Substituted burilnye connection or substituted pyridine and pharmaceutical compositions based on them

 

(57) Abstract:

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl. The compounds of formula (I) have an antagonistic effect against the glucagon receptor and can be used in the treatment glukuronizirovannah conditions such as diabetes. 8 C. and 12 C.p. f-crystals, 2 PL.

The invention relates to substituted billnum compounds that inhibit the action of glucagon, as well as to compositions based on them.

Glucagon is a peptide hormone whose main function is to increase the number of verbality. Together, these two hormones are necessary to maintain an appropriate level of glucose in the blood.

Diabetes is a complex disease characterized by hyperglycemia resulting from disorders of insulin secretion, insulin action or both. Diabetes is also associated with increased levels of glucagon. The heterogeneous nature of the disease requires different approaches in relation to different metabolic disorders found in patients.

In the diabetic state (all forms of Type I and Type II) hyperglycemia is often associated with elevated levels of glucagon. Accordingly, a method for the treatment of all forms of diabetes is blocking receptor glucagon suitable antagonist, inhibiting thus the amount of glucose produced by the liver and lowering the glucose level of the patient.

Known to many and various applications of receptor antagonists of glucagon, that is, compounds that block the action of endogenous glucagon. These applications include the following.

1. Treatment of hyperglycemia associated with diabetes of any origin and associated with any other diseases or conditions. Receptor antagonist glucal is.

2. Treatment of impaired glucose tolerance (IGT).

3. Treatment of syndromes of insulin resistance, including those that are a consequence of obesity, polycystic ovarian syndrome, Syndrome X," the use of drugs or hormones, endocrinopathy and genetic syndromes.

4. Reducing the level of free fatty acids and treatment of conditions associated with elevated levels of free fatty acids, such as insulin resistance, obesity, complete or partial Syndrome X, diabetes type I and II, hyperlipidemia and increased amount of glucose produced by the liver that is associated with insulin resistance, diabetes type I and II, obesity and Syndrome X.

5. Treatment of conditions associated with genetic abnormalities in insulin action, which are the result of changes in the structure and function of the insulin receptor or violations in the transduction of postreceptor signal. Treatment of diabetes-related antiinsulin antibodies, diabetes, caused by the use of drugs, diabetes-related endocrinopathy, diabetes associated with genetic syndromes.

6. Treatment of diabetes mellitus due to beremennostej known genetic defects of beta cells pancreatic disease, dysfunction of beta cells caused by the use of drugs or toxins, endocrinopathy, infections, malnutrition, associated with idiopathic diabetes type I.

8. Prevention and treatment of diabetic ketoacidosis and reduce the number of generated ketone.

9. Treatment of hyperglycemia that appears when diabetes.

10. The decrease in glucose levels that occur after fasting and eating.

11. Treatment of insulin resistance that occurs in the liver, muscles and fat cells.

12. Treatment of conditions of hyperlipidemia.

13. Treatment with glucagon and other conditions associated with elevated levels of glucagon.

14. Treatment of conditions associated with increased barren circulating glucose in the liver.

15. Increase insulin secretion.

16. Reducing the toxicity of glucose.

17. Reduced susceptibility of renal prostaglandin to protein and amino acids.

18. The reduction increased GFR and clearance of albumin resulting from diabetes or proteins or amino acids.

19. Reduced renal clearance of albumin and excretion.

20. Treatment about is a result of increased sacramenti heart muscle.

22. Treatment of cardiac hypertrophy of its consequences.

23. Use as a diagnostic agent and a diagnostic agent for the detection of patients with a defect of the glucagon receptor.

24. The treatment of gastro-intestinal disorders, treatment reduce the contractility of the gut.

25. The increase of gastric acid.

26. The change of intestinal hypomobility arising from injection of glucagon.

27. Treatment of catabolism and loss of nitrogen in the state of negative nitrogen balance and loss of protein, including all diabetes type I and II, starvation, AIDS, cancer, anorexia, aging and other conditions.

28. Treatment of any of the above conditions or diseases in the post and the operating period.

29. The decline in satiety and increased energy absorption.

The receptor antagonists of glucagon prior art, such as described in international application WO 9518153-A and presents here the links are primarily peptide analogues of glucagon. They are subjected to the action of endogenous proteases, can accelerate the production of antibodies and immune reactions, and can be difficult to ptx2">

There is evidence of the same ones the antagonist of the glucagon receptor (Collins et al., BioMed. Chem. Lett., 1992, 2, 915-918). Demonstrated that it is derived finokalia, WED-99,711, inhibits the binding of glucagon and glucagon in the hepatic plasma membrane of rats with micromolded concentrations. It is desirable to have easily obtainable ones receptor antagonists of glucagon, which are metabolically more stable than the peptide antagonists of the prior art, and which have good activity and bioavailability. Substituted pyridine compounds, and substituted biphenyls of the present invention are highly effective inhibitors of glucagon receptor. Accordingly, these compounds can be used for the treatment of glucagon-mediasound conditions such as the above.

This invention relates to substituted billnum compounds, which are represented by the formula (IC) shown below. The definition of this General formula disclosed in detail in the following description. In the following detailed description of this General formula is discussed in more detail in relation to its preferred and more preferred fragments of the molecule, methods of their preparation, examples concretised connections, having antagonistic action against glucagon receptor having the General formula (IC) below

< / BR>
In the General formula IC group X, R1a, R1b, R2, R3and Ah shall have the following meanings; X is N or CR8.

R8is hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6-alkoxycarbonyl, carboxy, formyl or-NR4R5. Substituents of the substituted phenyl or substituted alkyl groups, R8, which can be from 1 to 3 are, for example, hydroxy, fluorine, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6-alkoxycarbonyl, carboxy, formyl or-NR4R5.

Group R4and R5independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, pattalam, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. Substituents of the substituted phenyl or substituted naphthyl groups, R4and R5are from 1 to 3, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl or (C1-C4-alkoxygroup.

R4and R5can be combined together to form -(CH2)rA(CH2)s- where the indices r and s are independently equal to from 1 to 3 and a is CHR6, NR6, O or S(O)n, in which n is 0, 1 or 2; R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl.

R1aand R1bindependently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkenyl or (C1-C6-alkanoyl. Substituents of the substituted alkyl, substituted alkenyl and substituted quinil groups R1aand R1bindependently are 1 to 3, for example, OR4, -C(O)Rabout 3, for example, by halogen, (C1-C4)-alkyl or (C1-C4-alkoxygroup.

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl. Substituents of the substituted alkyl, substituted alkenyl, substituted quinil and substituted cycloalkyl group, R2independently are 1 to 3 halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7in which m is 0,1 or 2. Substituents of the substituted phenyl substituents of the group R2are from 1 to 3, for example, halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy.

R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted is substituted phenyl, substituted pyridyl or substituted naphthyl groups, R7are from 1 to 5, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano or hydroxy.

R2and R1bcan be combined, forming Allenby bridge containing from 3 to 5 carbon atoms between the carbon atoms of the ring, is attached to R2and R1b.

R3is hydroxy, TRIFLUOROACETYL, (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl. Substituents of the substituted alkyl and substituted alkenyl group, R3are from 1 to 3 hydroxy or triptoreline group.

AG is an optionally substituted aromatic or heteroaromatic ring. Examples of possible groups of AG are: family, nattily, pyridil, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline. Optional substituents group AG are independently from 1 to 3, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-al is but nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5or-S(O)mR7. Substituents of the substituted alkyl, substituted alkenyl and substituted quinil substituted group AG are from 1 to 3, for example, halogen, hydroxy, -NR4R5, phenyl or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl or (C1-C4-alkoxygroup.

Pharmaceutically acceptable salts of these materials is included in the scope of this invention.

The invention also relates to pharmaceutical compositions for use in the treatment of glucagon-mediasound conditions which include a compound having an antagonistic action against the glucagon receptor and the structure in the volume of General structural formula IC, plus a pharmaceutically acceptable carrier.

In the above structural formula (IC) terms have the following meanings:

The term "alkyl" refers to an alkyl group that is straight or branched chain and has the indicated number of carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopathy on the alkyl group in the form of a ring, which contains the indicated number of carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "alkoxy" refers to a group in which alkyl is straight or branched and has the indicated number of carbon atoms. Examples of such alkoxygroup are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert - butoxy, pentox, isopentane, hexose, isohexane.

The term "alkanoyl" refers to groups of the formula-C(O)-alkyl in which the alkyl group has the indicated number of carbon atoms. Examples include acetyl, propionyl and butanoyl.

The term "alkanoyloxy" refers to groups of the formula-OC(O)-alkyl in which the alkyl group has the indicated number of carbon atoms. Examples include: -OC(O)CH3, -OC(O)2H5and-OC(O)3H7.

The term "alkoxycarbonyl" refers to groups of the formula-C(O)O-alkyl in which the alkyl group has the indicated number of carbon atoms. Examples include: -C(O)och3, -S(O)OS2H5and-S(O)OS3H7.

The term "cycloalkyl-alkyl" refers to groups in which the alkyl group bears cycloalkenyl Deputy and W2H4-C5H9.

The term "phenylalkyl" refers to groups in which the alkyl group bears a phenyl substituent and the alkyl portion contains the indicated number of carbon atoms. Examples include: -C2H4-C6H5.

