Derivatives of pyridylcyanoguanidines and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyridylcyanoguanidines of the general formula (I):

or their pharmaceutically acceptable salts wherein 1 means hydrogen atom; X means hydrocarbon (C1-C12)-biradical; Y means a bond or oxygen atom (O); Z means 5-10-membered aromatic heterocyclic radical optionally substituted with hydroxy-group under condition that R1 is not bound to nitrogen atom in pyridyl ring. Compounds of the formula (I) and their salts possess antiproliferative activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 7 ex

 

The present invention relates to new pyridylcarbonyl medicines and pharmaceutical compositions containing them and to their use in the production of medicines.

At first, it was found that pyridylcarbonyl, such as pinacidil (N-1,2,2-trimethylpropyl-N'-cyano-N"-(4-pyridyl)guanidine), open potassium channels, after which they were developed as protivogipertonicheskoe funds. Replacing the side chain of pinacidil on the longer side chains containing aryl, leads to a decrease protivogipertonicheskoe activity of such compounds, however, it was found that the thus obtained compounds, on the other hand, possess antitumor activity when administered orally to a rat model bearing ascitic tumor Yoshida (Yoshida ascites tumours).

Different classes of pyridylcarbonyl with antiproliferative activity are disclosed, for example, in 660823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561. The dependence of activity on structure (SAR structure-activity relationships) for such compounds are described in C. Schou et al., Bioorganic and Medicinal Chemistry Letters 7 (24), 1997, pp. 3095-3100, where the antiproliferative effect of the number of pyridylcarbonyl analyzed in vitro in different cell lines of lung cancer and human breast, and normal human fibroblasts.

Then P-J V Hjarnaa et al., Cancer Res. 59, 1999, pp 5751-5757, has published the results of testing specific cyanoguanidine compounds, namely N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N"-(4-pyridyl)guanidine, in vitro and in vivo. This compound has activity in vitro comparable to the activity of cytostatic agents, daunorubicin and paclitaxel, but it demonstrates a much lower antiproliferative activity on normal endothelial cells. In the analysis of in vivo using Nude mice that were transplanted human tumor cells, the connection demonstrates significant antitumor activity as well as tumor cells that are resistant to traditional anti-cancer drugs such as paclitaxel.

For the successful application of a drug requires a reasonable relationship to factors such as the activity, bioavailability, toxicity level side effects, solubility, etc. that takes place in the case of advanced medicines on the basis of cyanoguanidine.

The authors of the present invention have found that the new pyridylacetonitrile compounds containing heterocyclic radical, are characterized by an extremely high antiproliferative activity.

Accordingly, this invention relates to compounds form the s I

where R1 denotes hydrogen, halogen or one or more linear or branched, saturated or unsaturated Cl-6hydrocarbon radicals, optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, alkoxy, alkoxycarbonyl, alkylcarboxylic, formyl, amino, aminoalkyl, aminocarbonyl, alkylcarboxylic, sulfo, aminosulfonyl, alkylsulfonyl, hydroxysulfonic, dihydroxypentanoic or phosphono;

X denotes a linear or branched, saturated or unsaturated Cl-12hydrocarbon biradical, optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, alkoxy, alkoxycarbonyl, alkylcarboxylic, formyl, amino, aminoalkyl, aminocarbonyl, alkylcarboxylic, sulfo, aminosulfonyl, alkylsulfonyl, hydroxysulfonic, dihydroxypentanoic or phosphono;

Y represents a bond, O, C(O), S, S(O), S(O)2C(O)O, NH, C(O)NH, OC(O) or NHC(O);

Z represents an aromatic or non-aromatic heterocyclic radical containing 5 to 12 atoms in the cycle, optionally substituted with halogen, hydroxy, cyano, nitro, alkoxy, alkoxycarbonyl, alkylcarboxylic, formyl, aminoalkyl, or a linear or branched, saturated or unsaturated Cl-4hydrocarbon radical, optionally Zam is illuminated by halogen, hydroxy, cyano, nitro, alkoxy, alkoxycarbonyl, alkylcarboxylic, formyl or aminoalkyl;

provided that R1not attached to the nitrogen atom in pyridinium cycle;

and their pharmaceutically acceptable salts, solvate, hydrates, N-oxides and proletarienne forms.

This invention also relates to the use of compounds of formula I in therapy and to pharmaceutical compositions comprising a compound of formula I.

This invention also relates to a method of treatment or prevention of disease involving the introduction of patient effective dose of the compounds of formula I.

In addition, this invention also relates to the use of compounds of formula I in the manufacture of medicinal products.

In the context of the present invention, the term "hydrocarbon" refers to a fragment comprising only hydrogen and carbon, preferably comprising 1 to 18, for example 1-12, for example 1 to 6, carbon atoms. Examples of the above-mentioned hydrocarbons include methane, ethane, Aten, ethyn, identical butane, butene, Boutin, isobutane, tert-butane, hexane, 1,3-dimethylhexane, octane, octene, nonin, dodecan, dodecen and other Appropriate radical or biradical is a fragment obtained by removal of the hydrocarbon, respectively, one or two hydrogen atoms.

The term "heterocyclic radical" denotes the mod is alcocebre ring, containing 1-3 heteroatoms selected from N, O and S, and a condensed bicyclic ring containing 1-4 heteroatoms from above. Examples include thienyl, furyl, pyranyl, isobenzofuranyl, bromanil, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, indolizinyl, purinol, hinely, naphthyridine, canonical, bromanil, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinil, morpholinyl, oxazinyl, tetrahydrofuranyl, oxazolidinyl, tetrahydropyranyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyrazinyl, benzimidazolyl and benzofuranyl.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

The term "pharmaceutically acceptable salt" refers to salts obtained by the interaction of compounds of formula I, including acidic or basic groups, with suitable bases or acids, respectively. Examples of such acids are hydrochloric, Hydrobromic, itestosterone, sulphuric, nitric, acetic, phosphoric, lactic, maleic, phthalic, citric, propionic, benzoic, glutaric, gluconic, methansulfonate, salicylic, succinic, tartaric, toluensulfonate, sulfamic and fumaric acid. Examples of such bases are potassium hydroxide, sodium hydroxide, ammonia and amines.

