Oxadiazolidinone compound

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

 

The scope of the invention

The present invention relates to a pharmaceutical agent, in particular to a new oxadiazolidine the compound or its pharmaceutically acceptable salts which are useful as a means of stimulating insulin secretion or means for the prevention/treatment of diabetes.

Background of the invention

Diabetes is a disease, the main symptom of which is chronically high levels of glucose in the blood that results from absolute or relative deficiency of insulin action. Clinically, it is roughly divided into insulin-dependent diabetes mellitus (IDDM) and insulin-independent diabetes mellitus (NIDDM). When the insulin-independent diabetes mellitus (NIDDM) decreased secretion of insulin from pancreatic β-cells is one of the main reasons manifestations of the disease, and, in particular, it was recognized that high levels of glucose in the blood after a meal occurs in the initial stage of disorder of insulin secretion.

In a recent large-scale clinical studies have confirmed that the correction of the high level of glucose in the blood after a meal is important for the expression and suppression of diabetic complications. In addition, there were reports that atherosclerosis develops on studiotalk high level of glucose in the blood after a meal and that continuing a slightly increased level of glucose in the blood after a meal increases mortality due to cardiovascular diseases, etc. This shows that the increased level of glucose in the blood after a meal is an independent risk factor for death from cardiovascular disease, even when it is slightly elevated. Based on the above information, it was considered necessary drug therapy from the increased level of glucose in the blood after a meal.

Currently, the main focus in the area of stimulating insulin secretion, are sulfonylurea (SU), but it is known that they can cause hypoglycemia and lead to secondary disabilities due to exhaustion of the pancreas in the case of long-term administration. In addition, SU drugs are effective to control the level of glucose in blood in the process of eating, but it is very difficult to suppress the level of glucose in the blood after a meal.

GPR40 is a associated with G protein receptor that was identified as the receptor for fatty acids and has a high level of expression in β-cells of the pancreas, and there were reports that it is associated with insulin-secretory action of fatty acids (non-patent reference document 1).

Therefore, since the correction of the high level of glucose in the blood after a meal, as expected, based on action by stimulating the secretion of insulin agonist of GPR40 receptor is the floor of the EIT as a means for the prevention/treatment of insulin-dependent diabetes mellitus (IDDM) insulin-independent diabetes mellitus (NIDDM) and mild forms of diabetes, borderline type (abnormal glucose tolerance and glucose levels in the blood on an empty stomach).

In the reference patent document 1 is reported that the compound represented by formula (A), including a wide range of compounds, has a controlling GPR40 receptor action and is useful as a means of stimulating insulin secretion, or a means for the prevention/treatment of diabetes. However, there is no illustrative disclosure compounds having the structure of oxadiazolidine.

(In the formula, the ring P is an aromatic ring which may contain a Deputy, and ring Q is an aromatic ring which may optionally contain a Deputy, other than

X and Y the spacers, and

the group capable of releasing cation.)

In the reference patent document 2 is reported that the compound represented by formula (B), has a controlling GPR40 receptor action and is useful as a means of stimulating insulin secretion or means for the prevention/treatment of diabetes. However, there is no illustrative disclosure compounds having with whom ructure of oxadiazolidine.

(Symbols in the formula refer to the specified publication.)

In the reference patent document 3 is reported that the compound represented by formula (C), has a controlling GPR40 receptor action and is useful as a means of stimulating insulin secretion or means for the prevention/treatment of diabetes. However, there is no illustrative disclosure compounds having the structure of oxadiazolidine.

(Symbols in the formula refer to the specified publication.)

In the reference patent document 4 reported that oxadiazolidine compound represented by the formula (D), has an inhibitory action in respect of an inhibitor of plasminogen activation (PAI)-1 and is useful for treatment of blood clots, atrial fibrillation, myocardial ischemia, diabetes, etc. But there is no description of his actions in relation to the GPR40 receptor.

(In the formula, X represents a

Other characters see in the specified publication)

In the reference patent document 5 is reported that the compound having two oxadiazolidine structure represented by formula (E), has the effect of enhancing the sensitivity of INSOL the well and is useful for the treatment of diabetes. However, there is no description of his actions on the GPR40 receptor.

(Symbols in the formula refer to the specified publication.)

In the reference patent document 6 reported that oxazolidinedione compound represented by the formula (F), has the action of lowering the level of glucose in the blood and action to reduce the level of lipids in the blood and is useful for the treatment of diabetes. However, the ring that corresponds to oxadiazolidine of the present invention, is oxazolidinedione. In addition, there is no description of his actions in relation to the GPR40 receptor.

(Symbols in the formula refer to the specified publication.)

In the reference patent document 7 reported that oxadiazolidine compound represented by the formula (G), has the action of lowering the level of glucose in the blood and is useful for the treatment of diabetes. But the ring, which corresponds to A ring of the present invention, is oxadiazoline ring. In addition, there is no description of his actions on the GPR40 receptor.

(Symbols in the formula refer to the specified publication.)

In the reference patent document 8 reported that connection, not only the TES formula (H), has the action of lowering the level of glucose in the blood and is useful for the treatment of diabetes. However, there is no description of his actions on the GPR40 receptor.

(Symbols in the formula refer to the specified publication.)

In the reference patent document 9 reported that oxadiazolidine compound represented by formula (J), has the action of lowering the level of glucose in the blood and is useful for the treatment of diabetes. But the ring, which corresponds to the ring of A compound of the present invention, is oxazole or thiazole. In addition, there is no description of his actions on the GPR40 receptor.

(X in the formula represents an oxygen atom or a sulfur atom. Other characters see in the specified publication.)

In the reference patent document 10 reported that the compound represented by formula (K), is useful from hyperlipemia, hyperglycemia, obesity, etc. But the ring, which corresponds to the ring of A compound of the present invention, is a morpholine or thiomorpholine. In addition, there is no description of his actions on the GPR40 receptor.

(In the formula represents an oxygen atom or a sulfur atom. Other what their characters see in this publication.)

In non-patent reference document 2 it is reported that oxadiazolidine compound represented by the formula (L), has the action of lowering the level of glucose in the blood and is useful for the treatment of diabetes. But the ring, which corresponds to the ring of A compound of the present invention, is a (di)azole ring. In addition, there is no description of his actions on the GPR40 receptor.

(In the formula, X represents O, S or N, Y is C or N, and n has a value of 1 or 2. Other characters see in the specified reference document.)

Non-patent reference document 1: Nature, (England), 2003, vol.422, RR-176.

Non-patent reference document 2: European Journal of Medicinal Chemistry, (France), 2001, vol.36, RR-42.

Patent reference document 1: international Publication No. 2004/041266.

Patent reference document 2: international Publication No. 2005/063729.

Patent reference document 3: international Publication No. 2005/063725.

Patent reference document 4: international Publication No. 2005/030203.

Patent reference document 5: international Publication No. 94/25448.

Patent reference document 6: JP-A-2000-212174.

Patent reference document 7: international Publication No. 95/30664.

Patent reference document 8: international Publicat what I No. 97/41097.

Patent reference document 9: U.S. Patent No. 5480896.

Patent reference document 10: JP-A-7-2848.

Disclosure of invention

The problems solved by the present invention

The present invention aims at providing a new connection, which has an agonistic action on the GPR40 receptor and is useful as a means of stimulating insulin secretion or means for the prevention/treatment of diabetes.

Means for solving problems

The authors of the present invention have conducted extensive studies of compounds with agonistic action on the GPR40 receptor, and found that the new oxadiazolidine compounds or their salts have excellent agonistic action on the GPR40 receptor. As a result, was created by the present invention by discovering that oxadiazolidine compounds have an excellent effect on the stimulation of insulin secretion and strongly inhibit the increase of blood glucose after glucose load.

Thus, the present invention relates to oxadiazolidine the compound represented by the following formula (I)or its pharmaceutically acceptable salt.

(Symbols in the formula represent the following meanings,

R1:-H, halogen, -R0halogeno-lower alkyl, -ORz, -S-R0or-O-halogeno-lower alkyl,

R0: lower alkyl,

Rz: the same or different from each other and each represents-H or lower alkyl,

L: *lowest alkylen-O-, *-lower alkylene-N(Rz)- or *-CON(Rz)-, where * L is a linking ring A,

ring A: benzene, pyridine, thiophene, piperidine, dihydropyridines, pyrimidine or tetrahydroquinolin,

ring B: benzene, or pyridine,

R2: respectively the same or different from each other, and each represents halogen,

-R0halogeno-lower alkyl, -ORz, -S-R0, -O-halogeno-lower alkyl, -O-lower alkylene-aryl, or oxo,

n: 0, 1 or 2,

R3: -halogen, -R0-halogeno-lower alkyl, -OR0, -S-R0, -O-halogeno-lower alkyl, -X-(phenyl which may be substituted) or-X-(heteroaryl, which may be substituted),

X: simple bond, O, S or N(Rz),

R4: -H or lower alkyl,

or R1and R4together may form a lower alkylene,

provided that

2-{4-[2-(4-methyl-6-oxo-2-propylpyrimidine-1(6H)-yl)ethoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione and

2-{4-[2-(2-ethyl-4-methyl-6-oxopiperidin-1(6H)-yl)ethoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione

excluded. The same applies to the description that follows.)

In addition, this is avca also relates to pharmaceutical means, in particular the GPR40 agonist, which is used oxadiazolidine the connection represented by the General formula (I)or its salt as an active ingredient.

In addition, the present application also relates to the use of compounds represented by formula (I)or its pharmaceutically acceptable salt for a GPR40 agonist, an agent stimulating insulin secretion or means for the prevention and/or treatment of diabetes, and to a method of prevention and/or treatment of diabetes, which includes an introduction to the patient an effective amount of the compound represented by formula (I)or its pharmaceutically acceptable salt.

Namely presents

(1) a pharmaceutical composition which contains a compound represented by formula (I)or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,

(2) the pharmaceutical composition described in paragraph(1), which is a GPR40 agonist,

(3) the pharmaceutical composition described in paragraph(1), which is a means of stimulating insulin secretion,

(4) the pharmaceutical composition described in paragraph(1), which is an agent for the prevention and/or treatment of diabetes,

(5) the use of compounds described in the formula (I)or its pharmaceutically acceptable salt for a GPR40 agonist,tools, stimulating insulin secretion, or a means for the prevention and/or treatment of diabetes,

(6) a method for preventing and/or treating diabetes, which comprises administration to the patient an effective amount of the compound described in the formula (I)or its pharmaceutically acceptable salt.

The effect of the present invention

The pharmacological activity of the compounds of the present invention was confirmed by the test methods described below.

Test method 1: determination of agonistic actions against GPR40

i) Cloning of human GPR40

Full sequence of GPR40 was obtained by implementation of the PCR method in accordance with the procedure below, using human genomic DNA (Clontech) as a matrix.

Oligonucleotide consisting of the nucleotide sequence presented as SEQ ID NO:1, was used as a forward primer, and the oligonucleotide consisting of the nucleotide sequence presented as SEQ ID NO:2 as a reverse primer. In this regard, the nucleotide sequence comprising a recognition areaXbaI added to the corresponding 5'-end of the above direct primer and reverse primer. PCR was carried out in the presence of 5% dimethyl sulfoxide (DMSO) using Taq DNA polymerase (x Taq DNA polymerase; Takara Bio) by repeating 30 times the cycle of 94°C (15 seconds)/55°C (30 seconds)/72°C (1 minute). As a result, was amplified DNA fragment of about 0.9 TPN This DNA fragment was digested byXbaI and then inserted into theXbaI site of the plasmid pEF-BOS-dhfr (Nucleic acids Research, 18, 5322, 1990) to obtain, thus, the plasmid pEF-BOS-dhfr-GPR40.

The nucleotide sequence of GPR40 gene in pEF-BOS-dhfr-GPR40 was determined by the method of dideoxy-terminator using DNA sequencing machine (ABI 377 DNA Sequencer, Applied Biosystems). The nucleotide sequence of the gene GPR40 was the same as the nucleotide sequence presented as SEQ ID NO:3. The nucleotide sequence presented as SEQ ID NO:3,

has an open reading frame (ORF) of 903 bases, and amino acid sequence deduced from this ORF (300 amino acids), were the same as the amino acid sequence presented as SEQ ID NO:4.

ii) Obtaining cells with stable expression of GPR40

As cells expressing the protein GPR, used cells CHO dhfr (dihydrotetrazolo(dhfr)-deficient CHO cells). Also as plasmids expressing GPR40 protein, used a plasmid pEF-BOS-dhfr-GPR40 obtained in the above stage i). Cells CHO dhfr was made in αMEM medium containing 10% fetal calf serum (FCS), using 6-Luna the aqueous tablet (Asahi Techno Glass) and cultured overnight to 80-90% of confluently, then used 2 μg per well of the plasmid pEF-BOS-dhfr-for GPR40 gene transfer using a reagent for transfection (Lipofectamine 2000; Invitrogen). After 24 hours of cultivation since the gene transfer, the cells were diluted and again brought into the environment. In this case, αMEM medium containing 10% FCS was replaced with αMEM medium that contained 10% FCS, but did not contain nucleic acid. After 20 days of cultivation educated thus a colony of cells was separately extracted and cultivated with obtaining CHO cells, stably expressing GPR40. One of them was selected cells with high reactivity in relation to the internal ligand is oleic acid and linolenic acid.

iii) Determining agonistic actions against GPR40

This test was carried out measurements using FLIPR (registered trademark, Molecular Device) using as an indicator of changes in intracellular calcium concentration. This test method described below.

The strain of CHO cells in which the expression of GPR40 man, made in 384-well black tablet (Becton Dickinson) at a density of 6×103cells per well and cultured overnight in CO2the incubator.

