected to column chromatography on silica gel (eluent: l3/CH3HE = 100/1 to 10/1)to give fractions. Each faction add a solution of hydrochloric acid in ether, then concentrated. The residue is diluted with water, filtered through a membrane filter and lyophilizers, obtaining the target compound (1.25 g, colorless powder).

MS (m/e): 523 (M+)

1H-NMR (DMSO-d6): δ: 2,69 (3H, s), 3,18-3,52 (N, m), 3,76 (1H, d), 3,82 (3H, d), 7,08-of 7.23 (3H, m), 7,43-7,72 (6N, m), 7,88-with 8.05 (3H, m), 8,54 (2H, d), 11,25 (1H, ush.)

Example 3

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-piperidino-piperidino)acetyl-N-(4-m is oxybenzenesulfonate)amino)phenyl)-ethynyl)pyridine

4-Piperidinyloxy acid (1.70 g)obtained by the method of reference example 1, is subjected to the interaction and subsequent processing by the method of example 2, obtaining the target compound (1.28 g, pale yellow powder).

MS (m/e): 591 (M+)

Elemental analysis for C32H38N4O5S·2HCl·8H2O:

Calculated (%): C, 47,58; N, Of 6.99; N, 6,94;

Found (Percent): C, 46,95; N, 6,72; N, 6,80.

1H-NMR (DMSO-d6): δ: 1,38-2,21 (12H, m), 2,86-3,36 (8H, m), of 3.80 (3H, s)to 3.89 (1H, d), 6,99 for 7.12 (3H, m), 7,35-7,69 (6N, m), 7,93-of 8.04 (3H, m), scored 8.38 (2H, d), 10,45 (1H, ush. ) of 11.15 (1H, ush.)

Example 4

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-pyrrolidinedione)acetyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

4-Pyrrolidinyloxyl acid (1,59 g)obtained by the method of reference example 1, is subjected to the interaction and subsequent processing by the method of example 2, obtaining the target compound (0.50 g, pale yellow powder).

MS (m/e): 577 (M+)

Elemental analysis for C31H36N4O5S·2HCl·7H2O:

Calculated (%): C, 48,00; N, 6,76; N, 7,22;

Found (Percent): C, 47,87; N, 6,76; N, 7,10.

1H NMR (DMSO-d6): δ: 1,91-2,17 (7H, m), 3.00 and-3,89 (14N, m), 4,24 (1H, d), 6,97-7,14 (3H, m), 7,32-7,69 (6N, m), of 7.90-with 8.05 (3H, m), scored 8.38 (2H, d), of 10.25 (1H, ush.), or 10.60 (1H, ush.).

Example 5

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-piperidineacetate)the dryer is l)ethynyl)pyridine

Piperidinomethyl acid (0,89 g)obtained by the method of reference example 1, is subjected to the interaction and subsequent processing by the method of example 2, obtaining the target compound (0,85 g, colorless powder).

MS (m/e): 508 (M+)

1H-NMR (DMSO-d3): δ: 1,67 (6N, ush.), 2,87 (2H, ush. ), to 3.35 (2H, ush.), 3,62 (3H, s), of 3.73 (1H, d), 4,19 (1H, d), 7,06-7,14 (3H, m), 7,41-7,71 (6N, m), of 7.90-8,07 (3H, m), 8,48 (2H, m), 9,99 (1H, ush.).

Example 6

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-isonicotinoyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

Isonicotinoyl acid (0.20 g) is subjected to interaction and subsequent processing by the method of example 2, obtaining the target compound (0.25 g, pale yellow powder).

TPL 198-200°C.

Elemental analysis for C26H21N3O5S·2hcl·0,5H2O:

Calculated (%): C, 54,84; N, 4,24; N, 7,37;

Found (Percent): C, 54,98; N, To 4.41; N, 7,39.

Example 7

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-nicotinoyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

Nicotinic acid (0.20 g) is subjected to interaction and subsequent processing by the method of example 2, obtaining the target compound (0.24 g, pale yellow powder). TPL 187-189°C.

Elemental analysis for C26H21N3O5S·2hcl:

Calculated (%): C, 55,72; N, 4,14; N, 7,50;

Found (Percent): C, 55,45; N, 4,30; N, 7,38.