The term "MES" means particles resulting from usamade the negative effects of the compounds in this case, the compounds of formula I with a solvent, such as alcohol, glycerine or water, where these particles exist in solid form. If water is the solvent, the MES is called a hydrate.

The term "N-oxide" refers to, for example, pyridyl-N-oxide derivatives of the compounds of this invention. Such compounds can be obtained by oxidation of N pyridyl suitable oxidizing agent, such as 3-chloroperbenzoic acid, in an inert solvent, for example dichloromethane.

The term "alkyl" refers to monologically derived from alkanes, preferably containing 1 to 8 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and cyclohexyl.

The term "alkoxy" refers to a radical of the formula-OR, where R is an alkyl, as defined above.

The term "alkoxycarbonyl" refers to a radical of the formula-C(O)-OR, where R is an alkyl, as defined above.

The term "alkylaryl" refers to a radical of the formula-C(O)-R, where R is an alkyl, as defined above.

The term "aminoalkyl" refers to a radical of the formula-R-NR'2where R is an alkyl, as defined above, and each R' independently represents an alkyl, as defined above, or hydrogen.

The term "aminocarbonyl" refers to a radical of the formula-C(O)-NR'2where each ' independently represents alkyl, as defined above, or hydrogen.

The term "aminosulfonyl" refers to a radical of the formula-S(O)2-NR'2where each R' independently represents an alkyl, as defined above, or hydrogen.

The term "alkylsulfonyl" refers to a radical of the formula N(R')S(O)2-R, where R is an alkyl, as defined above, and each R' independently represents an alkyl, as defined above, or Bogorodchany "amino" means a radical of the formula-NR'2where each R' independently represents an alkyl, as defined above, or hydrogen.

The term "prodrug" denotes a derivative of an active compound that has not, or not necessarily possess physiological activity of the active compounds, but with the introduction of proletarienne forms can be subjected to in vivo enzymatic cleavage, such as hydrolysis, with the release of the active compounds. Getting proletarienne forms of the compounds of the present invention are disclosed in international patent application PCT/DK01/00750.

In the preferred embodiment of this invention R1 represents hydrogen, halogen, or one or more linear or branched, saturated or unsaturated C1-6hydrocarbon radicals;

X denotes a linear or branched, saturated or unsaturated C1-12hydrocarbon birdy is al;

Y denotes O or C(O);

Z represents an aromatic or non-aromatic heterocyclic radical containing 5 to 10 atoms in the loop.

In the following preferred embodiment of this invention R1 represents hydrogen;

X denotes a linear C5-10hydrocarbon radical;

Y represents O;

Z represents an aromatic or non-aromatic heterocyclic radical containing 5 to 10 atoms in the loop.

In another preferred embodiment Z is selected from the group consisting of pyridyl, imidazolyl, chinoline or pyrimidinyl.

Specific examples of compounds of formula I include the

N-[6-(3-pyridyloxy)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(1-imidazolyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(2-hinomisaki)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(3-pyridyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(3-chinolin)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(5-pyrimidinyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine.

Moreover, it was found that the compounds selected from the group consisting of

3-[6-(N-tert-butoxycarbonylamino)-1-hexyloxy]-pyridine;

hydrochloride 3-[6-amino-1-hexyloxy]pyridine;

3-[6-amino-1-hexyloxy]pyridine;

1-[6-(N-tert-butoxycarbonylamino)-1-hexyl]imidazole;

hydrochloride of 1-(6-amino-1-hexyl)imidazole;

1-(6-amino-1-hexyl)imida the Ola;

2-[6-(N-tert-butoxycarbonylamino)-1-hexyloxy]-quinoline;

2-(6-amino-1-hexyloxy)-quinoline;

can be used to obtain compounds of formula I.

The compounds of formula I can be obtained by reacting the compounds of formula II where R1 is as defined in formula I, with a compound of formula III, where X, Y and Z are such as defined in formula I, see diagram.

The reaction can be carried out in a suitable solvent, such as pyridine, optionally in the presence of a tertiary amine such as triethylamine, and a catalyst such as 4-(N,N-dimethylamino)pyridine, and at temperatures in the range from room temperature up to 100°C. for reaction R1, X, Y and Z may temporarily contain suitable protective group.

Compounds of formulas II and III are known from the literature or can be obtained using methods well known to specialists in this field.

In another embodiment of the invention thiourea of formula IV, which contains the same substituents as defined for formula (I), and, if necessary, temporarily protected, interacts with one or more equivalents of N,N'-dicyclohexylcarbodiimide (into) and cyanamide in an inert solvent, such as acetonitrile, at a temperature above room temperature with the formation of the compounds of formula I, see diagram. The compounds of formula IV can be floor is obtained using methods well-known specialists in this field.

The pharmaceutical composition

In another aspect this invention relates to pharmaceutical compositions containing a compound of formula I. the Compositions of the present invention, designed for use in veterinary medicine and for treatment include active ingredients in combination with pharmaceutically acceptable carrier(s) and optionally other therapeutic ingredient(s). The carrier must be "acceptable" in the sense that it must be compatible with other ingredients of the compositions and not render harmful influence on the recipient.

Usually the active ingredient is 0.1-100 wt. % by weight of the composition. Typically, a single dose of the composition contains from 0.07 mg to 1 g of the compounds of formula I.

The term "single dose" means a single, i.e. a single dose which you can enter the patient and which can be easily processed and packaged, it remains physically and chemically stable dose containing either the active substance as such, or its mixture with a solid or liquid pharmaceutical diluents or carriers. Compositions include, for example, forms suitable for oral (including slow or controlled release), d is tal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intra-articular and intravenous), transdermal, ophthalmic, local, nasal or buccal administration.

