Derivative of 2-cyano-4-fluoropyrrolidine and its salt

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

 

The technical FIELD

The present invention relates to a new derivative of 2-cyano-4-terpinolene or its salt, which can be used as a medicine, particularly as an inhibitor of dipeptidylpeptidase-IV (referred to hereinafter, "DPP-IV"), and to pharmaceutical compositions containing this compound as an active ingredient.

BACKGROUND of the INVENTION

The dipeptidyl peptidase-IV (DPP-IV) is a serine protease that recognizes and cuts the sequence with Proline, hydroxyprolin or alanine in the second position with its N-Terminus (H-Xaa-Pro, H-Xaa-Hyp or H-Xaa-Ala, where XAA will boobsnaked amino acid). It is known that DPP-IV is widely represented in the human body, not only in the tissues of the kidneys, liver and salivary glands, but also in body fluids such as serum, urine and saliva. Although its physiological role is to date not fully clarified, DPP-IV may participate in the regulation of biological functions, because it it various physiologically active peptides (non-patent reference 1). In particular, the currently highlighted that DPP-IV can control the activity of the hormone incretin, which is involved in the inhibition of the increase in blood glucose.

Incretin is a hormone that is secreted in the human intestine after a meal,and it affects β -cells of the pancreas, increasing insulin secretion, thus regulating the level of glucose in the blood. It is known that the activity of incretin weakened in patients with type 2 diabetes (non-patent reference 2), and it is considered that the weakening of activity may be one of the reasons for the manifestation of diabetes. Accordingly, this suggests that hyperglycemia after meals in diabetics may increase.

Peptide similar to glucagon (hereinafter referred to as "GLP-1"), currently known as the compound which has the most effective incrediboy activity in humans. GLP-1 after secretion into the blood immediately inactivated, and it is known that this inactivation is mainly due to the actions of DPP-IV, which it splits (non-patent reference 3). Further, vaccine, GLP-1, split DPP-IV binds to the receptor GLP-1 and prevents active GLP-1 to contact the receptor. Therefore, assume that incredilby activity of GLP-1 therefore weakens (non-patent reference 4).

Due to these reasons suggest that the inhibitor of DPP-IV can prevent inactivation of GLP-1, thus increasing the impact of incretin on active GLP-1, and the result can be prevented hyperglycemia after meals in diabetics. In addition, since incretin increases hung is directly from glucose insulin secretion in humans, it is assumed that the inhibitor of DPP-IV can be a safe drug with no side effects, such as hypoglycemia, which is often observed when using existing medicines that cause insulin secretion.

On the other hand, there are some derivatives of 2-cyanopyrrolidine with inhibiting DPP-IV activity (patent references 1 to 7).

Of them in international publication WO 02/30890 (patent reference 5) specifically described compounds of General formula (A), and said that these compounds are effective for prophylaxis and treatment of diabetes and for the prevention and treatment of other diseases caused or exacerbated due to impaired glucose tolerance, hyperinsulinemia and complications of diabetes.

(Used in this formula the symbols have the meanings indicated in patent document).

On the other hand, in international publication WO 02/38541 (patent reference 6) describes compounds of General formula (V), and said that these compounds significantly inhibited the increase in blood glucose test, oral glucose tolerance in rats obesity Zucker (rats Zucker Fatty).

(Used in this formula the symbols have the meanings indicated in patent document is).

In international publication WO 03/002553 (patent reference 7) describes compounds of General formula (C), (D), (E), (F), (G) and (H) and said that these compounds can be used to treat diseases such as diabetes, obesity.

(Used in this formula the symbols have the meanings indicated in patent document).

Given this situation it is very desirable to develop drugs that are more excellent inhibiting DPP-IV activity.

Non-patent reference 1: Mentlein R., Regulatory Peptide, 1999, I. 85, p.9-24.

Non-patent reference 2: Nauck M.A. Diabetologia, 1986, T. 29, p.46-52.

Non-patent reference 3: Drucker D.J. Diabets, 1998, T. 47, str-169.

Non-patent reference 4: L.B. Knudsen European Journal of Pharmacology, 1996, t, str-435.

Patent reference 1: a compilation of international publication WO 98/19998.

Patent reference 2: a compilation of international publication WO 01/96295.

Patent reference 3: a compilation of international publication WO 00/34241.

Patent reference 4: a compilation of international publication WO 01/55105.

Patent reference 5: a compilation of international publication WO 02/30890.

Patent reference 6: a compilation of international publication WO 02/38541.

Patent reference 7: a compilation of international publication WO 03/002553.

Description of the INVENTION

The authors of the present invention have conducted extensive and thorough research in otnoshenoiyami, possessing inhibiting DPP-IV activity, which, as expected, are effective for the treatment of insulin-dependent diabetes (type 1 diabetes), insulin-independent diabetes (type 2 diabetes), diseases that are resistant to insulin, and obesity. In the result, it was found that the new derivative of 2-cyano-4-terpinolene or its salt according to the invention exhibits excellent inhibitory DPP-IV activity, which led to the creation of this invention.

Thus, this invention relates to a derivative of 2-cyano-4-terpinolene General formula (I) or its pharmaceutically acceptable salt that can be used as an inhibitor of DPP-IV.

where a is a piperidine-4-yl, oxetan-3-yl, pyrrolidin-3-yl, tetrahydro-2H-Piran-4-yl, pyrazolin-4-yl, 1,3-dioxane-5-yl, 8-azabicyclo[3.2.1]Oct-3-yl or tetrahydro-2H-thiopyran-4-yl, each of which may be substituted, except piperidine-4-yl, which is substituted by a group selected from the group comprising propane-2-sulfonyl, 2,4,6-trimethylbenzenesulfonyl, phenylmethanesulfonyl, 2-naphthalene-1-retensioned, 7,7-dimethyl-6-exorborant-1-elmersolver, 4-forfinal, 3,5-differenl, 4-nitrophenyl, 4-triptoreline, 4-cyanophenyl, 4-cyano-3-forfinal, 4-cyano-3,5-differenl, 3-cyano-5-forfinal, benzoxazol-2-yl and benzyl; pyrrolidin-3-the l which is substituted by a group selected from the group comprising propane-2-sulfonyl, 3-cyano-6-yl, 4-triptoreline, 4-forfinal and 4-terbisil; and 8-azabicyclo[3.2.1]Oct-3-yl, which is substituted by etoxycarbonyl.