Using the test kit Calcium-3 (Molecular Device) one flask with fluorescence pigment was dissolved in 10 ml of buffer HBSS-HEPES (pH 7.4, 1 × HBSS, 20 THE M HEPES, Invitrogen). 35,68 mg of probenecid (Sigma) was dissolved in 250 μl of 1M NaOH and regulated by adding 250 ál of buffer HBSS-HEPES. Solution fluorescence pigment was prepared by mixing 16 ml of buffer HBSS-HEPES, 640 μl fluorescence pigment and 32 μl of probenecid on one tablet. The medium was decanted from the tablet and solution fluorescence pigment, was divided into 40 μl per well and then incubated at room temperature for 2 hours. Each test compound was dissolved in DMSO and then diluted with buffer HBSS-HEPES and distributed in 10-μl portions into the tablet, thus starting the reaction, and changes in intracellular calcium concentration was measured using FLIPR. The value of EC50for each test compound was calculated by using the curve dose-response changes in fluorescence intensity after 1 minute measurements.

The test results are presented in table 1. The example represents the number of the example compounds described below.

14
Table 1
ExampleEC50(µm)
40,35
80,031
90,80
0,39
160,45
330,64
380,65
390,26
440,67
470,42
560,76
600,46
820,93
990,45
1170,29
1190,22
1660,22
1730,66
1890,059
1930,52
4060,12

Test method 2: the action of stimulation of insulin secretion using MIN6 cells

In this trial studied the effect of the test compounds to accelerate Secretary is tion of insulin using strain β-cells of the pancreas of the mouse, the MIN6 cells. This test method described below.

MIN6 cells were distributed at a density of 5×104cells/well (200 ml) in a 96-well plate. As the medium used DMEM (25 mm glucose)containing 10% FBS, 55 μm 2-mercaptoethanol, 100 U/ml penicillin and 100 μg/ml streptomycin. The medium was poured in 2 days using the aspirator, followed by a single wash with 200 μl KRB-HEPES (116 mm NaCl, of 4.7 mm KCl, 1.2 mm KH2PO4, 1.2 mm MgSO4, 0.25 mm CaCl2, 25 mm NaHCO3, 0,005% BSA without FFA, 24 mm HEPES (pH 7,4)containing 2.8 mm glucose, which was heated to 37°C, and then incubated at 37°C for 1 hour by adding 200 μl of the same buffer. After the above buffer was poured using the aspirator, and again washed with buffer (200 μl), the predetermined concentration of the test compounds were added to the KRB-HEPES containing 2.8 mm or 22.4 mm glucose, and added to the appropriate wells in portions of 100 μl and incubated at 37°C for 2 hours. The above samples were divided into fractions and diluted 100-fold, and the concentration of insulin was determined using a set of insulin RIA (Amersham RI). Activity is shown as relative activity (%) at 1 μm of each compound based on 100% of the control (DMSO).

The test results presented in table 2. In the result, it was confirmed that the connection is out of the present invention has an excellent effect, stimulating insulin secretion.

Table 2
ExampleThe effect on the stimulation of insulin secretion (%)
4177
34169
38228
39192
44287

Test method 3: test glucose tolerance after a single oral administration to healthy mice

In this trial studied the effect of the test compounds to suppress blood glucose after glucose load using normal mice. This test method described below.

Male ICR mice (age 6 weeks) 1 week pre-breeding were subjected to starvation during the night and used as test animals. Each test compound suspended in 0.5% methylcellulose and oral was administered at the dose of 10 mg/kg 30 minutes prior to the glucose load (2 g/kg). The introduction of 0.5% methylcellulose was used for control group. Reducing the level of glucose in the blood (%) 30 minutes after glucose is agrusti was calculated on the basis of the control group.

The test results presented in table 3. In the result, it was confirmed that the compound of the present invention has an excellent effect in reducing the level of glucose in the blood.

Table 3
ExampleThe rate of decrease of glucose level in blood (%)
1434
3926
4421
4736
5631
6035
11721
11922
16635
17321
18930
19346
40642

As a result of the above-described appropriate tests, it is obvious that the connection is s according to the present invention has excellent agonistic action against GPR40 and is therefore useful as a means of stimulating insulin secretion or means for the prevention/treatment of diseases involving GPR40, such as diabetes (insulin-dependent diabetes mellitus (IDDM), insulin-independent diabetes mellitus (NIDDM) and mild forms of diabetes, borderline type (abnormal glucose tolerance and glucose levels in the blood on an empty stomach)and so on

The best way of carrying out the invention

Below is a detailed description of the present invention.

In the present description, “alkyl” and “alkylene” means linear or branched hydrocarbon chain.

“Lower alkyl”preferably represents an alkyl group containing from 1 to 6 carbon atoms (hereinafter indicated as C1-6), more preferably C1-4alkyl and more preferably methyl and ethyl.

“Lower quinil”preferably represents a linear or branched C2-6alkylamino group, and illustration, you can specify ethinyl, PROPYNYL, butynyl, pentenyl, 1-methyl-2-PROPYNYL, 1,3-butadienyl, 1,3-pentadienyl or the like, More preferred is C2-4quinil and especially preferred is ethinyl or PROPYNYL.

“Lower alkylene” means a divalent group (C1-6alkylen), in which one optional hydrogen is removed from the above “lower alkyl” and, preferably, not only the em a C 1-4alkylene, more preferably methylene, ethylene, trimethylene, propylene or dimethylmethylene and even more preferably methylene or ethylene.

“Halogen” means F, Cl, Br and I.

“Halogeno-lower alkyl”preferably represents C1-6alkyl, substituted by at least one halogen, more preferred halogeno - C1-3alkyl, more preferred vermeil, deformity, trifluoromethyl, 1,1-dottorati, 2,2,2-triptorelin or 3,3,3-cryptochromes, more preferably trifluoromethyl, 1,1-dottorati or 2,2,2-triptorelin.

“Cycloalkyl” represents a C3-10saturated hydrocarbon ring group which may contain a bridge. Illustrative, you can specify cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted or the like, Preferred is C3-6cycloalkyl, cyclopropyl and even more preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

“Cycloalkenyl” represents a C3-15cycloalkenyl, which may contain a bridge, and includes an annular group condensed with a benzene ring at the site of a double bond. Illustrative, you can specify cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl, 1-indanyl, 9-fluorenyl or the like, Preferred is the C 5-10cycloalkenyl, and more preferred is cyclopentenyl, cyclohexenyl, 1-indanyl or 1-tetrahydronaphthyl.

“Aryl” represents a C6-14aromatic hydrocarbon radical, preferably phenyl, naphthyl or tetrahydronaphthyl, and more preferred is phenyl.

“Heteroaryl” means a group containing a ring selected from (i) monocyclic 5 - or 6-membered aromatic heterokonta containing from 1 to 4 heteroatoms selected from O, S and N, (ii) a bicyclic heterokonta in which heterokonta mentioned in the above (i), are condensed on the ring, where the condensed ring may be the same or different from each other, and (iii) a bicyclic heterokonta in which heterokonta specified in the above (i)is condensed with a benzene ring or a 5-7 membered cycloalkane. As an example, the ring constituting this group, you can specify, for example, (i) pyridine, pyrazin, pyrimidine, pyridazine, imidazole, pyrrole, thiophene, furan, triazine, triazole, thiazole, thiadiazole, oxadiazole, pyrazole, isothiazol, oxazol, isoxazol, ii) naphthiridine, imidazopyridine, pyrrolopyrimidine, thienopyridine, thienopyrrole, iii) quinoline, benzimidazole, benzofuran, benzothiophene, benzothiadiazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, inulin, isoquinoline, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, hinzelin, cinoxacin, phthalazine, indole, isoindole, tetrahydroimidazo, chroman and indazole. In addition, oxide can be formed through the oxidation of S atoms or N ring. Preferred is the above (i) monocyclic aromatic heterokonta.

“Heteroclite” or “heteroclada group” means a group containing a ring selected from (i) monocyclic 4-to 8-membered, preferably 5 to 7-membered, saturated, unsaturated or partially unsaturated heterokonta containing from 1 to 4 heteroatoms selected from O, S and N, (ii) a bicyclic heterokonta in which heterokonta mentioned in the above (i), are condensed on the ring, where the condensed ring may be the same or different from each other, and (iii) a bicyclic heterokonta in which heterokonta specified in the above i), is condensed with a benzene ring or a 5-7 membered cycloalkane. As an example, the ring constituting this group, you can specify, for example, (i) azetidine, piperidine, pyrrolidine, piperazine, ASEAN, diazepan, morpholine, thiomorpholine, dioxane, dioxolane, pyrazoline, piperidine, piperazine, oxetane, tetrahydrofuran, dihydropyridines, pyridine, pyrazin, pyrimidine, pyridazine, imidazole, pyrrole,thiophene, furan, triazine, triazole, thiazole, thiadiazole, oxadiazole, pyrazole, isothiazol, oxazol, isoxazol, ii) Hinkley, naphthiridine, imidazopyridine, pyrrolopyrimidine, thienopyridine, thienopyrrole, iii) dihydrobenzofuran, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, dihydrobenzofuran, benzodioxole, indolin, indazole, quinoline, benzimidazole, benzofuran, benzothiophene, benzothiadiazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, isoquinoline, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, hinzelin, cinoxacin, phthalazine, indole, isoindole, tetrahydroimidazo, chroman and indazole. In addition, oxide or dioxide can be formed through the oxidation of S atom or N ring. Preferred is the above (i) monocyclic heterokonta.

The term “may be substituted” means unsubstituted or substituted by identical or different from each other 1-5 substituents”. “Substituted” means “having the same or different from each other 1-5 substituents”.

Preferred as the acceptable substituent of the “phenyl which may be substituted”, and “heteroaryl, which may be substituted” in R3is a group selected from group G, below.

Group G: halogen, -CN, -R0halogeno-lower alkyl, -ORz, -O-halogeno-lower alkyl, -N(Rz)CO-Rz,-CO 2Rz, -CON(Rz)2, -CO-heteroclada group, -CON(Rz-the lowest quinil, -CON(Rz-cycloalkyl, -CON(Rz)-cycloalkenyl, -CON(cycloalkyl)(heteroclada group), -CON(Rz)-heteroclada group, -S-R0, -SO2-R0, -O-S(O)2-R0, -O-S(O)2-halogeno-lower alkyl, lower alkylene-ORzlowest alkylen-O-CORzlowest alkylene-N(Rz)2lowest alkylene-N(Rz)CO-Rzlowest alkylen-CORzlowest alkylene-CO2Rzlowest alkylene-CON(Rz)2, -O-lower alkylene-ORz, -O-lower alkylene-O-CORz, -O-lower alkylene-N(Rz)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-N(Rz)CO2-R0, -O-lower alkylene-CO-Rz, -O-lower alkylene-CO2-Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl which may be substituted by a group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz-cycloalkyl, -O-heteroclada group, -O-lower alkylene-heteroclada group, -O-lower alkylene-CO-heteroclada group, -O-lower alkylene-CON(Rz)-heteroclada group, -N(Rz)CO-lower alkylene-ORz, -CON(Rz)-halogeno-lower alkyl, -CON(Rz)-(lower alkyl substituted by a group-ORz), -CON(Rz-the lowest alkylen-CN, -CON(Rz)-ISSI alkylene-O-lower alkylene-OR z, -CON(lower alkylene-ORz)2, -CON(Rz-the lowest alkylen-O-CORz, -CON(Rz-the lowest alkylene-N(Rz)2, -CON(Rz-the lowest alkylene-N(Rz)CO-Rz, -CON(Rz-the lowest alkylen-CORz, -CON(Rz-the lowest alkylene-CO2Rz, -CON(Rz-the lowest alkylene-CON(Rz)2, -CON(Rz-the lowest alkylen-SO2Rz, -CON(Rz-the lowest alkylen-cycloalkyl, -CON(Rz-the lowest alkylen-O-cycloalkyl, -CON(Rz-the lowest alkylen-aryl, -CON(Rz)-(lower alkylene substituted by a group-N(Rz)2)-aryl, -CON(Rz-the lowest alkylene-O-aryl, -CON(Rz-the lowest alkylene-N(Rz)-aryl, -CON(Rz-the lowest alkylene-CO-aryl, -CON(lower alkylene-ORz-the lowest alkylen-aryl, -CON(Rz-the lowest alkylen-heteroclada group, -CON(Rz-the lowest alkylen-O-heteroclada group, -CON(Rz-the lowest alkylene-N(Rz)-heteroclada group, -CON(Rz-the lowest alkylene-CO-heteroclada group, -CON(lower alkylene-ORz-the lowest alkylen-heteroclada group, -CON(lower alkylen-CN)-the lowest alkylen-heteroclada group, and-CON(lower alkylen-heteroclada group)2.

In this regard in G the lowest alkylene may be substituted with halogen or-ORzand cycloalkyl, cycloalkenyl, aryl and heteroclada group may be substituted by a group selected from presents the th following group G 1.

Group G1: halogen, cyano, -R0halogeno-lower alkyl, -ORz, -O-halogeno-lower alkyl, -N(Rz)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-Rz, -CON(Rz)2, -CON(Rz-the lowest alkylen-ORz, -N(Rz)CO-Rz, oxo, lower alkylene-CN, lower alkylene-ORz, -aryl, -(lower alkylene, which may be substituted by a group-ORz)-aryl, lower alkylene-O-aryl, heteroclada group and the lowest alkylen-heteroclada group.

In this regard, the aryl and heteroclada group in group G1may be substituted by a group selected from the following group G2.

Group G2: halogen, cyano, halogeno-lower alkyl, -ORz, -O-halogeno-lower alkyl and oxo.

Preferred as the acceptable substituent for phenyl which can be substituted”, and “heteroaryl, which may be substituted” in R3more preferably, a is a group of the following group G3.

Group G3: halogen, -R0halogeno-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroclada group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-CORz, -O-lower alkylene-N(Rz)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2R0, -O-lower alkylene-CON(Rz )2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by a group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz-cycloalkyl, -O-lower alkylene-heteroclada group and-O-lower alkylene-CON(Rz)-heteroclada group.

In this regard, the lower alkylen in group G3may be substituted with halogen or-ORzand cycloalkyl, and heteroclada group may be substituted by a group selected from the above group G1.

Preferred as the acceptable substituent of the “phenyl which may be substituted”, and “heteroaryl, which may be substituted” in R3even more preferably, a is a group selected from halogen, -R0,-ORz, -O-halogeno-lower alkyl, a group-O-lower alkylene-ORzgroup-O-lower alkylene-CON(Rz)2and the group-O-lower alkylene-(cycloalkyl, which may be substituted by a group-ORz).