The term "nafcillin" refers to groups in which the alkyl group bears nattily Deputy and the alkyl portion contains the indicated number of carbon atoms. Examples include-C2H4-C10H7.

The term "pyridylethyl" refers to groups in which the alkyl group bears peredelnyj Deputy and the alkyl portion contains the indicated number of carbon atoms. Examples include-C2H4-pyridyl.

The term "alkenyl" refers to the groups with straight or branched chain having the indicated number of carbon atoms and containing a double bond of carbon-carbon. Examples include ethynyl, propen-1-yl, propen-2-yl and penten-1-yl.

The term "quinil" refers to the groups with straight or branched chain having the indicated number of carbon atoms containing a triple bond of carbon-carbon. Examples include: ethinyl, propyne-1-yl and buten-1-yl. The term "halogen" relative and, described for the various substituted groups in the above General formula (IC). These lists are exemplary substituents are not considered to be limiting; specialist in this field will determine what can be used other similar substituents.

Certain groups described above can be used in this description of the formulas more than one, in this case, each group is determined separately from the others.

The preferred and most preferred groups that make up the compounds of General formula (IC) are as follows.

X is preferably CR8.

If X is CR8, R8preferably is hydrogen, halogen, trifluoromethyl or (C1-C10)-alkyl. R8most preferably is hydrogen.

R1aand R1bpreferably are independently trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C3-C7-cycloalkyl or (C3-C7-cycloalkenyl. R1aand R1bmost preferably independently are (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl. The substituents on the substituted alkyl and substituted alkenyl R2groups are preferably independently from 1 to 3 times are halogen, phenyl, substituted phenyl, -C(O)NR4R5or-S(O)mR7where m is 0,1 or 2. The most preferred substituents are halogen or-S(O)mR7where m is 0.

Group R4and R5preferably independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. R4and R5most preferably are hydrogen, (C1-C6)-alkyl, (C3-C7-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl.

If R4and R5together form -(CH2)rA(CH2)s- this is> O or S(O)n, where n is 0,1 or 2 and R6is hydrogen, (C1-C6)-alkyl, phenyl or phenyl-(C1-C6)-alkyl.

R7preferably is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl. R7most preferable is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl. The substituents on the substituted group R7preferably from 1 to 3 times is halogen, trifluoromethyl or (C1-C6)-alkyl.

If R2and R1btogether form Allenby bridge, this bridge preferably contains from 3 to 4 carbon atoms.

R3preferably is (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C1-C6-alkenyl, in which the substituents are preferably 1 to 3 times with hydroxyl groups. Most preferably, R3is tumescent 1 to 2 hydroxyl groups.

Preference for aromatic and heteroaromatic groups AG structural formula (IC) is presented below. Compounds of General formula (IC) are further divided into four subgroups, represented by structural formulas 1A, 1B, 1C and 1D, which are respectively 4-heteroelement pyridinium, 4-arylsubstituted pyridinium, heteroelement the benzenes and the aryl-substituted benzenes.

4-Heteroarylboronic pyridine included in the formula (IC) have the formula 1A

< / BR>
in which R1aand R1bindependently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil,

(C3-C7-cycloalkyl or (C3-C7-cycloalkenyl, or (C1-C6-alkanoyl. Substituents of the substituted alkyl, substituted alkenyl and substituted quinil R1aand R1bgroups are independently from 1 to 3 times, for example, OR4, -C(O)R4, -CO2R4, -C(O)NR4R5, -NR4R5or phenyl, which is optionally substituted from 1 to 3 times, for example, halogen, (C1-C41-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. The substituents on the substituted phenyl or substituted naftalina R4and R5the groups are from 1 to 3 times with halogen, cyano, trifluoromethyl, (C1-C4)-alkyl or (C1-C4)-alkoxy.

R4and R5may together form -(CH2)rA(CH2)s- where subscripts g and s are independently equal to from 1 to 3 and a is CHR6, NR6, O or S(O)n, where n is 0,1 or 2, and R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl.

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6)-cyclol estately on the substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2groups independently from 1 to 3 times are halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7where m is 0,1 or 2. Substituents on the substituted phenyl groups, the substituents R2from 1 to 3 times are, for example, halogen or (C1-C4)-alkyl or (C1-C4)-alkoxy.

R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. The substituents on the substituted phenyl, substituted peredelnoj or substituted naftilos groups R7from 1 to 5 times are, for example, halogen, trifluoromethyl or (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano or hydroxy.

R2and R1btogether form Allenby bridge containing from 3 to 5 carbon atoms between the ring and what etiam, (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl. The substituents on the substituted alkyl and substituted alkenylphenol groups R3are from 1 to 3 times a hydroxyl or triptoreline groups.

Ah' is an optionally substituted heteroaromatic ring. Examples of possible AG' groups are pyridil, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazoline. Optional substituents on the group of AG' is independently from 1 to 3 times are, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5or-C(O)NR4R5or-S(O)mR7. Substituents on the substituted alkyl, substituted alkenyl and substituted etkinlik groups of the substituents on AG' are from 1 to 3 times, for example, halogen, hydroxy, -NR4R5, phenyl or zames the l or (C1-C4)-alkoxy.

Pharmaceutically acceptable salts of these compounds included in the scope of this invention.

In formula 1A, the preferred and most preferred groups R1a, R1b, R2, R3and additional groups of R4, R5, R6and R7presented here, and their different groups of substituents such as defined relative to the General formula (IC) above.

In formula 1A heteroaromatic ring AG' is preferably selected from the group consisting of spiridinov, TuranAlem, teofanov, pyrazolyl, triazolyl, oxazolyl and thiazolyl, and optional substituents on AG' preferably are independently from 1 to 3 times, for example, halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl, where the phenyl substituents are from 1 to 3 times by halogen or (C1-C4)-alkyl. Heteroaromatic ring AG' is most preferably selected from g is Ino are independently from 1 to 3 times, for example, by halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, -OR4or-OC(O)R4where R4is hydrogen or (C1-C6)-alkyl.

4-Arylsubstituted pyridine included in the formula (IC) have the formula 1B

< / BR>
in which R1aand R1bindependently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil,

(C3-C7-cycloalkyl, (C3-C7-cycloalkenyl or (C1-C6-alkanoyl. Substituents of the substituted alkyl, substituted alkenyl and substituted quinil R1aand R1bindependently are 1 to 3 times, for example, OR4, -C(O)R4, -CO2R4, -C(O)NR4R5, -NR4R5or phenyl, which is optionally substituted from 1 to 3 times with halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy.

Group R4and R5independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. The substituents on the substituted phenyl or substituted naftalina groups R4and R5are from 1 to 3 times with halogen, cyano, trifluoromethyl, (C1-C4)-alkyl or (C1-C6)-alkoxy.

R4and R5may together form -(CH2)rA(CH2)s- where subscripts g and s are independently equal to from 1 to 3 and a is CHR6, NR6, O or S(O)nwhere n is 0, 1 or 2 and R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl.

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl. The substituents on the substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2the>5or-S(O)mR7where m is 0, 1 or 2. Substituents on the substituted phenyl groups, the substituents R2from 1 to 3 times are, for example, halogen or (C1-C4)-alkyl or (C1-C4)-alkoxy.

R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. The substituents on the substituted phenyl, substituted peredelnoj or substituted naftilos groups R7from 1 to 5 times are, for example, halogen, trifluoromethyl or (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano or hydroxy.

R2and R1btogether form Allenby bridge containing from 3 to 5 carbon atoms between the ring carbon atoms to which are attached R2and R1b.

R3is hydroxy, TRIFLUOROACETYL, (C1-C6-alkanoyl, substituted (C1-C6)-alkyl or zemedeneh are from 1 to 3 times a hydroxyl or triptoreline groups.

AG is an optionally substituted aromatic ring. Examples of possible AG groups are finely and nattily. Optional substituents on the group of AG independently from 1 to 3 times are, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5or-C(O)NR4R5or-S(O)mR7. Substituents on the substituted alkyl, substituted alkenyl and substituted etkinlik groups of the substituents on AG are from 1 to 3 times, for example, halogen, hydroxy, -NR4R5, phenyl or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy.

Pharmaceutically acceptable salts of these compounds included in the scope of this invention.

In formula 1B, the preferred and most preferred groups R1a, R1b, R2, R3and additional groups of R4, Rthe sustained fashion the General formula (IC), above.

In formula 1B aromatic ring AG is preferably phenyl ring, in which the optional substituents are preferably independently are 1 to 3 times, for example, halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl, where the phenyl substituents are from 1 to 3 times by halogen or (C1-C4)-alkyl. Most preferably the optional substituents are independently from 1 to 3 times, for example, halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, -OR4or-OC(O)R4where R4is hydrogen or (C1-C6)-alkyl.

Heteroelement benzenes included in the formula (IC) have the formula 1C

< / BR>
in which R8is hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl-(formyl or-NR4R5. The substituents on the substituted phenyl or substituted alkyl, R8the groups are from 1 to 3 times, for example, hydroxy, fluorine, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy,

(C1-C6-alkoxycarbonyl carboxy, formyl or-NR4R5.

Group R4and R5independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. The substituents on the substituted phenyl or substituted naftalina R4and R5the groups are from 1 to 3 times with halogen, cyano, trifluoromethyl, (C1-C4)-alkyl or (C1-C4)-alkoxy.