The composition can usually be presented in the form of dosage form and may be obtained using any of the well-known pharmaceutical methods, for example, as disclosed in Remington, The Science and Practice of Pharmacy, 20th ed., 2000. All methods include the stage of mixing the active ingredient with the carrier which consists of one or more accessory ingredients. Basically the song is produced by uniform and thorough mixing of the active ingredient with a liquid carrier or a finely pulverized solid carrier, or both, and then, if necessary, shaping the product into the target composition.

Compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or suspension in aqueous or non-aqueous liquid, such as ethanol or glycerol; or in the form of an emulsion of the type oil-in-water or water in oil. Such oils can be of edible oil, such as for example the measures cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic or natural resins, such as tragakant, alginate, gum Arabic, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hypromellose, hydroxypropylcellulose, carbomer and polyvinylpyrrolidone. The active ingredients may also be introduced in the form of a bolus, electuary or paste.

Tablets can be obtained by molding or forming of the active ingredient optionally with one or more accessory ingredients. Molded tablets may be made by molding in a suitable device active ingredient(s) in free flowing form such as powder or granules, optionally mixed with a binder agent, such as, for example, lactose, glucose, starch, gelatin, Arabic gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hypromellose, polyethylene glycol, waxes and the like; a lubricating agent, such as, for example, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a leavening agent, such as, for example, starch, methylcellulose, agar, bentonite, crosscarmellose sodium, sodium salt Glick is late starch, crosspovidone or the like, or dispersing agent, such as Polysorbate 80. Molded tablets can be obtained by molding in a suitable device is a mixture of powdered active ingredient and a suitable carrier, uverennogo inert liquid diluent.

Compositions for rectal injection can be obtained in the form of suppositories in which the compound of the present invention is mixed with low-melting-soluble or water-insoluble solids, such as cocoa butter, hydrogenated vegetable oil, polyethylene glycol or esters of fatty acids and glycols, while elixirs can be obtained using myristoleate.

Compositions suitable for parenteral administration typically comprise sterile oil or aqueous preparations of the active ingredients, which are preferably isotonic with respect to blood recipient, such as isotonic saline, isotonic glucose solution or buffer solution. Typically, the composition can be sterilized, for example, filtration through a filter, inhibiting bacteria, the addition to the composition of the sterilizing agent, by irradiation or by heating the compositions. Liposomal compositions, as disclosed, for example, in Encyclopedia of Pharmaceutical Technology, vol. 9,1994, also suitable for couple who Teroldego introduction.

The alternate connection of the formula I can be represented in the form of sterile solid preparation, such as a lyophilized powder which is easily dissolved in sterile solvent immediately prior to use.

Percutaneous compositions can be presented in the form of strips or applicator.

Composition suitable for ophthalmic injection can be presented in the form of a sterile aqueous preparation of the active ingredients, which may be in microcrystalline form, for example in the form of a suspension of microcrystals in the water. For ophthalmic injection of the active ingredient can also be used liposomal composition or biorstwami polymer systems, for example, as disclosed in Encyclopedia of Pharmaceutical Technology. vol. 2,1989.

Compositions suitable for local or ophthalmic introduction, include liquid or semi-liquid preparations such as liniments, lotions, gels, application (applicants), the emulsion of the type oil-in-water or water in oil, such as creams, ointments or pastes; or solutions or suspensions such as drops.

Compositions suitable for nasal or buccal introduction, include powder composition composition introduced without the aid of auxiliary means (selfpropelling), and the composition in the form of a spray, such as aerosols and sprays.

In addition to vishey is related to the ingredients of the compositions based on the compounds of formula I may include one or more additional ingredients, such as diluents, buffers, flavouring tools, dyes, surfactants, thickeners, preservatives, such as methylhydroxybenzoate (including anti-oxidants), emulsifying means, etc.

Systemic treatment with use of the present invention is administered daily doses of the compounds of formula I, comprising 0.001 to 500 mg per kilogram of body weight, preferably of 0.002 to 100 mg/kg of body weight of the mammal, for example, 0.003 to 20 mg/kg, or 0.003 to 5 mg/kg, as a rule, in accordance with a daily dose for an adult human component from 0.01 to 37,000 mg, However, the present invention also provides compounds and compositions intended for use with longer intervals, e.g. every week, every three weeks or every month. The topical treatment of dermatological disorders impose ointments, creams or lotions containing 0.1-750 mg/g, preferably 0.1 to 500 mg/g, for example about 0.1-200 mg/g, the compounds of formula I. When applied topically in ophthalmology enter ointments, drops or gels containing 0.1-750 mg/g, preferably 0.1 to 500 mg/g, for example about 0.1-200 mg/g of compound of formula I. Oral compositions preferably receive in the form of tablets, capsules, or drops, containing 0.07 to 1000 mg, preferably 0.1 to 500 mg the compounds of formula I in dosage form.

It was found that derivatives of CYANOGEN what she is able to modulate the activity Iκ B kinase (hereinafter abbreviated IKK). By modulating the activity of IKK in cells can adjust the level of activated NFκB. Therefore, it is believed that such cyanoguanidine can be used to treat proliferative diseases and other conditions that are thought to be associated with the level of activated NFκB, for example, inflammation.