Preferred as the acceptable substituent for phenyl which can be substituted”, and “heteroaryl, which may be substituted” in R3more preferably, a is-O-lower alkylene-ORz, O-lower alkylene-CON(Rz)2or-O-lower alkylene-(cycloalkyl, which may be substituted by a group-ORz).

The preferred embodiment of the present image is the shadow below.

(a) is Preferred as R1is-H, -halogen, or-R0more preferably-H.

(b) is Preferred as R2is-halogen, -O-R0or-R0more preferably halogen or-R0.

(c) is Preferred as n is 0 or 1.

(d) is Preferred as R3is-X-(phenyl which may be substituted) or-X-(heteroaryl, which may be substituted), more preferably phenyl or pyridyl, which respectively may be substituted, more preferably phenyl which may be substituted, more preferably phenyl which may be substituted by a group selected from the above group G3particularly preferably phenyl, which is substituted by a group selected from the class comprising-O-lower alkylene-ORz, -O-lower alkylene-CON(Rz)2and-O-lower alkylene-(cycloalkyl, which may be substituted by a group-ORz), and may be further substituted, R0, halogen or-OR0.

(e) Preferred as R4is-H.

(f) Preferred as ring A is A benzene ring, a pyridine ring or a thiophene ring, more preferably a benzene ring.

(g) Preferred as ring B is a benzene ring.

(h) Preferred as L is s *lowest alkylen-O - or *-the lowest alkylene-NH-, more preferably *-CH2-O - or *-CH2-NH- (where * means the binding to the ring A). In addition, as the position of substitution of L in ring B 4-position relative to the-CH(R4)-(3,5-dioxo-1,2,4-oxadiazoline-2-yl) is preferred.

In another preferred variant embodiment of the compound containing a combination of the preferred groups described in the above paragraph.(a)-(h), is preferred.

Also another preferred embodiment of the compounds of the present invention represented by the General formula (I)below.

(1) the Compound described General formula (I), where the position of substitution of L in ring B represents a 4-position.

(2) the Compound described in paragraph(1), where ring A is a benzene ring.

(3) the Connection of p.(2), where R3represents phenyl or pyridyl, which may be respectively substituted.

(4) the Compound described in paragraph(3), where L is a *-CH2-O - or *-CH2-NH- (where * means the binding to the ring A).

(5) the Compound according to p.(4), where R4is a-H.

(6) the Compound described in paragraph(5), where R1represents-H, halogen, or R0.

(7) the Compound described in paragraph(6), where n is 0, or R2represents a halogen, or R0.

(8) Connection p.(7), g is e R 3represents phenyl, which is substituted by a group selected from the class comprising-O-lower alkylene-ORz, -O-lower alkylene-CON(Rz)2and-O-lower alkylene-(cycloalkyl, which may be substituted by a group-ORz), and may be optionally substituted 1 or 2 groups lower alkyl, halogen or-OR0.

(9) the Compound described by formula (I), which is selected from the group including

2-{[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}-N-methylacetamide,

2-(4-{[4'-(2-hydroxyethoxy)-2'-methylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,

2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,

2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,

2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2,2',6'-trimethylphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,

2-{4-[(4'-{[(3R)-3-hydroxybutyl]oxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,

2-{4-[(4'-{[(3S)-3-hydroxybutyl]oxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,

2-[4-({[4'-(3-hydroxy-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-yl]methyl}amino)benzyl]-1,2,4-oxadiazolidine-3,5-dione,

2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2'-methoxy-2-methylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dio is,

2-{4-[(4'-{[(3R)-3-hydroxybutyl]oxy}-2,2'6'-trimethylphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,

2-{4-[(4'-{[(3S)-3-hydroxybutyl]oxy}-2,2'6'-trimethylphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,

2-[(6-{[4'-(3-hydroxy-3-methylbutoxy)-2,2',6'-trimethylphenyl-3-yl]methoxy}pyridin-3-yl)methoxy]-1,2,4-oxadiazolidine-3,5-dione and

2-[4-({4'-[2-(1-hydroxyisopropyl)ethoxy]-2,2',6'-trimethylphenyl-3-yl}methoxy)benzyl]-1,2,4-oxadiazolidine-3,5-dione,

or its pharmaceutically acceptable salt.

There are cases where the compound of the present invention, represented by formula (I)forms a salt, and this salt is included in the compound of the present invention provided that it represents a pharmaceutically acceptable salt. Illustrative you can specify as an example, the acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, p-tawassul is about acid, aspartic acid, glutamic acid and the like, salts with inorganic bases, which contain metals (e.g. sodium, potassium, calcium, magnesium and the like), or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, ammonium salts, etc.

In addition, the compound of the present invention in some cases may contain asymmetric carbon atom, depending on the type of substituents, and may be present optical isomers. The present invention includes all of the mixture and selected forms of these optical isomers. In some cases, there may be the tautomers in the compound of the present invention, and the present invention includes the separated forms of these isomers or a mixture thereof. In addition, the present invention also includes a labeled substance, namely, a compound in which at least one atom of the compounds of the present invention substituted with a radioisotope or non-radioactive isotope.

In addition, different types of hydrate and solvate and polymorphism compounds of the present invention is also included in the present invention. In this regard, it should be clear that the compound of the present invention is not limited to the compounds described in the examples below, and all connections are presented in the i.i.d. formula (I), and their pharmaceutically acceptable salts are included in the present invention.

In this connection, all connections, which are converted into compounds of the present invention in a living organism, so-called prodrugs, are also included in the compound of the present invention. As groups, which form the prodrugs of the compounds of the present invention, it is possible to specify as an example, the groups described in “Progress in Medicine”, Lifescience Medica, 1985, vol.5, RR-2161, and the groups described in “Iyakuhin no Kaihatsu (Development of Medicines)”, vol.7 Bunshi Sekkei (Molecular Design), pp.163-198, published by Hirokawa Shoten, 1990.

(Methods of obtaining)

The compound of the present invention and its pharmaceutically acceptable salt can be obtained using various traditionally known synthesis methods, using the characteristics based on its basic skeleton or the type of substituents. Typical methods of obtaining given as an example below. In this regard, depending on the type of functional group, there is an effective way, from the point of view of production technology, substitution of specified functional group suitable protective group, namely a group which can be easily converted into a specified functional group, at the stage of initial substance to intermediate compounds. Then, the desired compound can be obtained PU is eating the removal of the protective group, as it will be needed in each case. As such functional groups, you can specify a hydroxyl group, carboxyl group, amino group and the like, as well as their protective group, the protective groups are described, for example, in “Protective Groups in Organic Synthesis” (USA), third edition, edited by Greene and Wuts, John Wiley & Sons, 1999, which is optional, can be used in accordance with the reaction conditions.

A method of obtaining a 1: cyclization reaction

(In the formula Lv is a deleted group. The same applies to the description that follows.)

This method of obtaining is a method in which compound (I) of the present invention is obtained by the cyclization reaction of the compound (1) and compounds (2). As the deleted group Lv preferred group is halogen (e.g. chlorine, bromine or the like) or alkoxygroup (for example, methoxy, ethoxy or the like).

The reaction may be carried out using compounds (1) and compounds (2) in equivalent amounts or one of them in excess, while cooling, at room temperature or under heating in a solvent such as ethers (e.g. diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane (DME) or the like), halogenated hydrocarbons (for example, dichloro the'étang, 1,2-dichloroethane, chloroform or the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene or the like) or the like

When the compound (1) contains a hydroxyl group other than hydroxyamino, this hydroxyl group in some cases subjected to carbamoylethyl. Remove carbamoyl group can be made by the method normally used by experts in this field to decarbamylated. For example, this can be done in a solvent such as alcohols (e.g. methanol, ethanol or the like), water or the like, under cooling, at room temperature or under heating using a base such as sodium methoxide, sodium ethoxide, sodium hydroxide or the like

A method of obtaining a 2: reaction mix

(In the formula of any one of the Lv1and Lv2represents a halogen or triftormetilfullerenov, and the other represents-B(OH)2, -B(OR00)2or SnR03, Ar represents a phenyl or heteroaryl, which may be respectively substituted, and R00represents a lower alkyl or two R00together form a lower alkylene. The same applies to the description that follows).

This method of obtaining is a method in which compound (I-a) according to the present invention, the floor is given by the reaction of a combination of compounds (3) and compound (4).

The reaction may be carried out with a palladium complex, such as tetranitropentaerithrite, palladium acetate or the like as the catalyst and using the compounds (3) and compound (4) in equivalent amounts or one of them in excess, while cooling, at room temperature or under heating in a solvent such as ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons, water or the like, in Addition, in some cases, to ensure a smooth reaction is advantageous implementation of the reaction in the presence of a base such as sodium carbonate, cesium carbonate, tert-piperonyl sodium or the like, or a lithium salt such as lithium chloride, lithium bromide or the like

The method of obtaining 3: reductive amination

(In the formula Alk represents lower alkylene, and R10is a bond or C1-5alkylene, and R11represents H or C1-5alkyl. However, the number of carbon atoms in R10and R11in General ranges from 0 to 5. The same applies to the description that follows.)

This method of obtaining is a method in which compound (I-b) according to the present invention receives, subjecting the compound (5) and the compound (6) Voss is univitelinos aminating.

The reaction is carried out using the compound (5) and compound (6) in equivalent amounts or one of them in excess, and with stirring in the presence of a reducing agent and in a reaction-inert solvent at temperatures from -45°C to the boiling temperature under reflux, preferably at a temperature from 0°C to room temperature, usually in a period of time from 0.1 hour to 5 days. As the solvent in this case, for example, you can specify alcohols, ethers, or their mixtures. As reducing agent, you can specify cyanoborohydride sodium, triacetoxyborohydride sodium, sodium borohydride and the like In some cases, preferably the reaction in the presence of a dehydrating agent such as molecular sieves or the like, or acid, such as acetic acid, hydrochloric acid, a complex of isopropoxide titanium(IV) or the like, depending on the reaction, when Eminova connection, which is formed in the reaction system as an intermediate connection, you can select a stable manner, the reaction of recovery can be performed separately after receipt iminovogo connection.

The method of obtaining 4: amidation

This method of obtaining is a method in which compound (I-c) what about the present invention receives, subjecting the compound (7) and the compound (6) to amidation.

Instead carbonbearing connection (7) you can also use its reactive derivative. The reaction may be carried out using carbonbearing compound (7) or its reactive derivative and the amino compounds (6) in equivalent amounts or one of them in excess, while cooling, at room temperature or under heating in a solvent such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1-methylpyrrolidine-2-he (NMP), dimethylsulfoxide (DMSO), ethyl acetate, pyridine, acetonitrile or the like

When used carbonisation connection (7), it is preferable to use N,N'-dicyclohexylcarbodiimide (DCC), PS-carbodiimide (Argonaut, USA), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC), 1,1'-carbonimidoyl (CDI), N,N'-disuccinimidyl, Bop reagent (Aldrich, USA), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrafluoroborate tetramethylurea (TBTU), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), azide diphenylphosphinic acid (DPPA), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium (DMT-MM) or the like as a condensing agent and, in some cases, the additional use of 1-hydroxybenzotriazole ((HOBt), N-guide is oxysuccinimide (HONSu), 1-hydroxy-7-asobancaria ((HOAt) or the like as an agent.

As the reactive derivative carbonbearing connection (7) you can specify as an example, halogenmethyl acid (the acid chloride acid, bromohydrin acid or the like), acid anhydride (mixed acid anhydride obtained by the interaction with atilglukuronida, benzylcarbamoyl, phenylcarbamates, p-toluensulfonate acid, isovalerianic acid, and the like, or a symmetric acid anhydride, an active ester (ester obtained using phenol, HOBt, HONSu or the like, which may be substituted by an electron-acceptor group such as the nitro-group, a fluorine atom or the like), lower alkilany ester, acid azide, etc. These reactive derivatives can be obtained by the General methods.

Depending on the type of reaction to ensure the smooth progress of the reaction is sometimes advantageous implementation of the reaction in the presence of a base, such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine (DMAP) or similar

The method of obtaining 5: other ways to get

In addition, some compounds represented by formula (I)can also be obtained from the compounds of the present invention obtained as described above, in an optional combination is traditionally known methods of amidation, oxidation, hydrolysis, etc. that can normally use the experts in this field. For example, you can use the following response.

5-1: amidation

The amidation can be performed in the same way as in method 4.

5-2: oxidation

Sulfoxide connection or sulfonic compound can be obtained by oxidation of the S atom of sulfide compounds in various oxidation agents. The reaction can be performed, for example, under cooling, at room temperature or under heating using an equivalent amount or excess amount of m-chloroperbenzoic acid, peracetic acid, aqueous solution of hydrogen peroxide, reagent Dess-Martin (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoyloxy-3(1H)-one) or the like as an oxidant in a solvent such as halogenated hydrocarbons, acetic acid, water or the like

5-3: hydrolysis

The compound containing carboxyl group, can be obtained by hydrolysis of compounds containing ester group. For example, this can be done at a temperature of from cooling to heating in a reaction-inert solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water or the like, in the presence of a mineral acid, such as sulfuric acid, chlorine is standardna acid, Hydrobromic acid or the like, or organic acids such as formic acid, acetic acid or the like, or the like; or in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonia or the like

(The means of obtaining the source connections)

Source materials for use in obtaining the compounds of the present invention can be obtained, for example, using the following methods, the methods described in the examples of the preparation, which is described later, is traditionally known methods or ways obvious to a person skilled in this field, or methods, which is a modification of these methods.

Synthesis of starting compounds

Synthesis of the starting compounds 1: O-alkylation

(In the formula Lv3represents-OH or delete a group, such as halogen, methanesulfonate, p-toluensulfonate or the like, The same applies to the description that follows.)

This method of obtaining is a method in which the compound (10) obtained by O-alkylation of compound (8) with compound (9).

When used as a compound (8)in which Lv3represents-OH, the synthesis can be performed using General method for the reaction of CIS is Nobu, normally used by experts in this field. For example, it can be done using the activating agent derived from phosphorus compounds (for example, tributylphosphine, triphenylphosphine or the like) and azodicarbonamide connection (for example, diethylazodicarboxylate, 1,1'-(azodicarbon)dipiperidino or the like), or using cyanomethylphosphonate or other reagent in a solvent such as halogenated hydrocarbons, ethers, aromatic hydrocarbons or the like, under cooling, at room temperature or when heated.