R4and R5may together form -(CH2)rA(CH2)s- where subscripts g and s are independently equal to from 1 to 3 and was CHR61-C6)-alkyl.

R1aand R1bindependently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl or (C3-C7-cycloalkenyl, or (C1-C6-alkanoyl. Substituents of the substituted alkyl, substituted alkenyl and substituted quinil R1aand R1bgroups are independently from 1 to 3 times, for example, OR4, -C(O)R4, -CO2R4, -C(O)NR4R5, -NR4R5or phenyl, which is optionally substituted from 1 to 3 times, for example, halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy.

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl. The substituents on the group independently from 1 to 3 times are halogen, the phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2. Substituents on the substituted phenyl groups, the substituents R2from 1 to 3 times are, for example, halogen or (C1-C4)-alkyl or (C1-C4)-alkoxy.

R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. Substituents on the substituted phenyl, substituted peredelnoj or substituted naftilos groups R7from 1 to 5 times are, for example, halogen, trifluoromethyl or (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano or hydroxy.

R2and R1btogether form Allenby bridge containing from 3 to 5 carbon atoms between the ring carbon atoms to which are attached R2and R1b.

R3is hydroxy, TRIFLUOROACETYL, (C1-C6)-alkanoates alkyl and substituted alkenylphenol groups R3are from 1 to 3 times a hydroxyl or triptoreline groups.

Ah' is an optionally substituted heteroaromatic ring. Examples of possible AG' groups are pyridil, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazoline. Optional substituents on the group of AG' is independently from 1 to 3 times are, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5or-C(O)NR4R5or-S(O)mR7. Substituents on the substituted alkyl, substituted alkenyl and substituted etkinlik groups of the substituents on AG' are from 1 to 3 times, for example, halogen, hydroxy, -NR4R5, phenyl or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy.

Pharmaceutically acceptable salts of repectfully group, R1a, R1b, R2, R3, R8and additional groups of R4, R5, R6and R7presented here, and their different groups of substituents, such as are defined relative to the General formula (IC) above.

In formula 1C heteroaromatic ring AG' is preferably selected from the group consisting of spiridinov, TuranAlem, teofanov, pyrazolyl, triazolyl, oxazolyl and thiazolyl, and optional substituents on AG' preferably are independently from 1 to 3 times, for example, halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl, where the phenyl substituents are from 1 to 3 times by halogen or (C1-C4)-alkyl. Heteroaromatic ring AG' is most preferably selected from the group consisting of spiridinov, TuranAlem and teofilov, and optional substituents most preferably are independently from 1 to 3 times, for example, halogen, (C1-C6)-alkyl, (<)-alkyl.

Aryl-substituted benzenes, included in the formula (IC) have the formula ID

< / BR>
in which R8is hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6-alkoxycarbonyl, carboxy, formyl or-NR4R5. The substituents on the substituted phenyl or substituted alkyl, R8the groups are from 1 to 3 times, for example, hydroxy, fluorine, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy,

(C1-C6-alkoxycarbonyl, carboxy, formyl or-NR4R5.

Group R4and R5independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-and naftalina groups R4and R5are from 1 to 3 times with halogen, cyano, trifluoromethyl, (C1-C4)-alkyl or (C1-C4)-alkoxy.

R4and R5may together form -(CH2)rA(CH2)s- where subscripts g and s are independently equal to from 1 to 3 and a is CHR6, NR6, O or S(O)n, where n is 0, 1 or 2 and R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl.

R1aand R16independently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkenyl or (C1-C6-alkanoyl. Substituents of the substituted alkyl, substituted alkenyl and substituted quinil R1aand R1bgroups are independently from 1 to 3 times, for example, OR4, -C(O)R4, -CO2R4, -C(O)NR4R5, -NR4R5or phenyl, which are optionally substituted 1 to 3 times with halogen, (C1-C4)-alkyl or (C1-Slalom, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl. The substituents on the substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2groups independently from 1 to 3 times are halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2. Substituents on the substituted phenyl groups, the substituents R2from 1 to 3 times are, for example, halogen or (C1-C4)-alkyl or (C1-C4)-alkoxy.

R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl. Substituents on the substituted phenyl, substituted pyrid the1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano or hydroxy.

R2and R1btogether form Allenby bridge containing from 3 to 5 carbon atoms between the ring carbon atoms to which are attached R2and R1b.

R3is hydroxy, TRIFLUOROACETYL, (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl. The substituents on the substituted alkyl and substituted alkenylphenol R3the groups are from 1 to 3 times a hydroxyl or triptoreline groups.

AG is an optionally substituted aromatic ring. Examples of possible AG groups are finely and nattily. Optional substituents on the group of AG independently from 1 to 3 times are, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5or-C(O)NR4R5or-S(O)mR7. Substituents which I from 1 to 3 times, for example, halogen, hydroxy, -NR4R5, phenyl or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy.

Pharmaceutically acceptable salts of these compounds included in the scope of this invention.

In the formula 1D preferred and most preferred groups R1a, R1b, R2, R3, R8and additional groups of R4, R5, R6and R7presented here and their different groups of substituents, such as are defined relative to the General formula (IC) above.

In the formula 1D aromatic ring AG is preferably phenyl ring, in which the optional substituents are preferably independently are 1 to 3 times, for example, halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl, where the phenyl substituents are from 1 to 3 times by halogen or (With1-C6)-alkyl, (C2-C6-alkenyl, -OR4or-OC(O)R4where R4is hydrogen or (C1-C6)-alkyl.

The basic compounds of this invention are usually isolated in the form of their pharmaceutically acceptable acid additive salts derived from organic or inorganic acids. Examples of such compounds include hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, triperoxonane, propionic, maleic, succinic and malonic acid. The compounds of this invention which contain acid functionality, such as carboxyl group, can be allocated in the form of a pharmaceutically acceptable additive salts derived from inorganic or organic bases. Ion forming a salt derived from such bases may be a metal ion such as sodium, potassium, lithium, calcium, magnesium and so on, or ion of an organic base, such as ammonium ion or substituted ammonium, derived from the amine. Examples of suitable amines for these purposes include ammonia, arylalkylamine, such as dibenzylamine and N,N-dibenziletilendiaminom, lower bonds alkylamines, such as methylamine, trillin or dicyclohexylamine, 1-adamantylamine, benzathine, or salts derived from amino acids such as arginine or lysine.

This invention also includes pharmaceutically acceptable prodrugs" of the compounds of formula (IC), which form such derivatives. They usually are acylated derivatives of alcohol-containing compounds of this invention, and other known types of prodrugs. Obtaining such derivatives are known in the art.

The inhibitors of this invention find application in the treatment of human and veterinary medicine. For such applications, the active agents(agent) used in the pharmaceutical compositions that comprise the active ingredient (the ingredient) plus a pharmaceutically acceptable carrier, which contains one or more diluents, fillers, binding agents or other fillers depending on the method of administration and dosage forms. Examples of such agents include media such as sucrose, lactose or starch; lubricating agents such as magnesium stearate; adjuvants, such as moisturizing agents; fillers such as coconut oil or suppozitornyj wax, emulsifiers and suspendresume agents, sweeteners, flavorings include one or more known anti-diabetic agents in addition to the composition of structural formula (IC). Examples of such anti-diabetic agents include inhibitors of a-glucosidase, such as acarbose or voglibose, insulin sensitizers, such as parlodel, preparations of thiazolidinediones, such as troglitazone, stimulators of insulin secretion, such as glimepiride, sulfonylureas, such as gliburid, GLP-1 and its derivatives, such as insulinotropic, Amylin and its derivatives, such as AC-137, calcitonin, insulin and its derivatives, such as NOAH-901, biguanides, such as Metformin, reductase inhibitors of aldose such as tolrestat, 3-agonists, such as BTA-243 and hypocholesterolemic, such as lovastatin.

The method of treatment glucagon-mediasound States the introduction of the antagonist of the glucagon receptor of the present invention can be used in warm-blooded animals, including humans, suffering from such diseases. A typical field of application is the treatment of diabetes.

The compounds of this invention can be administered orally, parenterally (for example intramuscularly, intraperitoneally, intravenously or podkoren injection, or implantation), nasal, vaginal, rectal, sublingual or topical application and can be formulated in dosage forms appropriate EULA, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms can also include, in normal practice, additional substances other than inert diluents, i.e., lubricating agents such as magnesium stearate. If the dosage form is prepared in the form of capsules, tablets and pills, they may also include buffering agents. Tablets and pills can also be prepared with acceptable abdominal cavity shells, such as system OROS-CT/OsmetTMand PULSINCAPTMfrom ALZA and Scherer Drag Delivery Systems.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as moistening agents, emulsifiers and suspendresume agents and podslastiteli, taste and aroma additives.

Formulations of the present invention for parenteral Vvedenie or fillers are propylenglycol, the polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters, such as etiloleat. Such dosage forms may also contain adjuvants such as preservatives, moisturizing agents, emulsifiers and dispersing agents. Alternative solutions for intramuscular, intra-articular and subcutaneous injection with or without encapsulation of the drug in decaying beads, for example, containing poly(DL-lactide-co-glycolide), can be used for preparative forms of prolonged selection. For convenience preparative forms you can use intraperitoneally implanted reservoirs and cept, such as Percuseal system from Pharmacia. Enhanced convenience, and the absorption by the patient can also be achieved by using either injectors (for example, NovoPen or Q-pen) or needleless injectors (for example, from Bioject, Mediject or Becton Dickinson). Prolonged isolation zero-order, or more precisely controlled selection can also be achieved if necessary by the use of an implantable pump with delivery of the drug through the cannula into the synovial space. Examples include implantable PADCO jazznova introduction prepared with standard fillers, well known in the art.

