Dpp-iv inhibitor containing beta amino group, method for making thereof and pharmaceutical composition containing it for prevention and treatment of diabetes or obesity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

where X represents OR1, SR1 or NR1R2 where R1 and R2 independently represent C1-C5 lower alkyl, and R1 and R2 in NR1R2 can form a 5-7-members ring including an O heteroatom; or to its stereoisomer, to a pharmaceutically acceptable salt, hydrate or solvate. Besides, the invention refers to a method for making thereof and to a based pharmaceutical composition exhibiting DPP-IV inhibitor activity.

EFFECT: new compounds which can find application in medicine for prevention or treatment of the DPP-IV associated diseases, such as diabetes or obesity are produced.

12 cl, 1 tbl, 2 dwg, 18 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a heterocyclic compound containing beta-amino group, which has an excellent inhibitory activity against dipeptidylpeptidase-IV (hereafter in this document referred to as "DPP-IV") and high bioavailability, and to pharmaceutical compositions containing the specified heterocyclic compound or its pharmaceutically acceptable salt as an active ingredient.

The LEVEL of TECHNOLOGY

The enzyme dipeptidyl peptidase IV, abbreviated herein as DPP-IV and other documents as DP-IV, DP-4 or DAP-IV) as well as according to the classification known as EC. 3.4.14.5, is a serine protease (Barrett, A. J. et al., Arch. Biochem. Biophys., 1995, 247-250), which it N-terminal dipeptide from peptides that begin with the sequence H-Xaa-Pro-Y or H-Xaa-Ala-Y, where Xaa represents any lipophilic amino acid, Pro is a Proline and Ala is an alanine (Heins J., et al., Biochim. et Biophys. Acta 1988, 161). DPP-IV is widely distributed and is found in various mammalian tissues, such as kidney, liver and small intestine (M. Hegen et al., J. Immunol, 1990, 2908-2914). First DPP-IV was identified as a membrane-bound protein. It was later identified a soluble form (Duke-Cohan, J. S. et al., J. Biol. Chem., 1995, 14107-14114). According to the recently published research and report it was found that this soluble form of DPP-IV has the same structure and function; membrane-bound form of the enzyme, and it is in the blood without a specific membrane-bound domain (Christine D. et al., Eur. J. Biochem., 2000, 5608-5613).

Initial interest in DPP-IV has been focused on its role in the activation of T-lymphocytes. DPP-IV is responsible for the activation of T-lymphocytes, was specifically identified as CD26. In the report, which showed that CD26 binds or interacts with the human immunodeficiency virus (HIV) (Guteil W. G. et al., Proc. Natl. Acad. Sci., 1994, 6594-6598), an assumption was made that inhibitors of DPP-IV may be suitable for treatment of AIDS (Doreen M. A. et al., Bioorg. Med. Chem. Lett., 1996, 2745-2748).

In addition to the key role of participation in the immune system the main function of DPP-IV is associated with its peptidomimetics activity, as described above. In particular, the role of DPP-IV attention, because it was found that DPP-IV is a key enzyme involved in the degradation of glucagon-like protein-1 (hereafter in this document referred to as "GLP-1") in the small intestine (Mentlein R. et al., Eur. J. Biochem., 1993, 829-835). GLP-1 is a peptide hormone consisting of 30 amino acids that is secreted by L-cells of the intestine in response of the small intestine for a meal (Goke R. et al., J. Biol. Chem., 1993, 19650-19655). Since it is known that GLP-1 exerts synergistic effects on dei is a journey of insulin to control the glucose levels in the blood after a meal (Hoist J. J. et al., Diabetes Care, 1996, 580-586), it was hypothesized that inhibitors of DPP-IV can also be appropriately used for the treatment of type 2 diabetes. Under this assumption, was developed early form of the inhibitor of DPP-IV, and some reports have demonstrated therapeutic efficacy of the drug in the animal experiments (Pauly, R. P. et al., Metabolism, 1999, 385-389). In addition, deficient DPP-IV mice or rats remained active GLP-1 and high levels of insulin, which resulted in a reduction of glucose levels in the blood, and this genetic disorder or mutation of a gene DPP-IV had no significant effect on the survival of individual animals (D. Marguet et al., Proc. Natl. Acad. Sci., 2000, 6874-6879). Therefore, it was suggested that DPP-IV is a possible potent drug for the treatment of type 2 diabetes, resulting in accelerated research and development is an inhibitor of DPP-IV.

Binding of GLP-1 receptor in various tissues leads to satiety (feeling of fullness), slow gastric emptying and the rapid growth of beta cells in the pancreas. Thus, there is an increasing number of clinical trials in the treatment of diabetes 2 by intravenous directly GLP-1 (Verdich, C. et al., J. Clin. Endocrinol. Metab., 2001, 4382-4389). The half-life of GLP-1 is only 2 min (Kieffer, T. J., et al. Endocrinology, 1995, 3585-3596), so that the short half-life is the main obstacle to a straightforward application of GLP-1 as a drug. After that, a large number of research groups and institutions was undertaken numerous attempts to obtain derivatives of GLP-1 that led to the development and commercialization of a peptide which is able to extend a short half-life ofin vivo(C. F. Deacon, Diabetes, 2004, 2181-2189). However, such a derivative of GLP-1 still has a significant limitation, which is that it is an injectable composition. In addition, considerable interest more and more focuses on the development of effective inhibitor of DPP-IV as active GLP-1 (7-36) are degraded by DPP-IV, and then becomes inactive GLP-1 (9-36) only for a short period of time, for example 2 minutes

The beginning of the development of inhibitors of DPP-IV was similar to that by the development of other inhibitors. This means that most of the research results was obtained for analogues of substrates. Representative analog of the substrate is a dipeptide derivative, which was received as of the early studies carried out on the source engine, has a structure similar to the structure of Proline (Pro), on the basis of the fact that DPP-IV has a pronounced affinity to the peptide, sod is rasamu specific amino acid - Proline (Chinnaswamy T. et al., J. Biol. Chem., 1990, 1476-1483). Typical examples polonophobic structures include pyrrolidin and thiazolidin, and derivatives containing these compounds with the original nuclei, are reversible and competitive inhibitory activity against the enzyme DPP-IV (Augustyns KJL., et al., Eur. J. Med. Chem., 1997, 301-309).

Among the results of such extensive research and development are ongoing experiments on the mechanism of action and efficacy of certain compounds, specifically Val-Pyr (valine-pyrrolidide), Ile-Thia (isoleucine-thiazolidin), etc. In particular, great attention is paid Ile-Thia because the structure Val-Pyr has a relatively weak inhibitory activity on DPP-IV (Hanne B. R., et al., Nat. Struct. Biol., 2003, 19-25), which, essentially, has led to an intensive research and study of derivatives of compounds Ile-Thia.

Of derivative compounds Ile-Thia, in which was concentrated the above study and research, and which have been received, the connection with the most pronounced activity was a series connection thiazolidine beta-amino acids, which tried to get Merck & Co., Inc. However, according to the results of pharmacodynamic and pharmacokinetic experiments conducted in rats, the compound obtained had a significantly low bioavailability in combination with the obvious limitation is m in the inhibition of enzyme activity (Jinyou Xu, et al., Bioorg. Med. Chem. Lett., 2004, 4759-4762). Therefore, compounds of this class was interrupted due to the material weaknesses.

During the above research at Merck, it was noted that beta-amino acid, in addition to thiazolidinone the original kernel, is also a key factor that has pronounced effects on the inhibitory activity of DPP-IV. This discovery was applied in the approach of replacing thiazolidine original kernel characterized by the connection of the source engine (Linda L. B., et al., Bioorg. Med. Chem. Lett., 2004, 4763-4766). In this subsequent study was synthesized many derivatives having the replacement thiazolidine original kernel piperazinonyl source engine, testing the efficacy of drugs and pharmacodynamic studies. Unfortunately, pieperazinove derivatives Merck still had a largely insufficient bioavailability. Based on the optimization of the connection to eliminate such a disadvantage has been developed product MK-0431 (brand name: JANUVIA) with a modification of piperazino group to triazolopyridazines group. This product is currently available in the framework of the approval of new drugs US FDA in 2006. In addition, after MK-0431, is currently developing a connection with the inclusion of a group of diazepinone (semiline ring) WO 2004037169; WO 2005011581; WO 2006104997; and Bioorg. Med. Chem. Lett, 2007, 49-52). In particular, according to an article published in the journal (Bioorg. Med. Chem. Lett., 2007, 49-52), it was shown that imidazole (five-membered ring) and piperazine (six-membered ring) have a significantly lower activityin vitrocompared with diazepinones that, therefore, led to increased focus on optimizing diazepinone.