In the formula (I) And, preferably, is a piperidine-4-yl or 8-azabicyclo[3.2.1]Oct-3-yl, each of which may be substituted, more preferably a group of General formula (II):

where In represents carbonyl, sulfonyl or single bond;

R1represents lower alkyl, aryl or aromatic heterocycle, each of which may be substituted;

R2represents lower alkyl, which is optionally substituted by a group selected from the group comprising HE, and O-lower alkyl, or represents-N.

In the formula (II) preferably represents a carbonyl or sulfonyl.

In the formula (II) R1,preferably represents lower alkyl, which is optionally substituted, more preferably lower alkyl, which is optionally substituted by a group selected from the group comprising-Oh or fluorine, more preferably, methyl or ethyl, each of which is optionally substituted by a group selected from the group comprising-Oh or fluorine, more preferably, methyl or ethyl, each of which is optionally substituted-is N.

In the formula (II) R2,preferably represents lower alkyl, which is optionally substituted-HE, more preferably, methyl or ethyl, each of which is optionally substituted-HE, even more preferably methyl, ethyl or hydroxymethyl, most preferably, methyl.

The chemical structure of the derivatives of 2-cyano-4-terpinolene according to this invention is characterized in that the optionally substituted non-aromatic a heterocycle attached to the 1-position of the skeleton 2-cyano-4-terpinolene through aminomethylpropanol, and its pharmaceutical characteristics is the fact that these derivatives possess inhibiting DPP-IV activity.

Among the compounds of formula (I) preferred are those where a is a piperidine-4-yl or 8-azabicyclo[3.2.1]Oct-3-yl, each of which is optionally substituted; more preferred are those where a is a group of formula (II); more preferred are those in which a represents a group of formula (II), A represents a carbonyl or sulfonyl, R1optionally substituted lower alkyl, R2represents methyl, ethyl or hydroxymethyl; and most preferred are those in which a represents a group of formula (II), A represents a carbonyl or sulfonyl, R1presented yet a methyl or ethyl, each of which is optionally substituted by a group selected from the group comprising-Oh or fluorine, R2represents methyl.

Of these compounds, especially preferred are the following:

4-fluoro-1-({[1-(methanesulfonyl)piperidine-4-yl]amino}ayil)pyrrolidin-2-carbonitrile,

4-fluoro-1-({[4-methyl-1-(methanesulfonyl)piperidine-4-yl]amino}ayil)pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-glycopolypeptides-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-glycolyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-peracetyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-formylpiperidine-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-formyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile or

4-fluoro-1-({[1-(morpholine-4-ylcarbonyl)piperidine-4-yl]amino}ayil)pyrrolidin-2-carbonitrile or its pharmaceutically acceptable salt;

more preferred are the following:

4-fluoro-1-({[4-methyl-1-(methanesulfonyl)piperidine-4-yl]amino}ayil)pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-glycolyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile or their pharmaceutically acceptable salt.

In another preferred example of the compounds of formula (I) And represents a group of formula (II) and a represents a carbonyl.

From Britanie further relates to pharmaceutical compositions, containing as active ingredient a compound as defined above, in particular, pharmaceutical compositions containing as active ingredient a compound as defined above for the treatment and/or prevention of insulin-dependent diabetes (type 1 diabetes), insulin-independent diabetes (type 2 diabetes), diseases associated with resistanceto to insulin or obesity; and to pharmaceutical compositions containing as active ingredient a compound as defined above, as an inhibitor of dipeptidylpeptidase IV.

Compounds according to this invention is described hereafter.

In the present description "lower alkyl" means1-6linear or branched alkyl, for example, more specifically, includes methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl and hexyl, etc. Preferably, it is methyl, ethyl, propyl or isopropyl, more preferably methyl or ethyl.

"Aryl" means6-14monocyclic-tricyclic aromatic monovalent group composed of carbon atoms, for example, more specifically, includes phenyl, naphthyl, etc. Preferably is phenyl.

"Aromatic heterocycle" means a monocyclic-tricyclic aromatic monovalent group containing at least one heteroatom selected from the group containing the nitrogen atoms is, oxygen and sulfur, for example, more specifically, includes furanyl, thienyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, triazolyl, benzofuranyl, benzothiazol, benzothiadiazoles, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, quinapril, isoquinolin, quinarsal, imidazopyridines and imidazopyrimidines etc. is Preferably pyridyl.

An acceptable substitute for optional substituted "piperidine-4-yl, oxetan-3-yl, pyrrolidin-3-yl, tetrahydro-2H-Piran-4-yl, pyrazolin-4-yl, 1,3-dioxane-5-yl, 8-azabicyclo[3.2.1]Oct-3-yl or tetrahydro-2H-thiopyran-4-Il" And may be any and every one generally used for these groups, and group And may contain one or more, preferably from 1 to 4 substituents. Including the carbon atom in a, which is directly attached to the NH group in formula (I), the carbon atom or the nitrogen atom of the ring may be substituted. In addition, the sulfur atom of the ring may be oxidized.

Deputy attached to the carbon atom, and includes the Deputy X, -OH, -O-h, halogen, -CO-X, -COO-X, -SO2-X and-CONRR'. Preferably, it represents a lower alkyl or aryl, each of which is optionally substituted by one or more groups selected is from the group including-OH, -O-lower alkyl, -O-aryl, halogen, cyano and nitro, more preferably lower alkyl, optionally substituted Deputy, selected IT and fluorine.

R and R'may be the same or different and represent lower alkyl, optionally substituted-HE, or-N (the same is true in this case). "The group of substituents X" denotes lower alkyl, lower alkenyl, lower quinil, cycloalkyl, cycloalkenyl, the aryl, the non-aromatic heterocycle, aromatic heterocycle, each of which is optionally substituted by one or more groups selected from the group comprising-OH, -O-lower alkyl, -O-aryl, halogen, cyano and nitro (the same is true in this case).