Example 8

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(N-dimethylphenyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

N,N-Dimethylglycine (0.65 g) is subjected to interaction by the method of example 2. The reaction solution is filtered and the filtrate concentrated. The residue is diluted with toluene and isopropyl ether and stirred. The precipitated crystals are filtered off, washed with water, dried and recrystallized from acetonitrile. The obtained white crystals suspended in water, then add IN an aqueous solution of hydrochloric acid and stirred. The mixture is filtered through a membrane filter and lyophilizers, obtaining the target compound (0,62 g, colorless powder). TPL 158-162°C.

MS (m/e): 468 (M+)

Elemental analysis for C24H25N3O5S·HCl·4H2O:

Calculated (%): C, 50,04; N, 5,95; N, 7,29;

Found (Percent): C, 49,73; N, 5,67; N, 7,37.

1H NMR (DMSO-d6): δ: 2,70 (6N, s), 3.75 to 4,18 (2H, m), of 3.84 (3H, s), 6,95-to 7.15 (3H, m), of 7.36-7,70 (6N, m), to $ 7.91-with 8.05 (3H, m), compared to 8.26 (2H, d), 9,87 (1H, ush.).

Example 9

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-(4-(2-pyridyl)piperazine derivatives)acetylamino)phenyl)ethynyl)pyridine

4-(2-Pyridyl)piperazine-1-luksusowe acid (1.10 g)obtained by the method of reference example 1, is subjected to the interaction by the method of example 2. Then the reaction solution is treated by the method of example 8, obtaining the target compound (0,67 g, colorless powder). TPL 167°C (decomposition).

MS (m/e): 586 (M+)

Elemental analysis the C 31H31N5O5S·2HCl·4H2O:

Calculated (%): C, 50,96; N, To 5.66; N, 9,58;

Found (Percent): C, 51,40; N, 6,00; N, 9,46.

1H-NMR (DMSO-d6): δ: 3,0-4,0 (12H, m), 4,19 (1H, d), 6,82-to 7.15 (5H, m), 7,37-of 7.82 (7H, m), 7,94 (2H, d), 8,02-8,10 (2H, m), with 8.33 (2H, d).

Example 10

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-(3-pyridyl)piperazine derivatives)acetyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

4-(3-Pyridyl)piperazine-1-luksusowe acid (1.39 g)obtained by the method of reference example 1, is subjected to the interaction and subsequent processing by the method of example 2, obtaining the target compound (1.30 grams, pale yellow powder). TPL 167°C (decomposition).

MS (m/e): 586 (M+)

Elemental analysis for C31H31N5O5S·2HCl·4H2O:

Calculated (%): C, 50,96; N, To 5.66; N, 9,58;

Found (Percent): C, 51,31; N, 6,00; N, 9,40.

1H NMR (DMSO-d6): δ: 3,0-4,0 (N, m), 4,22 (1H, d), 6,98-7,14 (3H, m), of 7.36-7,69 (6N, m), 7,80-with 8.05 (5H, m), 8,23-8,50 (4H, m).

Example 11

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(3-(4-piperidino-piperidino)propionyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

Hydrochloride 3-(4-piperidinylidene)propionic acid obtained by the method of reference example 2, and triethylamine is subjected to interaction and subsequent processing by the method of example 2, obtaining the target compound (0,13 g, pale yellow powder).

MS (m/e): 605 (M+)

Elemental analysis for C33H40N4O5S·2HCl·4H2O:

Calculated (%): C, 52,87; N, 6,72; N, 7,47;

Found (Percent): C, 52,13; N, 7,24; N, 7,47.

1H NMR (DMSO-d6): δ; 1,10-to 2.40 (10H, m), 2,6-3,05 (6N, m), 3,06-of 3.80 (7H, m), of 3.84 (3H, S), 6,88-7,21 (3H, m), 7,38-to 7.64 (6N, m), 7,89-of 8.04 (3H, m), a 8.34 (2H, d), and 10.5 (1H, ush.), of 10.7 (1H, ush.).

Example 12

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-(4-piperidinylidene)butyryl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

Hydrochloride 3-(4-piperidinylidene)butyric acid obtained by the method of reference example 2, and triethylamine is subjected to interaction and subsequent processing by the method of example 2, obtaining the target compound (0.88 g, pale yellow powder).

MS (m/e): 619 (M+)

Elemental analysis for C34H42N4O5S·2HCl·8H2O:

Calculated (%): C, 48,86; N, 7,24; N, 6,70;

Found (Percent): C, 48,54; N, 6,60; N, 6,61.