[MK-0431]

The result is a variety of extensive and intensive studies and experiments to solve the problems described above and to achieve the optimization of interest connection the authors of the present invention discovered that when a group of piperazinone made replacement that includes a heteroatom, modified thus the connection not only has excellent inhibitory activity against DPP-IV, but also able to achieve significantly increased bioavailability compared to conventional inhibitor of DPP-IV, and then successfully carried out the synthesis of new heterocyclic compounds containing beta-amino group. The present invention was made on the basis of these discoveries.

Description of the INVENTION

TECHNICAL PROBLEM

The present invention is the provision of heterocyclic compounds containing beta-amino group and having and hibitory activity against DPP-IV, or its pharmaceutically acceptable salt, hydrate or MES.

Another objective of the present invention is to provide pharmaceutical compositions for the prevention and treatment of diabetes or obesity, comprising as active ingredient the above heterocyclic compound or its pharmaceutically acceptable salt, hydrate or MES.

TECHNICAL SOLUTION

Further, the present invention is described in more detail. The present invention relates to getarticles compounds with beta-amino group, represented by formula 1:

where X represents OR1, SR1, or NR1R2, where R1 and R2 independently represents a C1-C5lower alkyl, and R1 and R2 in NR1R2 may form a 5-7-membered ring with the inclusion of O heteroatom; or their pharmaceutically acceptable salts.

Preferably, the compound of formula 1 in accordance with the present invention includes a compound of formula 2, which is a stereoisomer that induce optical activity on the carbon atom in the 3 position of the ring of piperazinone, and corresponds to the formula 2, below.

where X is as defined for formula 1.

Therefore, the compound of formula 1 can have two asymmetric center. Specifically, the compound of formula 1, as shown the and formula 2, can have asymmetric centers at the beta-carbon and the carbon in the 3 position of the ring of piperazinone, so it can be presented in the form of one diastereoisomer, racemate, racemic mixture or diastereoisomeric mixture, all of which belong to the compound of formula 1 in accordance with the present invention.

In addition, the compound of formula 1 may be partly present as tautomers. Also in the compound of formula 1 is included individual tautomers, and mixtures thereof.

Stereoisomeric form of the compounds of formula 1 can be obtained stereoselective synthesis in accordance with a conventional method known in this field, using optically pure starting material or of a known reactant.

Preferred examples containing beta-amino heterocyclic compounds of formula 1 in accordance with the present invention may include the following connections:

1) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

2) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(methoxymethyl)piperazine-2-it;

3) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(ethoxymethyl)piperazine-2-it;

4) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(isopropoxyphenyl)piperazine-2-it;

5) hydrochloride (R)-4-[(R)-3-amino-4-2,4,5-tryptophanyl)butanoyl]-3-(cyclopentylacetyl)piperazine-2-it;

6) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(diethylamino)methyl]piperazine-2-it;

7) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(ethylmethylamino)methyl]piperazine-2-it;

8) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(morpholinomethyl)piperazine-2-it;

9) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butylthioethyl)piperazine-2-it;

10) hydrochloride (S)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

11) (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-he;

12) tartrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

13) citrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

14) phosphate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

15) acetate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

16) malate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;

17) succinate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-she; and

18) adipate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it.

Containing beta-amino heterocyclic compound of formula 1 in accordance with the crust is Asim invention includes its pharmaceutically acceptable salt, as well as hydrate and MES, which you can get from it.

Pharmaceutically acceptable salt of the heterocyclic compounds of formula 1 can be obtained by any conventional method of obtaining salts known in this field.

As used herein, the term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic base and an inorganic or organic acid. Examples of pharmaceutically acceptable salts may include salts of compound 1 with an inorganic base, for example with an ion of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganate, manganese, potassium, sodium or zinc. Especially preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Solid salt can have one or more crystalline structures, or otherwise, it may take the form of a hydrate. Examples of pharmaceutically acceptable non-toxic organic salts may include salts of compound 1 with primary, secondary or tertiary amine, substituted amine, such as naturally occurring substituted amines, cyclic amine, or a basic ion exchange resins, such as arginine, betainovuyu, caffeine, Kalinova, N,N'-dibenzylamino Ndjamena, diethylamino, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylendiamine, N-ethylmorpholine, N-ethylpiperidine, glucagonoma, glucosamine, his-tag, Gidravlika, Isopropylamine, lysine, methylglucamine, Martinova, pieperazinove, piperidino, polianinova resins, procaine, purine, theobromine, triethylamine, trimethylamine, Tripropylamine and tromethamine.

When the compound of the present invention is based, its salt can be obtained from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Examples of the acid may include acetic acid, benzosulfimide acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, gluconic acid, glutamic acid, Hydrobromic acid, chloride-hydrogen acid, isetionate acid, lactic acid, maleic acid, malic acid, almond acid, methanesulfonate acid, muzinovy acid, nitric acid, pambou acid, Pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluensulfonate acid and adipic acid. Especially preferred are acetic, citric, chloride-hydrogen, yab is full-time, phosphoric, succinic, tartaric and adipic acid.

When this document provides a compound of formula 1, the term includes its pharmaceutically acceptable salt.

As used herein, the term "hydrate" means a compound of formula 1 or its pharmaceutically acceptable salt, which further includes a stoichiometric or non-stoichiometric amount of water associated through non-covalent intermolecular forces. The hydrate may contain more than 1 equivalent of water, usually from 1 to 5 equivalents of water. The hydrate can be obtained by crystallization of the compounds of formula 1 or its pharmaceutically acceptable salt in water or water-containing solvent.

As used herein, the term "MES" means a compound of formula 1 or its salt, which further includes a stoichiometric or non-stoichiometric amount of solvent, associated by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and/or acceptable for administration to humans. For example, there may be mentioned ethanol, methanol, propanol, methylene chloride, etc.

In accordance with another aspect of the present invention provides a method of obtaining heterocyclic compounds with beta-amino group, presented the military formula 1, or its pharmaceutically acceptable salt.

The present invention, as shown in the reaction scheme 1, below, includes a method of obtaining a heterocyclic compound represented by formula 2, including: 1) the reaction of the compound of formula 3 with beta-amino group, substituted heterocyclic compound of the formula 4 in the presence of 1-hydroxybenzotriazole (HOBT), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the tertiary amine with obtaining, thus, the compounds of formula 5 with a peptide bond, and 2) the reaction of compounds of formula 5 in the presence of acid to obtain heterocyclic compounds of formula 2, having beta-amino group.

[Reaction scheme 1]

where X is as defined for formula 1.

For example, the intermediate compound of formula 5 can be obtained by reaction of compounds of formula 3 and the compound of formula 4 in the usual way in a solvent such as N,N-dimethylformamide (DMF) or dichloromethane, in the presence of coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or 1-hydroxybenzotriazole (HOBT), and bases, such as diisopropylethylamine or triethylamine, at a temperature of from 0°C. to room temperature for from 3 to 48 hours.

To prevent the participation of connections in participatie the nitrogen atom of the intermediate compounds of formula 5 to the / establishment, which received participatie, protect protecting group. The desired heterocyclic compound of formula 2 with beta-amino group, can be obtained by removing the protective group by the reaction of removing the protective group. Therefore, because the protecting group is a Boc, the removal of the protective group can be carried out in acidic conditions, typically using a mixture triperoxonane acid/dichloromethane, a mixture of ethyl acetate/chloride-hydrogen acid, a mixture of chloride-hydrogen acid/dichloromethane or methanol/chloride-hydrogen acid, at a temperature of from 0°C. to room temperature for from 1 to 24 hours.

If necessary, the compound of formula 2 obtained by reaction of the peptide bond and the removal of the protective group, can be cleaned from unwanted side products by any conventional means such as recrystallization, poroshkovaya, preparative thin layer chromatography, flash chromatography on silica gel (see W.C. Still et al., J. Org. Chem., 43, 2923 (1978)) or HPLC. The compound is purified by HPLC, can be identified as corresponding salts thereof. The compound of formula 5 can also be cleaned the same way.

In the present invention, a mixture of stereoisomers of the compounds of formula 1 is obtained using a mixture of stereoisomers as a starting material, and the resulting mixture is separated into a separate article is rosamary with obtaining, thus, the compounds of formula 1. In addition, each stereoisomer of the compounds of formula 1 can be obtained using each stereoisomer as the source material. Selection stereoisomer can be conventional column chromatography or recrystallization.

Upon receipt of the compounds of formula 2 compound of formula 3 used in the reaction scheme 1, is commercially available or can easily be obtained by any method known in this field.

Upon receipt of the compounds of formula 2 compound of formula 4 used in the reaction scheme 1, can be obtained in accordance with the synthetic cascade scheme of reaction 2 and reaction scheme 3.

In the reaction scheme 2 compound 6 may be commercially available, or it may not be commercially available, depending on the substituent X, so that the connection 6 is commercially available or can easily be obtained by any method known in this field, for example, shown in reaction scheme 3, below.