When used as a compound (8)in which Lv3represents a removable group, such as halogen, methanesulfonate, p-toluensulfonate or the like, synthesis, for example, can be carried out using the compound (8) and compound (9) in equivalent amounts or one of them in excess, in the presence of a base such as potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride or the like, in a solvent such as halogenated hydrocarbons, ethers, aromatic hydrocarbons or the like, DMF or the like, under cooling, at room temperature or when heated.

Synthesis of the starting compounds 2

First stage: the formation of oxime

This article is Diya, where the compound (12) are obtained, subjecting the compound (11) the reaction of formation of the oxime.

With regard to the formation of the oxime, you can use the method of formation of the oxime, usually used by the experts in this field. For example, this can be done using the compounds (11) and hydroxylamine or its salts in equivalent amounts or one of them in excess amount in a solvent such as alcohols, acetic acid, pyridine, water or the like, under cooling, at room temperature or when heated. Depending on the type of connection in some cases to ensure the development of the reaction is advantageous to add sodium acetate, p-toluensulfonate acid or the like

Second stage: recovery

This is the stage in which the compound (1) is produced by reconnection (12).

As for the reduction reaction of the oxime, you can use the recovery method oxime, usually used by the experts in this field. For example, this can be done using the compounds (12) and a reducing agent, such as a complex of borane-pyridine, cyanoborohydride sodium or the like, in equivalent amounts or one of them in excess amount in a solvent such as ethers, alcohols, aromatic hydrocarbons, acetic acid sludge is so, while cooling, at room temperature or when heated.

The compound of the present invention, thus obtained, is isolated and purified directly as such or as a salt of such a compound, using conventional processing for the formation of salts. Isolation and purification carried out using a General chemical procedures such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, etc.

Different types of isomers can be distinguished in the usual way using the differences in physicochemical properties between the isomers. For example, the racemic mixture can be converted to optically pure isomer by using a General method of separation of racemic mixtures, such as, for example, the way in which such compounds are converted into diastereomeric salt with an optically active acid such as tartaric acid or the like, and then subjected to optical separation. Also diastereomer mixture can be divided, for example, by fractionated crystallization or various types of chromatography. In addition, the optically active compound can also be obtained using the corresponding optically active compounds as source materials.

Farmatsevticheskiy the composition, which contains one or more compounds of the present invention or their pharmaceutically acceptable salts as the active ingredient are in the form of tablets, powders, fine chemicals, granules, capsules, pills, solutions, injections, suppositories, ointments, plasters, etc. using carriers, fillers and other additives are commonly used to obtain pharmaceutical preparations and administered orally or parenterally.

Clinical dose of the compound of the present invention for a person, not necessarily, determined with regard to symptoms, age, sex, etc. of each patient, but in the case of oral administration the daily dose is generally from about 0.0001 to 50 mg/kg, preferably from about 0.001 to 10 mg/kg, even more preferably from 0.01 to 1 mg/kg, and administered as a single dose or divided into 2-4 parts. In the case of intravenous administration, the daily dose per body weight is from about 0.0001 to 1 mg/kg, preferably from about 0.0001 to 0.1 mg/kg, and administered as a single dose or divided into two or more injections per day. Since the dose varies depending on various conditions, in some cases, a satisfactory effect is obtained by using lower quantities than the above dose limits.

As the firmness of the DOI composition for oral administration according to the present invention using pills, powders, granules, etc. In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum-magnesium silicate or the like Typically the composition may contain other additives, in addition to the inert diluent, such as lubricants (e.g. magnesium stearate or the like), baking powder (for example, the glycolate, calorically or the like), a stabilizer, solubilizer substance, etc. If necessary, tablets or pills may be coated, such as sugar coating or film coating of the gastro - or Intercollege substances, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or similar

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as distilled water or ethanol (EtOH). In addition to the inert diluent, this composition may contain a wetting agent, suspendisse substance and such auxiliary substances, as well as sweeteners, flavors, fragrances and preservatives.

As preparations DL the injections for parenteral administration are included in the invention aseptic aqueous or non-aqueous solutions, suspensions and emulsions. As aqueous solutions and suspensions, for example, included distilled water for injection and physiological saline. As non-aqueous solutions and suspensions, for example, use propylene glycol, polyethylene glycol, vegetable oil (such as olive oil or the like), alcohols (e.g., EtOH or the like), Polysorbate 80 and the like, Such a composition may further contain auxiliary substances, such as antiseptics, wetting agent, emulsifier, dispersing agent, stabilizer, solubilizer substance or the like, They are sterilized, for example, by filtration through a retaining bacteria filter, mixing with a bactericidal substance or radiation. They can also be used by obtaining solid compositions and dissolving them in sterile water or a sterile solvent for injection before use.

As external preparations included ointments, solid creams, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, etc. Such drugs include commonly used basis for ointments, the basis for a lotion, an aqueous or non-aqueous solutions, suspensions, emulsions and the like, for Example, as the basis for ointment or lotion you can specify as an example, polyethylene glycol, propylene glycol, petrolatum, white beeswax, polyoxyethylene-hydrogenomonas to Stanovoi oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, servicesecurity etc.

Preparations for inhalation, preparations for the introduction of a mucous membrane, such as drugs for insertion through the nose and so on, used in solid, liquid or semi-solid form and can be obtained in accordance with the traditionally known ways. For example, you can add, but not necessarily, traditionally known filler and, in addition, the agent regulating pH, antiseptic, surfactant, lubricant, stabilizer, thickener, etc. For introduction you can use the appropriate device for inhalation or insufflation. For example, using a measuring device for administration by inhalation or similar traditionally known device or Spreebogen device connection can be entered separately or in the form of powder formulated mixture, or in the form of a solution or suspension by combining with acceptable from a medical point of view, the media. Inhaler dry powder or the like may be designed for single or multiple applications, and you can use powder or containing powder capsule. Alternatively, it may be pressurized aerosol spray or similar form, which is used chlorphenesin, hydrofluroalkane dioxide or of plastics technology : turning & the Yes or similar suitable gas.

EXAMPLES

The following is an illustrative description of the present invention based on examples, but the present invention is not limited to these examples. In this regard, because new substances are included in the initial compounds for use in these examples, methods of obtaining such starting compounds described as the examples of receipt.

In this regard, use the following abbreviations in the examples and tables. Prol.: the number of sample receipt, Etc.: the number of the example, n: number of connections, P.: structural formula (When in the structural formula is HCl, this means that the compound is a hydrochloride.), Sint.: the method of obtaining (when specified numbers only, they show the number of the example in which the connection get in the same way, and when the figure is R, it indicates the number of sample receipt, in which connection receive in the same way, respectively). Data: physicochemical data (AMR: δ (ppm) data1H NMR in DMSO-d6, AMR: δ (ppm) data1H NMR in CDCl3, FAB: FAB-MS (cation), FAB-N; FAB-MS (anion), ESI: ESI-MS (cation), ESI-N: ESI-MS (anion), EI: EI-MS (cation), CI: CI-MS (cation)), Me: methyl, Et: ethyl, Ac: acetyl, TBS: tert-butyldimethylsilyl, Boc: tert-butoxycarbonyl, Ts: p-toluensulfonyl.

Example obtain 1

By adding thionyl chloride and DMF to 1-(2,6-dimetilfenil)oxo-1,6-dihydropyridin-3-carboxylic acid and stirring the reaction mixture at 60°C for 2 hours was obtained 1-(2,6-dimetilfenil)-6-oxo-1,6-dihydropyridin-3-carbonylchloride. The obtained 1-(2,6-dimetilfenil)-6-oxo-1,6-dihydropyridin-3-carbonylchloride was dissolved in DMF was added sodium borohydride under ice cooling, followed by stirring for 0.5 hours to obtain 1-(2,6-dimetilfenil)-5-(hydroxymethyl)pyridine-2(1H)it.

Example of getting 2

Under nitrogen atmosphere a solution of 1.0 M diisobutylaluminium in THF was added dropwise at -78°C to a solution in THF methyl 1-(2,6-dimetilfenil)-6-oxo-1,6-dihydropyridines-3-carboxylate. After stirring at -78°C for 2 hours the temperature was raised to 0°C, followed by stirring at 0°C for 1.5 hours. The reaction mixture was heated to room temperature, followed by stirring at room temperature for 2 hours. A solution of 1.0 M diisobutylaluminium in THF was added dropwise to the reaction mixture at 0°C followed by warming to room temperature and stirring for 1 hour to obtain methyl 1-(2,6-dimetilfenil)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate. In the atmosphere of nitrogen sociallyengaged was added to the obtained methyl 1-(2,6-dimetilfenil)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate while cooling in an ice bath-methanol. Then, while stirring the reaction mixture for 2 hours while heated to the boiling temperature under reflux was obtained [1-(2,6-dim is terphenyl)piperidine-3-yl]methanol.

Example of getting 3

By adding tert-butyl(dimethyl)similiarity to a solution in DMF 4'-hydroxy-2',6'-dimethylbiphenyl-3-carbaldehyde and imidazole and under stirring at room temperature for 10 hours was obtained 4'-{[tert-butyl(dimethyl)silyl]oxy}-2',6'-dimethylbiphenyl-3-carbaldehyde.

Example 4

In nitrogen atmosphere n-utility (solution in hexane) was added at -75°C to a solution in THF (4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane, followed by stirring at -75°C for 1 hour. To the reaction mixture was added triisopropylsilyl, followed by stirring at room temperature for 30 minutes. The reaction mixture was treated with hydrochloric acid to obtain (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)Bronevoy acid.

Example of getting 5

Under nitrogen atmosphere a mixture of methyl 3-bromo-2-methylbenzoate, bis(pinacolato)Debora, dichloride bis(triphenylphosphine)palladium(II), triphenylphosphine, tribalista and dioxane was stirred at 100°C for 3 days with obtaining, thus, methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

An example of obtaining 6

Under nitrogen atmosphere a mixture of (2,6-dimetilfenil)Bronevoy acid, ethyl 3-bromobenzoate, tetrakis(triphenylphosphine)palladium aqueous solution of 1 M sodium carbonate, toluene and ethanol p is remedial when heated at 80°C with obtaining, thus, ethyl 2',6'-dimethylbiphenyl-3-carboxylate. A mixture of ethyl 2',6'-dimethylbiphenyl-3-carboxylate, aqueous 1 M sodium hydroxide and ethanol was stirred under heating at 60°C with obtaining, thus, 2',6'-dimethylbiphenyl-3-carboxylic acid.

Example of getting 7

In the atmosphere of nitrogen, tetrakis(triphenylphosphine)palladium were added to a mixture of 2-bromo-1,3-xylene, (5-formyl-2-methoxyphenyl)Bronevoy acid, aqueous solution of 1M sodium carbonate, ethanol and dimethoxyethane, followed by stirring at 80°C for 25 hours to obtain 6-methoxy-2',6'-dimethylbiphenyl-3-carbaldehyde.

Example obtain 8

Triftormetilfullerenov anhydride was added dropwise under ice cooling to a mixture of 4-hydroxy-3,5-dimethylbenzonitrile, pyridine and dichloromethane, followed by stirring at room temperature for 2 hours to obtain 4-cyano-2,6-dimethylbenzenesulfonyl. Under nitrogen atmosphere a mixture of 4-cyano-2,6-dimethylbenzenesulfonyl, (3-formylphenyl)Bronevoy acid, palladium acetate, DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine, tribalista, toluene and water was stirred at room temperature for 6 hours with 3'-formyl-2,6-dimethylbiphenyl-4-carbonitrile.

Example of getting 9

Under nitrogen atmosphere a mixture of methyl 2-methyl-3-(4,4,5,5-tetramethyl-,3,2-dioxaborolan-2-yl)benzoate, 4-bromo-3,5-dimethylphenol, palladium acetate, DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine, tribalista, toluene and water was stirred for 14,5 hours while heating at 60°C to obtain methyl 4'-hydroxy-2,2',6'-trimethylphenyl-3-carboxylate.

Example 10

Under nitrogen atmosphere a mixture of (4-{[tert-butyl(dimethyl)silyl]oxy}-2,6-dimetilfenil)Bronevoy acid, 6-bromopyridin-2-carbaldehyde, palladium acetate, 2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, tribalista, toluene and water was stirred for 20 hours under heating at 60°C with obtaining, thus, 6-(4-{[tert-butyl(dimethyl)silyl]oxy}-2,6-dimetilfenil)pyridine-2-carbaldehyde.

Example of getting 11

In nitrogen atmosphere under ice cooling sodium borohydride was added to the ethanol solution of 4'-chloro-2'-methylbiphenyl-3-carbaldehyde, followed by stirring for 1 hour to obtain (4'-chloro-2'-methylbiphenyl-3-yl)methanol.

Example 12

In nitrogen atmosphere under ice cooling methyl 4'-(methylsulphonyl) - biphenyl-3-carboxylate was added to the suspension in THF of sociallyengaged, followed by stirring for 20 minutes to obtain [4'-(methylsulphonyl) - biphenyl-3-yl]methanol.

Example of getting 13

Under nitrogen atmosphere a mixture of methyl 3-bromo-4-chlorobenzoate, (2,6-dimetilfenil)Bronevoy acid chloride l is ment, sodium carbonate, water, ethanol, dimethoxyethane and tetrakis(triphenylphosphine)palladium was stirred at 90°C for 15 hours with obtaining, thus, methyl 6-chloro-2',6'-dimethylbiphenyl-3-carboxylate. Sociallyengaged was added under ice cooling to a solution in THF obtained methyl 6-chloro-2',6'-dimethylbiphenyl-3-carboxylate followed by warming to room temperature and stirring for 2 hours to obtain (6-chloro-2',6'-dimethylbiphenyl-3-yl)methanol.