Compositions for rectal or vaginal injection are preferably suppositories which may contain, in addition to the active compound, excipients such as coconut oil or suppozitornyj wax.

The compounds of this invention can be obtained in the above formulation by the addition of various therapeutically inert, inorganic or organic carriers, well known in the art. Examples include, but are not limited to, lactose, corn starch or its derivatives, talc, vegetable oils, waxes, fats, polyols, such as glycol, water, sucrose, alcohols, glycerin and the like. Formulation can be sterilized, for example, by filtration through catching bacteria filter, the introduction of sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be obtained in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable media immediately before use. Various preservatives, emulsifiers, dispersing Ali, the buffers and the like may also be added depending on the requirements, to facilitate stabilization of the formulation or to assist in increasing the bioavailability of the active ingredients (ingredient) or to obtain a formulation with acceptable taste or smell when administered orally.

The number of pharmaceutical compositions used depends on the patient and his condition. The required amount can be determined without undue experimentation using protocols known to specialists in this field. Alternative required quantity can be calculated based on the determination of the quantity of the target receptor, which must be Engibarov to treat the condition. An effective amount of the active ingredient is usually in the range from 0.0001 to 100 mg/kg body weight.

The method of treatment according to this invention is not limited to the introduction of the above-described pharmaceutical compositions. In addition, this mode of treatment may be used in combination with conventional methods of treatment of diabetes (as I and type II) or other painful conditions, which are sometimes found in patients with diabetes. Thus, for example, treatment can provocational; (C) treatment of hyperlipidemia other drugs, such as lovastatin or treatment of cardiovascular disease drugs, such as enalapril; (d) the treatment of diabetic complications such preparations, as epalrestat and (e) the weight of such preparations, as dexfenfluramine.

Antagonists of glucagon receptor of the present invention is used not only for treatment of pathophysiological conditions previously described, but in other areas, for example, as a diagnostic agent. For example, these compounds can be administered to the human in vivo in a state of starvation as a diagnostic agent for the direct determination whether the glucagon receptor. Serum samples taken before and after such an introduction can be used to determine the glucose level; to determine the capabilities of the glucagon receptor of the patient to modulate the release of glucose by the liver carry out a comparison of the level of glucose in the blood in each of these samples. Alternative the compounds of this invention can be used to search for new antagonists of glucagon. For example, the test on swasanie using radioactively labeled derivatives (such as3H) compounds of the background. Such tests are used to determine structural new antagonists, which may provide advantages relative to simplify the modification of selectivity and oral bioavailability.

The compounds of this invention can contain centers of asymmetry in the molecule, depending on the nature of the various substituents. Each of these centers of asymmetry has two optical isomers. In some cases, the asymmetry may also be due to the opposite rotation around the Central connection attached to two aromatic rings of certain compounds. For example, certain compounds of formula (IC) in which AG is substituted by phenyl, due to the opposite rotation around the Central communication aryl-aryl, there are additional isomers depending on the Deputy.

< / BR>
It is assumed that all the isomers arising from natural centers of asymmetrie or due to the opposite rotation described above, separated, pure or partially purified isomers or racemic mixtures included in the scope of this invention. For the compounds of formula (IC) in which R3is 1-hydroxyethyl, found that the isomer in which the hydroxyl h way more preferable than the other compounds in which the hydroxyl Deputy is at the bottom of the structural plane.

< / BR>
Examples representatives used in this invention nomenclature given below:

2,6-dimethyl-3-hydroxymethyl-4-(3-bromophenyl)-5-isobutylene

< / BR>
3,5-di-tert-butyl-2-(phenylthio)methyl-6-hydroxymethyl-3', 5'-dichloro-1,1'-biphenyl

< / BR>
Compounds of General formula (IC) of the present invention receives, as shown in the following reaction schemes.

Connection phenylpyridine formula (IC) (X=N) is obtained from a common intermediate 6, using well-known methods of synthesis of Hantzsch pyridines, as shown in figure 1 (see end of description) (Stout, D. M., Myers, A. I. Chem. Rev., 1982, 223).

Ketoester 1 (commercially available or obtained by the method Deslong-champs, Synth. Comm. , 1976, 6, 169) is treated with ammonium salt such as ammonium acetate, in an inert solvent, such as cyclohexane, capable of forming an azeotrope with water, obtaining enamine 2. Compound 2 is then treated with Betaferon 3, which may be identical or non-identical ketoether 1, and an aromatic aldehyde in a polar solvent such as ethanol, with the formation of dihydropyridines 5. In protective groups can be found in Protective Groups in Organic Synthesis. Second Edition, t.w. Green, John Wiley and Sons, New York, 1991. Oxidation of compound 5 is conducted according to any known method. For example, by treating compound 5 2,3-dichloro-5,6-disinsertion (DDH) in a solvent such as methylene chloride (CH2CL2) or cerium ammonium nitrate (SIC) in a mixture of solvents such as aqueous acetone, to obtain the intermediate compound 6. Department of unwanted side products and purification of the intermediate compounds is administered by chromatography on a column of silica gel using flash chromatography (Still, W. C., Khan, M.; Mitra, A. J. Org. Chem., 1978, 43, 2923).

Alternative synthesis of Hantzsch pyridine intermediate compound 6, in which R1aand R1bformula (IC) are the same, can be carried out according to the method Chucholowski (U.S. patent 4950675), scheme 2 (see the end of the description). Dihydropyridines 5 is obtained directly by heating two equivalents of keeeper 1 with ammonium hydroxide and the aldehyde 4 in polar solvent such as methanol. Connection 5 are oxidized to the pyridine 6 according to the method described in scheme 1.

In figure 3 (see end of description) presents another alternative synthesis of Hantzsch pyridine intermediate compound 6. Ketoester 1 condense with the aldehyde 4 processing is inane 7. Treatment of compound 7 with Betaferon 3 in the presence of a base such as sodium methoxide, in a polar solvent such as methanol, get diketone 8. The cyclization of compound 8 reaches the processing of ammonium salt such as ammonium acetate, in a polar solvent such as acetic acid, to obtain the previously described of dihydropyridines 5 (scheme 1), which is oxidized to the pyridine 6 according to the method shown in scheme 1.

Synthesis of derivatives of eilperin formula (IC) in which R2is alkyl and R3is hydroxymethyl (IIA) described in scheme 4 (see end of description).

When monooctyltin of pyridinediamine 6 with obtaining alcohol 9 use of chemical reducing agents such as sodium bis-(2-methoxyethoxy)alumoweld (Red-Al), in an inert solvent, such as tetrahydrofuran (THF) or diethyl ether (Et2O). Oxidants, such as pyridylcarbonyl (PQQ), in a solvent such as CH2Cl2make the connection 9 to the aldehyde 10. The Wittig reaction with compound 10 and ridom 11a in an inert solvent, such as THF or Et2O, gives the olefin 12, usually, but not always, in the form of a mixture of E and Z isomers. Reagent 11a is obtained from postnasal salt alkylate sodium amide, by known methods (Maercker A. In Organic Reactions, vol. 14, Ed.: Wiley, New York, 1965, Chapter 3). Olefin 12 successfully treated regenerating agent, such as socialogical (LAS) in an inert solvent, such as THF or Et2O, and hydrogen in the presence of metalicheskogo catalyst, such as palladium on charcoal, in a polar solvent such as ethanol, to obtain the compounds of formula IIA. In some of these compounds, R2may contain substituents, such as alcohol, acetate, ether, carboxylic acid and amide. These products can be obtained directly by the method presented in scheme 4 with or without the use of suitable protective groups or using additional stages, such known in this field. For example, the primary alcohol can be converted to carboxylic acid by standard methods of oxidation, such as described by Eisenbraun (Eisenbraun, E. J. Org. Syn. Coll., 1973, 5, 310).

If the Wittig reaction is carried out with methoxybutyrophenone as ilide (11b), followed by treatment with an acid, such as hydrochloric acid, the result is a homologue of aldehyde 13. Such processing can be performed by another Wittig reaction to obtain olefin 14 (see figure 5 at the end of the description). This known technique (Wi is a chain (R2), which cannot be directly obtained by the conventional Wittig reaction due to limited availability of the desired alkyltrimethylammonium salt.

Oxidation of compounds of formula IIA according to the method described in scheme 4, provides intermediate compounds that can be converted into the homologues of the compounds of formula IIA, containing communications-CH2CH2between the pyridine nucleus and a hydroxyl group (IIb).

Synthesis of derivatives of arylpyrimidine formula (IC) in which R2is alkyl containing a heteroatom, such as sulfur, and3is hydroxymethyl (IIIa and IIIb), presented in figure 6 (see the end of the description). Alcohol 9 turn in 15 alkyl by treatment with a suitable reagent, such as libraryversion, in an inert solvent. The process of joining 15 thiol and a base, such as N-methylmorpholine, in an inert solvent gives the intermediate connection 16. The sulfur atom of the compound 16 can be oxidized (n=1 or 2) with the help of several known techniques. For example, the oxidation can be carried out by treating compound 16 in which n=0, oxidant, such as m-chloroperbenzoic acid, in a solvent such as CH2CL2. Chemical reducing agents, such kanowit ether 16 to the compounds of formula IIIA. Intermediate soedinenie may also interact with alcohols, followed by the application of the methodology depicted in scheme 6, to obtain the compounds of formula S.