In the reaction scheme 2 compound 4 used to obtain the compounds of the present invention, can be obtained from compound 6. Specifically, the connection 6 is subjected to reaction with N-butyloxycarbonyl-2-aminoacetaldehyde in the presence of a reducing agent to obtain compound 7, which then receive the connection 8, and uusee secondary amine, protected benzyloxycarbonyl (Cbz), with the subsequent removal of the protective group with obtaining, thus, compound (9), where butyloxycarbonyl (Boc) removed. Then the connection 9 is subjected to cyclization using trimethylaluminum (or mixture diisopropylethylamine/ethanol, a mixture of sodium hydrogen carbonate/methanol etc) to obtain compound 10, followed by removing the protective group Cbz getting connection 4. Examples of reducing agents that can be used to obtain compound 7 from compound 6 may include cyanoborohydride sodium, triacetoxyborohydride sodium, sodium borohydride, etc.

[Reaction scheme 2]

where X is as defined in formula 1.

When the connection 6 to the reaction scheme 2 is not commercially available, can be obtained analogously to the reaction scheme 3, below. Connection 6 with many of the substituents R1 to the reaction scheme 3, are methyl substitution of ester of D-serine by Fritillaria with obtaining the compound (11) and replacing the hydroxyl group of compound (11) mesyl group, followed by boiling under reflux with obtaining, thus, the compounds of aziridine 12. Then trailing connection group 12 is removed using triperoxonane acid, and then protect benzyloxycarbonyl (Cbz) obtaining from the organisations 13. Then the connection 13 is subjected to reaction with HX, with many of the substituents R1, receiving of the connection 14, with subsequent removal of the Cbz getting connection 6.

[Reaction scheme 3]

where X is as defined in formula 1.

To facilitate interest of the reaction or to avoid the formation of undesirable reaction product for some of the compounds of formula 1 according to the present invention, the above reaction conditions, and sequencing reactions can be varied, if desired.

As described above, the compounds of formula 1 according to the present invention, starting materials and intermediate compounds can be synthesized by various methods known in this field.

In accordance with the following aspect of the present invention provides a pharmaceutical composition for the prevention and treatment of diabetes or obesity, containing the compound of formula 1 or its pharmaceutically acceptable salt as an active ingredient.

The compound of formula 1 in accordance with the present invention has excellent inhibitory activity against DPP-IV. When determined the inhibitory ability of the compounds of formula 1 in respect of the enzyme DPP-IV, IC50the concentration of drug required to inhibit the enzyme is active reaction DPP-IV by 50% was almost equal to the range from 0.5 to 20 nm, which corresponds to a higher inhibitory activity against DPP-IV in comparison with the conventional inhibitor of DPP-IV, which describes the IC50from several hundred nm to several thousand nm or even up to several thousand nm (Jinyou Xu, et al., Bioorg. Med. Chem. Lett., 2004, 4759-4762; and Linda L. B., et al., Bioorg. Med. Chem. Lett., 2004, 4763-4766).

In addition, the compound of formula 1 in accordance with the present invention has high oral glucose tolerance. Thus, in the test, oral glucose tolerance (OGTT) was measured that the compound of formula 1 has the effect of lowering blood glucose more than 35%, preferably more than 50%, thus demonstrating that it has a higher bioavailability compared to conventional inhibitors of DPP-IV. In addition, the results of experimentsin vivoincluding pharmacokinetic/pharmacodynamic correlation, measurement of the duration of the period inhibitory activity of DPP-IV and experiments kineticsin vivodemonstrate that the compound of the present invention has a higher inhibitory activity against DPP-IV and bioavailability.

Thus, the pharmaceutical composition comprising as active ingredient a compound of formula 1, can be used effectively to Le the surveillance and prevention of diabetes and obesity, which are representative of the diseases caused by using a DPP-IV.

In accordance with another aspect of the present invention provides for the application of the above compositions for the prevention and treatment of diabetes or obesity and how the prevention and treatment of diabetes or obesity, comprising introducing an effective amount of the above composition to a mammal (including humans).

Pharmaceutical composition containing as active ingredient a compound of formula 1 or a stereoisomer, pharmaceutically acceptable salt, hydrate or MES, can be made in the form of the following oral or parenteral dosage forms, not limited to.

Examples of dosage forms for oral administration may include tablets, pills, soft and hard capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, etc. These pharmaceutical compositions may contain, in addition to the above-indicated active ingredient, one or more conventional diluents or excipients such as fillers, diluents, wetting agents, dezintegriruetsja substances, substances promoting sliding, binders and surfactants. Examples dezintegriruetsja substances may include agar, starch, alginic acid or its freeway salt, waterless monohydratefast calcium, etc. are Examples of substances that contribute to slip may include silicon dioxide, talc, stearic acid or its magnesium or calcium salt, polyethylene glycol and the like, Examples of the binder may include a silicate of magnesium, starch paste, gelatin, tragakant, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, nitrosamino hydroxypropylcellulose, etc. in Addition, the pharmaceutical composition may contain diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine. If desired, the composition may additionally contain widely known effervescent mixtures, absorbents, colorants, flavors and sweeteners.

Pharmaceutical composition containing as active ingredient a compound of formula 1 or its pharmaceutically acceptable salt, you can enter parenterally, for example by means of a suppository, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. For the preparation of compositions according to the present invention in the form of a preparation for parenteral administration, the compound of formula 1 or its pharmaceutically acceptable salt is mixed with a stabilizer or buffer in the presence of water to obtain a solution or suspension from which zagotavlivayut unit dosage form in ampoules or vials.

The composition may be sterilized and/or may contain adjuvants such as preservatives, stabilizers, hydrating agents, emulsifiers, salts for control of osmotic pressure and/or buffers, and therapeutically suitable substance, and can be produced in accordance with conventional ways, such as mixing, granulation and coating.

If desired, the compound of formula 1 or a pharmaceutical composition containing it as active ingredient, can be introduced in combination with other drugs, such as antidiabetic drugs.

When the compound of formula 1 or a pharmaceutical composition containing it as active ingredient, are made as a standard dosage forms, the compound of formula 1 is used preferably in a unit dose of from about 0.1 to 1,500 mg in terms of the active ingredient. As will be obvious to experts in the field, an effective dose of the active compounds in accordance with the present invention can be determined in accordance with the physician, depending on various factors such as body weight and age of patients, type and severity of the disease, etc. For adults effective dose of an active compound, as a rule, is in the range arr is siteline from 1 to 500 mg/day, taking into account the frequency and intensity of the introduction. In the case of intramuscular or intravenous injection adults may be suitable from 5 to 300 mg total dose is divided into several individual doses, although some patients may require an even higher daily dose.

The PREDOMINANT EFFECTS

As specifically illustrated further herein, the present invention relates to a heterocyclic compound containing beta-amino group and having excellent inhibitory effects on the enzymatic activity of DPP-IV. The pharmaceutical composition containing the specified connection according to the present invention as an active ingredient, has excellent inhibitory activity against DPP-IV and bioavailability, and therefore it may be suitable for the prevention or treatment of various diseases considered to be caused by DPP-IV, such as diabetes and obesity.

Description of the DRAWINGS

Figure 1 shows the correlation between the activity of DPP-IV in the plasma and the dose of the drug, obtained for MK-0431 and compounds of example 1; and

figure 2 shows the results of measuring and comparing the duration of the inhibitory activity of DPP-IV obtained for MK-0431, and compounds of example 1 in laboratory rats.

The METHOD of carrying out the INVENTION

the alley of the present invention is described in more detail using the following examples. These examples are provided only to illustrate the present invention and they should not be construed as limiting the scope and essence of the present invention.

Example 1: obtaining hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-critterfritter]-3-(tert-butoxymethyl)piperazine-2-it

Stage 1: obtaining (R)-methyl-1-trailside-2-carboxylate

200 g of the hydrochloride of the methyl complex ester of D-serine was added to 1.8 l of chloroform, and the reaction solution was cooled to 0°C., and then thereto was slowly added 448 ml of triethylamine. In the reaction mixture was slowly added 358,4 g Fritillaria and then it was stirred for 1 hour. The reaction mixture was heated to room temperature, and thereto was added 1 l of chloroform, and then washed with 2.5 l of water. The organic layer was dried over magnesium sulfate and cooled to 0°C, and then it consistently was slowly added 484 ml of triethylamine and 15.7 g of 4-methylaminopropane. The reaction mixture was stirred for 5 min and to it was slowly added 139 ml sulphonylchloride methane. The reaction mixture was heated to room temperature, stirred for 4 hours and then boiled under reflux for 12 hours. The reaction mixture was cooled to room temperature and washed with 4 l of water, and then 3 l of brine. The organic layer was dried over sulfate MAGN who I am and concentrated to dryness under reduced pressure. To the obtained precipitate was added 3 l of ethanol, and then stirred. The obtained solid substance was filtered with getting 329 g specified in the connection header.