Example of getting 14

In nitrogen atmosphere tetranitropentaerithrite was added to a mixture of 2-bromo-1,3-xylene, 2-fluoro-5-formylphenylboronic acid, aqueous solution of 1M sodium carbonate, ethanol and toluene, followed by stirring at 80°C for 8 hours to obtain 6-fluoro-2',6'-dimethylbiphenyl-3-carbaldehyde. When cooled in a bath of ice-methanol, sodium borohydride was added in small portions to the ethanol solution of the obtained 6-fluoro-2',6'-dimethylbiphenyl-3-carbaldehyde and the reaction mixture was stirred at the same temperature for 1 hour to obtain (6-fluoro-2',6'-dimethylbiphenyl-3-yl)methanol.

Example get 15

Thionyl chloride was added to (4'-chloro-2'-methylbiphenyl-3-yl)methanol while cooling using ice baths-methanol, followed by stirring at room temperature for 1 hour from receipt of the m 4-chloro-3'-(chloromethyl)-2-methylbiphenyl.

Example 16

Potassium carbonate was added to a solution in DMF 4-chloro-3'-(chloromethyl)-2-methylbiphenyl and 4-hydroxybenzaldehyde, followed by stirring at room temperature for 20 hours to obtain 4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]benzaldehyde.

Example of getting 17

Tributylphosphine and 1,1'-(azodicarbon)piperidin was added to a solution in THF (4-{[tert-butyl(dimethyl)silyl]oxy}-2',6'-dimethylbiphenyl-3-yl)methanol and 4-hydroxybenzaldehyde, followed by stirring at room temperature for 14 hours to obtain 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2',6'-dimethylbiphenyl-3-yl)methoxybenzaldehyde.

Example of getting 18

In nitrogen atmosphere sodium hydride was added under ice cooling to a solution in THF (2',6'-dimethylbiphenyl-3-yl)methanol, followed by stirring at the same temperature for 15 minutes. Then to the reaction mixture were added 6-chloronicotinamide under ice cooling followed by warming to room temperature and stirring for 3 hours to obtain 6-[(2',6'-dimethylbiphenyl-3-yl)methoxy]nicotinanilide.

Example of getting 19

Under nitrogen atmosphere a solution of 1.0 M diisopropylaminoethyl in toluene was added dropwise at -78°C to a toluene solution of 6-[(2',6'-dimethylbiphenyl-3-yl)methoxy]nicotinanilide followed the by stirring at -78°C for 1.5 hours to obtain 6-[(2',6'-dimethylbiphenyl-3-yl)methoxy]nicotinanilide.

Example of getting 20

Under nitrogen atmosphere a solution in THF methyl 4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]-2-perbenzoate was added dropwise to the suspension in THF of sociallyengaged under cooling in an ice bath-methanol, followed by stirring at room temperature for 1 hour to obtain 4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]-2-fermentelos alcohol. Adding manganese dioxide to a solution in THF obtained 4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]-2-fermentelos alcohol and under stirring at 40°C for 17 hours was obtained 4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]-2-forbindelse.

Example of getting 21

In nitrogen atmosphere sodium borohydride was added to a methanol solution of 4-{[2',6'-dimethyl-4'-(2-oxopropoxy)biphenyl-3-yl]methoxy}benzaldehyde under ice cooling, followed by stirring at room temperature for 2 hours to obtain 1-[(-3'-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]propan-2-ol. Adding chloroform manganese dioxide to the resulting connection and under stirring at 60°C for 5 hours was obtained 4-{[4'-(2-hydroxypropoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzaldehyde.

Example of getting 22

Methanesulfonamide was added dropwise under ice cooling to a mixture of 4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, is ritilin and ethyl acetate, followed by stirring at 0°C for 2 hours with 3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-ylmethanone.

An example of retrieving 23

A mixture of 4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, 2-Bromeliaceae, cesium carbonate and DMF was stirred at 60°C for 21 hours to obtain 2-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)acetic acid ethyl ester.

Example of getting 24

Under nitrogen atmosphere a mixture of 2-hydroxyethylacrylate, sodium hydride and DMF was stirred at room temperature for 15 minutes and then was added 1-bromo-4-fluoro-2-(trifluoromethyl)benzene, followed by stirring at room temperature for 1.5 hours to obtain 2-[4-bromo-3-(trifluoromethyl)phenoxy]ethanol.

Example get 25

Methanesulfonamide was added dropwise to a mixture of 1-(3-hydroxypropyl)pyrrolidin-2-it, triethylamine and ethyl acetate under ice cooling, followed by stirring at 0°C for 2 hours to obtain a colorless oil. 4-[(4'-Hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, cesium carbonate and DMF was added to the obtained oil, followed by stirring under heating at 60°C for 19 hours to obtain 4-({2',6'-dimethyl-4'-[3-(2-oxopyrrolidin-1-yl)propoxy]biphenyl-3-yl}methoxy)benzaldehyde.

Example of getting 26

Under nitrogen atmosphere a solution in THF of methylmagnesium was added dropwise under ice cooling to a solution in THF 1-[(3'-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dime iluvenis-4-yl)oxy]acetone, followed by stirring at room temperature for 30 minutes to obtain 1-[(3'-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]-2-methylpropan-2-ol.

Example of getting 27

A mixture of 1-[(3'-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]-2-methylpropan-2-ol, manganese dioxide and chloroform was stirred under heating at 50°C for 20 hours to obtain 4-{[4'-(2-hydroxy-2-methylpropoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzaldehyde.

Example of getting 28

A mixture of 4-{[4'-(3-hydroxypropoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzaldehyde, acetylchloride, triethylamine and dichloromethane was stirred at room temperature for 3.5 hours to obtain 3-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)propyl.

An example of obtaining 29

A mixture of 4-{[4'-(3-hydroxy-3-methylbutoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzaldehyde, acetic anhydride, pyridine, DMAP and chloroform was stirred at room temperature for 2 days to obtain 3-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)-1,1-dimethylpropyleneurea.

Example 30

A solution of 4 M hydrogen chloride in ethyl acetate was added dropwise under ice cooling to a solution of ethyl acetate tert-butyl [2-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]carbamate, followed by stirring at 0°C for 2 hours. Dichloromethane, acetylchloride and triethylamine was added to the obtained compound, followed by stirring at room temperature the re for 12 hours to obtain N-[2-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]ndimethylacetamide.

An example of retrieving 31

Triftormetilfullerenov anhydride was added dropwise under ice cooling to a mixture of 4-[(4'-hydroxy-2,2'-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, pyridine and dichloromethane, followed by stirring at 0°C for 1 hour with 3'-[(4-formylphenoxy)methyl]-2,2'-dimethylbiphenyl-4-intraformational.

Example of getting 32

Hydroxylamine hydrochloride and an aqueous solution of sodium acetate was added to the ethanol solution of 4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]benzaldehyde, followed by stirring at room temperature for 18 hours to obtain 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2',6'-dimethylbiphenyl-3-yl)methoxy]benzaldehyde. Cyanoborohydride sodium was added to a mixed solution of methanol-THF obtained 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2',6'-dimethylbiphenyl-3-yl)methoxy]benzaldehyde and then to the mixture was added dropwise a solution of 4 M hydrogen chloride in dioxane, followed by stirring at room temperature for 1 hour to obtain N-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2',6'-dimethylbiphenyl-3-yl)methoxy]benzyl)hydroxylamine.

An example of obtaining 33

In the atmosphere of nitrogen TRIFLUORIDE complex of sulfur and diethylamine was added dropwise at -75°C to a solution in methylene chloride; 4-(4-bromo-3-methylphenoxy)-2-methylbutane-2-ol and the temperature is raised to room temperature to obtain 1-bromo-4-(3-fluoro-3-methylbutoxy)-2-methylbenzene.

An example of retrieving 34

Under nitrogen atmosphere a mixture of 1-bromo-4-(3-fluoro-3-methylbutoxy)-2-methylbenzene, methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, palladium acetate, DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine, tribalista, toluene and water was stirred at 80°C for 12 hours to obtain methyl 4'-(3-fluoro-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-carboxylate. Sociallyengaged was added to a solution in THF obtained methyl 4'-(3-fluoro-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-carboxylate under ice cooling followed by warming to room temperature and stirring for 1 hour to obtain [4'-(3-fluoro-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-yl]methanol.

Example of getting 35

In nitrogen atmosphere sodium hydride was added under ice cooling to a mixture of 5-bromo-4-methylpyridin-2-ol and DMF, followed by stirring at room temperature for 1 hour. Then to the mixture was added 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate, followed by stirring at 40°C for 14 hours to obtain 4-[(5-bromo-4-methylpyridin-2-yl)oxy]2-methylbutane-2-ol and 5-bromo-1-(3-hydroxy-3-methylbutyl)-4-methylpyridin-2(1H)-it.

Example of getting 36

Under nitrogen atmosphere a mixture of (4-{[tert-butyl(dimethyl)silyl]oxy}-2-were)Bronevoy acid, 6-[(3-bromo-2-methylbenzyl)oxy]nicotinanilide, acetate palla is Oia, of DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine, tribalista, toluene and water was stirred while heating at 60°C for 2 days to obtain 6-[(4'-{[tert-butyl(dimethyl)silyl]oxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]nicotinanilide.

An example of retrieving 37

Under nitrogen atmosphere a mixture of tert-butyl[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]dimethylsilane, 6-[(3-bromo-2-methylbenzyl)oxy]nicotinanilide, palladium acetate, DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine, tribalista, toluene and water was stirred while heating at 60°C for 3 days to obtain 6-[(4'-{[tert-butyl(dimethyl)silyl]oxy}-2,2',6'-trimethylphenyl-3-yl)methoxy]nicotinanilide.

An example of retrieving 38

In nitrogen atmosphere tert-piperonyl potassium was added under ice cooling to a mixture of cyclobutanone, ethylchloride and THF for 40 minutes, followed by stirring at 0°C for 2 hours, raising the temperature to room temperature, and with stirring at room temperature for 1 day with obtaining, thus, ethyl 1-oxaspiro[2,3]hexane-2-carboxylate. A solution of the obtained ethyl 1-oxaspiro[2,3]hexane-2-carboxylate in diethyl ether was added to the suspension sociallyengaged in THF under ice cooling in a nitrogen atmosphere, followed by stirring at room temperature for 7 hours with what rucenim 1-(2-hydroxyethyl)cyclobutanol. The mixture obtained 1-(2-hydroxyethyl)cyclobutanol, 4-methylbenzenesulfonamide, triethylamine and THF was stirred at room temperature for 16 hours to obtain 2-(1-hydroxycyclopent)ethyl 4-methylbenzenesulfonate.

In the same way as in the above examples of ways of obtaining 1-38, obtained compounds of examples obtain 39-299 using appropriate starting compounds, respectively. The structure of the compounds of examples of the preparation are presented in tables 4-44 and methods of preparation and physico-chemical data in tables 45-52.

Example 1

Chlorocarbonylsulfenyl (0.10 ml) was added dropwise under cooling in an ice bath-methanol to a solution in THF (10 ml) of N-{4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]benzyl}hydroxylamine (430 mg) and the temperature was raised to room temperature, followed by stirring for 1 hour. To the reaction mixture solution was added 1 M hydrochloric acid (30 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. By purifying the obtained residue using column chromatography on silica gel (chloroform-methanol) was obtained a colorless foamy substance. The obtained foamy substance was dissolved in ethanol (5 ml) and to the mixture was added water rest is R 1 M sodium hydroxide (1,06 ml) followed by concentration under reduced pressure. By recrystallization of the resulting residue from water-isopropanol received sodium 2-{4-[(4'-chloro-2'-methylbiphenyl-3-yl)methoxy]benzyl}is 3.5-dioxo-1,2,4-oxadiazolidine-4-ID (347 mg) as colorless crystals.

Example 2

Chlorocarbonylsulfenyl (0,14 ml) was added dropwise under cooling in an ice bath-methanol to a solution in THF (15 ml) of 4-({[3'-({4-[(hydroxyamino)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (792 mg), followed by raising the temperature to room temperature and then stirring for 1 hour. To the reaction mixture solution was added 1 M hydrochloric acid (40 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. By purifying the obtained residue using column chromatography on silica gel (chloroform-methanol) was obtained colorless foamy substance (777 mg). The sodium methoxide (50 mg) was added to a methanol solution (10 ml) of the obtained foamy substance (116 mg), followed by stirring at room temperature for 30 minutes. Then to the mixture was added sodium methoxide (200 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was heated to 60°C, stirred for 2 hours and then spontaneously about what was ladli to room temperature. To the reaction mixture solution was added 1 M hydrochloric acid (10 ml) and water (20 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was dissolved in methanol (5 ml)-THF (10 ml) was added an aqueous solution of 1 M sodium hydroxide (0,20 ml) followed by concentration under reduced pressure. By washing the obtained residue with a mixture of isopropanol-diethyl ether there was obtained sodium 2-[4-({4'-[(4-hydroxycitrate-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methoxy)benzyl] - for 3,5-dioxo-1,2,4-oxadiazolidine-4-ID (80 mg) as a pale yellow solid.

Example 3

Chlorocarbonylsulfenyl (0,14 ml) was added dropwise under cooling in an ice bath-methanol to a solution in THF (15 ml) of 4-({[3'-({4-[(hydroxyamino)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (792 mg), followed by raising the temperature to room temperature and further stirring for 1 hour. To the reaction mixture solution was added 1M hydrochloric acid (40 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. By purifying the obtained residue using column chromate is graphy on silica gel (chloroform-methanol) was obtained colorless foamy substance (777 mg). When cooled in a bath of ice-methanol m-chloroperbenzoic acid (630 mg) was added to a solution in chloroform (20 ml) of the obtained foamy substance (600 mg), followed by stirring for 30 minutes. To the reaction mixture were added water (20 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. By purifying the obtained residue using column chromatography on silica gel (chloroform-methanol) was obtained colorless foamy substance (510 mg). The obtained foamy substance (510 mg) washed with diisopropyl ether-ethyl acetate-hexane and dried under reduced pressure to obtain a slightly yellowish solid (432 mg). The sodium methoxide (800 mg) was added to a methanol solution (30 ml) obtained a slightly yellowish solid (387 mg), followed by stirring at 60°C for 2 hours and then spontaneous cooling to room temperature. To the reaction mixture solution was added 1 M hydrochloric acid (30 ml) and water (50 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was dissolved in methanol (5 ml)-THF (15 ml), was added an aqueous solution of 1 M hydroxide is the atrium (0.63 ml) followed by concentration under reduced pressure. By washing the obtained residue with a mixture of isopropanol-diethyl ether there was obtained sodium 2-[4-({4'-[(4-hydroxy-1,1-dioxotetrahydrofuran-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methoxy)benzyl] - for 3,5-dioxo-1,2,4-oxadiazolidine-4-ID (252 mg) as colorless solids.