On the other hand, Deputy attached to the nitrogen atom, contains a Deputy X, -X, -COO-X, -SO2-X and-CONRR'. Preferably, it represents a lower alkyl, cycloalkyl, aryl or aromatic heterocycle, each of which is optionally substituted by one or more groups selected from the group comprising-OH, -O-lower alkyl, -O-aryl, halogen, cyano and nitro; or-SO2-lower alkyl (optionally substituted by one or more groups selected from the group comprising-OH, -O-lower alkyl, -O-aryl, halogen, cyano and nitro; or-SO2aryl (optionally substituted by one or more is a group, selected from the group comprising-OH, -O-lower alkyl, -O-aryl, halogen, cyano and nitro).

The term "lower alkenyl" means2-6alkenyl, for example, more specifically, includes vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term "lower quinil" means2-6quinil, for example, more specifically, includes ethinyl, 1-PROPYNYL, 1-butynyl, 2-butynyl and 3-butynyl.

The term "cycloalkyl" means3-14monovalent residue carbon cycle, which may be condensed with the formation of bridging ties. Specifically, for example, it includes cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, substituted, bornyl, norbornyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and bicyclo[3.3.1]nonyl.

The term "cycloalkenyl" means the residue From3-14carbon ring, which corresponds to cycloalkyl", but is partially unsaturated, for example, more specifically, includes cyclopentenyl, cyclohexenyl and norbornanyl.

The term "halogen" includes fluorine, chlorine, bromine and iodine. Preferably it is fluorine, chlorine or bromine, more preferably fluorine.

The compounds of this invention include mixtures of various stereoisomers such as tautomeric isomers and optical isomers, and one separated from the other.

Compounds according to this invention may OBR is, its salts of addition of acid. Depending on the type of substituent, they can form salts with bases. More specifically, the salts include the salts of addition of the acid formed with mineral acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, axalingua acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid; salts with acidic amino acids such as aspartic acid, glutamic acid, or with inorganic bases, such as sodium, potassium, magnesium, calcium, aluminum, or with organic bases such as methylamine, ethylamine, ethanolamine; or with basic amino acids such as lysine, ornithine; and ammonium salts.

Compounds according to this invention further includes hydrates, various pharmaceutically acceptable solvate and polymorph crystals. Of course, this invention should not be limited to the compounds described in the examples, and it includes all derivatives of the formula (I) and their pharmaceutical is Eski acceptable salt.

In this regard, the connection according to this invention includes all so-called prodrugs, i.e. compounds that will undergo metabolism and is converted to the compound of the above General formula (I) or its salt in the human body. As groups suitable for the formation of prodrugs, you can specify group, described inProg. Med.,5, 2157-2161 (1985) andIyakuhin No Kaihatsu(Development of Drugs), v.7, "Molecular Desighn", 163-198 (1990), Hirokawa Publishing Co.

(Production method)

The connection according to the invention and its pharmaceutically acceptable salt can be obtained by various methods of synthesis taking into account the characteristic properties of its basic skeleton or deputies. In this regard, in some cases, is effective in the method of receipt, depending on the type of functional group, at the stage of initial or intermediate material to replace the functional group protective group, i.e. a group which can be easily converted into the functional group. Further, if so desired, the protective group is removed, thus allowing to obtain the desired compound. Examples of such functional groups include hydroxyl group, carboxyl group and amino group. Examples of protective groups include protective groups are described in Green and Wuts,Protective Groups in Organic Synthesis (third edition)and they can be used to meet the current way depending on the reaction conditions.

One typical way of obtaining described below.

where a has the values specified above; and X represents a removable group, such as halogen or sulfonyloxy.

This method involves the alkylation of compound (II) with the amine (III) General formula A-NH2with the formation of compound (I) according to the invention. The interaction may be carried out in the absence or in the presence of a solvent. The solvent may be any of aromatic hydrocarbons such as toluene, xylene; ketones such as methyl ethyl ketone, acetone; ethers, such as dioxane, tetrahydrofuran, diglyme; alcohols, such as methanol, ethanol, isopropanol, chloroform, methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, water; and their mixtures. For the reaction can be selected suitable solvent depending on the type of the reaction substances and the reaction conditions.

Adding to the reaction base is preferred for mild reaction. Specific examples of such bases are carbonates of alkali metals such as sodium carbonate, potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate; and organic amines such as triethylamine, diisopropylethylamine, pyridine.

Some compounds according to the invention m which may be obtained from compounds (I), obtained as described above, by combining, in any desired way, some well-known stages, which are usually used by experts in this field, such as alkylation, acylation, oxidation, reduction, hydrolysis, etc.

Thus obtained compounds according to the invention may be conventional method isolated and purified in the form of the free compounds or after converting it to a salt in the form of their salts. Isolation and purification can be performed by usual chemical method such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatography methods, etc.

When the compounds according to the invention have asymmetric carbon, they include optical isomers. The optical isomers can be separated in the usual way, for example by fractional crystallization with recrystallization in the form of a corresponding salt, or by column chromatography. Optically active compounds can be derived from the corresponding optically active compounds.

INDUSTRIAL APPLICABILITY

Compounds according to the invention have an inhibiting DPP-IV activity. In particular, they have activity on the inhibition of the degradation of GLP-1, a hormone that affects β-cells of the pancreas, increasing secrets the Yu insulin and thereby regulating the concentration of glucose in the blood.

Based on their action, the compounds according to the invention can be used for the treatment and/or prevention of insulin-dependent diabetes (type 1 diabetes), insulin-independent diabetes (type 2 diabetes), diseases associated with insulin resistance, and obesity.

Excellent inhibiting DPP-IV activity of the compounds according to the invention is confirmed by research methods, as described below.

(1) a study to determine the DPP-IV-inhibiting activity

The reaction was carried out in flat-bottomed 96-well tablet for micrometrology. Changing the concentration of the tested compound was added to an aqueous solution containing 25 mm Tris-HCl, 140 mm sodium chloride, 10 mm potassium chloride, 1% bovine serum albumin for radioimmunoassay analysis and 0.01 mm Gly-Pro-AMC (Bachem). To this reaction solution (95 μl/well) was added 5 μl of plasma collected in adult healthy volunteers and incubated at room temperature for 20 minutes After completion of the reaction was measured by the intensity of the fluorescence (emission at 355 nm/emission 460 nm) in each well (ARVO, Perkin Elmer). The measurement results for the 3 holes in the same conditions were averaged.