1H NMR (DMSO-d6): δ: 1,64-of 2.26 (15 NM, m), 2,85 (6N, ush. ), 3,30-3,63 (4H, m), 3,83 (3H, s), 7,05-7,13 (3h, m), of 7.36-to 7.61 (6N, m), 7,88-8,03 (3H, m), 8,30 (2H, d), 10,84 (2H, ush.).

Example 13

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl) -N-morpholinosydnonimine)phenyl)ethynyl)pyridine

Specified in the header of the compound obtained by the method of example 2, using morpholinos acid obtained by the method of reference example 1.

MS (m/e): 510 (M+)

1H NMR (DMSO-d6 ): δ: 2,80-3,30 (4H, m), 3,55-4,20 (N, m), to 6.95 (1H, d), 7,09-to 7.15 (2H, m), of 7.36-of 7.96 (6N, m), 7,89-with 8.05 (3H, m), 8,24 (2H, d), the 10.40 (1H, ush.).

Example 14

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-pyrrolidinedione)phenyl)ethynyl)pyridine

Specified in the header of the compound obtained by the method of example 2, using pyrrolidinyloxy acid obtained by the method of reference example 1.

MS (m/e): 494 (M+)

1H NMR (DMSO-d6): δ: 1,65 is 2.00 (4H, m), 2,80-3,10 (2H, m), 3,20-of 3.60 (2H, m), of 3.80 (3H, s), 3,84-3,93 (1H, m), 4,19-to 4.28 (1H, m),? 7.04 baby mortality (1H, d), 7,10-7,16 (2H, m), 7,34-7,69 (6N, m), 7,88-of 8.04 (3H, m), of 8.25 (2H, d), 10,11 (1H, ush.).

Example 15

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(3-pyridylethyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

Hydrochloride 3-pyridyloxy acid and triethylamine subjected to interaction and subsequent processing by the method of example 2, obtaining the target compound (1.06 g).

MS (m/e): 502 (M+)

1H NMR (DMSO-d6): δ: 3,59 (1H, d), of 3.84 (3H, s), 3,85 (1H, d), 7,01 (2H, d), 7,35-8,10 (11N, m), 8,40 (1H, d), 8,54 (2H, d), 8,77 (1H, s), 8,82 JN, d), for 9.90 (1H, ush).

Example 16

The dihydrochloride of 1-oxide (E)-4-(2-(2-(N-(3-morpholine-propionyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine

Hydrochloride 3-morpholinopropan acid obtained by the method of reference example 2, and triethylamine is subjected to interaction and subsequent processing by the method of example 2, getting relevo the compound (1.08 g).

MS (m/e): 524 (M+)

1H NMR (DMSO-d6): δ; to 2.57-3,92 (15 NM, m), 7,12 (2H, d), 7,25 (1H, d), 7,42-to 7.67 (6N, m), to $ 7.91 (2H, d), 8,02 (1H, d), to 8.45 (2H, d), 11,04 (1H, ush.).

Example 17 (another way of obtaining)

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-morpholinoethyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)-pyridine

Morpholinothio acid (5,18 g)obtained by the method of reference example 1 was dissolved in methylene chloride (230 ml) and add triethylamine (4,86 g). To the mixture under ice cooling are added dropwise chlorocarbonate (a total of 5.21 g) and the mixture is stirred for thirty minutes at room temperature. To the mixture was added 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine (7,65 g) and the mixture is stirred for another three hours at room temperature. The reaction solution was washed with water, dried over magnesium sulfate and concentrated. The resulting residue is dissolved in acetonitrile. To the solution add a solution of hydrogen chloride in methanol and the mixture is stirred over night at room temperature. The precipitated crystals are filtered off, washed with acetonitrile and an additional portion of ether and obtain crude crystals. Recrystallization from methanol gives the target compound (8,16 g).

Example 18

Hydrochloride of 1-oxide (E)-4-(2-(2-(N-(N',N'-dimethylamino-propionyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)-pyridine

Hydroch Oric N,N-dimethylaminopropionic acid and triethylamine subjected to interaction and subsequent processing by the method of example 2, receiving the target connection.