Example 4

A mixture of 2-{4-[(3-bromobenzyl)oxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (500 mg), 2,6-debtor-4-methoxyphenylacetic acid (325 mg), tetranitroaniline (80 mg), lithium chloride (6 mg), aqueous sodium carbonate (562 mg/5 ml), ethanol (5 ml) and 1,2-dimethoxyethane (25 ml) was stirred at 90°C for 5 hours in nitrogen atmosphere. To the reaction mixture was again added 2,6-debtor-4-methoxyphenylalanine acid (325 mg), followed by stirring at 90°C for 13 hours. To the reaction mixture were added the following additional amount of 2,6-debtor-4-methoxyphenylacetic acid (325 mg), followed by stirring at 90°C for 2 hours. To the reaction mixture were added the following additional amount of 2,6-debtor-4-methoxyphenylacetic acid (325 mg), followed by stirring at 90°C for 5 hours and spontaneous cooling to room temperature. To the reaction mixture solution was added 1 M hydrochloric acid (50 ml) followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution x is orida sodium and then dried over anhydrous magnesium sulfate and filtered. To the filtrate was added silica gel (3 g), followed by concentration under reduced pressure. The product, thus obtained, was purified using column chromatography on silica gel (chloroform-methanol) to obtain the yellow foamy substance (614 mg). The obtained foamy substance (614 mg) was dissolved in THF (5 ml)-ethanol (5 ml), was added an aqueous solution of 1 M sodium hydroxide (1,32 ml) followed by concentration under reduced pressure. By recrystallization of the resulting residue from isopropanol-water received sodium 2-{4-[(2',6'-debtor-4'-methoxybiphenyl-3-yl)methoxy]benzyl}is 3.5-dioxo-1,2,4-oxadiazolidine-4-ID (366 mg) as colorless solids.

Example 5

An aqueous solution of 1 M sodium hydroxide (5 ml) was added to a mixture of methyl 3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylic (196 mg), methanol (5 ml) and THF (5 ml) followed by stirring for 1 hour while heating at 60°C. To the reaction mixture solution was added 1 M hydrochloric acid (7 ml), followed by stirring at room temperature. The precipitated solid was collected by filtration and dried by heating under reduced pressure to obtain 3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-4-biphenylcarbonic acid (176 mg) as a white solid.

<> Example 6

WSC hydrochloride (163 mg) was added to a mixture of 3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-4-biphenylcarbonic acid (293 mg), (2-ethoxyethyl)amine (0,11 ml), HOBt (142 mg) and DMF (10 ml) followed by stirring at room temperature for 27 hours. The solvent is evaporated under reduced pressure and to the residue was added chloroform/methanol (4/1) with subsequent washing with water and saturated aqueous ammonium chloride. The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (chloroform/methanol)obtained foamy substance was then led by adding diethyl ether and the resulting crystals are recrystallized from methanol to obtain 3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-N-(2-ethoxyethyl)-4-biphenylcarboxylic (135 mg) as white crystals.

Example 7

DMT-MM (653 mg) was added to ice a mixture of 3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-4-biphenylcarbonic acid (329 mg), 2-aminoethanol (0,14 ml), THF (20 ml) and methanol (4 ml), followed by stirring at room temperature for 25 hours. The solvent is evaporated under reduced pressure and to the residue was added a saturated aqueous solution of ammonium chloride followed by extraction with chloroform/what ethanol (4/1). The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (chloroform-methanol). The obtained pale-yellow solid (276 mg) was dissolved in THF (5 ml)-methanol (5 ml) was added an aqueous solution of 1 M sodium hydroxide (0,79 ml) followed by stirring at room temperature for 10 minutes. The precipitated solid was collected by filtration and dried by heating under reduced pressure to obtain sodium 2-{4-[(4'-{[(2-hydroxyethyl)amino]carbonyl}biphenyl-3-yl)methoxy]benzyl}is 3.5-dioxo-1,2,4-oxadiazolidine-4-IDA (188 mg) as a white solid.

Example 8

A solution of 1.0 M tetrabutylammonium (TBAF) in THF (1,94 ml) was added dropwise to ice a mixture of 2-(4-{[4'-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)biphenyl-3-yl]methoxy}benzyl-1,2,4-oxadiazolidine-3,5-dione (532 mg) and THF (10 ml), followed by a gradual temperature increase to room temperature and further stirring for 13 hours. The reaction mixture was diluted with chloroform/methanol (4/1) and washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The solvent is then evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform-methanol) and the resulting solid substances is about recrystallized from ethyl acetate-hexane-diethyl ether to obtain 2-(4-{[4'-(2-hydroxyethoxy)-3-biphenyl]methoxy}benzyl-1,2,4-oxadiazolidine-3,5-dione (171 mg) as white crystals.

Example 9

Hydroxylamine hydrochloride (12,85 g) and an aqueous solution of sodium acetate (19, 22 the g/110 ml) was added to ethanol (800 ml) suspension of 4-[(3-bromobenzyl)oxy]benzaldehyde (17,94 g), followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added water (100 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain a colorless solid matter (19,94 g). To a solution in methanol (350 ml)-THF (350 ml) of the obtained colorless solid (19,94 g) was added cyanoborohydride sodium (19,36 g). Then a solution of 4 M hydrogen chloride in dioxane (160 ml) was slowly added dropwise while cooling with ice. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture were added an aqueous solution of 1 M sodium hydroxide (700 ml) under ice cooling, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a yellowish solid (25,53 g). Chlorocarbonylsulfenyl (5,00 ml) was added dropwise to a solution in THF (380 ml) of the obtained yellow solid fuel is Dogo substances (25,53 g) under cooling in an ice bath-methanol, followed by stirring at room temperature for 2 hours. To the reaction mixture solution was added 1 M hydrochloric acid (400 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and then dried at 50°C under reduced pressure to obtain 2-{4-[(3-bromobenzyl)oxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (between 6.08 g) as a colourless solid.

Example 10

A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (500 mg), 4'-chloro-2'-methylbiphenyl-3-carbaldehyde (668 mg), acetic acid (0.33 ml) and THF (40 ml) was stirred at room temperature for 24 hours. To the reaction mixture was added triacetoxyborohydride sodium (767 mg), followed by stirring at room temperature for 15 minutes. The solvent is evaporated under reduced pressure and to the residue was added water, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, the solvent evaporated under reduced pressure, to the residue was added toluene and the solvent is again evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane-ethyl acetate) was added in THF (5 ml), methanol (5 ml) and an aqueous solution of 1 M sodium hydroxide (1,47 ml) to the resulting pale yellow foam is breznau substance (620 mg), followed by stirring at room temperature for 5 minutes. The solvent is evaporated under reduced pressure, the residue was purified through ODS column chromatography (water-acetonitrile) and utverjdali by adding diethyl ether. This solid substance was collected by filtration and then dried by heating under reduced pressure to obtain sodium 2-(4-{[(4'-chloro-2'-methylbiphenyl-3-yl)methyl]amino}benzyl)3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (160 mg) as a white solid.

Example 11

A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (365 mg), 2-[(3'-formyl-2,6-dimethylbiphenyl-4-yl)oxy]acetic acid ethyl ester (660 mg), acetic acid (0.3 ml), THF (20 ml) and molecular sieves 4A (1 g) was stirred at room temperature for 22 hours. To the reaction mixture was added triacetoxyborohydride sodium (560 mg), followed by stirring at room temperature for 22 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, to the residue was added toluene, and the solvent is again evaporated under reduced pressure and then the residue was purified using column chromatography on silica gel (hexane-ethyl acetate). Methanol (10 ml) and sodium methoxide (52 mg) was added to the resulting pale yellow is the foamy substance (406 mg), followed by stirring for 2 hours while heating at 60°C. The solvent is evaporated under reduced pressure and to the residue was added chloroform, followed by washing with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and THF (5 ml), methanol (5 ml) and an aqueous solution of 1 M sodium hydroxide (0,81 ml) was added to the resulting pale yellow foamy substance (373 mg), followed by stirring at room temperature for 5 minutes. The solvent is evaporated under reduced pressure, the residue was purified through ODS column chromatography (water-acetonitrile), was obtained a pale yellow foamy substance was converted into a solid by adding diethyl ether. This solid substance was collected by filtration and then dried by heating under reduced pressure to obtain sodium 2-[4-({[4'-(2-hydroxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methyl}amino)benzyl] - for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (226 mg) as a pale yellow solid.

Example 12

A mixture of 3-[(3'-formyl-2,2'-dimethylbiphenyl-4-yl)oxy]-1,1-dimethylpropyleneurea (479 mg), 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (340 mg) and acetic acid (6 ml) was stirred at room temperature for 20 hours. To the reaction solution was added triacetoxyborohydride sodium (573 mg), followed by stirring PR the room temperature for 2 hours. After evaporation of the solvent under reduced pressure the residue was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate) and the mixture obtained pale yellow foamy substance (719 mg), THF (5 ml), methanol (5 ml) and aqueous 1 M sodium hydroxide (4 ml) was stirred at 50°C for 4 hours. pH brought up to 4-5 by adding a solution of 1 M hydrochloric acid followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate) and an aqueous solution of 1 M sodium hydroxide (0,89 ml) was added to the mixture obtained pale-yellow oil (448 mg), THF (3 ml) and methanol (3 ml) followed by stirring for 10 minutes. After evaporation of the solvent under reduced pressure, the obtained residue was washed with diethyl ether to obtain sodium 2-[4-({[4'-(3-hydroxy-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-yl]methyl}amino)benzyl] - for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (398 mg) as a white solid.

Example 13

The mixture is 3-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)propyl (675 mg), of hydroxylamine hydrochloride (217 mg), sodium acetate (307 mg), ethanol (15 ml) and water (4 ml) was stirred at room temperature for 18 hours. The solvent is evaporated under reduced pressure and to the residue was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and to the residue was added acetic acid (5 ml) and cyanoborohydride sodium (196 mg), followed by stirring at room temperature for 7 hours. The reaction system was podslushivaet by adding a saturated aqueous solution of sodium carbonate followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then the solvent is evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform-methanol) and THF (10 ml) was added to the obtained colorless oil (256 mg), followed by ice cooling. To the mixture was added dropwise chlorocarbonylsulfenyl (0.05 ml) followed by stirring for a 15.5 hours at room temperature. The solvent is evaporated under reduced pressure and to the residue was added chloroform, followed by washing with a solution of 1 M hydrochloric acid and nasy the n aqueous solution of sodium chloride. The solvent is evaporated under reduced pressure, the residue was purified using column chromatography on silica gel (hexane-ethyl acetate) and to the resulting colorless oil (242 mg) was added methanol (10 ml) and sodium methoxide (92 mg), followed by stirring under heating at 60°C for 2 hours. The solvent is evaporated under reduced pressure and to the residue was added water, followed by extraction with chloroform and washing with a saturated aqueous solution of sodium chloride. The solvent is evaporated under reduced pressure, the residue was purified using column chromatography on silica gel (hexane-ethyl acetate) and to the resulting colorless oil (152 mg) was added THF (5 ml), methanol (5 ml) and an aqueous solution of 1 M sodium hydroxide (0.33 ml), followed by stirring at room temperature for 5 minutes. The solvent is evaporated under reduced pressure, the residue was purified through ODS column chromatography (water-acetonitrile), the obtained colorless oil was converted into a solid by adding diethyl ether, and this solid substance was collected by filtration and then dried by heating under reduced pressure to obtain sodium 2-(4-{[4'-(3-hydroxyphenoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzyl)for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (126 mg) as a white solid.

Example 14

SMEs-({3'-[(4-formylphenoxy)methyl]-2-methylbiphenyl-4-yl}oxy)ethyl acetate (935 mg), of hydroxylamine hydrochloride (480 mg), an aqueous solution of sodium acetate (760 mg/3 ml) and ethanol (15 ml) was stirred at room temperature for 1.5 hours. After evaporation of the solvent under reduced pressure the residue was added water (20 ml) followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain a colorless oil (1.07 g). Cyanoborohydride sodium (430 mg) and acetic acid (1 ml) were added in this order under ice cooling to a mixture of the obtained oil, methanol (10 ml) and THF (10 ml) followed by stirring for 5 minutes. During the gradual heating of the reaction liquid to room temperature to a mixture of the appropriate solution was added 4 M hydrogen chloride in dioxane (1 ml) followed by stirring for 5 hours. To the reaction liquid was added a saturated aqueous solution of sodium bicarbonate (20 ml) followed by extraction with chloroform. Then the organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate) to give colorless oil (0.50 g). Chlorocarbonylsulfenyl (190 mg) to allali to a mixture of the obtained oil and THF (5 ml) followed by stirring at room temperature for 15 minutes, then allowing the mixture to stand over night. To the reaction liquid were added water (10 ml) followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. By evaporation of the solvent under reduced pressure was obtained a colorless oil (413 mg). Mix this oil with an aqueous solution of 1 M sodium hydroxide (3 ml), methanol (3 ml) and THF (6 ml) was stirred at 60°C for 3 hours. To the reaction liquid was added a solution of 1 M hydrochloric acid (3.5 ml) followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane-ethyl acetate) to give colorless oil (331 mg). THF (10 ml), methanol (1 ml) and an aqueous solution of 1 M sodium hydroxide (0.7 ml) was added to the resulting oil and solvent evaporated under reduced pressure. To the obtained residue was added diethyl ether and the solid is collected by filtration and dried at 60°C under reduced pressure to obtain sodium 2-(4-{[4'-(2-hydroxyethoxy)-2'-methylbiphenyl-3-yl]methoxy}benzyl)for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (243 mg) as a colourless t is ejogo substances.