Synthesis of derivatives of arylpyrimidine formula (IC) in which R2is alkyl containing a heteroatom, such as nitrogen, and 3is hydroxymethyl (IVa), depicted in figure 7 (see the end of the description). Treatment of compound 15, a primary or secondary amine in an inert solvent gives the intermediate connection 17. Chemical reducing agents, such as socialogical, in an inert solvent, such as tetrahydrofuran or diethyl ether, can restore the ether 17 to the compounds of formula IVa. Recovery of aldehyde 13 according to the method depicted in scheme 4, gives an intermediate compound that can be converted into the homologues of the compounds of formulas IIIA and IVa, containing communications-CH2-CH2between the pyridine nucleus and a Deputy in the form of a sulfur atom or nitrogen (IIIb and IVb).

Synthesis of derivatives of arylpyrimidine formula (IC) in which R2is alkyl and R3is 1-hydroxyethyl (Va), shown in figure 8 (see end of description). Oxidants, such as pyridylcarbonyl (PQQ), used for premelanosomes or motility in an inert solvent, such as THF or Et2O, give racemic compounds of formula Va. Chiral derivatives of 1-hydroxyethylpiperazine formula Vb get re-dissolving the racemate Va classical methods. For example, re-dissolution can be achieved by the formation of diastereomeric products attach racemic compounds with optically active reagents, such as methoxy--(trifluoromethyl)phenylacetic acid (Dale J. A. , Dull, D. L.; Mosher, H. S. J. Org. Chem., 1969, 34, 2543). Alternative separation of enantiomers is carried out by using GHUR on chiral solid phase. Determination of the absolute stereochemistry can be done in several ways well known in the art, including x-ray analysis of a suitable crystalline derivative, such as ether Moser.

Alternative synthesis of derivatives of arylpyrimidine formula Vb is carried out by treatment of aldehyde 18 anion methylcellulose 19 obtaining diastereomeric mixture of alcohols 20, as shown in figure 9 (see end of description) (Blase F. R. , Le H. Tet. Lett., 1995, 36, 4559). The diastereomers share flash chromatography and treated separately by Raney Nickel and hydrogen in ethanol to obtain pure enantiomers (enantiomeric excess etelnost, consisting of (a) oxidation of a mixture of 20 dioxide magnesium in an inert solvent with subsequent stage (b) recovery of the ketone chemical reducing agent, such as LAG, to obtain enantiomerically pure alcohol 21. Treatment of compound 21 Raney Nickel and hydrogen in a polar solvent gives the net enantiomer (>99% of the E. I.) compounds of the formula Vb.

The preferred alternative enantioselective synthesis of derivatives of arylpyrimidine formula Vb is shown in scheme 10 (see the end of the description). Treatment of the racemic mixture of compounds of formula Va oxidant, such as pyridylcarbonyl (PQQ), gives the ketone 22. Reconnection 22 complex LAG and N-methylephedrine (M. Kawasaki, Susuki Y., Terashima, S. Chem. Lett., 1984, 239) in an inert solvent gives the alcohol of formula Vb with an enantiomeric excess of 95%.

Synthesis of derivatives of arylpyrimidine formula (IC) in which R2is alkyl and R3is 1,2-dihydroxyethyl (VI) described in scheme 11 (see the end of the description). Methyltriphenylphosphonium salt is treated with a suitable base, such as utility, in an inert solvent and is subjected to interaction with the intermediate connection 18 with obtaining olefin 23. Processing connection 23 with a suitable oxidant, such karoznedsy of arylpyrimidine formula (IC), in which R2and R1btogether form Allenby bridge and R3is hydroxymethyl (VIIa) described in scheme 12 (see the end of the description). Ketoester 1 is treated with an aromatic aldehyde and a catalyst, such as acetic acid and piperidine in ethanol, to obtain the , -unsaturated keeeper 24. Treatment of compound 24 cyclic ketone 25 and a base such as lithium bis(trimethylsilyl)amide, in an inert solvent, such as TTF, gives an intermediate compound, which is treated with ammonium acetate and copper acetate in acetic acid to obtain pyridine 26. Chemical reducing agents restore ether 26 to analogues of the formula VIIa. It may be noted that these analogues can be used as intermediates in obtaining new derivatives of the formula (IC) in which R2and R1bconnected and R3is 1-hydroxyethyl (VIIb), according to the method described in scheme 8.

Synthesis derived compounds arylpyrimidine IIA, in which1bis CH2HE described in scheme 13 (see the end of the description). Alcohol 27 (eilperin IIA in which R1bis CH3) process trialkylsilanes, such as tert-butyldiphenylsilyl chloride, and cos is the solvent, such as chloroform, gives N-oxide 29. N-Oxide is treated with acetic anhydride to obtain pyridylacetate 30. Treatment of compound 30 aqueous methanol in the presence of potassium carbonate gives the alcohol 31. Ether silila split tetrabutylammonium fluoride in THF to obtain a derived compounds arylpyrimidine 32.

Synthesis of derivatives of arylpyrimidine Ha, in which R1bis CH2NR4R5described in figure 14 (see end of description). Oxidation of alcohol 31, as shown in figure 4, gives the aldehyde 33. Treatment of the aldehyde with the amine in the presence of a Lewis acid such as zinc chloride and a reducing agent, such as Lamborgini sodium, gives the amine 34. Removing protection from alcohol, as shown in figure 13 gives the derivative of arylpyrimidine Ha.

Alternative synthesis of amine 34 shown in figure 15 (see the end of the description). Processing of pyridine N-oxide 29 phosphorus oxychloride and a base, such as triethylamine, in CH2CL2gives chloromethylpyridine 35. Chloride is treated with amine to obtain amine 34.

Synthesis of derivatives of arylpyrimidine b, in which R1bis-CH=CHR, described in scheme 16 (see the end of the description). Alcohol 31. converted into the corresponding bromide as shown in scheme is m as sodium hydride, and then the aldehyde with obtaining olefin 38. Removing protection from alcohol, as described, gives pyridine b.

Alternative synthesis of olefin 38 shown in scheme 17 (see the end of the description). Aldehyde 33 is treated with ridom, as shown in figure 4, with the receipt of olefin 38.

Synthesis of derivatives of arylpyrimidine CH in which R1bis-CH2CH2R described in scheme 18 (see end of description). Hydrogenation of the olefin b, as shown in figure 4, gives alkane XC.

Synthesis derived arylpyrimidine Xd, in which R1bis-CH(OH)R, described in figure 19 (see end of description). Treatment of aldehyde 33 Grignard reagent in an inert solvent, such as THF, gives the alcohol 39. Removing protection from alcohol, as described, gives the derived connection aryl pyridine Xd.

Synthesis of derivatives of arylpyrimidine Heh, in which R1bis-COR, described in scheme 20 (see end of description). Oxidation of alcohol 39, as shown in figure 4, gives the ketone 40. Removing protection from alcohol, as described, gives the derivative compound arylpyrimidine Heh.

Synthesis of derivatives of arylpyrimidine Xf, in which R1bis-C(OH)RR', described in scheme 21 (see the end of the description). Adding the Grignard reagent to the ketone 40, as described in scheme 19, des derivative arylpyrimidine Xg, in which R1bis C(OR4)RR', described in scheme 22 (see end of description). Treatment of alcohol 41 base such as sodium hydride, and an alkylating agent in THF gives the ester 42. Removing protection from alcohol, as described, gives the derivative compound arylpyrimidine Xg.

The biphenyl analogues described by formula (IC) (X=C-R8where R8is N), get on the techniques described by Fey et al., U.S. patent 5138090. A key step in the synthesis is the coupling of dimer relallade with aryl Grignard reagent (see scheme 23 in the end of the description).

A separate example of this technique is shown in scheme 24 (see end of description). Treatment of diol 43 (obtained by the method of Fey et al., U.S. patent 5138090) (2-methoxy)ethoxymethylene and diisopropylethylamine in solvent CH2CL2gives MEM ether 44. Oxidation of the resulting alcohol 44, as shown in figure 4, gives the aldehyde 45. Treatment of aldehyde aniline in the presence of catalytic amount of para-toluensulfonate acid (n-TAC) and molecular sieves in toluene gives Imin 46. Imin turn in the palladium dimer 47 treatment with palladium acetate in acetic acid. The process of joining 47 triphenylphosphine, then 4-performancebased (obtained from 1-brandegeana part biphenyl 48 in turn pentelow group according to the method described in scheme 4. MEM ether is treated with 50 trimethylsilylpropyne and sodium iodide in acetonitrile and then with sodium acetate in DMF to obtain acetate 51. Saponification of the acetate with potassium hydroxide in methanol gives the alcohol 52. Hydroxymethylbilane 52 is transformed into the racemic hydroxyethylidene 54, as described in scheme 8.

Alternative synthesis of biphenyls of formula (IC) is a combination of suitable functionalized benzene derivatives 57 (where X can be triftoratsetata, methoxy, bromide or iodide) with arylmethylidene reagent ArMYn(in which M can be In, Sn or Mg and Y is a ligand) (see scheme 25 in the end of the description).