Expected inhibition of the studied groups regarding added with a solution groups and the value of the IC50received by logical analysis. The results are presented in table 1.

Table 1
The analyzed compound compoundIC50/nmThe analyzed connectionIC50/nm
Example 14,2Example 285,1
Example 147,2Example 348,2
Example 194,2Example 367,5
Example 216,0Example 415,9

The above confirms DPP-IV inhibitory activity of the compounds according to this invention.

(2) a study to determine the duration of DPP-IV-inhibiting activity in mice

Male ICR mice (Nippon SLC) were divided into the study group and the control group of 5 animals each. The analyzed compound (10 mg/kg) was dissolved in purified water and administered orally. The control group mice orally was administered only purified water. Half an hour later, 6 and 12 h after injection were collected the blood of each mouse from the orbital venous plexus. The collected blood was immediately centrifuged to separate plasma and measured the activity of DPP-IV plasma.

The method for determining the activity of DPP-IV plasma following: the Reaction is carried out in 96-well pad. 5 μl of the collected plasma to allali in aqueous solution (95 μl/well), containing 25 mm Tris-HCl, 140 mm sodium chloride, 10 mm potassium chloride, 1% bovine serum albumin and 0.01 mm Gly-Pro-AMC (Bachem), and incubated at room temperature for 20 minutes was Measured intensity of fluorescence (emission at 355 nm/emission 460 nm) in each well (ARVO, Perkin Elmer).

The intensity of the fluorescence of the wells, which was added to plasma, collected from the control group was taken as 100%. Based on this, calculate the activity of DPP-IV plasma collected from mice entered the investigated compound, and received the difference in activity difference between the control group and intervention group. The data showed the effect of inhibition in the study group. The results are shown in table 2.

(3) a Study on the duration of DPP-IV-inhibiting activity in rats

Male SD rats (Clea Japan) were divided into the study group and the control group of 5 animals each. The analyzed compound (10 mg/kg) was dissolved in purified water and administered orally. Rats of the control group was injected only with purified water. Half an hour later, 6 and 12 h after injection were collected the blood of each rat from the tail vein. The collected blood was immediately centrifuged to separate the plasma, we measured the activity of DPP-IV plasma in accordance with the same method for determining the duration of the inhibitory activity of dipeptidylpeptidase-IV (DPP-IV, described in (2).

The intensity of the fluorescence of the wells, which was placed plasma, collected from the control group was taken as 100%. Based on this, calculate the activity of DPP-IV plasma collected in rats entered the investigated compound, and the difference in activity between the control group and intervention group. The data show inhibition in the study group. The results are shown in table 3.

Table 2
The analyzed connectionInhibiting the activity of DPP-IVplasma

after 6 h/%
Inhibiting the activity of DPP-IV plasma

after 12 h/%
Example 17459
Example 146665
Example 197261
Example 217871
Example 348579
Example 368178
Example 418378

Table 3
The analyzed connectionInhibiting the activity of DPP-IV plasma

after 6 h%
Inhibiting the activity of DPP-IV plasma

after 12 h/%
Example 149287
Example 349694
Example 369286
Example 419389
Compare the connection16538
Compare the connection27755
Compare the connection38045

In table 3 the comparison compound 1 is a compound in example 4-9, described in patent reference 5, the reference compound 2 is a connection example 4-17 described in patent reference 5, benchmark 3 connection is a connection example 33, described in patent reference 7; each patent the link above. Structure comparison of compounds 1-3 are presented next.

In table 2 and table 3 above demonstrates that the compounds of the present invention have good activity when administered orally, and their activity is maintained even after 6 h and 12 h after injection. These results confirm that the compounds of the present invention exhibit improved the military activity by oral administration and duration of in vivo compared with the compared compounds 1-3.

Pharmaceutical composition, which contains as active ingredient one or more compounds and their pharmaceutically acceptable salts according to the invention, can be obtained using a carrier, filler and other additives commonly used in the preparation of pharmaceutical compositions. It can be administered orally or parenterally in the form of tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments or poultices.

Clinical dose of the compounds according to the invention can be appropriately determined depending on the condition, body weight, age and sex of patients, which it is introduced, but favorable is usually from 0.1 to 500 mg/day for adult humans by oral administration and from 0.01 to 100 mg/day for an adult parenteral. The dose may be administered to patients all at once or may be divided into several portions for insertion into a few tricks. Since the dose varies depending on various conditions, it can be reduced in some cases, above.

Can be used a solid composition for oral administration of the compounds according to the invention, tablets, powders, granules, etc. Solid composition of this type contains one or more active substances are mixed, rainy least with one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicates magnesium. By the usual method, the composition may include some other additives, in addition to inert diluents mentioned above, for example, a binder such as magnesium stearate, baking powder, such as cellulosome calcium, stabilizer such as lactose, solubilizer or stimulator of dissolution, such as glutamic acid or aspartic acid. If desired, tablets and pills may be coated with a film of sugar or stable in the stomach or gut connection, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose.

Liquid composition for oral administration includes, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, which contain normal inactive solvent such as pure water or ethanol. In addition to the inert solvents such compositions may also contain pharmaceutical AIDS such as solubilization, stimulants dissolution, the promoters of wetting, the promoters of the suspensions, as well as sweeteners, flavorings, aromatizers and conser the anty.

Injections for parenteral administration include, for example, sterile aqueous or nonaqueous solutions, suspensions and emulsions. The solvent for the aqueous solutions and suspensions include, for example, distilled water and physiological solution for injection. Solvents for non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylenglycol, vegetable oils, such as olive oil, alcohols such as ethyl alcohol, Polysolvate 80 (trade mark).

These compositions can also contain additives, such as regulators isotonicity, preservatives, promoters wetting, emulsifying agents, disintegrating agents, stabilizers (e.g., lactose), soljubilizatory, stimulants dissolution. They are sterilized by filtration through a bacterial filter or by adding compounds that kill microorganisms or their irradiation with radiation. Sterile solid compositions can be obtained in advance, and they can be dissolved in sterile water or a sterile solvent for injection before use.

The BEST METHODS of APPLICATION of the INVENTION

The present invention is more specifically illustrated in the following examples, which, however, does not imply a restriction of the scope of the invention. Some of the original compounds used in the examples are new, and methods for their production issuesthe compounds described in reference examples.