1H NMR (400 MHz, CDCl3): 7,42-7,49 (m, 6H), 7.18 in-7,32 (m, 9H), 7,68 (s, 1H), 3,74 (s, 3H), 2,24 (m, 1H), 1,87 (m, 1H) and 1.40 (m, 1H).

Stage 2: Obtaining (R)-1-benzyl-2-methylaziridine-1,2-in primary forms

328,4 g (R)-methyl-1-trailside-2-carboxylate was dissolved in 1.4 l of chloroform, and the reaction solution was cooled to 0°C., and then thereto was slowly added 462 ml triperoxonane acid. The reaction mixture was stirred for 1 hour, and then thereto was added 2 l of water, and then was stirred for 10 min and removing the organic layer. The aqueous layer neutralize with sodium bicarbonate and used in subsequent reactions without further purification.

To the aqueous layer was added 2 l of diethyl ether 120.5 g of sodium bicarbonate, and the reaction solution was cooled to 0°C, and then it slowly was added dropwise 165 ml benzylchloride. The reaction mixture was stirred for another 2 hours and the aqueous layer was removed. The organic layer was dried over magnesium sulfate, concentrated and dried under reduced pressure, and purified column chromatography, obtaining, thus, to 108.5 g specified in the connection header.

1H NMR (400 MHz, DMSO): to 7.32 and 7.36 (m, 5H), to 5.13 (s, 2H), to 3.09 (DD, J=3,2, a 5.4 Hz, 1H), 2,58 (Shostakovich J=1,2, 3.2 Hz, 1H) and 2,47 (Shostakovich J=1,2, 5.4 Hz, 1H).

Stage 3: obtain methyl ether complex (R)-2-amino-3-tert-butoxypropan

1.1 g of (R)-1-benzyl-2-methylaziridine-1,2-in primary forms was dissolved in 11 ml of chloroform, and then thereto was added 18 ml of tert-butanol. To the reaction mixture slowly was added dropwise 1.2 ml BF3OEt2and then was stirred for 12 hours. The reaction was completed by adding to the reaction mixture of 2 l of water. Then the organic layer was separated and dried over magnesium sulfate, concentrated and dried under reduced pressure, and then used in subsequent reactions without further purification.

The precipitate was dissolved in 10 ml of methanol, and then thereto was added 740 mg of a mixture of palladium/carbon in 2 ml of ethyl acetate, then was barbotirovany hydrogen for 1 hour at an external atmospheric pressure. The reaction mixture was filtered and dried under reduced pressure to obtain 736 mg specified in the connection header.

1H NMR (400 MHz, CD3OD): is 4.21 (m, 1H), 3,82 (s, 3H), 3,74-3,88 (m, 2H) and 1.20 (s, 9H)

Stage 4: obtain methyl ether complex (R)-3-tert-butoxy-2-(2-(tert-butoxycarbonylamino)ethylamino)propionic acid

736 mg of ester methyl (R)-2-amino-3-tert-butoxypropan, obtained in stage 3, was dissolved in 14 ml of dichloromethane and to it was slowly added mg N-tert-butoxycarbonyl-2-aminoacetaldehyde methanol. The reaction mixture was cooled to 0°C. and then slowly added 1.2 ml of triethylamine and 1.78 g of triacetoxyborohydride sodium. The reaction mixture was heated to room temperature and then was stirred for 12 hours. For completion of the reaction was added a saturated solution of sodium bicarbonate and the organic layer was washed with 10 ml water and brine, concentrated and dried under reduced pressure. The obtained residue was purified column chromatography to obtain, therefore, 355 mg specified in the connection header.

1H NMR (400 MHz, CDCl3): 5,10 (m, 1H), 3,71 (s, 3H), of 3.56 (m, 2H), 3,40 (m, 1H), 3.15 and of 3.28 (m, 2H), 2,81 (m, 1H), to 2.67 (m, 1H), of 1.42 (s, 9H) and of 1.13 (s, 9H)

Stage 5: obtain methyl ether complex (R)-2-((benzyloxycarbonyl)(2-tert-butoxycarbonylamino)ethyl)amino)-3-tert-butoxypropyl acid

355 mg of ester methyl (R)-3-tert-butoxy-2-(2-(tert-butoxycarbonylamino)ethylamino)propionic acid obtained in stage 4, was dissolved in 11 ml of tetrahydrofuran, and the reaction mixture was cooled to 0°C., and then thereto was added 187 mg of sodium bicarbonate. To this mixture slowly dropwise added 192 μl of benzylchloride and the reaction mixture was heated to room temperature. After 12 hours the reaction mixture was dried under reduced pressure, and then added 10 ml of ethyl acetate and the organic layer washed with 10 ml of the odes. The organic layer was dried over magnesium sulfate, dried under reduced pressure and was purified column chromatography, obtaining, thus, 410 mg specified in the connection header.

1H NMR (400 MHz, CDCl3): of 7.36-7,25 (m, 5H), of 5.82-5,72 (m, 1H), 5,17-to 5.03 (m, 2H), 4,15 (m, 1H), 3,98 (m, 1H), 3,81 (m, 1H), of 3.73 (s, 3H), of 3.60 (m, 1H), 3,42 of 3.28 (m, 3H), of 1.40 (s, 9H) and 1,l4 (s, 9H).

Step 6: obtaining (R)-benzyl 2-(tert-butoxymethyl)-3-oxopiperidine-1-carboxylate

410 mg of ester methyl (R)-2-((benzyloxycarbonyl)(2-tert-butoxycarbonylamino)ethyl)amino)-3-tert-butoxypropyl acid, obtained in stage 5, was dissolved in 10 ml of methanol and the reaction mixture was cooled to 0°C. and to it was slowly added 4 ml of a mixture of 2-N-chloride-hydrogen acid/diethyl ether, and then was stirred for 3 hours. The reaction mixture was dried under reduced pressure and used in subsequent reactions without further purification.

The precipitate was dissolved in 10 ml dichloromethane and the reaction mixture was cooled to 0°C., and then thereto was slowly added 152 μl of triethylamine. To this mixture was slowly added 1.1 ml of trimethylaluminum (2.0 M solution in toluene)and the reaction mixture was heated to room temperature and then was stirred for 12 hours. The reaction mixture was cooled to 0°C and for the completion of the reaction was added saturated aqueous solution of ammonium chloride. the reaction mixture was added 10 ml of ethyl acetate, and then it was washed with 10 ml brine. The organic layer was dried over magnesium sulfate and dried under reduced pressure. The obtained residue was purified column chromatography to obtain 103 mg specified in the connection header.

1H NMR (400 MHz, CDCl3): 7,34-7,25 (m, 5H), 6,27 (m, 1H), 5,14 (m, 2H), 4,57 (m, 1H), 4,19 (m, 1H), 4,08 (m, 1H), 3,94 (m, 1H), 3,74 (m, 1H), to 3.64 (m, 1H), 3,42 (m, 1H), 3,29 (m, 1H) and 1.09 (s, 9H)

Step 7: obtain (R)-(3-tert-butoxymethyl)piperazine-2-it

103 mg (R)-benzyl-2-(tert-butoxymethyl)-3-oxopiperidine-1-carboxylate, obtained in stage 6, was dissolved in 2 ml of methanol and then thereto was added 50 mg of a mixture of palladium/carbon in 1 ml of ethyl acetate, and then was barbotirovany hydrogen for 1 hour at normal atmospheric pressure. The reaction mixture was filtered and dried under reduced pressure to obtain 58 mg specified in the connection header.

1H NMR (400 MHz, CDCl3): 6,41 (Sirs, 1H), 3,76 (m, 3H), 3,63 (m, 1H), 3,52 (m, 1H), 3,42 (m, 1H), or 3.28 (m, 1H), and 3.16 (m, 1H), 2.95 and (m, 1H), 2,45 (Sirs, 1H) and at 1.17 (s, 9H).

Step 8: obtain tert-butyl(R)-4-[(R)-2-(tert-butoxymethyl)-3-oxopiperidin-1-yl]-4-oxo-1-(2,4,5-tryptophanyl)butane-2-ylcarbamate

104 mg of (3R)-tert-butoxycarbonylamino-4-(2,4,5-tryptophanyl)butane acid and 58 mg of (R)-(3-tert-butoxymethyl)piperazine-2-it was added to 4 ml of N,N-dimethylformamide, and then thereto was added 63 mg of 1-hydroxybenzotriazole (HOBT) and 217 μl of diiso is propylethylene. The reaction mixture was cooled to 0°C. and to it was added 78 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and then stirred at room temperature for 12 hours. The reaction mixture was diluted with 10 ml ethyl acetate and washed twice with brine. The organic layer was dried over magnesium sulfate and concentrated. The obtained residue was purified column chromatography to obtain 97 mg specified in the connection header.