An example of such a combination of biaryl is the Suzuki reaction (Miyaura, N., Yanagi T., Suzuki A. Synth. Comm., 1981, 11, 513-519; Oh-e, T., N. Miyaura, A. Suzuki, J. Org. Chem., 1993, 58, 2201-2208), which is a derivative of benzene 58 (where X can be triftoratsetata, bromide or iodide) combined with airborne acid (see scheme 26 in the end of the description).

Required kilborne acid 60 can be obtained by the sequential interaction of the halide 59 (X=Br or I) with metal magnesium, boron ether and hydrochloric acid (see scheme 27 in the end of the description).

A specific example of the use of the t successively with sodium hydride and allylbromide in dimethylformamide to obtain allyl ether 62. Rearrangement of Clausena ether gives phenol 63. Phenol is treated triftormetilfullerenov anhydride (triflic anhydride and pyridine in CH2Cl2obtaining triflate 64. Treatment 4-ftorpolimernoj acid, tetrahetarenoporphyrazines(0), potassium phosphate (trehosnovnoy) and potassium bromide in 1,4-dioxane gives the biphenyl 65. Catalytic hydrogenation as described in scheme 4, and the recovery of the ketone lydialydia in THF gives the desired analog biphenyl 67.

Alternative synthesis of biphenyl type I using cycloaromatization of certifire 68 ketone in the presence of catalytic amounts of sodium methoxide in methanol gives the phenol 69. The phenol is then combined with airborne acid as described in scheme 28, with getting biphenylether 70. Fluids are then transformed, as described in schemes 4, 8 and 10, obtaining similar with the desired group R2and R3(see diagram 29 in the end of the description).

An alternative method of conversion of phenol 69 in the biphenyl 70 shown in scheme 30 (see end of description). Treatment of phenol by dimethylsulfate and a base such as potassium carbonate, gives methyl ether 71. The ether is treated with aryl Grignard reagent with getting biphenyl 70.

Fluids 70 mobilegov with the desired group R2and R3. The use of chemical reducing agents, such as bis-(2-methoxyethoxy)aluminiumhydride sodium (Red-Al) when carrying out the reaction monovoltine diapir 70 gives the alcohol 72. Alcohol 72 can be attached to a polymeric substrate, such as Wang resin, treatment with a base such as sodium hydride in DMF to obtain intermediate compound 73. The ether group of the intermediate compound 73 can be turned into alkylhalogenide using the two-stage method, the connection handle 73 regenerating agent such as LAG, then tribromide phosphorus obtaining connection 74. Alkylhalogenide 74 treated with alkylthiols and a base, such as N-methylmorpholine, then TN for cleavage of the ether connection with a polymer resin with obtaining alcohol 75.

It should be clear that the synthesis of some compounds of formula (IC) may require the use of protective groups at different stages of the process. They are removed at the subsequent stages. For example, removal of O-benzyl protective groups of the ether is carried out by treatment with hydrogen in the presence of a metal catalyst such as palladium on charcoal, in a polar solvent such as ethanol. The removal of the silyl protective GnRH. The conditions required to remove the other protective groups which may be present can be found in Protective Groups in Organic Synthesis, Second Edition, T. W. Green, John Wiley and Sons, New York, 1991.

The procedure of stages presented above schemes is not always significant, and change the order of the reaction to facilitate the carrying out of the reaction or to avoid unwanted reaction products is within the competence of the specialist in this field.

The following examples are given to illustrate but not to limit the scope of the present invention.

EXAMPLE 1

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine

Stage A. Ethyl ester 3-amino-4-methyl-2-pentenol acid

To 100 g (0.63 mol) of utilizability add ammonium acetate (68.2 g, 0.89 mol), cyclohexane (230 ml) and isopropanol (74 ml). The mixture is heated under reflux in an argon atmosphere to trap Dean-stark. 2 hours to the reaction mixture add the second portion of ammonium acetate (14.6 g, 0.19 mol). The reaction mixture is heated under reflux for 12 hours and then cooled to room temperature. All the water (about 30 ml) is collected in the trap Dean-stark. For cooling the reactions the definition layer is separated, dried with sodium sulfate, filtered and concentrated to obtain a yellow oil. The crude product (90.0 g, 0.58 mmol, 92%) taken directly to the next stage without further purification.

Stage C. Diethyl 1,4-dihydro-2,6-aminobutiramida-4-(4-forfinal)-3,5-pyridinedicarboxylate

To the ethyl ether of 3-amino-4-methylpent-2-ene acid (phase A) (90 g, 57 mmol) added utilizability (90 g, 57 mmol) and 4-forbindelse (61.4 ml, 0.57 mmol). The mixture is heated in an argon atmosphere to a temperature of 130oWith over 26 hours (caution: check reverse the fridge a few hours later, as the excess of ammonium acetate litters a reflux). The reaction mixture is cooled to room temperature and left to crystallize for 4 days. The solid is collected by filtration under vacuum (46.9 g, 116 mmol, 20%) and taken directly to the next stage without further purification.

Stage C. Diethyl ether 2,6-aminobutiramida-4-(4-forfinal)-3,5-pyridinedicarboxylic acid

To the intermediate compound obtained in stage (33 g, 82 mmol), in dichloromethane (400 ml) was added 2,3-dichloro-5,6-disinsertion (DH, 20.5 g, 90 mmol) in an argon atmosphere and the mixture is stirred for 2 cha is l) and take out. The filtrate is concentrated to obtain a brown solid, which handle flash chromatography (6:4 mixture of dichloromethane/hexane) to give pure white solid (25.8 g, 64.3 mmol, 78%).

1H NMR (300 MHz, CDCl3): 7.28 (m, 2H);, 7.06 (m,2H); 4.03(q, J=7.0 Hz, 4H); 3.11 (septet, J=6.6 Hz, 2H); 1.32( d, J=6.5 Hz, N); 0.979(t, J= 3.3 Hz, 6N). The Belarusian library Association-MS: calculated for (C23H28NO4F) 401, found 402 (M+H). Anal. Rasch. for (C23H28NO4F): 68.64; N, 7.24; N, 3.48; F 4.72. Found: 69.12; H 6.98; N, 3.42; F 4.96. so pl. 72-74oC. Rf=0.4(10% ethyl acetate/hexane).

Stage D. Ethyl ester of 2,6-aminobutiramida-4-(4-propenyl)-5-hydroxymethyl-3-pyridineboronic acid.

To a solution of the intermediate obtained in stage C (23.4 g, 58.3 mmol) in anhydrous tetrahydrofuran (300 ml), stirred in an argon atmosphere at a temperature of 0oC, add a solution of 3.4 M sodium bis-(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (61 ml, 204 mmol, 65 wt.% in toluene) via syringe over 20 minutes the Reaction mixture was stirred at room temperature for 7 hours, then cooled again to 0oC and carefully quenched by adding water dropwise. The solution is decanted from the resulting solids and restdent. Elution with 5% solution of diethyl ether/hexane gives 6.6. g (16.4 mmol, 28%) of recovered starting compound and elution of 40% solution of diethyl ether (Et2O)/ hexane gives the desired product as a yellow prapinabracni solid (14 g, 39 mmol, 67%).

1H NMR (300 MHz, CDCl3): 7.27 (m, 2H); 7.10 (m,2H); 4.46(d, J=5.2 Hz, 2H); 3.98(q, J=7 Hz, 2H); 3.48 (Sept, J=6.6 Hz, 1H); 3.05 (Sept, J=6.6 Hz, 1H); 1.32( t, J=6.6 Hz, N); 0.97(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H26FNO3) 359, found 360 (M+H). Rf=0.2(20% ethyl acetate/hexane).

Stage E. 5-Carboethoxy-2,6-aminobutiramida-4-(4-forfinal)-3-pyridinecarboxamide

To a solution of the intermediate obtained in stage D (13 g, 36 mmol) in dichloromethane (1 l) add neutral alumina Brockman I (7.4 g, 72 mmol). The suspension is stirred at room temperature and treated with pyridylamino (PQQ) (16 g, 72 mmol) in three portions. The suspension is stirred at room temperature for 1 hour, then poured into 1:1 diethyl ether/hexane (1 l), filtered through a layer of silicon dioxide, the layer is washed with diethyl ether (500 ml) and the combined eluent concentrated to obtain a viscous oil which slowly solidified (12.8 g, 35.9 mmol, 99%). Rf=88(Sept, J=6.6 Hz, 1H); 3.12 (Sept, J=6.6 Hz, 1H); 1.33(t, J=6.6 Hz, N); 1.00(t, J=7 Hz, 3H). EI-MS: calculated for (C21H24FNO3) 357, found 358 (M+H). Anal. Rasch. for C21H24FNO3: 70.57; H 6.77; N, 3.92. Found: 70.62; H 6.78; N, 3.84.

Stage F. Ethyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(1-pentenyl)-3-pyridineboronic acid

Butyldiphenylchlorosilane (2.7 g, 6.76 mmol) suspended in anhydrous THF (75 ml) in an argon atmosphere and stirred at a temperature of -78oC. are added dropwise 1.6 M solution of n-utility in hexane (4.2 ml, 6.76 mmol). The reaction mixture is heated to 0oC and then stirred at this temperature for 1.5 hours Obtained brightly coloured solution is cooled again to -78oC and treated dropwise with a solution of the intermediate obtained in stage E (2 g, 5.60 mmol) in THF (20 ml). The reaction mixture was stirred at 0oC for 1 hour, then quenched by addition of water (5 ml). THF is removed in vacuo, the residue is divided between ethyl ether (200 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried over Mg2SO4and concentrate. Flash chromatography with silica (5% diethyl ether/hexane) to give a viscous oil (2 g, 5 mmol, 90%) of (E,Z mixture).