NFκB is a member of a family of transcription factors Rel, which are ubiquitous in animal cells. Rel proteins can form dimers, the most common of which are denoted by NFκB. NFκB represents heterodimer p50/p65, which can activate the transcription of genes containing the corresponding binding site κb. In unstimulated cells, the NF levelκB is maintained in the cytoplasm through interactions with proteins, any abscopal NFκB, IκBs. In response to stimulation of cells, for example, antiproliferative drugs or ionizing radiation IκB kinase complex (IKK) is rapidly activated and phosphorylates two serine residue in NFκB-binding domain IκB. Phosphorylated IκB then destroyed by the 26S protease, whereas NFκB is not subject to destruction and moves into the nucleus [Wang, Science, 274,784-787,1996, Cusak, Cancer Research, 60,2323-2330,2000; Karin, Immunology. 12,2000,85-98]. Thus, NFκB always Pris is tstuat in the cell, but in unstimulated cells in non-activated form. After moving into the nucleus NFκB induces, among other things, anti-apoptotic genes c-IAP1, c-IAP2, TRAF1, TRAF2, Bfl-1/A1, Bcl-XLand Mn-SOD [Platel, Oncogene, 19, 2000, 4159-41699]that is the reason for the resistance of cells to apoptosis. This effect is referred to as the anti-apoptotic effect of NFκB. Thus, antiproliferative drugs and ionizing radiation contribute to the emergence of cells resistance to impacts, which make them ineffective. Accordingly, activated NFκB is a key factor in ensuring the stability, for example, cancer cells to antiproliferative drugs and/or to ionizing radiation. This is further confirmed by the fact that constitutively activated NFκB detected in cells resistant cancers [Patel, Oncogene, 19, 4159-4169, 2000]. Regardless of the reduction of resistance to any impact, reducing the level of activated NFκB in the cell, for example, due to suppression of IKK activity reduces the levels of expression of genes encoding anti-apoptotic factors, inducing apoptosis in cells [Schwartz, Surgical Oncology, 8, 1999,143-153].

The role of activated NFκB is not limited to the prevention of apoptosis. NFκB is the main activator of genes involved in vocalic is selected and immunological processes. Activated NFκB induces the gene encoding cyclooxygenase 2 (COX2), which catalyzes the synthesis of Pro-inflammatory prostaglandins. In addition, in the later stages of inflammation COX2 catalyzes the synthesis of anti-inflammatory cyclopentenone prostaglandins. It is also known that COX2 has an antiviral effect, suggesting that NFκB may also be targets in the treatment of inflammatory and viral diseases [Rossi, Nature, 403, 2000, 103-108]. NFκB is also responsible for the transcriptional regulation of genes that play an important role in many important cellular processes. For example, NFκB regulates genes encoding cytokines and growth factors, adhesion factors, acute phase reactant agents, receptors and chemoattractant [Schwartz, Surgical Oncology, 8, 1999,143 .153]. This is further confirmed by Rossi in Nature, 403, 103-108, 2000, where he reveals that another type of connection, namely cyclopentenone prostaglandins inhibited IκB kinase and that it makes cyclopentenone prostaglandins are potentially useful for the treatment of cancer, inflammation and viral infections. IκB ecovalence associated with NFκB and masking the signal nuclear translocation, thus preventing its movement in the core. Were identified various IκBs, for example, IκBα and IκBβ expressed in most the e cells, where they are associated with Rel proteins p65, i.e., NFκB. Different IκB fosfauriliruyutza under the influence of various factors, ensuring the activation of NFκB in response to various stimuli.

Complex IκB kinases consists of three subunits, namely IKKα, IKKβ IKKγwith a total molecular weight of 900 kDa. IKKα and IKKβ both have IκB kinase activity and phosphorylate IκB, whereas IKKγ is the regulatory subunit. IKKα is a protein mass of 85 kDa, and IKKβ is a protein mass of 87 kDa, and the two subunits have a high degree of homology. Although IKKαand IKKβ are catalytically active, unexpectedly it was found that only IKKβ required for IKK phosphorylation IκB.

As described above, regulation of the level of activated NFκB by suppressing the activity of IKK can be used as a therapeutic activity in the treatment of proliferative diseases such as cancers and in particular sustainable forms of cancer. Suppression of IKK activity can also be used for the treatment of inflammatory or viral diseases. Regulation of IKK activity can be either therapy with a single agent, or it may constitute a part of combined treatment.

Apoptosis is a genetically encoded is the TEP cell death, characterized by "active decision" cells to die, adopted on the basis of information received from the environment, the history of its development, etc. In contrast to cells undergoing necrosis, cells entering apoptosis, often able to survive, but prefer to die for the good of the whole organism. Apoptosis differs from necrosis that necrosis is often associated with tissue trauma and damage to the cells, while cells following the course of apoptosis, destroyed from the inside in a controlled way [Tran, Science and Medicine, 6, 18-27, 1999; Williams, Trends Cell Biol., 2, 263-267, 1992].

In the preferred embodiment, the invention provides pharmaceutical compositions comprising a compound of formula I in combination with one or more other pharmacologically active compounds used for the treatment of proliferative diseases. Examples of compounds used for the treatment of proliferative diseases, which can be used together with the compounds of the present invention include derivatives of S-triazine, such as altretamin; enzymes such as asparaginase; antibiotic agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubitsin, mitomycin, epirubicin and plicamycin; alkylating agents such as busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, and ashamed, lomustin, mechlorethamine, melphalan, procarbazine, thiotepa; antimetabolites, such as cladribine, cytarabine, floxuridine, fludarabine, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, gemcitabine, pentostatin and tioguanin; antimitoticescoy tools, such as etoposide, paclitaxel, teniposide, vinblastine, vinorelbine and vincristine; hormonal drugs such as aromatase inhibitors such as aminoglutethimide, corticosteroids, such as dexamethasone and prednisone, as well as the factor that stimulates luteinizing hormone (LH-RH - luteinizing hormone releasing hormone); antiestrogens such as tamoxifen, formestane and letrozole; antiandrogens, such as flutamin; modulators of biological response, such as lymphokines, such as aldesleukin and other interleukins; an interferon such as interferon-α; growth factors such as erythropoietin, filgrastim and sargramostim; differenziali agents, such as derivatives of vitamin D, for example seocalcitol, and all-TRANS retinoic acid; immunoregulatory, such as levamisole; and monoclonal antibodies, tumor necrosis factor and inhibitors of angiogenesis. Finally, ionizing radiation, although not quite determined as the compound is widely used for the treatment of neoplastic diseases and can be combined with the compounds of the present invention. Due to the fact that PAC is coefficients, receiving anticancer treatment usually experience severe side effects, it is often desirable drug delivery, which themselves are not cancer, but sufficiently help alleviate side effects. Such compounds include amifostine, leucovorin and mesna.