1H NMR (400 MHz, CDCl3): 7,03 (m, 1H), to 6.88 (m, 1H), 5,97 (m, 1H), 5,48 (m, 1H), 4,16-4,07 (m, 1H), was 4.02-3,91 (m, 1H), 3,74 (m, 2H), 3,37 (m, 2H), 3,24 (m, 1H), 2,92 (m, 2H), 2,80 (m, 1H), 2,59 (m, 2H), 1,34 (d, 9H) and 1,13 (, 9H)

Step 9: obtaining hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

97 mg of tert-butyl(R)-4-[(R)-2-(tert-butoxymethyl)-3-oxopiperidin-1-yl]-4-oxo-1-(2,4,5-tryptophanyl)butane-2-ylcarbamate obtained at stage 8, was dissolved in 3 ml of methanol, and then added 2 ml of a mixture of 2N chloride-hydrogen acid/diethyl ether and stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to obtain 64 mg specified in the connection header in the form of a foamy solid.

1H NMR (400 MHz, CD3OD): 7,37 (m, 1H), 7.23 percent (m, 1H), 4,80 (m, 1H), 4,59-and 4.40 (m, 1H), 3,93 (m, 1H), 3,90-a 3.83 (m, 2H), 3,70 (m, 1H), 3,38 (m, 2H), 3.27 to (m, 1H), of 3.07 (m, 2H), 2,89-of 2.66 (m, 2H), 1,18 (s, 3H), and a 1.11 (s, 6H)

Mss (M+1): 402

Example 2: obtain the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(methoxymethyl)piperazine-2-it

Instead of tert-butanol stage 3 of example 1 was used methanol, and then synthesized 40 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,34 (m, 1H), 7.23 percent (m, 1H), 4,82 (m, 1H), 4,62-to 4.46 (m, 1H), 3,92 (m, 1H), a 3.87-3,82 (m, 2H), 3,66 (m, 1H), 3,35 (m, 2H), 3,24 (m, 1H), 3.04 from (m, 2H), 2,94-of 2.72 (m, 2H) 3.27 (s, 3H)

Mass (M+1): 360

Example 3: obtaining hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(ethoxymethyl)piperazine-2-it

Instead of tert-butanol stage 3 of example 1 was used ethanol, and then synthesized 66 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,38 (m, 1H), 7.23 percent (m, 1H), a 4.83 (m, 1H), 4,54-of 4.44 (m, 1H), 3,98 (m, 1H), 3,93-3,82 (m, 2H), 3,71 (m, 1H), 3,53 (m, 2H), 3,36 (m, 2H), 3,26 (m, 1H), of 3.07 (m, 2H), 2,90-2,70 (m, 2H) and a 1.11 (t, 3H)

Mass (M+1): 374

Example 4: obtaining hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(isopropoxyphenyl)piperazine-2-it

Instead of tert-butanol stage 3 of example 1 was used isopropanol, and synthesized 69 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,38 (m, 1H), 7.23 percent (m, 1H), a 4.86 (m, 1H), 4,62-4,43 (m, 1H), 3.96 points (m, 1H), 3,90-a 3.87 (m, 2H), of 3.77 (m, 1H), 3,69 (m, 1H), 3,44 (m, 2H), 3,26 (m, 1H), is 3.08 (m, 2H), 2.95 and-2,69 (m, 2H), and 1.15(m, 6H)

Mass (M+1): 388

Example 5: receiving hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(cyclopentylacetyl)piperazine-2-it

Instead of tert-butanol stage 3 of example 1 was used Cyclopentanol, and synthesized 51 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,38 (m, 1H), 7.23 percent (m, 1H), 4,82 (m, 1H), br4.61 was 4.42 (m, 1H), 3,93 (m, 1H), 3,90-3,82 (m, 2H), to 3.67 (m, 1H), 3,40 (m, 1H), 3,36 (m, 2H), 3,25 (m, 1H), is 3.08 (m, 2H), 3,01-2,62 (m, 2H) and 1.67-1,50 (m, 8H)

Mass (M+1): 414

Example 6: obtain the dihydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(diethylamino)methyl]piperazine-2-it

Instead of tert-butanol was added diethylamine and instead of adding BF3OEt2were boiled under reflux in stage 3 of example 1, and synthesized 68 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,41 (m, 1H), 7,24 (m, 1H), total of 5.21 (m, 1H), 3,59-of 3.53 (m, 2H), 3,53-to 3.50 (m, 4H), 3,43-3,37 (m, 4H), to 3.35 (m, 2H), to 3.09 (m, 2H), 2,97-of 2.81 (m, 2H) and of 1.37 (m, 6H)

Mass (M+1): 401

Example 7: getting dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanon-3-[(ethylmethylamino)methyl]piperazine-2-it

Instead of tert-butanol was added ethylmethylamine and instead of adding BF3OEt2were boiled under reflux in stage 3 of example 1, and then synthesized 67 mg ukazannoj the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,42 (m, 1H), 7,24 (m, 1H), 5,22 (m, 1H), 4,08-a 3.87 (m, 2H), 3,86 of 3.75 (m, 2H), 3,68 is 3.57 (m, 2H), 3,56-to 3.33 (m, 4H), to 3.09 (m, 2H), 3,02-of 2.81 (m, 5H), and 1.38 (m, 3H)

Mass (M+1): 387

Example 8: getting dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(morpholinomethyl)piperazine-2-it

Instead of tert-butanol was added morpholine and instead of adding BF3OEt2were boiled under reflux in stage 3 of example 1, and then synthesized 27 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,37 (m, 1H), 7.23 percent (m, 1H), 5,32 (m, 1H), 4,12-3,98 (m, 4H), 3,97-of 3.77 (m, 4H), 3,74-to 3.52 (m, 4H), 3,48-3,39 (m, 2H), 3,14-only 2.91 (m, 4H) and 2.86-of 2.72 (m, 2H)

Mass (M+1): 415

Example 9: obtaining hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butylthioethyl)piperazine-2-it

Instead of tert-butanol was used tert-butylthio in stage 3 of example 1, and then synthesized 25 mg specified in the header connection similar stages 4 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,34 (m, 1H), 7,25 (m, 1H), 5,04 (m, 1H), 4,60 (s, 1H), 4,60-to 4.41 (m, 1H), 3,86 (m, 2H), 3,70 (m, 1H), 3,40 (m, 2H), 3,25 (m, 1H), 3,05 (m, 2H), 2.95 and (m, 1H), 2,81 (m, 2H), and 1.26 (s, 9H)

Mass (M+1): 418

Example 10: Obtaining hydrochloride (S)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

Instead of hydrochloride of the methyl complex ester of D-serine used hydrochlorid methyl ether complex of L-serine in stage 1 of example 1, and then synthesized 31 mg specified in the connection header is similar to the stages 2 through 9 of example 1.

1H NMR (400 MHz, CD3OD): 7,34 (m, 1H), 7,24 (m, 1H), 4,79 (m, 1H), 4,580-and 4.40 (m, 1H), 3.96 points (m, 1H), 3,86-3,74 (m, 2H), 3,70 (m, 1H), 3,36 (m, 2H), 3,19 (m, 1H), 3,05-of 2.86 (m, 3H), to 2.67 (m, 1H)and 1.15 (s, 4H) and 1.03 (s, 5H)

Mass (M+1): 402

Example 11: obtain (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

60 mg of the compound obtained in example 1, was added to 10 ml of 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with twice 10 ml of a mixed solution of dichloromethane/2-propanol (4/1 (about./vol.)). The organic layer was dried under reduced pressure to obtain 55 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,27 (m, 1H), 7,14 (m, 1H), 4,56-4,39 (m, 1H), 3.96 points-3,81 (m, 3H), 3,70 (m, 1H), 3.46 in (m, 1H), 3.43 points-of 3.32 (m, 1H), 2,83-to 2.65 (m, 3H), 2,58-to 2.40 (m, 2H), 1,16 (s, 3H) and a 1.11 (s, 6H)

Mass (M+1): 402

Example 12: getting tartrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

55 mg of the compound obtained in example 11, was dissolved 0.56 ml of acetone and then thereto was slowly added a solution of 26 mg of L-tartaric acid of 0.35 ml of a mixture of ethanol/water (9/1 (about./vol.), and then was stirred for 30 minutes To this mixture was added to 0.56 ml of 2-propanol, and then was stirred for 10 min and filtered to obtain 77 mg specified in the agolove connection in the form of solids.