Example test 1

Solubility in water

The solubility of the compounds of the present invention is measured at 25°C. as control compounds using 1-oxide (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-amino)phenyl)ethynyl)pyridine (compound a) and 1-oxide (E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethynyl)pyridine (compound). Found that the solubility of the compounds of the present invention, i.e. the compounds obtained in examples 1-16, exceeds 10 mg/ml, whereas the solubility of the compounds a and the connection is 29 and 18 μg/ml, respectively.

Sample test 2

Anticancer activity against cells of the Colon-26 (colon cancer mouse), transplanted mice

The cells of the Colon-26, cultured in vitro, and transplanted subcutaneously using an injection syringe in the right axillary region of male Balb/c mice aged 5 weeks (5×105cells/animal). When tumor volume reaches approximately 120 mm3(experiment 1) or approximately 100 mm3(experiment 2), mice are divided into groups of 6 animals each. The test drug dissolved in 5% glucose solution, is injected just 5 times, once a day at intervals of 4 days. Mice of the control group treated in the same way a 5% solution of Glu is eskers. Tumor volume calculated according to equation 1 below based on the major and minor axes of the tumor, measured with predetermined intervals calipers.

Equation 1

Tumor volume = 1//(major axis)x(minor axis)2

Then according to equation 2 based on the tumor volume calculated the growth rate, which is then used in equation 3 to calculate the degree of growth inhibition in the group treated with the medication, compared with the control group.

Equation 2

Equation 3

The degree of inhibition of tumor growth and the number of surviving animals on day 21 after the start of injection are shown in table 1.

Table 1
ConnectionDose (mg/kg)The degree of inhibition of tumor growth (%)The number of surviving animals
Experiment 1
Control  6/6
Example 55078,06/6
7587,76/6
Example 850of 87.05/6
75 95,95/6
Example 95080,86/6
7593,65/6
Experiment 2
Control  6/6
Example 135073,86/6
7592,66/6
Example 145078,66/6
 7584,16/6

Compounds of the present invention exhibit extremely high activity against inhibition of tumor growth.

Example compositions 1

Composition for injection (1 ml)

The compound of example 9 of 10 mg

Mannitol 50 mg

Water for injection quantity necessary to obtain a 1 ml solution

The way to obtain

The compound of the present invention and mannitol are dissolved in water for injection, filtered through a membrane filter (0.22 μm) under sterile conditions contribute in a bottle and lyophilizers, getting composition for injection intended for dilution immediately before use.

Example composition 2

Composition for injection (1 ml)

The compound of example 9 of 10 mg

Maltose 100 mg

Water for inj the work number, necessary to obtain 1 ml solution

The way to obtain

The compound of the present invention and maltose dissolved in water for injection, filtered through a membrane filter (0.22 μm) under sterile conditions contribute in a bottle and lyophilizers, getting composition for injection intended for dilution immediately before use.

Industrial applicability

The compound of the present invention is water-soluble and has a strong anticancer activity and low toxicity. Accordingly, it can be used as an active ingredient of pharmaceutical compositions in the form of solutions, especially solutions for injection, which over a long period can safely be used to treat patients unable to take oral medication, various malignancies, such as lung cancer, breast cancer, cancer of the gastrointestinal tract, prostate cancer, blood cancer, etc.

1. The compound of the formula [I] or its salt:

A-B-D-E [1]

where

And denotes optionally substituted 5 - or 6-membered heteroaryl, in a loop containing one or two nitrogen atom or its oxide;

In denotes optionally substituted ethenylene;

D represents optionally substituted phenylene; and E represents a group of formula is:

where G denotes optionally substituted phenyl;

and R denotes an optionally substituted 5 - or 6-membered heteroaryl, in a loop containing one or two nitrogen atom, or a 5 - or 6-membered heteroaromatic, in a loop containing one or two nitrogen atom, or a group of the formula:

where n is an integer from 1 to 5; R5and R6are the same or different and independently selected from the group consisting of hydrogen, C1-C6of alkyl, hydroxyalkyl, aminoalkyl; or R5and R6taken together with the adjacent nitrogen atom, may form a 5-7-membered cyclic amino group-NR5(R6), which may be optionally substituted, and, in addition to the nitrogen atom, may optionally include an oxygen atom, sulfur or nitrogen as a freezing cycle of a member.