In particular, such antiproliferative compounds like paclitaxel, fluorouracil, etoposide, cyclophosphamide, cisplatin, carboplatin, vincristine, gemcitabine, vinorelbine, chlorambucil, doxorubicin, melphalan and seocalcitol, successfully used in the combination compositions of the present invention.

It is assumed that the combined composition of the present invention may be provided in the form of mixtures of compounds or in the form of individual compounds intended for simultaneous or sequential administration. The choice of time intervals in sequential injection can be done by an experienced doctor or veterinarian.

In particular, the proliferative disease or condition to be treated using the method of the present invention include a number of cancer and tumor diseases or conditions, such as leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphatic leukemia, myelodysplasia, multiple mielo is a, Hodgkin's disease or non-jackinsky lymphoma, small cell or non-small cell carcinoma of the lung, cancer of the stomach, intestine or colon, rectum, prostate cancer, ovarian cancer, or breast cancer, cancer of the head, brain or neck, cancer of the urinary tract, kidney or bladder cancer, malignant melanoma, liver cancer, uterine cancer, or pancreatic cancer.

This invention also relates to the use of compounds of formula I, optionally together with other anticancer compounds described above, in the production of pharmaceuticals. In particular, if you intend to utilize the drug for the treatment of proliferative diseases such as cancers, such as described above.

WAYS to GET

The values of chemical shifts for spectra1H nuclear magnetic resonance (NMR) (300 MHz) and13C NMR (75,6 MHz) lead relative to internal standards trimethylsilane (δ=0,00), chloroform (δ=7,25) or deuterochloroform (δ=76,81 for13C NMR). The value of a multiplet, either definite (the singlet (s), doublet (d), triplet (t), Quartet (q)), or uncertain (wide (W)), in the approximate mid-point lead, if not defined interval. Use of anhydrous organic solvents.

The method of obtaining 1

3-[6-(N-tert-butoxycarbonylamino)-1-Huck is yloxy]pyridine

3 Hydroxypyridine (262 mg) are added to a suspension of 60% sodium hydride (128 mg) in N,N-dimethylformamide (5 ml) and the mixture is stirred for 30 minutes at 60°C. After cooling on ice is added dropwise a solution of N-(tert-butoxycarbonyl)-6-brompheniramine (770 mg) (Helv. Chim. Acta 76 891 (1993) in N,N-dimethylformamide (3 ml) and stirring is continued overnight at room temperature. Add water and ice and the mixture extracted three times with diethyl ether. The organic phase was washed with a saturated solution of sodium chloride, dried and evaporated, receiving a yellow oil, which was then purified by chromatography on silica gel using diethyl ether as eluent, obtaining the target compound as a colourless oil.

1H NMR (CDCl3) δ = 8,29 (users, 1H), to 8.20 (m, 1H), 7,18 (m, 2H), 4.53-in (users, 1H), 4.00 points (t, 2H), 3,13 (square, 2H), 1,80 (m, 2H), of 1.44 (s, 9H), 1.60-to of 1.30 (m, 6H)

The method of obtaining 2

3-[6-amino-1-hexyloxy]pyridine hydrochloride

3-[6-(N-tert-Butoxycarbonylamino)-1-hexyloxy]pyridine (180 mg) is treated with a large excess of hydrogen chloride in diethyl ether with stirring for 45 minutes, then evaporated in vacuum. Triturated with diethyl ether, decanted and evaporated, getting mentioned in the title compound as a colorless powder.

1H NMR (DMSO) δ = 8,64 (d, 1H), 8,46 (d, 1H), 8,08 (m, 1H), 8,08 (users, 3H), 7,88 (DD, 1H), 4,20 (t, 2H), 2,74 (m, 2H), 1,76(m, 2H), 1,59 (m, 2H), 1,41 (m, 4H)

The method of obtaining 3

3-[6-amino-1-hexyloxy]pyridine

A solution of the hydrochloride of 3-[6-amino-1-hexyloxy]pyridine in water strongly alkalinized with sodium hydroxide and extracted twice with chloroform. The organic phase is dried and evaporated in vacuum, obtaining oil, which is used in the next stage without additional purification.

The method of obtaining 4

1-[6-(N-tert-Butoxycarbonylamino)-1-hexyl]imidazole

The imidazole (70 mg) and 1,4M sodium methoxide (1 ml) are added to N,N-dimethylformamide (3 ml) and the mixture is stirred at room temperature for 30 minutes. Add a solution of N-(tert-butoxycarbonyl)-6-brompheniramine (280 mg) in N,N-dimethylformamide (1 ml) and after heating at 80-90°C within 30 minutes and stirring is continued overnight at room temperature. After evaporation in vacuum is stirred with acetone and filtered, receiving the filtrate, after evaporation purified by chromatography on silica gel using ethyl acetate/methanol (4: 1) as eluent, and get mentioned in the title compound as a colourless oil.

1H NMR (CDCl3) δ = 7,46 (t, 1H), 7,05 (t, 1H), 6.90 to (t, 1H), 4,60 (users, 1H), 3,92 (t, 2H), is 3.08 (square, 2H), 1,76 (m, 2H), of 1.44 (s, 9H), of 1.44 (m, 2H), 1,32 (m, 4H)

The method of obtaining 5

1-(6-Amino-1-hexyl)imidazole hydrochloride

Receive, as described in the production method of 2, but 3-[6-(N-tert-butoxy is ebonyline)-1-hexyloxy]pyridine substituted with 1-[6-(N-tert-butoxycarbonylamino)-1-hexyl]imidazole. Colorless crystals.