Reference example 1

A suspension of 1.4 g of monohydrochloride (2S,4S)-4-ftorpirimidinu-2-carboxamide, obtained by the method similar to that described in patent reference (international publication WO02/38451), and 3.0 ml of N,N-diisopropylethylamine in 10 ml of chloroform was added dropwise to a solution to 0.73 ml chloroacetanilide in 14 ml of chloroform under cooling in an ice-water bath, and the reaction mixture was stirred for 30 minutes under cooling in an ice-water bath. Then the reaction mixture was concentrated under reduced pressure. To a solution of the obtained residue in 14 ml of chloroform was added dropwise 2.4 ml of anhydride triperoxonane acid under cooling in an ice-water bath. Then the reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was concentrated under reduced pressure, the resulting residue was added a 0.1 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed and the solvent was removed under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: chloroform to chloroform/methanol =30/1) to give 0.84 g of (2S,4S)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitrile.

NMR: 2,33-to 2.67 (2H, m), 3,60-of 4.05 (2H, m), 4,35-4,55 (2H, m,), 4,95-5,05, 5,30-5,60( 2H, m).

In the same manner as in reference example 1, soo the appropriate starting compounds were obtained compounds of reference examples 2-4, shown in table 4.

Reference example 5

To a suspension of 790 mg of the hydrochloride tert-butyl Exo-8-azabicyclo[3.2.1]Oct-3-ylcarbamate obtained by the method described inJ. Med. Chem. (1991), 34, 656-663 orJ.Heterocycl. Chem.(1892), 19, 485-488, in 10 ml of methylene chloride and 5 ml of N,N-dimethylformamide was added 1.3 g of triethylamine and 1.05 g of methanesulfonamide. The reaction mixture was stirred at room temperature for 1 day and concentrated under reduced pressure. To the obtained residue was added water and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 7/3) and was led from diethyl ether - hexane to obtain 600 mg of tert-butyl Exo-8-(methanesulfonyl)-8-azabicyclo[3.2.1]Oct-3-ylcarbamate in the form of a colorless solid product.

In the same way as in reference example 5, from the corresponding starting compounds were obtained compounds of reference examples 6 to 16 shown in table 4.

Reference example 17

A solution of 2.0 g of tert-butyl piperidine-4-ylcarbamate in chloroform was added to a mixed solution of 4.7 ml of acetic anhydride and 1.9 ml of formic acid and the reaction mixture peremeshivaniya room temperature for 15 hours To the reaction mixture was added water and was extracted with EtOAc. The organic layer washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and a saturated solution of salt. Was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol (MeOH) = 50/1) to obtain 1.7 g of tert-butyl (1-formylpiperidine-4-yl)carbamate.

In the same way as in reference example 17, from the corresponding starting compound were obtained compound in reference example 18, are shown in table 4.

Reference example 19

To a solution of 3.0 g of tert-butyl piperidine-4-ylcarbamate in 60 ml of methylene chloride was added 2.5 ml of triethylamine, 2.4 g of butanol (HOBt), 1.3 g hydroxyoctanoic acid and 3.5 g of WSCD hydrochloride and the reaction mixture was stirred at room temperature for 18 hours To the reaction mixture was added 1M hydrochloric acid and was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated salt solution. Was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol (MeOH) = 50/1) to obtain 2.8 g of tert-butyl [1-(hydroxyacetic)piperidine-4-and the)]carbamate.

In the same way as in reference example 19, from the corresponding starting compound were obtained compounds of reference examples 20-24, shown in table 4.

Reference example 25

A suspension of 1.0 g of the hydrochloride tert-butyl piperidine-4-ylcarbamate and 0.6 ml of triethylamine in 15 ml of methylene chloride was added to a solution of 418 mg of triphosgene in 10 ml of methylene chloride under cooling in an ice-water bath. The reaction mixture was stirred for 2 hours under ice cooling and then was added a solution of 358 mg of piperidine and 0.6 ml of triethylamine in 5 ml of methylene chloride and stirred at room temperature for 15 hours To the reaction mixture were added 10% aqueous citric acid solution and was extracted with EtOAc. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained solid product was washed with ether to obtain 440 mg of tert-butyl [1-(piperidine-1-carbonyl)piperidine-4-yl]carbamate.

In the same way as in reference example 25, from the appropriate source materials were obtained compounds of reference examples 26 and 27, shown in table 4.

Reference example 28

2.0 g m-chlormadinone acid was added to 1.0 g of tert-butyl [1-(thiomorpholine-4-carbonyl)piperidine-4-yl]carbamate in 10 ml of methylene chloride under cooling in an ice-water bath, the Reaction mixture was allowed to reach room temperature and was stirred for 18 hours To the reaction mixture were added saturated aqueous sodium thiosulfate solution and was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained solid product is washed with diisopropyl ether to obtain 607 mg of tert-butyl [1-(1,1-diocletianopolis-4-carbonyl)piperidine-4-yl]carbamate.

Reference example 29

A solution of 500 mg of tert-butyl piperidine-4-ylcarbamate and 345 mg of ethylformate in 1 ml of triptoreline was heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was added 1 M hydrochloric acid. Then was extracted with EtOAc and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution. Was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: chloroform to chloroform/methanol = 30/1) to give 345 mg of tert-butyl [1-(peracetyl)piperidine-4-yl]carbamate.

In the same way as in reference example 29, from the corresponding starting compound was obtained the compound of reference example 30, shown in table 4.

silecky example 31

15 ml of 4 M hydrogen chloride in EtOAc was added to a solution of 500 mg of the compound of reference example 5 in 15 ml EtOAc and the reaction mixture was stirred at room temperature for 9 hours. The obtained solid product was collected by filtration to obtain 400 mg of colorless solid product hydrochloride Exo-8-(methanesulfonyl)-8-azabicyclo[3.2.1]Oct-3-ylamine.

In the same manner as in reference example 31, from the corresponding starting compounds were obtained compounds of reference examples 32-49, shown in table 4.

Reference example 50

300 mg of 10%palladium-on-coal was added to a solution of 1.4 g of the compound in reference example 22 in 30 ml MeOH and the reaction mixture was stirred in hydrogen atmosphere at room temperature. Insoluble products were removed by filtration and the filtrate was concentrated under reduced pressure to obtain 400 mg of colorless solid product 2-(4-amino-4-methylpiperidin-1-yl)-2-oxetanone.