); 5.33(dt,J=7, 16.2 Hz,0.6 H); 4.00(q, J=7 Hz, 0.8 H); 3.98(q, J=7 Hz, 1.2 H); 3.39 (Sept, J= 6.6 Hz, 0.6 H); 3.27 (Sept, J=6.6 Hz, 0.4 H); 3.06(m, 1H); 1.95(DQC, J=1.5, 7 Hz, 1H); 1.26(m,13H); 1.19(m, 2H); 0.97(t, J=7 Hz, 3H); 0.77(t, J= 7 Hz, 1.2 H); 0.76(t,J=7 Hz, 1.8 H). EI-MS: calculated for (C25H32FN2) 397, found 397 (M+). Rf=0.5(10% ethyl acetate/hexane).

Stage G. of 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-pentenyl)pyridine

The intermediate compound obtained in stage F (2 g, 5.03 mmol) dissolved in anhydrous THF (100 ml) in an argon atmosphere and treated dropwise at room temperature lydialydia (1.0 M in THF, 10 ml, 10 mmol). The reaction mixture was stirred at reflux for 1 hour, cooled to room temperature and quenched by the addition of 0.38 ml of N2Oh, 0.38 ml of 20% aqueous NaOH and 1.1 ml of N2O. the resulting suspension is filtered through a layer of celite and the filtrate is concentrated and purified by chromatography on a column of silica (5% ethyl acetate/hexane) to give a white foam (1.42 g, 4.0 mmol, 80%). Rf= 0.2 (10% ethyl acetate/hexane).

Stage N. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine

The intermediate compound obtained in stage G, is dissolved in absolute ethanol (50 ml) in an argon atmosphere, processing uwci system with argon, the catalyst was removed by filtration through a layer of celite. The solvent is removed and the product dried in vacuum to obtain the target compound as a white solid (1.4 g, 3.9 mmol, 98%).

1H NMR (300 MHz, CDCl3): 7.15 (m, 4H); 4.33(d, J=4.4 Hz, 2H); 3.41(Sept, J=6.6 Hz, 1H); 3.23 (Sept, J=6.6 Hz, 1H); 2.26(m, 2H); 1.33(d, J= 6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.27(m, 2H); 1.13(m,5H); 0.79(t, J=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H32FN) 357, found 358 (M+H). Anal. Rasch. for C23H32FNO: 77.27; N, 9.02; N, 3.92. Found: 77.46; N, 8.95; N, 3.78. Rf=0.3(20% ethyl acetate/hexane). So PL 100-101oC.

EXAMPLE 2

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2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-(2-methyl-1-propenyl)-pyridine

The target compound is obtained from ethylacetoacetate, benzaldehyde and isopropyltriphenylphosphonium by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.34 (m, 3H); 7.10 (m,2H); 5.70(s, 1H); 4.42(s, 2H); 2.69(s, 3H); 2.43 (s, 3H); 1.60(s, 3H); 1.35(s, 3H). EI-MS: calculated for (C18H21NO) 267, found 267 (M+). So PL 48-50oC. Rf=0.3(90% ethyl acetate/hexane).

EXAMPLE 3

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2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine

The target compound is obtained from ethylacetoacetate, benzaldehyde and butyldiphenylchlorosilane by the method of example 1, stage A-G. the Product is obtained in a mixture of 3:1 TRANS:CIS and the& 2.68(2s, 3H); 2.57&2.46 (2s, 3H); 1.91& 1.69(2Q, J= 7 Hz, 2H); 1.52(SHS, 1H); 1.19(m, 2H); 0.77(m,3H). EI-MS: calculated for (C19H23NO) 281, found 281. Rf=0.4(90% ethyl acetate/hexane).

EXAMPLE 4

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2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine

The target compound is obtained from 2,6-dimethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (example 3) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.42 (m, 3H); 7.15 (m,2H); 4.33(s, 2H); 2.65(s, 3H); 2.56(s, 3H); 2.27(m, 2H); 1.29(m, 2H); 1.11(m, 4H); 0.76(t, J=7 Hz, 3H). EI-MS: calculated for (C19H25NO) 283 found 283 (M+). Anal. Rasch. for C19H25NO: 80.52; N, 8.89; N, 4.94. Found: 80.39; N, 8.85; N, 4.85. so pl. 99-100oC. Rr=0.3(90% ethyl acetate/hexane).

EXAMPLE 5

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2,6-Diethyl-3-hydroxymethyl-4-phenyl-5-(2-methyl-1-propenyl)pyridine

The target compound is obtained from ethylpropylamine, benzaldehyde and isopropyltriphenylphosphonium iodide according to the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.34 (m, 3H); 7.11 (m,2H); 7.56(s, 1H); 4.44(d, J= 5.5 Hz, 2H); 3.01(q, J=7.4 Hz, 2H); 2.75(q, J=7.4 Hz, 2H); 1.58(s, 3H); 1.35(m, 7H); 1.21(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C20H25NO) 295 found 296 (M+H). Anal. Rasch. for C20H25NO: 81.31; N, 8.53; N, 4.74. Found: 81.03; N, 8.55; N, 4.65. So pl. 103-104o
The target compound is obtained from ethylpropylamine, benzaldehyde and butyldiphenylchlorosilane by the method of example 1, stage A-G. the Product is obtained in the form of a mixture of 6:4 TRANS:CIS isomers.

1H NMR (300 MHz, CDCl3): 7.36 (m, 3H); 7.14 (m,2H); 6.00(m, 1H); 5.37(m, 1H); 4.42(m, 2H); 2.90(m, 4H); 1.89&1.67(2Q, J=7 Hz, 2H); 1.25(m, N); 0.76(m, 3H). The Belarusian library Association-MS: calculated for (C21H27NO) 309, found 310 (M+H). Anal. Rasch. for C21H27NO: 81.51; N, 8.79; N, 4.53. Found: 81.95; N, 8.90; N, 4.45. T. pl. 74-76oC. Rf=0.5(50% ethyl acetate/hexane).

EXAMPLE 7

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2,6-Diethyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine

The target compound is obtained from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (example 6) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.42 (m, 3H); 7.18 (m,2H); 4.34(d, J=6 Hz, 2H); 2.96(q, J= 7.7 Hz, 2H); 2.84(q, J=7.7 Hz, 2H); 2.28(m, 2H); 1.34(m, N); 1.09(m, 4H); 0.76(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H29NO) 311, found 312 (M+H). So pl. 76-77oC. Rf=0.5(50% ethyl acetate/hexane).

EXAMPLE 8

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2,6-Diethyl-3-hydroxymethyl-4-phenyl-5-(1-ethynyl)pyridine

The target compound is obtained from ethylpropylamine, benzaldehyde and methyltriphenylphosphonium/sodium amide by the method of example 1, stage A-G.

18H21NO) 267, found 268 (M+H). Anal. Rasch. for C18H21NO: 80.86; N, 7.92; N, 5.24. Found: 80.65; N, 8.06; N, 5.09. So pl. 84-85oC. Rf=0.4(50% ethyl acetate/hexane).

EXAMPLE 9

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2,5,6-Triethyl-3-hydroxymethyl-4-phenylpyridine

The target compound is obtained from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-ethynyl)pyridine (example 8) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.44 (m, 3H); 7.18 (m,2H); 4.33(d, J=6 Hz, 2H); 2.97(q, J= 8 Hz, 2H); 2.86(q, J=8 Hz, 2H); 2.36(q, J=8 Hz, 2H); 1.34(m, 7H); 0.93(t, J= 8 Hz, 3H). The Belarusian library Association-MS: calculated for (C18H23NO) 269 found 270 (M+H). Anal. Rasch. for C18H23NO: 80.26; N, 8.61; N, 5.20. Found: 79.70; N, 8.54; N, 5.08. So pl. 100oC. Rf=0.4(50% ethyl acetate/hexane).

EXAMPLE 10

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridi

The target compound is obtained from ethylisopropylamine, benzaldehyde and butyldiphenylchlorosilane by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.35 (m, 3H); 7.14 (m,2H); 5.99(m, 1H); 5.35(m, 1H); 4.41(m, 2H); 3.36( m, 2H); 1.89&1.70(2Q,J=7 Hz, 2H); 1.24(m, 15 NM); 0.80& 0.72(2T, J= 7 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H31BUT) 337, found 338 (M+H). Anal. Rasch. for C23N EXAMPLE 11

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-(2-methyl-1-propenyl)pyridine

The target compound is obtained from ethylisopropylamine, benzaldehyde and isopropyltriphenylphosphonium by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.32 (m, 3H); 7.11 (m,2H); 5.75(s, 1H); 4.43(MS, 2H); 3.46(Sept, J=6.6 Hz, 1H); 3.18(Sept, J=6.6 Hz, 1H); 1.57(s, 3H); 1.31(m, 15 NM). The Belarusian library Association-MS: calculated for (C22H29NO) 323, found 324 (M+H). Anal. Rasch. for C22H29NO: 81.69; N, 9.04; N, 4.33. Found: 81.59; N, 8.94; N, 4.29. So pl. 93-95oC. Rf=0.1(10% ethyl acetate/hexane).