1H NMR (400 MHz, CD3OD): 7,38 (m, 1H), 7,22 (m, 1H), 4,80 (m, 1H), 4,59-and 4.40 (m, 1H), and 4.40 (s, 2H), 3,93 (m, 1H), 3,90-a 3.83 (m, 2H), 3,70 (m, 1H), 3,38 (m, 2H), 3.27 to (m, 1H), of 3.07 (m, 2H), 2,89-of 2.66 (m, 2H)and 1.15 (s, 3H) and a 1.11 (s, 6H)

Mass (M+1): 402

Example 13: getting citrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

496 mg of the compound obtained in example 11, was dissolved in 2 ml of ethanol and then thereto was slowly added a solution of 273 mg of anhydrous citric acid in 1 ml of water, and then was stirred for 30 minutes, the Reaction mixture was concentrated and then thereto was added 2 ml of ethyl acetate and 1 ml of 2-propanol with stirring. To this mixture was added 15 ml of hexane, and then was stirred for 10 min and filtered with getting 637 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,34 (m, 1H), 7,22 (m, 1H), to 4.81 (m, 1H), 4,58-and 4.40 (m, 1H), 3,94 (m, 1H), a 3.87 (m, 2H), 3,70 (m, 1H), 3,36 (m, 2H), 3,25 (m, 1H), 3,03 (m, 2H), 2,94-2,70 (m, 4H), of 1.18 (s, 3H) and 1.12 (s, 6H)

Mass (M+1): 402

Example 14: receiving phosphate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

501 mg of the compound obtained in example 11, was dissolved in 3 ml of 2-propanol and then thereto was slowly added 84 ál of 85% aqueous phosphoric acid under stirring for 30 minutes were added 3 ml of 2-propanol, and the resulting mixture was stirred for 10 min was filtrowanie with receiving 100 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,33 (m, 1H), 7,19 (m, 1H), to 4.81 (m, 1H), 4,58-to 4.41 (m, 1H), 3,94 (m, 1H), 3,85 (m, 2H), 3,65 (m, 1H), 3,37 (m, 2H), up 3.22 (m, 1H), 2.95 and (m, 2H), 2,69 (m, 2H), 1,17 (s, 3H), and 1.12 (s, 6H)

Mass (M+1): 402

Example 15: getting acetate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

500 mg of the compound obtained in example 11, was dissolved in 3 ml of ethyl acetate and thereto was slowly added a solution of 74.5 mg of acetic acid in 1 ml of ethyl acetate, and then was stirred for 30 minutes, the Reaction mixture was concentrated and then thereto was added 2 ml of ethyl acetate and 1 ml of 2-propanol, and then stirred. To this mixture was added 15 ml of hexane, and the resulting mixture was stirred for 10 min and filtered to obtain 495 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,32 (m, 1H), 7,20 (m, 1H), 4,79 (m, 1H), 4,60-and 4.40 (m, 1H), 3,94 (m, 1H), a 3.87 (m, 2H), 3,70 (m, 1H), 3,34 (m, 2H), 3,24 (m, 1H), 2,90 (m, 2H), was 2.76-of 2.58 (m, 2H), was 1.94 (s, 3H), of 1.17 (s, 3H) and 1.12 (s, 6H)

Mass (M+1): 402

Example 16: getting malate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

498 mg of the compound obtained in example 11, was dissolved in 4 ml acetone and thereto was slowly added a solution of 166 mg of L-malic acid in 1 ml of acetone, and then was stirred for 30 minutes, the Reaction mixture was concentrated and then thereto was added 2 ml of ethyl acetate and 1 ml propanol, and then stirred. To this mixture was added 15 ml of hexane, and the resulting mixture was stirred for 10 min and filtered with getting 506 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,34 (m, 1H), 7,21 (m, 1H), 4,80 (m, 1H), 4,58-4,39 (m, 1H), 4.26 deaths (m, 1H), 3,94 (m, 1H), 3,84 (m, 2H), 3,71 (m, 1H), 3,36 (m, 2H), up 3.22 (m, 1H), to 3.02 (m, 2H), 2.82 from 2.63 in (m, 3H), of 2.50 (m, 1H), 1,17 (s, 3H) and 1.12 (s, 6H)

Mass (M+1): 402

Example 17: getting succinate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

498 mg of the compound obtained in example 11, was dissolved in 3 ml of acetone and then thereto was slowly added a solution of 147 mg of succinic acid in 2 ml of a mixture of acetone/water (20/1 (about./vol.), and then was stirred for 30 minutes, the Reaction mixture was concentrated to dryness under reduced pressure to obtain 596 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,34 (m, 1H), 7,21 (m, 1H), to 4.81 (m, 1H), 4,58-and 4.40 (m, 1H), 3,95 (m, 1H), 3,85 (m, 2H), 3,70 (m, 1H), 3,36 (m, 2H), 3,25 (m, 1H), 2,92 (m, 2H), 2,81-of 2.64 (m, 2H), of 2.51 (s, 4H), of 1.18 (s, 3H) and 1.12 (s, 6H)

Mass (M+1): 402

Example 18: Getting adipate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it

503 mg of the compound obtained in example 11, was dissolved in 4 ml of ethyl acetate and then thereto was slowly added a solution of 183 mg of adipic acid in 3 ml of a mixture of Aceto the/water (30/1 (about./vol.), and then was stirred for 30 minutes, the Reaction mixture was concentrated and thereto was added 2 ml of ethyl acetate and 1 ml of 2-propanol, and then stirred. To this mixture was added 15 ml of hexane, and the resulting mixture was stirred for 10 min and filtered to obtain 336 mg specified in the connection header in the form of solids.

1H NMR (400 MHz, CD3OD): 7,32 (m, 1H), 7,19 (m, 1H), 4,80 (m, 1H), 4,56-and 4.40 (m, 1H), 3,94 (m, 1H), a 3.87 (m, 2H), 3,70 (m, 1H), 3,35 (m, 2H), 3,25 (m, 1H), 2,92 (m, 2H), 2,83-of 2.58 (m, 2H, in), 2.25 (m, 4H), and 1.63 (m, 4H), 1,21 (s, 3H) and 1.12 (s, 6H)

Mass (M+1): 402

Experimental example 1: analysis of the inhibitory activity of DPP-IV

To study the inhibitory ability of DPP-IV compounds of formula 1 according to the invention obtained in examples 1-18, conducted the following experiments.

DPP-IV, known as serine protease was purchased from R & D Systems. MK-0431 as control received in accordance with the method described in J. Med. Chem., 2005, 48, 141-151. For the evaluation of drug efficacy of compounds of formula 1 according to the invention was measured binding activity of synthetic inhibitors of DPP-IV using fluorogenic substrate Gly-Pro-AMC. The enzymatic reaction was carried out at 25°C in a buffer solution containing 25 mm Tris/HCl (pH 8.0) with 50 μm Gly-Pro-AMC relative to 100 ng/ml DPP-IV with different concentrations of inhibitor. IC50that is the fight the inhibition constant for inhibitor, was obtained by measuring fluorescence spectrophotometer after the enzymatic reaction for 1 hour with subsequent calculation of the concentration of inhibitor required to inhibit the enzymatic reaction DPP-IV by 50%. The spectrophotometer was a spectrophotometer Tecan SpectraFluor with wavelength excitation 360 nm and the wavelength of emission of 465 nm. In the IC50measured as the ability of the compounds of formula 1 can inhibit the activity of DPP-IV, was in the range of from 0.5 to 20 nm (table 1: inhibitory activity against DPP-IV manin vitro). From this result, we can see that the connection according to the invention of formula 1 has excellent inhibitory activity against DPP-IV, in comparison with the value of the IC50described for commercially available or generally accepted JANUVIA inhibiting DPP-IV compounds (in the range from several hundred nm to several thousand nm).

Table 1
Example No.IC50(nm)
MK-043128,3
Example 10,72
Example 27,4
Example 32,2
Example 44,3
Example 51,7
Example 611,0
Example 717,4
Example 85,2
Example 91,3
Example 1048,7
Example 110,8
Example 121,05
Example 130,81
Example 140,92
Example 150,87
Example 160,73
Example 171,2
Example 180,71

Experimental example 2: oral test glucose tolerance (OGTT)

For research antidiabetic effects of a pharmaceutical composition containing as ActionEvent connection according to the invention of formula 1, conducted oral test glucose tolerance (OGTT), by which measure the body's ability to metabolize glucose during this period of time.

For this purpose laboratory animals (mice C57BL/6) were subjected to fasting for 16 to 17 hours before experiments. Blood was collected from tail veins of the animals in the morning on the day of the experiment and measured the level of glucose in blood using Accu-Chek Active Blood Glucose Meter (Roche Diagnostics). Pharmaceutical composition with a carrier is administered orally 30 min before the injection of glucose (-30 min), and then orally injected with a glucose solution (2 g/kg/10 ml) over 30 min (0 min). The blood collection was performed within a specified time - just before the introduction of the medicinal product, just before the introduction of glucose and after 5, 15, 30, 60 and 90 min after administration of glucose.