In the same way as in reference example 50, from the corresponding starting compounds were obtained the compounds of reference examples 51-55, shown in table 4.

Reference example 56

20 ml of 6 M hydrochloric acid was added to 2.2 g of the compound of reference example 42 and the reaction mixture is boiled under reflux for 24 hours. The reaction mixture was concentrated, to the residue was added then the Wal and MeOH and again concentrated. The obtained residue was led from MeOH-diethyl ether and collected to obtain 1.22 g of [4-amino-1-(methanesulfonyl)piperidine-4-yl]methanol.

Acronyms are indicated in the table below (the same is true here).

no: number of the reference example;

Salt: salt (HCl: hydrochloride, FUM: fumarate, not described: free stuff);

Structure: structural formula;

Data: physicochemical data (NMR: peak δ (ppm)1H-NMR, in which the internal standard is presented (CH3)4Si, and the solvent for measurement represents dimethylsulfoxide (DMSO-d6), FAB-MS: mass spectrometry with the bombardment of accelerated atoms, TPL - melting point);

Me: methyl, Boc: tert-butyloxycarbonyl, Ms: methanesulfonyl, Bn:benzyl.

Example 1

To a suspension 451 mg monohydrochloride 1-(methanesulfonyl)piperidine-4-amine, obtained by the method described in international publication WO0218380, and 435 mg of potassium carbonate in 8 ml of acetonitrile were added 200 mg of (2S,4S)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitrile, and the reaction mixture was stirred at room temperature for 4 days. Insoluble products was separated by filtration and to the filtrate was added 1.20 g of silica gel, reaction the second mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/28% aqueous ammonia = 100/1/0,1 to 20/1/0,1) to give 487 mg of a colorless amorphous product. To the obtained colorless amorphous product was added 10 ml of ethanol and the reaction mixture was stirred at room temperature for 30 minutes, the Insoluble product was collected by filtration, washed with ethanol and dried under reduced pressure. 230 mg of the obtained colorless solid product was dissolved in 2 ml of tetrahydrofuran and 4 ml of methanol, to which was added 80 mg of fumaric acid. The resulting solution was concentrated under reduced pressure until such time as the amount of solvent does not become approximately 2 ml, and then added 5 ml of ethanol, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to obtain 217 mg of colorless crystals of monopolarity (2S,4S)-4-fluoro-1-({[1-(methanesulfonyl)piperidine-4-yl]amino}ayil)pyrrolidin-2-carbonitrile.

In the same way as in example 1 from the corresponding starting compounds were obtained compounds of examples 2-47, are given in table 5 and table 6.

Acronyms in the tables shown below (the same applies hereinafter).

Example: example

And: Deputy in the General formula

<> tBu: tert-butyl, Et: ethyl, n-Pr: n-propyl, i-Pr: isopropyl, Ac: acetyl (table 5).

Hereinafter NMR data for compounds of some examples are shown in table 7.