Example 15

A mixture of {[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}acetic acid (482 mg), dimethylamine hydrochloride (165 mg), WSC hydrochloride (388 mg), triethylamine (of 0.56 ml) and DMF (10 ml) was stirred at room temperature for 22.5 hours. The solvent is evaporated under reduced pressure and to the residue was added a solution of 1 M hydrochloric acid followed by extraction with chloroform/methanol (4/1). The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (hexane-ethyl acetate and chloroform-methanol). Methanol (5 ml), THF (5 ml) and an aqueous solution of 1 M sodium hydroxide (0,36 ml) was added to the obtained pale-yellow oil (178 mg), followed by stirring at room temperature for 5 minutes. The solvent is evaporated under reduced pressure and the residue was purified through ODS column chromatography (water-acetonitrile). The obtained colorless foamy substance was utverjdali by adding diethyl ether and this solid substance was collected by filtration and then dried by heating under reduced pressure to obtain sodium 2-[4-({4'-[2-(dimethylamino)-2-oksidoksi]-2',6'-dimethyl shall iphenyl-3-yl}methoxy)benzyl] - for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (52 mg) as a white solid.

Example 16

Oxalidales (0.15 ml) was added to a solution in THF (10 ml) of 2',6'-dimethylbiphenyl-3-carboxylic acid (277 mg), followed by stirring at room temperature for 5 minutes. Then added DMF (1 drop) followed by stirring at the same temperature for 1 hour. The solvent is evaporated under reduced pressure and a solution of the obtained residue in THF (10 ml) was added dropwise to a mixture of 2-(4-aminobenzyl-1,2,4-oxadiazolidine-3,5-dione (380 mg) and saturated aqueous sodium bicarbonate solution (10 ml) followed by stirring at room temperature for 2 hours. To the reaction liquid was added a solution of 1 M hydrochloric acid (20 ml) followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. Methanol (5 ml), THF (5 ml) and an aqueous solution of 1 M sodium hydroxide (1.2 ml) was added to the obtained residue, and the solvent evaporated under reduced pressure. To the obtained residue were added THF-hexane and the solvent evaporated under reduced pressure, followed by drying at 50°C under reduced pressure obtaining, thus, sodium 2-(4-{[(2',6'-dimethylbiphenyl-3-yl)carbonyl]amino}benzyl)for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (530 mg) is the form of a yellow solid.

Example 17

A mixture of {[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}acetic acid (500 mg), an aqueous solution of 12 M ethylamine (0,175 ml), WSC hydrochloride (302 mg), HOAt (214 mg) and DMF (10 ml) was stirred at room temperature for a period of 21.5 hours. To the reaction mixture solution was added 1 M hydrochloric acid and water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (chloroform-methanol and hexane-ethyl acetate). Methanol (3 ml), THF (3 ml) and an aqueous solution of 1 M potassium hydroxide (0,611 ml) was added to the resulting colorless foamy substance (308 mg), followed by stirring at room temperature for 10 minutes. The solvent is evaporated under reduced pressure, to the residue was added ethyl acetate, the solvent is again evaporated under reduced pressure. The precipitated solid was collected by filtration and then dried by heating under reduced pressure to obtain potassium 2-[4-({4'-[2-(ethylamino)-2-oksidoksi]-2',6'-dimethylbiphenyl-3-yl}methoxy)benzyl] - for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (300 mg) as a white solid.

Example 18

A mixture of 2,2,2-Cryptor-1-[({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)methyl]ethyl acetate (590 mg), hydroxylamine hydrochloride (253 mg), sodium acetate (378 mg), ethanol (15 ml) and water (4 ml) was stirred at room temperature for 21 hours. The solvent is evaporated under reduced pressure and to the residue was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue was purified using column chromatography on silica gel (hexane-ethyl acetate) and to the resulting colorless oil (310 mg) was added acetic acid (8 ml) and cyanoborohydride sodium (127 mg), followed by stirring at room temperature for 4 hours. The solvent is evaporated under reduced pressure and the residue was podslushivaet by adding an aqueous solution of 1 M sodium hydroxide followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue was purified using column chromatography on silica gel (chloroform-methanol). To the resulting colorless foamy substance (266 mg) was added THF (10 ml) with posledovaniem ice. Then to the mixture was added dropwise ethoxycarbonylethyl (0,065 ml) followed by stirring at 0°C for some time, and then stirring at room temperature for 4 days. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then the solvent is evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane-ethyl acetate) and THF (5 ml) and to the resulting colorless foamy substance was added an aqueous solution of 1 M sodium hydroxide (0,36 ml) followed by stirring at room temperature for 6 hours. The solvent is evaporated under reduced pressure and to the residue was added a solution of 1 M hydrochloric acid followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (hexane-ethyl acetate). Methanol (4 ml), THF (4 ml) and an aqueous solution of 1 M potassium hydroxide (0,31 ml) was added to the resulting colorless foamy substance (164 mg), followed by stirring at room temperature for 10 minutes. The solution is tel evaporated under reduced pressure, to the residue was added ethyl acetate and the solvent is again evaporated under reduced pressure. To the residue was added diethyl ether, followed by stirring at room temperature. The precipitated solid was collected by filtration and then dried by heating under reduced pressure to obtain potassium 2-(4-{[2',6'-dimethyl-4'-(3,3,3-Cryptor-2-hydroxypropoxy)biphenyl-3-yl]methoxy}benzyl)for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (163 mg) as a white solid.

Example 19

A mixture of 2-(4-{[4'-(2-hydroxypropoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione (240 mg), 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoyloxy-3(1H)-she (320 mg) and dichloromethane(10 ml) was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform-methanol and hexane-ethyl acetate) and to the resulting colorless foamy substance (196 mg) was added methanol (3 ml), THF (3 ml) and an aqueous solution of 1 M sodium hydroxide (0,41 ml) followed by stirring at room temperature for 10 minutes. The solvent is evaporated is under reduced pressure and the residue was purified through ODS column chromatography (water-acetonitrile). The obtained colorless foamy substance was utverjdali by adding diethyl ether and this solid substance was collected by filtration and dried by heating under reduced pressure to obtain sodium 2-(4-{[2',6'-dimethyl-4'-(2-oxopropoxy)biphenyl-3-yl]methoxy}benzyl)for 3,5-dioxo-1,2,4-oxadiazolidine-4-IDA (70 mg) as a white solid.

Example 20

A mixture of tert-butyl[2-({3'-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]carbamate (505 mg), hydroxylamine hydrochloride (221 mg), sodium acetate (331 mg), ethanol (15 ml) and water (4 ml) was stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure and to the residue was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and to the residue was added acetic acid (10 ml) and cyanoborohydride sodium (167 mg), followed by stirring at room temperature for 4 hours. The reaction mixture was podslushivaet by adding an aqueous solution of 1 M sodium hydroxide followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated the ri reduced pressure and to the resulting colorless foamy substance (528 mg) was added THF (8 ml) and then cooled with ice. To the reaction mixture was added dropwise chlorocarbonylsulfenyl (0,094 ml) followed by stirring at room temperature for a period of 14.5 hours. The solvent is evaporated under reduced pressure and to the residue was added a saturated aqueous solution of ammonium chloride followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (hexane-ethyl acetate). To the resulting colorless foamy substance was added ethyl acetate (3 ml) and then cooled with ice. To the reaction mixture was added dropwise a solution of 4 M hydrogen chloride in ethyl acetate (12 ml), followed by stirring at 0°C for 2 hours. The solvent is evaporated under reduced pressure and to the resulting pale yellow foamy substance was added diethyl ether-hexane, followed by stirring at room temperature. This solid substance was collected by filtration and then dried by heating under reduced pressure to obtain hydrochloride of 2-(4-{[4'-(2-aminoethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione (200 mg) as a pale yellow solid.

Example 21

A mixture of ethyl 2-({'-[(4-formylphenoxy)methyl]-2,2'-dimethylbiphenyl-4-yl}oxy)-2-methylpropanoate (1,87 g), of hydroxylamine hydrochloride (378 mg), sodium acetate (515 mg), ethanol (36 ml) and water (9 ml) was stirred at room temperature for 3 hours. After evaporation of the solvent under reduced pressure the residue was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. Cyanoborohydride sodium (790 mg) was added to the solution in acetic acid (20 ml) of the obtained pale yellow foamy substance (1,95 g), followed by stirring at room temperature for 3 hours. The reaction solution was podslushivaet by adding a saturated aqueous solution of sodium bicarbonate and sodium carbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (chloroform-methanol) to a solution of the obtained colorless foamy substance (1,17 g) in THF (15 ml) was added chlorocarbonylsulfenyl (0,234 ml) under ice cooling, followed by stirring at room temperature for 24 hours. To the reaction mixture solution was added 1 M hydrochloric acid followed by extraction with chloroform. The organic layer was dried the hell anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. A mixture of the obtained colorless foamy substance (1,43 g), THF (15 ml), methanol (15 ml) and aqueous 1 M sodium hydroxide (15 ml) was stirred at 60°C for 1 hour. The solvent is evaporated under reduced pressure and the obtained residue was added a solution of 1 M hydrochloric acid followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure to obtain 2-{[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}-2-methylpropanoic acid (1.29 g) as a colorless foamy substance. To the mixture obtained 2-{[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}-2-methylpropanoic acid (291 mg), THF (3 ml) and methanol (3 ml) was added an aqueous solution of 1 M sodium hydroxide (1,15 ml) followed by stirring for 10 minutes. The solvent is then evaporated under reduced pressure. By recrystallization of the resulting residue from ethanol-water received disodium 2-{[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}-2-methylpropanoate (149 mg) as white crystals.

Example 22

Under ice cooling a solution of 4 M hydrogen chloride in dioxane (15 ml) was added dropwise to a mixture of tert-butyl (3-{[3'-({4-[(3,5-dioxo-1,2-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}propyl)carbamate (1,95 g) and ethyl acetate (5 ml) followed by stirring at 0°C for some time and then stirring at room temperature within 1.5 hours. The solvent is evaporated under reduced pressure and the precipitated solid substance was collected by filtration and dried by heating under reduced pressure to obtain hydrochloride of 2-(4-{[4'-(3-aminopropoxy)-2,2'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione (1,53 g) as a white solid.

Example 23

A mixture of sodium 2-{4-[(4'-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methoxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]benzyl}is 3.5-dioxo-1,2,4-oxadiazolidine-4-IDA (467 mg), 1 M hydrochloric acid (5 ml) and THF (5 ml) was stirred at 50°C for 2 hours. After cooling to room temperature, to the reaction mixture were added water (10 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. An aqueous solution of 1 M sodium hydroxide (0,977 ml) was added to a solution of the obtained residue in THF (5 ml) followed by concentration under reduced pressure. By washing the obtained residue in diethyl ether was obtained sodium 2-{[(4'-{[(2S)-2,2-dihydroxypropyl]oxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]benzyl}is 3.5-dioxo-1,2,4-oxadiazolidine-4-ID (392 mg) as a white solid.

Example 24

A mixture of 2,2-debtor-2-({3'-[(4-formylphenoxy)methyl]-2,2'-dimethylbiphenyl-4-yl}oxy)-N-methylacetamide, hydrochloride hydroxyl is mine (122 mg), sodium acetate (167 mg), ethanol (12 ml) and water (3 ml) was stirred at room temperature for 16 hours. To the reaction mixture was added water, followed by extraction with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. Cyanoborohydride sodium (257 mg) was added to a solution in methanol (5 ml)-THF (5 ml) of the obtained colorless foamy substance (594 mg) and then under ice cooling to the reaction mixture was slowly added dropwise a solution of 4 M hydrogen chloride in dioxane (2 ml). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture were added an aqueous solution of 1 M sodium hydroxide (7 ml) under ice cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (chloroform-methanol), to the resulting colorless oil was added THF (6 ml) (559 mg) followed by cooling with ice. To the reaction mixture was added dropwise ethoxycarbonylethyl (0,152 ml) followed by stirring at 0°C for 30 minutes and then stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous solution of 1 M Ki is rockside sodium (3 ml) followed by stirring at room temperature for 12 hours. To the reaction mixture solution was added 1 M hydrochloric acid (4 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. By purifying the obtained residue using column chromatography on silica gel (chloroform-methanol) was obtained 2-{[3'-({4-[(3,5-dioxo-1,2,3-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}-2,2-debtor-N-methylacetamide (76 mg) as a colorless foamy substance and {[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}(debtor)acetic acid (217 mg) as a colorless foamy substance. To a solution in THF (5 ml) obtained {[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}(debtor)acetic acid was added an aqueous solution of 1 M sodium hydroxide (0,847 ml) followed by concentration under reduced pressure. By washing the obtained residue in diethyl ether was obtained disodium {[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-4-ID-2-yl)methyl]phenoxy}methyl)-2,2'-dimethylbiphenyl-4-yl]oxy}(debtor)acetate (203 mg) as a white solid.

Example 25

3'-({4-[(3,5-Dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10,8 mg) was dissolved in a mixed solution of THF-methanol 1 ml, 4:1 (V/V)] and the solution was added to pyrrolidine (3.2 mg). Added DMT-MM (12 mg), followed by stirring overnight at room temperature. Then to the reaction liquid was added chloroform and the organic layer was washed with a solution of 1 M hydrochloric acid. The organic layer was concentrated and the residue was purified by fractionated using HPLC (Waters, product name: Waters SunFireTMPrep C18OBDTM(19×100 mm, 5 μm)) to obtain 2-(4-{[2'-methyl-4'-(pyrrolidin-1-ylcarbonyl)biphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione (8.2 mg).

Example 26

3'-({4-[(3,5-Dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10,8 mg) was dissolved in a mixed solution of THF-methanol [1 ml, 4:1 (V/V)] and the solution was added to the hydrochloride 4-(methoxymethyl)piperidine (7.5 mg). Added DMT-MM (12 mg) and triethylamine (20 μl), followed by stirring overnight at room temperature. Then to the reaction liquid was added chloroform and the organic layer was washed with a solution of 1 M hydrochloric acid. The organic layer was concentrated and the residue was purified by fractionated using HPLC (Waters, product name: Waters SunFireTMPrep C18OBDTM(19×100 mm, 5 μm)) to obtain 2-{4-[(4'-{[4-(methoxymethyl)piperidine-1-yl]carbonyl}-2'-methylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazol the in-3,5-dione (9.0 mg).