In the examples 1, 3 and 12 had the highest effects of reducing blood glucose, constituting 54%, 52% and 62%, respectively, at a dose of 1 mg/kg, compared with the control group (without introducing a composition with a carrier). From these results we can see that the connection according to the invention of formula 1 may be appropriate for treatment associated with DPP-IV diseases, including diabetes and obesity, due to its high bioavailability.

Experimental example 3: pharmacokinetic/pharmacodynamic who correlate inhibitor of DPP-IV activity of DPP-IV in the plasma relative to the dose of the drug)

To identify the antidiabetic effects of the compounds according to the invention of formula 1 comparative evaluation of inhibitory activity against DPP-IV between the compounds according to the invention and MK-0431. Mice aged 8 weeks C57BL6 oral was administered MK-0431 and the connection according to the invention (the compound of example 1) in individual doses, and then injected glucose in a dose of 2 g/kg over 1 hour. After 10 min, the blood was collected through the eyes of animals. The collected blood was obtained blood plasma and measured the activity of DPP-IV in plasma and the concentration of drug in plasma.

The activity of DPP-IV in plasma was determined by measuring the amount of fluorescent AMC (7-amino-4-methylcoumarin), released under the action of DPP-IV when used as a substrate Gly-Pro-AMC (Bachem, Switzerland). For this purpose, to the reaction solution were added 50 μl of plasma (100 mm HEPES, pH of 7.6, 0.1 mg/ml, 50 μm Gly-Pro-AMC) and calculated the rate of release of AMC at 25°C for 5 minutes

As a result, the compound of formula 1 (example 1) had 4 to 5 times higher inhibitory activity in plasma concentration of 10 ng/ml and 8 to 9 times higher than EC50(50% effective concentration) and EC80(80% effective concentration), compared to MK-0431 (see figure 1).

Experimental example 4: analysis of DPP-IVin vivo(the duration of the inhibitory activity against DP IV)

For research antidiabetic effects of the compounds according to the invention of formula 1 comparative evaluation of inhibitory activity against DPP-IV in plasma and its duration between MK-0431 and connection according to the invention (example 1), after the introduction of drug compounds with the normal SD rats.

For this purpose laboratory animals (rats SD) were subjected to fasting for 16 to 17 hours before experiments. On the day of the experiment the hungry animals was performed under anesthesia with ether, and then kanalirovanie abdominal aorta. Then MK-0431 and the connection according to the invention (example 1) was diluted to 0.5% MC and introduced animals. Before the introduction of drugs (0 h) and after the indicated periods of time after administration of medicines blood was collected in pre-prepared 500-µl heparinized tubes and separated plasma. In each reaction solution were added 50 μl of plasma (0.1 M HEPES, pH of 7.6, 0.1 mg/ml, 50 μm Gly-Pro-AMC) and conducted a study of the kinetics for 5 min to calculate the reaction rate.

In the result, it was revealed that the compound according to the invention at a dose of 10 mg/kg save 90% or more inhibitory activity against DPP-IV up to 24 hours after administration, which is significantly higher activity considering the fact that MK-0431 retained only 50% of inhibitory activity in related and DPP-IV after the same period, of 24 hours (see figure 2).

Experimental example 5: kinetic experimentsin vivo

To measure the half-life ofin vivocompounds according to the invention of formula 1 normal SD rats (aged 8 weeks) oral was administered MK-0431 and the connection according to the invention (examples 1, 3 and 12) at a dose of 10 mg/kg. conducted periodic sampling of blood from the femoral aorta and measured retention time of the parent compoundin vivo. As a result, the connection according to the invention had a higher half-life ofin vivo(T1/2) relative to the half-life of MK-0431.

Table 1
Example 1Example 3Example 12MK-0431
T1/2 (hour)7,97,65,54,8

INDUSTRIAL APPLICABILITY

As apparent from the above description, the present invention provides products of heterocyclic compounds containing beta-amino group, which has an excellent inhibitory effects on the activity of DPP-IV. In addition, the pharmaceutical composition is tereasa the connection specified by the present invention as an active ingredient, has excellent inhibitory activity against DPP-IV and bioavailability, and therefore it may be suitable for the prevention or treatment of various diseases considered to be caused by DPP-IV, such as diabetes and obesity.

1. The compound represented by formula 1

where X represents OR1, SRI or NR1R2, where R1 and R2 independently represents a C1-C5lower alkyl, and R1 and R2 in NR1R2 may form a 5-7-membered ring that includes a heteroatom About; or a stereoisomer, pharmaceutically acceptable salt, hydrate or MES.

2. The compound according to claim 1, where the compound represented by formula 2

where X is as defined in claim 1, or a stereoisomer, pharmaceutically acceptable salt, hydrate or MES.

3. The compound according to claim 1, where the compound is selected from the group consisting of:
1) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(methoxymethyl)piperazine-2-it;
2) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(ethoxymethyl)piperazine-2-it;
3) of the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(isopropoxyphenyl)piperazine-2-it;
4) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
5) of the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(cyclopentyloxy is methyl)piperazine-2-it;
6) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(diethylamino)methyl]piperazine-2-it;
7) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(ethylmethylamino)methyl]piperazine-2-it;
8) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(morpholinomethyl)piperazine-2-it;
9) of the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butylthioethyl)piperazine-2-it;
10) hydrochloride (S)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
11) (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-he;
12) tartrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
13) citrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
14) phosphate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
15) acetate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
16) malate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
17) succinate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it
18) adipate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it.

4. The method of obtaining the compound represented by formula 2 according to claim 2, including:
1) the reaction of the joint is of the formula 3, having beta-amino group substituted with a heterocyclic compound of the formula 4 in the presence of 1-hydroxybenzotriazole (NOVT), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the tertiary amine with obtaining thus the compounds of formula 5, and
2) treatment of compounds of formula 5 obtained in stage (1), acid to obtain the compounds of formula 2



where X represents OR1, SR1, or NR1R2, where R1 and R2 independently represents a C1-C5lower alkyl, and R1 and R2 in NR1R2 may form a 5-7-membered ring that includes a heteroatom O.

5. Pharmaceutical composition for the prevention and treatment of diabetes or obesity, containing a compound according to claim 1, represented by formula 1, or a stereoisomer, pharmaceutically acceptable salt, hydrate or MES as an active ingredient.

6. The composition according to claim 5, where the compound is selected from the group consisting of:
1) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
2) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(ethoxymethyl)piperazine-2-it;
3) of the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(isopropoxyphenyl)piperazine-2-it;
4) hydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butano the]-3-(methoxymethyl)piperazine-2-it;
5) of the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(cyclopentylacetyl)piperazine-2-it;
6) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(diethylamino)methyl]piperazine-2-it;
7) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-[(ethylmethylamino)methyl]piperazine-2-it;
8) dihydrochloride (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(morpholinomethyl)piperazine-2-it;
9) of the hydrochloride of (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butylthioethyl)piperazine-2-it;
10) hydrochloride (S)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
11) (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-he;
12) tartrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
13) citrate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
14) phosphate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
15) acetate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
16) malate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it;
17) succinate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it
18) adipate (R)-4-[(R)-3-amino-4-(2,4,5-tryptophanyl)butanoyl]-3-(tert-butoxymethyl)piperazine-2-it.

7. Method of prevention and treatment of diabetes or obesity, comprising introducing an effective amount of a composition containing the compound according to any one of claims 1 to 3, to a mammal in need of it.

8. The use of pharmaceutical compositions containing a compound according to any one of claims 1 to 3, to obtain drugs for prevention and treatment of diabetes or obesity.

9. The method according to claim 4, where PG denotes the Sun.

10. The compound represented by formula 4, is designed to obtain the compounds of formula 2 according to claim 2

where X is OR1, SR1, or NR1R2, where R1 and R2 independently represent a1-C5lower alkyl, and R1 and R2 in NR1R2 may form a 5-7-membered ring that includes a heteroatom O.

11. The connection of claim 10, where X is chosen from the group consisting of tert-butoxy, methoxy, ethoxy, isopropoxy, cyclopentyloxy, diethylamino, ethylmethylamino, morpholino and tert-butylthio.

12. The connection of claim 10, where X is tert-butoxy.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of 3-cyanonaphthalene-1-carboxylic acid and perhydroxyalkylmethylpiperazine of formula

, where R1 means C1-C4alkyl, R2 and R3 mean halogen, R4 is selected from the group consisting of 2-furanyl, 3-furanyl, 2-thiophen, 3-thiophen, phenyl, benzyl, 2-benzofuranyl, etc., R5 is selected from the group consisting of hydrogen and R6, R6 means a subgroup of general formula

which are antagonists of tachykinin receptors. Also, there are described pharmaceutical compositions containing such compounds, and methods for making such compounds and intermediate products for making the compounds according to said methods.