1H NMR (DMSO) δ = 14,99 (users, 1H), 9,31 (t, 1H), 8,23 (users, 3H), 7,86 (t, 1H), 7,71 (t, 1H), 4,22 (t, 2H), by 2.73 (m, 2H), is 1.81 (m, 2H), 1,58 (m, 2H), 1,36 (m, 2H), 1,23 (m, 2H)

The method of obtaining 6

1-(6-Amino-1-hexyl)imidazol

Receive, as described in the method of obtaining a 3, but hydrochloride 3-[6-amino-1-hexyloxy]-pyridine substituted hydrochloride 1-(6-amino-1-hexyl)imidazole. A colorless oil.

The method of obtaining 7

2-[6 - (N-tert-Butoxycarbonylamino)-1-hexyloxy]quinoline

This connection receive, as described in the method of obtaining 1, but 3-hydroxypyridine substituted 2-hydroxyquinolin. The crude product is purified by chromatography on silica gel with ethyl acetate as eluent, obtaining the target compound as a colourless oil.

1H NMR (CDCl3) δ = 7,66 (d, 1H), 7,56 (m, 2H), 7,35 (userd, 1H), 7,22 (m, 1H), 6,70 (d, 1H), 4,57 (users, 1H), 4,28 (m, 2H), 3,12 (m, 2H), of 1.75 (m, 2H), of 1.44 (s, 9H), of 1.55 and 1.35 (m, 6H)

The way to obtain 8

2-(6-Amino-1-hexyloxy)quinoline

2-[6-(N-tert-butoxycarbonylamino)-1-hexyloxy]quinoline (480 mg) is treated with a large excess of hydrogen chloride in diethyl ether under stirring for 1 hour at room temperature. Crystalline product are filtered and re-dissolved in water, after which the solution strongly alkalinized with sodium hydroxide and extracted twice with chloroform. The organic phase is dried over carb is the gateway potassium, filtered and evaporated, getting mentioned in the title compound as a colourless oil.

1H NMR (CDCl3) δ = 7,66 (d, 1H), 7,56 (m, 2H), was 7.36 (m, 1H), 7,22 (m, 1H), 6,69 (d, 1H), 4,29 (m, 2H), 2,70 (t, 2H), 1,76 (m, 2H), 1,65 (users, 2H), 1,45 (m, 6H)

Example 1

N-[6-(3-pyridyloxy)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine

A mixture of 3-[6-amino-1-hexyloxy]pyridine (150 mg), S-methyl-N-cyano-N'-4-pyridinediamine (123 mg), triethylamine (0,18 ml), 4-(N,N-dimethylamino)pyridine (3.5 mg) and pyridine (5 ml) is stirred over night at 60°C. After cooling to room temperature, the pyridine is removed, twice mpariwa in vacuo with toluene, and the residue distributed between water and ethyl acetate. The organic phase is dried and evaporated, obtaining the crude product which is purified by chromatography on silica gel, using as eluent a mixture of ethyl acetate/methanol/aqueous ammonia (40:10:2,5). Pure fractions are combined and evaporated, getting mentioned in the title compound, which crystallized from ethyl acetate

1H NMR (DMSO) δ = 9,40 (users, 1H), scored 8.38 (userd, 2H), 8,28 (d, 1H), 8,15 (DD, 1H), 7,86 (ushort, 1H), 7,37 (m, 1H), 7,31 (DD, 1H), 7,22 (users, 2H), Android 4.04 (t, 2H), 3,28 (square, 2H), 1,74 (m, 2H), and 1.56 (m, 2H), 1,40 (m, 4H)

Example 2

N-[6-(1-imidazolyl)-1-l-N'-cyano-N"-(4-pyridyl)guanidine

This connection receive, as described in example 1, but 3-[6-amino-1-hexyloxy]pyridine substituted with 1-(6-amino-1-hexyl)imidazol

1 H NMR (DMSO) δ = 9,35 (users, 1H), 8,39 (m, 2H), 7,86 (ushort, 1H), to 7.61 (t, 1H), 7,22 (m, 2H), 7,14 (t, 1H), to 6.88 (t, 1H), 3,94 (t, 2H), 3,26 (square, 2H), 1.70 to (m, 2H), of 1.52 (m, 2H), 1.27mm (m, 4H)

Example 3

N-[6-(2-Hinomisaki)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine

Receive, as described in example 1, but 3-[6-amino-1-hexyloxy]pyridine to replace 2-(6-amino-l-hexyloxy)quinoline.

1H NMR (DMSO) δ = 9,39 (users, 1H), scored 8.38 (m, 2H), of 7.90 (d, 1H), 7,87 (ushort, 1H), 7,73 (m, 1H), 7.62mm (m, 1H), 7,55 (userd, 1H), 7,30-7,10 (m, 3H), of 6.61 (d, 1H), 4,23 (m, 2H), 3.27 to (square, 2H), 1.61 of (m, 2H), and 1.54 (m, 2H), 1.39 in (m, 4H)

Example 4

N-[6-(3-Pyridyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine

Receive, as described in example 1, but 3-[6-amino-1-hexyloxy]pyridine substituted with 3-(6-amino-1-hexyl)pyridine.

13C NMR (DMSO) δ = 157,0, 150,1, 149,5, 146,9, 145,8, 137,4, 135,6, 123,3, 116,4, 114,5, 41,7, 31,9, 30,4, 28,5, 28,1, 25,8

Example 5

N-[6-(3-chinolin)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine

Receive, as described in example 1, but 3-[6-amino-1-hexyloxy]pyridine substituted with 3-(6-amino-1-hexyl)quinoline.

13C NMR (DMSO) δ = 157,0, 151,9, 150,1, 146,2, 145,7, 135,0, 133,7, 128,5, 128,4, 127,7, 127,5, 126,4, 116,4, 114,5, 41,7, 32,1, 30,3, 28,5, 28,1, 25,8

Example 6

N-[6-(5-pyrimidinyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine

Receive, as described in example 1, but 3-[6-amino-1-hexyloxy]pyridine substituted for 5-(6-amino-1-hexyl)pyrimidine.