2. The compound of the formula [I] according to claim 1, or its salt, where a denotes a 4-pyridyl or 1-oxido-4-pyridyl; In denotes ethenylene; D represents optionally substituted phenylene; and E denotes a group of the formula:

where R and G are as defined in claim 1.

3. The compound of the formula [I] according to claim 1, or its salt, where a denotes a 4-pyridyl or 1-oxido-4-pyridyl; In denotes ethenylene; D denotes NeoMaster is but substituted phenylene; and E denotes a group of the formula:

where G denotes optionally substituted phenyl, and R denotes a group of the formula:

where n, R5and R6are as defined in claim 1.

4. The compound according to claim 3, or its salt, where R5and R6are the same or different and independently selected from the group consisting of hydrogen, C1-C6of alkyl; or R5and R6taken together with the adjacent nitrogen atom, may form an optionally substituted 5-6-membered cyclic amino group-NR5(R6).

5. The compound of the formula [I] according to claim 1, or its salt, where a denotes a 4-pyridyl or 1-oxido-4-pyridyl; In denotes ethenylene; D is phenylene; and E denotes a group of the formula:

where G denotes optionally substituted phenyl; R represents optionally substituted 5-6-membered heteroaryl, in a loop containing one or two nitrogen atom, or a 5-6-membered heteroaromatic, in a loop containing one or two nitrogen atom.

6. Salt according to claim 1, where the salt is hydrochloride.

7. Pharmaceutical anti-cancer composition comprising as active ingredient a compound of the formula [I]or its salt according to claim 1.

8. The pharmaceutical composition according to claim 7, which is located as injectable form.

9. Anticancer agent comprising as an active ingredient a compound of the formula [I] according to claim 1, or its salt.

10. Anticancer agent according to claim 9, which is in injectable form.

Priority signs:

And denotes a 4-pyridyl or 1-oxido-4-pyridyl;

In denotes ethenylene;

D represents optionally substituted phenylene; and E denotes a group of the formula:

,

where G denotes optionally substituted phenyl; and R denotes an optionally substituted 5 - or 6-membered heteroaryl, in a loop containing one or two nitrogen atom, or a 5 - or 6-membered heteroaromatic, in a loop containing one or two nitrogen atom, or a group of the formula:

,

where n is an integer from 1 to 5;

R5and R6are the same or different and independently selected from the group consisting of hydrogen, C1-C6of alkyl, hydroxyalkyl, aminoalkyl; or R5and R6taken together with the adjacent nitrogen atom, may form a 5-7-membered cyclic amino group-NR5(R6), which may be optionally substituted, and, in addition to the nitrogen atom, may optionally include an oxygen atom, sulfur or nitrogen, as forming a loop member, a priority from 14.12.199, for other signs installed priority from 04.07.2000.



 

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FIELD: organic chemistry or heterocyclic compounds, chemical technology.

SUBSTANCE: invention relates to technology for manufacturing heterocyclic compounds, in particular, to technology for manufacturing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that is known as a substance for pharmaceutical designation "thiotriazoline". Invention describes a method for preparing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that involves reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in liquid medium wherein methylene chloride is used as a liquid medium. Method provides significant elevating the yield percent of the end product, enhances its quality and significant reducing industrial consumptions.

EFFECT: improved preparing method.

4 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

The invention relates to organic chemistry and can find application in medicine

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

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of formula (I)

where a represents a 5 - or 6-membered monocyclic aromatic ring containing in the ring 1 or 2 nitrogen atom and unsubstituted or substituted by 1-3 substituents, A represents N; D represents a 2-indolyl, 2-benzimidazolyl or 2-benzo[b]furanyl and is unsubstituted or substituted by 1-3 halogen atoms, except 1-(5-chlorobenzophenone-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and its pharmaceutically acceptable salts

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to new arylpiperazine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, esters, where Y is O; Q is CH; X, Z and Z' each independently represent CH or N; m=0-1; n=0-4; R1and R2independently selected from H, F, Cl, Br, OCH3OC2H5, OCH2CF3CH3WITH2H5, CF3isopropylate; R3represents H; R4and R5represent H or phenyl, except that R1represents H, R2represents H, Cl or CF3, R3, R4and R5=N, Y=0, and Q=CH, if m=0 and n=1; and also except that R1represents H, R2is OCH3, R3, R4and R5=H, Y=0, Q=CH, if m=0 and n=2

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

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

14 cl, 3 tbl, 26 ex

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