EFFECT: preparation of new compounds.

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new derivatives of benzo {b} {1, 4} dioxepin formulas (I) where B, X, Y, Z, R1 and R2 accept the value specified in the description of the invention, and also them pharmaceutically comprehensible salts.

EFFECT: pharmaceutical compositions containing these bonds, are applied to treatment and/or preventive maintenance of the diseases modulated by the ACCβ inhibitors.

20 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula (I) , and their salts used in pharmacology, and their hydra as well as others, where W represents or and R3, R7, R16, R17, R20, R21 and R21 are identical or different and each of them represents a hydrogen atom or assumes other values, given in the formula of invention. The invention also relates to pharmaceutical compositions and medicinal preparations based on these compounds, cultures, used for obtaining them, methods of inhibition and treatment and use.

EFFECT: formula (I) can be used as medicinal preparations for curing solid malignant tumours.

43 cl, 4 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds with formula , where R, selected from H, SiR'3, SOR', SO2R', C(=O)R' or not necessarily substituted C1-C6alkyl; R' is selected from the C1-C6alkyl group; R" is selected from CH2OR, C1-C6alkyl, C1-C6halogenalkyl, C2-C6alkenyl or C1-C6alkylidene; substitutes are the alkoxigroup. The invention also relates to the compounds with the formula , , , , where R1, R2, R4 and R6 are selected from PMB, benzyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 2,6-dichlorbenzyl, 3,4-dichlorbenzyl, TBS, TES, TBDPS, TIPS and TMS; R5 is selected from OR', N(R')2, N(R')(C1-C4alkoxi); and -R' is selected from C1-C6alkyl and C7-C10aralkyl, L is the stereospecific leaving group. The method for synthesis of the compound with formula 5 is invented, which includes removal of the protective groups from the precursor's hydroxyl groups. The methods for producing the compounds with the formulas 14 and 26 are invented, which include the precursor's tailing by interacting with CH3C(O)R5, where R5 is the group selected from OR', N(R')2, N(R')(C1-C4alkoxi); and R' is C1-C6alkyl and C7-C10aralkyl. The method for producing the compounds with the formulas 19 and 30 , which include the precursor's tailing by interacting with ethylmagnesiumbromide. The pharmaceutical composition based on the compound with the formula I with the cytotoxic activity is invented.

EFFECT: production of pharmaceutical agent for tumor treatment is available.

47 cl, 1 tbl, 93 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 1-[1-(hetero)aryl-1-perhydroxyalkylmethyl]piperazine compounds of the general formula (I): wherein A means naphthyl, phenyl optionally substituted with methoxy-group, heteroaryl chosen from group comprising thienyl, furyl, indolyl or (C3-C6)-alkenyl optionally substituted with phenyl; Z means subgroup of the general formula: wherein k, l, m and n mean 0 or 1; R6 and R7 mean halogen atom, and to their physiologically acceptable acid-additive salt. Compounds possess antagonistic activity with respect to tachykinin receptors and can be used in treatment of digestive tract functional and inflammatory disorders. Also, invention describes a method for synthesis of proposed compounds and intermediate substances used in realization of this method, and medicinal agents containing indicated compounds.

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

9 cl, 3 tbl, 40 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

The invention relates to derivatives of 1-(N-phenyliminomethyl)piperazine of the formula I, where R is H, alkyl -, cycloalkyl-substituted cycloalkyl-WITH or monocyclic heteroaryl-CO; R1Is h or lower alkyl; R2- halogen, alkoxy, phenoxy, NO2, CN, acyl, NH2, NH(acyl), alkyl-SO2NH, alkoxycarbonyl, NH2WITH, (alkyl)NHCO (alkyl)2NCO, (acyl)NHCO, CF3or polyporaceae; benzyl or mono - or bicyclic aryl, or heteroaryl, all of which are optionally substituted

FIELD: medicine.

SUBSTANCE: invention relates to novel compounds of formula or to its pharmaceutically acceptable salts, where n is 0 or 1; R1 represents H or F; R2 represents C1-4alkyl; R7 represents H or C1-4alkyl; and Z represents hydroxyl C1-6alkyl or C1-6alkoxycarbonyl, or 5- or 6-member heteroaromatic ring, which belongs to aromatic rings which have given number of atoms, of which at least one is N, O or S, the remaining being carbon atoms, and which also optionally has methyl substituting group. Invention also relates to pharmaceutical composition, to application of compounds, as well as to method of obtaining formula I compounds.

EFFECT: obtaining novel biologically active compounds, possessing activity of receptor 5-HT2A antagonists.

9 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted diketopiperazines of the general formula (I) or their physiologically acceptable salts wherein R1 means 5-membered cycloalkyl group optionally substituted with one or some hydroxyl groups that is condensed with optionally substituted benzene ring; R2 means (C1-C6)-alkyl; R3 means optionally substituted phenyl, 5- or 6-membered heteroaryl group, or condensed bicyclic ring system comprising 9-10 ring members; R4 means -OH, -O-(C1-C4)-alkyl or -NR5R6. Compounds possess antagonistic effect with respect to oxytocin in oxytocin receptors. Also, invention describes a pharmaceutical composition based on compound of the formula (I), using compounds of the formula (I) for preparing a medicinal agent and methods for synthesis of compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 227 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention relates to derivatives of arylamidine or its salts of the general formula (I): wherein X represents unsubstituted lower alkylene or alkenylene group or that substituted with hydroxy-group, alkyl or alkoxy-group; G1 represents oxygen atom, sulfur atom or imino-group; G2 represents carbon atom or nitrogen atom; Ra represents hydrogen atom, halogen atom and alkyl or alkoxy-group; R1 represents unprotected or protected amidino-group or unsubstituted amidino-group or that substituted with hydroxy-group or alkyl; R2 represents amino-substituted or substituted cyclic amino-group. Proposed compound possess the antifungal effect and high safety.

EFFECT: valuable biological properties of compounds.

10 cl, 14 tbl, 164 ex

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

SUBSTANCE: invention relates to using hydroxylamine esters for decreasing molecular mass of polypropylene, propylene copolymers or polypropylene mixtures. Method involves addition to propylene polymers subjected for destruction at least one hydroxylamine ester chosen from group including compound of the formula (IA): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; R'1, R'2 and R'3 mean independently of one another hydrogen atom or methyl group; G means aliphatic carboxylic acid acyl-acyl radical comprising from 1 to 18 carbon atoms or aromatic carboxylic acid acyl-acyl radical comprising from 7 to 18 carbon atoms of the formula (IB): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; each R'1, R'2 and R'3 means independently of one another hydrogen atom or methyl group; G1 means hydrogen atom, (C2-C18)-alkanoyl; G2 means hydrogen atom, (C1-C8)-alkyl, aliphatic carboxylic acid acyl-acyl radical comprising from 1 to 18 carbon atoms of the formula (IC): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; each R'1, R'2 and R'3 means independently of one another hydrogen atom or methyl group; G means (C2-C8)-alkylene, (C4-C22)-acyloxyalkylene or aliphatic carboxylic acid acyl radical comprising from 1 to 18 carbon atoms and this mixture is heated to temperature below 280°C. Addition of hydroxylamine esters results to increasing the destruction degree of used polypropylene polymer that is reflected by the melt efflux velocity value in comparison with this index of the parent polymer.

EFFECT: improved method for molecular mass decreasing.

3 cl, 15 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 new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

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

The invention relates to new compounds of the formula I

Y-(CmH2m-CHR1)n-CO- (NH-CHR2CO)r-Z

where Y denotes

< / BR>
or

< / BR>
Z denotes

< / BR>
or if Y

< / BR>
also means

< / BR>
R1, R2and R7each means-CtH2t-R9,

R3means H or H2N-C(=NH)-,

R4and R6each means (H,H) or =O,

R5means H2N-C(=NH) -, or H2N-C(=NH)-NH,

R8means OH or OA,

R9denotes H or COOH,

A denotes alkyl with 1-4 C-atoms,

m and t each is 0, 1 or 2,

n and r each denotes 0 or 1 and

p is 0, 1 or 2,

and their salts

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention aims at a pharmaceutical composition in the form of a clear solution or a water mixture, a suspension or a semisolid composition containing at least one peptide compound of water solubility more than 1 mg/ml at room temperature and pH value within 4.0 to 6.0 selected from the group consisting of hGLP-1 (7-36)-NH2, as well as its analogues and derivatives, hGLP-1 (7-37)-OH, as well as its analogues and derivatives and/or exendin-4, as well as its analogues and derivatives, zinc and a solvent where less than 95 % of said peptide compound are dissolved by the solvent.

EFFECT: invention provides a long-term effect of the preparation with lower initial plasma concentrations.

20 cl, 1 dwg

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