13C NMR (DMSO) δ = 157,1, 156,6, 156,2, 149,9, 145,5, 135,3, 116,3, 114,4, 41,7, 29,9, 29,2, 28,4, 28,0, 25,7

Example 7

Pharmaceutical the song in the form of tablets 0.1 mg of the compound of example 1, 300 mg of glucose, 6,2 mg of lactose, 0.6 mg of magnesium stearate, 30 mg of starch are thoroughly mixed and pressed into a suitable device for forming tablets.

The pharmacological activity

The tests were performed by assessing cell proliferation in small cell carcinoma of the human lung (NYH). Methodology and experimental techniques correspond to the traditional used in similar studies.

The results of the tests in vitro assessment of cell proliferation in small cell carcinoma of the human lung (NYH).

ConnectionNYH/IC50(nM)
Example No. 3 of the Present invention0,02
Example No. 4 of the Present invention0,6
Example No. 5 of the Present invention0,08

As can be seen from the table, these compounds are able to inhibit the proliferation of cancer cells in vitro at low concentrations.

1. The compound of the formula I

where R1 denotes hydrogen;

X denotes a linear or branched, saturated or unsaturated With1-12hydrocarbon biradical;

Y represents a bond or O;

Z represents a 5-10 membered aromatic heterocyclic radical, optionally substituted Hydra is XI;

provided that R1 is not joined to the nitrogen atom in pyridinium cycle;

as well as its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1 represents hydrogen; X represents linear C4-12hydrocarbon biradical; Y represents a bond or O; Z represents a 5-10 membered aromatic heterocyclic radical with 1-3 nitrogen atoms.

3. The compound according to claim 1, where R1 represents hydrogen; X represents a linear saturated With5-10hydrocarbon biradical; Y represents O; Z represents a 5-10 membered aromatic heterocyclic radical with 1-3 nitrogen atoms.

4. The compound according to claim 1, where Z denotes pyridyl, imidazolyl, chinolin or pyrimidinyl.

5. The compound according to claim 1, selected from the group consisting of N-[6-(3-pyridyloxy)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(1-imidazolyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(2-hinomisaki)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(3-pyridyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(3-chinolin)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine;

N-[6-(5-pyrimidinyl)-1-hexyl]-N'-cyano-N"-(4-pyridyl)guanidine.

6. The compound according to any one of claims 1 to 5 for the manufacture of a medicinal product for the treatment of proliferative diseases.

7. Pharmaceutical composition having anti-proliferative activity, including connection is the yubom one of claims 1 to 5, together with pharmaceutically acceptable excipients.

8. The composition according to claim 7 in the form of a single dosage form.

9. The use of compounds according to any one of claims 1 to 5 in the manufacture of drugs for the treatment of proliferative diseases.



 

Same patents:

FIELD: organic chemistry, polymers, chemical technology, catalysts.

SUBSTANCE: invention relates to ligands, different precursors of catalysts and catalytic systems prepared from these ligands and designated for the oligomerization reaction of ethylene to synthesize linear alpha-olefins with high yield and selectivity. Also, invention relates to a method for synthesis of indicated alpha-olefins, namely, to mixed bis-iminepyridine ligands of the formula (II) given in the invention description wherein indicated atoms form cyclopentadienyl or aryl moiety of π-coordinated metal complex, to mixed complexes of bis-iminepyridine-MXn comprising ligand of the formula (II) wherein M represents metal atom chosen from Fe or Co; n = 2 or 3; X represents halide atom, (C1-C30)-hydrocarbon radical optionally comprising one or more functional inert groups comprising heteroatom and chosen from fluoride, chloride, silanes, stannans, ethers and amines, alkoxides, amides or hydrides, to mixed complexes [bis-iminepyridine MYp . Ln+][NC-]q comprising ligand of the formula (II) wherein Y represents ligand that is able to incorporation of olefin; M represents metal atom chosen from Fe or Co; NC- represents non-coordinated anion; p + q = 2 or 3 in accordance of formal degree of oxidation of indicated metal atom; L represents the Lewis neutral donor molecule; n = 0, 1 or 2, and to a method for synthesis of alpha-olefins from ethylene with using indicated complexes.

EFFECT: valuable properties of ligands and systems.

6 cl, 2 tbl, 4 dwg, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formulas (1) , (2) , (3) or (4) , or isomers of compounds of formulas (2) and (3) wherein symbol values are determined in the invention claim. Also, invention relates to their pharmaceutically acceptable salts showing the improved solubility in aqueous media and improved bioavailability wherein indicated compounds possess the inhibitory activity with respect to secretion of gastric acid.

EFFECT: valuable medicinal properties of compounds.

35 cl, 44 sch, 4 tbl, 165 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the formula (I): m means a whole number from 1 to 3; R1 represents halogen atom or (C1-C3)-alkyl; X1 represents -O-; R2 represents (C1-C5)-alkyl-R3 wherein R3 represents piperidine-4-yl that can comprise one or two substitutes chosen from (C1-C4)-alkyl and to their salts. Also, invention relates to methods for synthesis of these compounds and pharmaceutical compositions comprising compound of the formula (I) or its pharmaceutically acceptable salts as an active component. Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit effect of VEGF that is a valuable property in treatment of different pathological states including cancer and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

28 cl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein X means -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO, -SO2; m = 1; A represents a direct bond; R1 means hydrogen atom (H); R2 and R3 are chosen independently from H, (C1-C6)-alkyl, heterocycloalkyl, phenyl, heteroaryl, phenylalkyl, phenylheteroalkyl, heteroarylalkyl, heterocycloalkylalkyl; R4 represents H; R5 represents monocyclic, bicyclic or tricyclic group. Also, invention describes a pharmaceutical composition and using compounds in preparing a medicinal agent for using in treatment of diseases or states mediated by one ore more enzymes representing metalloproteinase. Compounds of the formula (I) are useful as inhibitors of metalloproteinases being especially as inhibitors of MMP12.