Example 27

3'-({4-[(3,5-Dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10,8 mg) was dissolved in a mixed solution of THF-methanol [1 ml, 4:1 (V/V)] and the solution was added to 1-ethylpiperidine-3-amine (5.8 mg). Added DMT-MM (12 mg), followed by stirring overnight at room temperature. Then to the reaction liquid was added chloroform and the organic layer was washed with water. The organic layer was concentrated and the residue was purified by fractionated using HPLC (Waters, product name: Waters SunFireTMPrep C18OBDTM(19×100 mm, 5 μm)) to give 3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-N-(1-ethylpiperidine-3-yl)-2-methylbiphenyl-4-carboxamide (3.4 mg).

In the same way as in the methods of examples 1-27, obtained compounds of examples 28-407 presented in the tables below, using the appropriate starting compounds, respectively. The structure of the compounds of the examples presented in tables 53-113, and methods of preparation and physico-chemical data in tables 114-135.

In addition, the structures of other compounds of the present invention are presented in tables 136-138. They can be easily synthesized using the above methods of preparation, methods described in the examples and ways obvious to a person skilled in this field, or ways of t is engaged in a modification of such methods.

Industrial applicability

Because the connection of the present invention has excellent agonistic action against GPR40, it is useful as a means of stimulating insulin secretion or means for the prevention/treatment of diseases associated with GPR40, such as diabetes (insulin-dependent diabetes mellitus (IDDM), insulin-independent diabetes mellitus (NIDDM), a mild form of diabetes, borderline type (abnormal glucose tolerance and glucose levels in fasting blood) etc.

Separately presents the list of sequences

The explanation is “Artificial sequence” presents under the digital designation <223> the following list of sequences. Illustrative nucleotide sequence presented as SEQ ID NO:1 in the list of sequences is the nucleotide sequence artificially synthesized primer. Also the nucleotide sequence presented as SEQ ID NO:2 in the sequence is a nucleotide sequence artificially synthesized primer.

1. Oxadiazolidine the compound represented by the following formula (I)or its pharmaceutically acceptable salt

the symbols in the formula represent the SL is blowing values:
R1- -H,
R0- lower alkyl,
Rzthe same or different from each other and each represents-H or lower alkyl,
L - *-CH2-O - or *-CH2-NH-, where * L is the linking ring and the position of substitution of the group L in the ring is a 4-position
ring And benzene,
the ring is a benzene or pyridine,
R2respectively the same or different from each other, and each represents halogen or-R0,
n is 0 or 1,
R3is phenyl which may be substituted by a group selected from group G3,
group G3- halogen, -R0halogeno-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroclada group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-CORz, -O-lower alkylene-N(Rz)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(RZ)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by a group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz-cycloalkyl, -O-lower alkylene-heteroclada group and-O-lower alkylene-CON(Rz)-heteroclada group,
where the lowest alkylen in group G3may be substituted with halogen or-ORzand cycloalkyl and heteroclada group in group G3 may be substituted by a group selected from group G1,
group G1- halogen, cyano, -R0, -ORz, -N(Rz)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-Rz, -CON(Rz)2, -CON(Rz-the lowest alkylen-OR2, -N(Rz)CO-Rz, oxo, - (lower alkylene, which may be substituted by a group-ORz)-aryl, heteroclada group and the lowest alkylen-heteroclada group,
where aryl and heteroclada group in group G1may be substituted by a group selected from the following group G2,
group G2- halogen, cyano,
where "heteroclada group" means a group containing a ring selected from (i) monocyclic 5-7-membered, saturated or unsaturated heterokonta containing from 1 to 3 heteroatoms selected from O, S and N, (ii) a bicyclic heterokonta in which heterokonta mentioned in the above (i), are condensed on the ring, where the condensed ring may be the same or different from each other, and (iii) a bicyclic heterokonta in which heterokonta specified in the above (i)is condensed with a benzene ring or a 5-7 membered cycloalkane,
R4- N.

2. The compound according to claim 1, where R3represents phenyl, which is substituted by a group selected from the class including-About-nor is the highest alkylen-OR z, -O-lower alkylene-(Rz)2and-O-lower alkylene-(cycloalkyl, which may be substituted by a group-ORz), and may be optionally substituted 1 or 2 groups lower alkyl, halogen or-OR0.

3. The compound according to claim 1, which is selected from the group including
2-{[3'-({4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}-N-methylacetamide,
2-(4-{[4'-(2-hydroxyethoxy)-2'-methylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,
2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,
2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,
2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2,2',6'-trimethylphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,
2-{4-[(4'-{[(3R)-3-hydroxybutyl]oxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,
2-{4-[(4'-{[(3S)-3-hydroxybutyl]oxy}-2,2'-dimethylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,
2-[4-({[4'-(3-hydroxy-3-methylbutoxy)-2,2'-dimethylbiphenyl-3-yl]methyl}amino)benzyl]-1,2,4-oxadiazolidine-3,5-dione,
2-(4-{[4'-(3-hydroxy-3-methylbutoxy)-2'-methoxy-2-methylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione,
2-{4-[(4'-{[(3R)-3-hydroxybutyl]oxy}-2,2'6'-trimethylphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,
2-{4-[(4'-{[(3S)-3-hydroxybutyl]oxy}-2,2'6'-Tr is methylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione,
2-[(6-{[4'-(3-hydroxy-3-methylbutoxy)-2,2',6'-trimethylphenyl-3-yl]methoxy}pyridin-3-yl)methoxy]-1,2,4-oxadiazolidine-3,5-dione and
2-[4-({4'-[2-(1-hydroxyisopropyl)ethoxy]-2,2',6'-trimethylphenyl-3-yl}methoxy)benzyl]-1,2,4-oxadiazol lidin-3,5-dione,
or its pharmaceutically acceptable salt.

4. A pharmaceutical composition comprising a compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, where the pharmaceutical composition is a GPR40 agonist, tool, stimulating insulin secretion and/or agent for the prevention and/or treatment of diabetes.

5. The pharmaceutical composition according to claim 4, which is a GPR40 agonist.

6. The pharmaceutical composition according to claim 4, which is a means of stimulating insulin secretion.

7. The pharmaceutical composition according to claim 4, which is an agent for the prevention and/or treatment of diabetes.

8. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for a GPR40 agonist, an agent stimulating insulin secretion, or a means for the prevention and/or treatment of diabetes.

9. The method of prevention and/or treatment of diabetes, which includes an introduction to the patient an effective amount of a compound according to claim 1 or its salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, where R1 denotes H; R6, R7, R8, R9, R10 independently denote H, F, Cl, Br, CF3, OCH3, OCF3, OCHF2, SCH3, SCF3, phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or NR3R4, where the alkyl and phenyl can be substituted with R2 once or many times, and where any two residues from R6, R7, R8, R9, R10 in neighbouring positions of the phenyl ring can form a -CH=CH-CH-CH- residue together; m equal 0, 1, 2 or 3; X denotes -(CH2)2-; R2 denotes F, Cl, Br, CN, OCH3, OCF3, CH3, CF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl, where the alkyl can be substituted once or many times with OH, F, Cl, Br or CN; R3, R4 independently denote H or (C1-C6)-alkyl; or physiologically acceptable salts thereof, provided that the compound 3-(2-o- tolylamino-benzoxazol-6-yl)-propionic acid is excluded. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent which activates GPR40 receptors and use of said compounds to prepare a medicinal agent for lowering blood sugar level, for treating diabetes and for increasing insulin secretion.

EFFECT: compounds of formula I which activate GPR40 receptors are obtained.

6 cl, 2 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), where A1, A2, A3, A4, A5 ad A6 are independently selected from a group comprising CR3 and N; provided that the biggest one of A1, A2, A , A4, A5 and A6 denotes N; B1, B2 and B3 are independently selected from a group comprising CR2 and N; each R3 independently denotes H or C1-C6 alkyl; and R1, R2, R4, R5, W and n are as given in the description, or salts thereof which are suitable for use in agriculture. The invention also relates to compositions containing compounds of formula (1), and insect-pest control methods which involve contact between the pest or habitat thereof with a biologically effective amount of the compound or composition according to the present invention, as well as to methods of protecting seeds and animals from insects-pests.

EFFECT: high effectiveness of the obtained compounds in insect-pest control.

29 cl, 12 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula I: or salt thereof, where: y equals 0; R1 and R2 are taken together to form a 3-tetrahydrofuran ring; R9 is hydrogen; R10 is 5-oxazolyl; R11 is a methoxy-, ethoxy- or isopropoxy group; each V1 is independently selected from halogen, NO2, CN, OR12, OC(O)R13, OC(O)R12, OC(O)OR13, OC(O)OR12, OC(O)N(R13)2, OP(O)(OR13)2, SR13, SR12, S(O)R13, S(O)R12, SO2R13, SO2R12, SO2N(R13)2, SO2NR12R13, SO3R13, C(O)R12, C(O)OR12, C(O)R13, C(O)OR13, NC(O)C(O)R13, NC(O)C(O)R12, NC(O)C(O)OR13, NC(O)C(O)N(R13)2, C(O)N(R13)2, C(O)N(OR13)R13, C(O)N(OR13)R12, C(NOR13)R13, C(NOR13)R12, N(R13)2, NR13C(O)R12, NR13C(O)R13, NR13C(O)OR13, NR13C(O)OR12, NR13C(O)N(R13)2, NR13C(O)NR12R13, NR13SO2R13, NR13SO2R12, NR13SO2N(R13)2, NR13SO2NR12R13, N(OR13)R13, N(OR13)R12, P(O)(OR13)N(R13)2 and P(O)(OR13)2; where each R12 is a monocyclic or bicyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 4 heteroatoms selected from N, O or S, and where CH2 lying next to said N, O or S can be substituted with C(O); and each R12 optionally contains up to 3 substitutes selected from R11; where each R13 is independently selected from H, (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl; and where each R13 optionally contains a substitute which is R14; where R14 is a monocyclic or bicyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 4 heteroatoms selected from N, O or S, and where CH2 lying next to said N, O or S can be substituted with C(O); and each R14 optionally contains up to 2 substitutes independently selected from H, (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl, 1,2-methylenedioxy-, 1,2-ethylenedioxy group or (CH2)n-Z; where Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C4)alkyl, SO(C1-C4)alkyl, SO2(C1-C4)alkyl, NH2, NH(C1-C4)-alkyl, M((C1-C4)alkyl)2, COOH, C(O)O(C1-C4)alkyl or O(C1-C4)-alkyl; and where any carbon atom in any R13 is optionally substituted with O, S, SO, SO2, NH or N(C1-C4)alkyl; where said method includes a step for reacting a compound of formula II with a compound of formula III in a polar or nonpolar aprotic, virtually anhydrous solvent or mixture thereof, and optionally in an acceptable base selected from an organic base, inorganic base or a combination of an organic base and an inorganic base; and while heating the reaction mixture to temperature ranging from approximately 30°C to approximately 180°C for approximately 1 to 48 hours in a virtually inert atmosphere: where: LG is -OR16; where R16 is -(C1-C6)-straight or branched alkyl; -(C2-C6)-straight or branched alkenyl or alkynyl; or a monocyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 3 heteroatoms selected from N, O or S, and each R16 optionally contains up to 5 substitutes independently selected from (C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or (CH2)n-Z; n equals 0, 1, 2, 3 or 4; V1, y, Z, R1, R2, R9, R10 and R11 are as indicated above; and provided that R16 is not a halogen-substituted (C2-C3)-straight alkyl.

EFFECT: improved method.

19 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: medicine.

SUBSTANCE: there is described application of 1-hetaryl-2-nitro-2-(3-phenyl-1,2,4-oxadiazole-5-yl)ethanes of general formula I a-m 1a, e, and R1=NO2, R2=H; 1b, f, to R1=NO2, R2=Me; 1c, g, l R1=CO2Et, R2=H; 1d, h, m R1 =CO2Et, R2 =Me; 1a-d R2 =piperidino; 1e-h R3 =1-pyrrolidinyl, 1j-m R3=morpholino as psychotropic substances.

EFFECT: substances are low-toxic and have an evident psychotropic effect on rats.

4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to sulphonic 2-nitro-2-(3-aryl-1,2,4-oxadiazole-5-yl)ethane derivatives of formula I a-g la R=3-NO2C6H4, R1=NO2, R2=H; b R=3-NO2C6H4, R1=NO2, R2=CH3; c R=4-CH3OC6H4, R1=NO2, R2=H; d R=4-CH3OC6H4, R1=NO2, R2=CH3; e R=4-CH3OC6H4, R1=CO2Et, R2=H; f R=4-CH3OC6H4, R1=CO2Et, R2=CH3; g R=4-CH3C6H4, R1=CO2Et, R2=H.

EFFECT: preparation of the compound exhibiting antileprous and antituberculous activity.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel sulphone derivatives of 2-nitro-2-(3-aryl-1,2,4-oxadiazol-5-yl)ethane of general formula I, which can be used as potential antimicobacterial preparations Ia-g, where la R-3-NO2C6H4, R1=NO2, R2=H; b R=3-NO2C6H4 R1=NO2, R2=CH3; c R=4-CH3OC6H4, R1=NO2, R2=H; d R=4-CH3OC6H4, R1=NO2, R1=CH3; e R=4-CH3OC6H4 R1=CO2Et, R2=H; f R=4-CH3OC6H4, R1=CO2Et, R2=CH3; g R=4-CH3C6H4, R1=CO2Et, R2=H. The method involves heating and mixing substituted 2-nitro1-chloro-2-(3-aryl-1,2,4-oxadiazol-5-yl)ethane with an equimolar amount of sodium 4-tolysulphinate in a solvent and then holding the reaction mixture at room temperature.

EFFECT: method avoids solvent preparation and increases output of the desired product.

1 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to tritium-labelled 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid of formula I .

EFFECT: obtaining a tritium-labelled analogue of a physiologically active compound which is used to correct a range of genetic disorders.

1 cl, 2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

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