Table 7
Example

(Sol)
Data
1(FUM.)NMR: 1,30-1,50(2H, m), 1,65-of 2.05(2H, m), 2,20-2,60(2H, m), 2,60-of 3.00(6H, m), 3,40-of 3.85(5H, m), 3,85-was 4.02(1H, m,), 4,90-5,04, 5,30-5,60( 2H, m), to 6.57(2H, s).
2(FUM.)NMR: 1,95-to 2.40(2H, m), 3,30-4,30(9H, m), 4,40-4,75, 5,20-5,60(2H, m), 6,55(2H, s).
3(FUM.)NMR: 1,30-1,50(2H, m), 1,75-1,90(2H, m), 1,95-2,15(2H, m), 2,25-2,70(3H, m), of 2,75 2,95(2H, m), 3.45 points-of 3.60(3H, m), 3,60-of 3.85(2H, m), 3,85-4,20(1H, m,), 4,80-5,38, 5,38-5,60( 2H, m), 6,56(2H, s), 7,20-7,37(5H, m).
4(FUM.)NMR: 1,00-of 1.15(3H, m), 1,45 is 1.70(1H, m), 1,90-2,10(1H, m), 2,25-2,75(3H, m), of 2,75 2,95(2H, m), 3,12-of 3.25(1H, m), 3.25 to 4,10(6H, m), 4,90-5,38, 5,38-5,60(2H, m), to 6.58(2H, s), 7,20-7,40(5H, m).
5(FUM.)NMR: 1,25-2,05(16H, m), 2,20-2,90(5H, m)3,00-4,00(7H, m), 4,75-5,38, 5,38-5,60(2H, m), is 6.54(2H, s).
6(FUM.)NMR: 0,75-0,90(9H, m), 0,90-1,10(2H, m), 1,20-of 1.55(7H, m), 1.55V is 2.10(4H, m), 2,10-4,05(10H, m), 4,60-5,38, 5,38-5,60(2H, m), 6,55(4H, s).
7(FUM.)NMR: 1,20-to 1.45(2H, m), 1,70-1,90(2H, m), 2,30-2,60(2H, m), 2,60-2,90(1H, m), 3,20-to 3.35(2H, m), 3,35-3,55(1H, m), 3,55-3,70(2H, m), 3,70-of 4.05(3H, m), 4,90-5,3, 5,34-the ceiling of 5.60(2H, m), to 6.57(2H, s).
8(FUM.)NMR: 0,98(6H, t), of 2.25 is 2.80(8H, m)3,00-3,20(2H, m), 3,30-of 3.80(5H, m), 3,80-4,30(1H, m), 4,70 is 5.38(1H, m), 5,38-the 5.65(1H, m), 3,70-of 4.05(3H, m), 4,90-5,34, 5,34-5,60(2H, m), 6,60(4H, s).
9(FUM.)NMR: 1,35-of 1.55(6H, m), 2,10-of 2.45(2H, m), 2,60-of 2.75(1H, m), 2,98-the 3.65(4H, m), 3,80-of 3.95(1H, m), 4,00 is 4.35(1H, m,), 4,70-4,95, 5,15-5,40( 3H, m), 6,59(2H, s), 7,15 was 7.45(5H, m).
10(FUM.)NMR: 1,24 of 1.50(2H, m), 1.70 to 2,04(2H, m), 2,30 totaling 3.04(4H, m), 3,40-to 4.15(7H, m), 4,90-5,05, 5,30-5,60(2H, m), to 6.58(2H, s), 7,02(2H, d), at 7.55(2H, d).
11(FUM.)NMR: 1,20-1,40(2H, m), 1.70 to a 2.00(2H, m), 2,30-3,20(4H, m), 3,40-4,10(5H, m), 4,20-and 4.40(2H, m), 4,90-the ceiling of 5.60(2H, m), to 6.57(2H, s), to 6.95(1H, d), 7,83(1H, m), to 8.45(1H, d).
13(FUM.)NMR: 1,35-of 1.53(2H, m), 1,55-1,75(2H, m), 1.85 to was 2.05(4H, m), 2,30-2,60(2H, m), 2,88 totaling 3.04(4H, m), 3,35-4,00(4H, m), 4,05-of 4.25(2H, m,), 4,90-5,04, 5,28-5,60( 2H, m).
14(FUM.)NMR: 1,05-1,20(3H, s)of 1.45 and 1.80(4H, m), 2,30-to 2.65(2H, m), 2,85(3H, s), 3.00 and-3,30(4H, m), 3,35-of 3.85(3H, m), 3,92-4,10(1H, m,), 4,97-5,02, 5,30-5,62( 2H, m), to 6.58(2H, s).
15(FUM.)NMR: 1,25-to 1.60(2H, m), 1.60-to was 2.05(2H, m), 2,20-2,90(5H, m), 3.00 and-of 4.25(6H, m), 4,70-5,00, 5,20-5,60(2H, m), of 6.52(1H, s), 7,70-of 8.00(2H, m), 8,05-to 8.20(2H, m).
19(FUM.)NMR: 1,04-of 1.35(2H, m), 1,75-of 1.95(2H, m), 2,30-2,60(2H, m), 2,65-2,90(2H, m), 3,01-3,10(1H, m), 3,38-of 4.05(6H, m), 4,96-5,35, 5,36-5,56(2H, m), to 6.58(2H, s), of 7.97(1H, s).
21(FUM.)NMR: of 1.05 to 1.40(2H, m)to 1.86(2H, usher.), 2,30-to 2.65(1H, m), 2.77-to of 2.81(2H, m), 2,90 was 3.05(1H, m), 3,47-4,16(11H, m), 4,98-5,40, 5,34-5,57(2H, m), to 6.58(2H, s).
28(FUM.)NMR: 1,20-of 1.36(2H, m), 1,72-1,90(2H, m), 2,30-2,621H, m), 2,70-2,82(3H, m), 3,05-3,15(4H, m), 3,50-4,00(9H, m), 4.95 points lower than the 5.37(1H, m), 5.40 to-ceiling of 5.60(1H, m), to 6.57(2H, s).
34(FUM.)NMR: 1,05-1,20(3H, s), 1,30-1,70(4H, m), 2,30-to 2.65(2H, m), 3,10-4,10(10H, m), 4,92-5,05, 5,32-5,62(2H, m), to 6.58(2H, s).
36(FUM.)NMR: 1,08, is 1.11(3H, s), 1.30 and of 1.65(4H, m), 2,30-2,70(2H, m), 3,20-4,10(8H, m), 4,90-5,05, 5,33-5,60(2H, m), 6,59(2H, s), of 7.96(1H, s).
41(FUM.)NMR: 1,06, a 1.08(3H, s), 1,38-of 1.56(4H, m), 2,33-to 2.67(2H, m), 3,17-4,03(8H, m), 4,98-5,57(4H, m), 6,60(2H, s).

Structural formulas of other compounds according to the invention are shown in table 8. They are easy to obtain in accordance with the methods of obtaining mentioned above, in accordance with the methods described in the examples, in accordance with any other methods obvious to a person skilled in this field, or in accordance with modifications of these methods.

The value of the reduction are shown in the table below.

no: the connection number

1. Derivative of 2-cyano-4-terpinolene represented by the following General formula (I)or its pharmaceutically acceptable salt:

where a represents a group of the following General formula (II):

where a represents a carbonyl or sulfonyl;

R1represents a C1-6alkyl, which can be the t optionally substituted group selected from the group comprising-Oh or fluorine, chlorine, bromine or iodine; phenyl, optionally substituted by CN; or morpholinyl, or when a represents a carbonyl, R1can be hydrogen.

R2represents a C1-6alkyl, optionally substituted hydroxy, or hydrogen;

2. The compound according to claim 1, where In represents a carbonyl or sulfonyl, R1represents lower alkyl, which is optionally substituted, R2represents methyl, ethyl or hydroxymethyl.

3. The compound according to claim 2, where R1represents methyl or ethyl, each of which is optionally substituted by a group selected from the group comprising-HE and fluorine, and R2represents methyl.

4. The compound according to any one of claims 1 to 3, which represents the following connection:

4-fluoro-1-({[1-(methanesulfonyl)piperidine-4-yl]amino}acetyl)pyrrolidin-2-carbonitrile,

4-fluoro-1-({[4-methyl-1-(methanesulfonyl)piperidine-4-yl]amino}acetyl)pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-glycopolypeptides-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-glycolyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-peracetyl-4-methylpiperidin-4-yl)amino] acetyl} pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-formylpiperidine-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile,

4-fluoro-1-{[(1-formyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidin-2-carbonitrile, or

4-fluoro-1-({[1-(morpholine-4-ylcarbonyl)piperidine-4-yl]amino}acetyl)pyrrolidin-2-carbonitrile,

or its pharmaceutically acceptable salt.

5. The compound according to claim 3, where In represents a carbonyl.

6. Pharmaceutical composition, which is an inhibitor dipeptidylpeptidase IV, containing as active ingredient a compound according to claim 1.

7. The pharmaceutical composition according to claim 6, which is intended for the treatment of insulin-dependent diabetes (type 1 diabetes), insulin-independent diabetes (type 2 diabetes), diseases associated with insulin resistance, or obesity.

8. The pharmaceutical composition according to claim 7, which is an inhibitor dipeptidylpeptidase IV.



 

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FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

32 cl, 1 tbl, 132 ex

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

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15 cl, 14 tbl, 118 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology, biochemistry.