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

14 cl, 16 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

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

15 cl, 1 tbl, 9 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new crystalline form of substance known as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (general name is omeprazole), titled in present description as C form omeprazole. Claimed omeprazole has the next pattern obtained by powdered X-ray diffraction:

valuesof dÅrelative intensity9.5-9.6very strong7.9-8.0strong7.4-7.5weer7.2very strong5.9-6.0medium5.6medium5.1-5.2very strong4.88-4.90weer4.81-4.84weer4.65-4.67medium4.57-4.60medium4.48-4.51strong4.34-4.36medium4.16-4.19weer3.94-3.97weer3.72-3.73strong3.58-3.59medium3.46-3.47strong3.29-3.30medium3.23-3.25strong3.19-3.20medium3.11-3.12weer3.03-3.04weer

Methods for production of C form omeprazole, pharmaceutical composition for treatment of gastrointestinal diseases, containing target product in combination with pharmaceutically acceptable excipients, and application of C form omeprazole in preparation of drug for treatment of gastrointestinal diseases also are described.

EFFECT: new drug for treatment of gastrointestinal diseases.

13 cl, 8 dwg, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

Kahalalide f // 2292216

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to novel compositions and using kahalalide F, to a set containing the kahalalide F composition and to a reduced solution prepared from the kahalalide F composition. Combination of non-ionic surface-active substance and organic acid is suitable for using with a filling agent for preparing lyophilized formulation of kahalalide F.

EFFECT: improved preparing method.

10 cl, 7 ex

FIELD: pharmaceuticals, organic chemistry.

SUBSTANCE: invention relates to method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (II). Claimed method includes heat treatment of microcrystalline cis-dichlorodiamineplatinum (II) salt of high purity (not less than 99.5 mol %) at 160°C for 6 hours.

EFFECT: new method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (II).

2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: preparation belongs to gestagen class as 17α-acetoxy-3β-butanoyloxy-6-methyl-pregna-4,6-dien-20-on allowing peroral application. The compound shows no toxic activity and has no androgenic side effect. It is found to be better than Depo-Provera gestagen used in clinical practice and possesses chemosensitizing activity. The preparation is obtained by megestrol acetate reduction with sodium borohydride with following product etherification with butyric acid anhydride. The reaction mixture is treated with ammonia solution after etherification with butyric acid excess being removed to increase output and target product separation.

EFFECT: enhanced effectiveness of treatment.

3 cl, 3dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves applying chlorocholine chloride as antitumor means.

EFFECT: enhanced effectiveness of treatment; reduced risk of adverse side effects manifestation; low toxicity.

FIELD: medicine.

SUBSTANCE: method involves preparing composition comprising epotilone analogs by dissolving said epotilone analog in aqueous butanol. The produced solution is dried in two stages to produce lyophilized product being lyophilized epotilone analog and pharmacological means for treating cancer diseases containing lyophilized epotilone analog.

EFFECT: high solubility of obtained product.

20 cl,1 tbl

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the formula (I): m means a whole number from 1 to 3; R1 represents halogen atom or (C1-C3)-alkyl; X1 represents -O-; R2 represents (C1-C5)-alkyl-R3 wherein R3 represents piperidine-4-yl that can comprise one or two substitutes chosen from (C1-C4)-alkyl and to their salts. Also, invention relates to methods for synthesis of these compounds and pharmaceutical compositions comprising compound of the formula (I) or its pharmaceutically acceptable salts as an active component. Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit effect of VEGF that is a valuable property in treatment of different pathological states including cancer and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

28 cl, 14 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to using compound of the formula (I) as the first anti-tumor agent for preparing a medicinal preparation that in administration with the second anti-tumor agent prevents development of resistance of malignant cells to apoptosis as result of activation of NFKB by the indicated second anti-tumor agent. Invention provides enhancing effectiveness of treatment.

EFFECT: improved and valuable medicinal properties of agent.

15 cl, 4 tbl, 3 ex

FIELD: medicine, pharmacology.

SUBSTANCE: agent represents flavolignans chosen from silybinine, silydianine, silycrystine, dehydrosilybinine, their mixtures or extracts prepared from plant spotted milk thistle (Silybium marianum (L.) Gaertn) containing these components. Agent is used for inhibition of excessive or pathological proliferation of vascular endothelium. Proposed agent expands assortment of agents directed for treatment pathologies associated with angiogenesis disorders. Invention can be used in development of medicinal preparations used in therapy of pathologies associated with angiogenesis disorders, namely, for inhibition of excessive or pathological proliferation of vascular endothelium.

EFFECT: valuable medicinal properties of agent.

1 tbl, 2 dwg, 2 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an agent based on extractive substances from horse chestnut seeds (Fructus aesculi hippocastani) used as an agent in treatment of vein varicosity, thrombosis and post-traumatic edemas. Agent possessing vein-tonic, anti-inflammatory and capillary-protecting effects represents the horse chestnut seeds tincture (Fructus aesculi hippocastani) prepared by extraction of the raw with 35-45% ethyl alcohol in the ratio raw to extractant = 1:10 and containing saponins as measured for escein 0.2-3.0 wt.-% and horse chestnut extractive substances in the amount 1.0-5.0 wt.-% of the total tincture mass. Agent is designated for treatment of vein varicosity, thrombosis and post-traumatic edemas in the dose 15-20 drops, 3 times per a day, for 2-3 weeks. Method for preparing the agent possessing the vein-tonic, anti-inflammatory and capillary-protective effect involves extraction of horse chestnut seeds (Fructus aesculi hippocastani) with 35-45% ethyl alcohol in the ratio raw to extractant = 1:10. During this extraction process the raw is kept in extractant medium for swelling for 4-6 h, stirred and heated if necessary to temperature 40°C, not above, and the prepared extract is settled at temperature 4-8°C for 30 h, not less. The prepared horse chestnut tincture possesses the broad spectrum of therapeutic effect and improves blood rheological properties, shows tonic effect on vessels and optimizing effect of hemocirculation.

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

3 cl, 11 tbl

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