SUBSTANCE: invention relates to a method for preparing compound of the formula (I) wherein R1 and R2 represent independently of one another hydrogen atom or methyl; R3, R4, R5 and R6 represent independently of one another hydrogen atom (H), halogen atom, formyl group, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkylenyloxycarbonyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylcarbonylamido-group, (C3-C7)-cycloalkylcarbonylamido-group, phenylcarbonylamido-group, benzyl, phenyl or naphthyl wherein benzyl, phenyl and naphthyl are substituted optionally and independently of one another with substitutes in amount up to two and chosen independently from halogen atom, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three and (C1-C4)-alkoxy-(C1-C4)-alkyl. Proposed method involves the following successive stages: (a) interaction of compound of the formula (II) wherein R3, R4, R5 and R6 are determined independently as given above with lithium-organic compound in the presence of sulfur source in medium of the first reactively inert solvent to form the reactive intermediate compound of the formula (IIa) (b) interaction of indicated reactive intermediate compound of the formula (IIa) with compound of the formula (III) to form compound of the formula (IV) (c) interaction of indicated compound of the formula (IV) with alkaline (C1-C2)-alkoxide in (C1-C2)-alkanol medium to form derivative of simple ether of the formula (V) wherein Alk represents (C1-C2)-alkyl; (d) interaction of indicated compound of the formula (V) with mineral acid to form compound of the formula (VI) and (e) oxidation of compound of the formula (VI) in the second reactively inert solvent to form compound of the formula (I). Prepared pyridazinone compounds are effective inhibitors of aldose reductase activity and can be used in prophylaxis and/or treatment of diabetes mellitus complications, such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. Also, invention relates to new intermediate compounds of the formula (IV) used in synthesis of indicated inhibitors of aldose reductase, to a method for synthesis of compound of the formula (IV) and a method for synthesis of preferable pyridazinone compound of the formula (XI) .

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

10 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel condensed cyclopropylpyrrolidines of the formula: wherein x means 0 or 1 and y means 0 or 1 under condition that x means 1 when y means 0, and x means 0 when y means 1; and wherein n means 0 or 1; X means hydrogen atom (H) of group -CN; R1, R2, R3 and R4 are similar or different and chosen independently from H, (C1-C10)-alkyl, (C2-C12)-alkenyl, saturated (C3-C10)-cycloalkyl, saturated (C3-C10)-cycloalkyl-(C1-C10)-alkyl, saturated (C3-C10)-bicycloalkyl, saturated (C3-C10)-tricycloalkyl, hydroxyl-(C1-C10)-alkyl-saturated (C3-C10)-cycloalkyl, (C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkyl, 5- or 6-membered heteroaryl comprising one nitrogen atom (N) or one oxygen atom (O), 5- or 6-membered heteroaryl comprising one atom N condensed with (C6-C10)-aryl ring, 5- or 6-membered heteroaryl comprising one atom N or one atom O, (C1-C10)-alkyl, cycloheteroalkyl that represents (C5-C8)-saturated ring comprising one heteroatom, such as N or O; if necessary, all compounds comprise 1, 2, 3, 4 or 5 groups of substitutes at corresponding carbon atom chosen from halogen atom, (C1-C10)-alkyl, (C2-C12)-alkenyl, hydroxy-group, hydroxy-(C1-C10)-alkyl or cyano-group; R1 and R4 can form in common, if necessary, the group -(CR5R6)m- wherein m means 2-6, and R5 and R6 are similar or different and chosen independently from hydroxy-group, H or (C1-C10)-alkyl including all their stereoisomers; and their pharmaceutically acceptable salt, or prodrug esters and all their stereoisomers. These compound inhibit activity of dipeptidyl peptidase IV that allows their using in pharmaceutical compositions used in treatment of diabetes mellitus of type-2.

EFFECT: valuable medicinal properties of compounds.

20 cl, 6 tbl, 113 ex

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

SUBSTANCE: invention relates to a new method for synthesis of 5-bromo-6-[(2-imidazolin-2-yl)amino]quinoxaline L-tartrate (brimonidine L-tartrate) of the formula (I): that is a highly effective medicinal agent used in glaucoma treatment. Method involves condensation of N,N-dimethyldichloromethylene immonium chloride of the formula: (CH3)2N+=CCl2Cl- with 5-bromo-6-aminoquinoxaline in organic solvent medium followed by treatment with ethylenediamine of formed N,N-dimethyl-N1-(5-bromoquinoxalin-6-yl)-α-chloroformamidine of the formula: RN=C(Cl)N(CH3)2 wherein R means 5-bromoquinoxalin-6-yl. Synthesized intermediate compound is extracted from reaction and mass and subjected for cyclization to 5-bromo-6-[(2-imidazolin-2-yl)amino]quinoxaline that is converted to L-tartrate by interaction with L-tartaric acid in acetone medium. Invention provides simplifying the technological process that is carried out under mild conditions and without isolation of intermediate substances that allows preparing the end preparation with the high yield about 40% as measure for 5-bromo-6-aminoquinoxaline.

EFFECT: improved method of synthesis.

1 cl, 2 ex

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

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to series of new compounds that are inhibitors of enzyme dipeptidyl peptidase IV. Invention proposes a compound chosen from derivatives of the formula (1) its tautomers and stereomers and pharmaceutically acceptable salts of indicated derivatives, tautomers and isomers wherein R1 represents hydrogen atom (H) or -CN; X1 represents sulfur atom (S), oxygen atom (O), -SO2 or -CH2; X2 represents -CO, -CH2 or a covalent bond; Het represents nitrogen-containing heterocycle; n = 1-5. Invention proposes a pharmaceutical composition possessing properties of inhibitor of enzyme dipeptidyl peptidase IV, and a method for treatment of at least one diseases among diabetes mellitus type 2, reduced tolerance to glucose, growth hormone deficiency, polycystic ovary syndrome and autoimmune and inflammatory diseases. Invention provides preparing series of inhibitors of dipeptidyl peptidase IV showing the improved affinity to enzyme, preparing pharmaceutical compositions and their using in treatment of some human diseases including the reduced tolerance to glucose and diabetes mellitus of type 2.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

14 cl, 6 tbl, 123 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, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

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