EXAMPLE 12

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-(1-propenyl)pyridi

The target compound is obtained from ethylisopropylamine, benzaldehyde and ethyltriphenylphosphonium by the method of example 1, stage A-G. the Product is obtained in the form of a mixture 1:1 TRANS:CIS isomers; sticky oil.

1H NMR (300 MHz, CDCl3): 7.4 (m, 3H); 7.2 (m,2H); 6.0(m, 1H); 5.5& 5.4(2m, 1H); 4.4(m, 2H); 3.4&3.2(2m, 2H); 1.6(m, 2H); 1,4(m, 7H); 1.3(m, 7H). The Belarusian library Association-MS: calculated for (C21H27NO) 309, found 310 (M+H). Anal. Rasch. for C21H27NO: 81.53; N, 9.98;

N 3.96. Found: 79.06; N, 9.65; N, 3.61. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 13

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-ifosphamide by the method of example 1, stage A-G. the Product is obtained in the form of a mixture 1:1 TRANS:CIS isomers; sticky oil.1< / BR>
H NMR (300 MHz, CDCl3): 7.4 (m, 3H); 7.2 (m,2H); 6.0(m, 1H); 5.4(m, 1H); 4.4(m, 2H); 3.3(m, 3H); 1.9& 1.7(2m, 2H); 1,3(m, N); 0.7(m, 3H). The Belarusian library Association-MS: calculated for (C22H29NO) 323, found 324 (M+H). Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 14

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (example 10) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.41 (m, 3H); 7.18 (m,2H); 4.33(s, 2H); 3.42(Sept, J= 6.6 Hz, 1H); 3.23(Sept, J=6.6 Hz, 1H); 2.26(m, 2H); 1.32(m, 13H); 1.11(m, 5H); 0.76(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H33NO) 339.2640 found 340.2640 (M+H). So pl. 81-82oC. Rf=0.1(10% ethyl acetate/hexane).

EXAMPLE 15

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2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-(1-hexenyl)pyridi

The target compound is obtained from ethylisopropylamine, benzaldehyde and pentyltrichlorosilane by the method of example 1, stage A-G. the Product is obtained in the form of a mixture 1:1 TRANS:CIS isomers; sticky oil.

1H NMR (300 MHz, CDCl3): 7.35 (m, 3H); 7.14 (m,2H); 5.99(m, 1H); 5.35(m, 1H); 4.40(m, 2H); 3.36(m, 2H); 1.92&1.70(2m, 2H); 1,2(m, 17H); 0.80(m, 3H). The Belarusian library Association-MS: expect the network: 81.58; N, 9.50; N, 4.62. Rf=0.1(10% ethyl acetate/hexane).

EXAMPLE 16

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2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-hexylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-(1-hexenyl)pyridine (example 15) by the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.40 (m, 3H); 7.18 (m,2H); 4.33(d, J=5 Hz, 2H); 3.42(Sept, J=7 Hz, 1H); 3.23(septet, 3=7 Hz, 1H); 2.26(m, 2H); 1.31(m, 13H); 1.12(m, 8H); 0.80(t, J=7 Hz, MN). The Belarusian library Association-MS: calculated for (C24H35NO) 353, found 354 (M+H). Anal. Rasch. for C24H35NO: 81.53; N, 9.98; N, 3.96. Found: 79.06; N, 9.65; N, 3.61. So pl. 71-72oC. Rf=0.1(10% ethyl acetate/hexane).

EXAMPLE 17

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2,6-Aminobutiramida-3-hydroxymethyl-4-phenyl-5-propylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-(1-propenyl)pyridine (example 12) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.41 (m, 3H); 7.17 (m, 2H); 4.33(s, 2H); 3.42(Sept, J=6.6 Hz, 1H); 3.23(Sept, J=6.6 Hz, 1H); 2.25(m, 2H); 1.33(d, J= 6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.27(m, 2H); 1.20(m, 1H); 0.74(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H29NO) 311, found 312 (M+H). Anal. Rasch. for C21H29NO: 80.98; N, 9.38; N, 4.50. Found: 80.72; N, 9.47; N, 4.38. So pl. 89-90oC. Rf=0.4(20% ethyl acetate/hexane).

The USE of the isopropyl-3-hydroxymethyl-4-phenyl-5-(1-butenyl)pyridine (example 13) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.41 (m, 3H); 7.17 (m,2H); 4.33(s, 2H); 3.42(Sept, J=6.6 Hz, 1H); 3.24(Sept, 3=6.6 Hz, 1H); 2.28(m, 2H); 1.33(d, J= 6.6 Hz, 6N); 1.31(d, J=6.6 Hz, 6N); 1.28(m, 2H); 1.14(m, 3H); 0.71(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H31NO) 325, found 326 (M+H). Anal. Rasch. for C22H31NO: 81.18; N, 9.60; N, 4.30. Found: 81.28; N, 9.87; N, 4.07. So pl. 83-84oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 19

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-hexenyl)pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and pentyltrichlorosilane by the method of example 1, stage A-G. the Product is obtained in the form of a mixture of 6:4 TRANS:CIS isomers; sticky oil.

1H NMR (300 MHz, CDCl3): 7.10 (m,4H); 5.98(m, 1H); 5.42(dt, J=7,11.4 Hz, 0.4 H); 5.29(dt, J=7,16.2 Hz, 0.6 H); 4.40(d, J=5.5 Hz, 2H); 3.44(m, 1H); 3.36(Sept, J=6.6 Hz, 0.6 H); 3.24(Sept, J=6.6 Hz, 0.4 H); 1.94(m, 1H); 1.36(m, 6N); 1.23(m, 8H); 1.12(m, 4H); 0.82(m, 3H). The Belarusian library Association-MS: calculated for (C24H32FNO) 369, found 370 (M+H). Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 20

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-butenyl)pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and propylthiophenethylamine by the method of example DCl3): 7.10 (m,4H); 5.97(m, 1H); 5.39(dt, J=7,11.4 Hz, 0.5 H); 5.32(dt, J=7, 16.2 Hz, 0.5 H); 4.41(d, J=5.5 Hz, 2H); 3.45(m, 1H); 3.36(Sept, J= 6.6 Hz, 0.5 H); 3.24(Sept, J=6.6 Hz, 0.5 H); 1.95(m, 1H); 1.70( m, 1H); 1.35(d, J=6.6 Hz, 3H); 1.34(d, J=6.6 Hz, 3H); 1,25(m, 7H); 0.79(t, J=7.5 Hz, 1.5 H); 0.78(t, J=7.5 Hz, 1.5 H). The Belarusian library Association-MS: calculated for (C22H28FNO) 341, found 342 (M+H). Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 21

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-propenyl)pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and ethyltriphenylphosphonium by the method of example 1, stage A-G. the Product is obtained in the form of a mixture 1:1 TRANS:CIS isomers.

1H NMR (300 MHz, CDCl3): 7.11(m,4H); 6.04(d, J=11.7 Hz, 0.5 H); 5.96(d, J= 16.1 Hz, 0.5 H); 5.53(m, 0.5 H); 5.33(m, 0.5 H); 4.41(m, 3H); 3.42(m, 1.5 H); 3.20(Sept, J= 6.6 Hz, 0.5 H); 1.61(d, J= 6 Hz, 2H); 1.3(m, 13H). The Belarusian library Association-MS: calculated for (C21H26FNO) 327, found 328 (M+H). Anal. Rasch. for C21H26FNO: 77.03; N, 8.00; N, 4.28. Found: 77.15; N, 8.07; N, 4.11. So pl. 46-47oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 22

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-ethenylpyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and methyltriphenylphosphonium/sodium amide by the method of example 1, stage A-G.

EXAMPLE 23

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-hexylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-hexenyl)pyridine (example 19) by the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.14 (m,4H); 4.33(s, 2H); 3.41(Sept, J=6.6 Hz, 1H); 3.23(Sept, J= 6.6 Hz, 1H); 2.26(m, 2H); 1.33(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.26(m, 1H); 1.14(m,7H); 0.82(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO) 371, found 372 (M+H). So pl. 93-95oC. Rf= 0.4(20% ethyl acetate/hexane).

EXAMPLE 24

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-butylpyrazine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-butenyl)pyridine (example 20) by the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.15 (m,4H); 4.33(d, J=5.2 Hz, 2H); 3.41(Sept, J=6.6 Hz, 1H); 3.23(Sept, J=6.6 Hz, 1H); 2.27(m, 2H); 1.34(d, J= 6.6 Hz. 6N); 1.30(d, J=6.6 Hz, 6N); 1.27(m, 1H); 1.16(m, 3H); 0.73(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30

o
C. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 25

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-propylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-propenyl)pyridine (example 21) by the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.15 (m,4H); 4.33(s, 2H); 3.41(Sept, J=6.6 Hz, 1H); 3.23(Sept, J= 6.6 Hz, 1H); 2.25(m, 2H); 1.33(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.27(m, 1H); 1.19(m, 1H); 0.76(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H28FNO) 329, found 330 (M+H). Anal. Rasch. for C21H28FNO: 76.56; N, 8.57; N, 4.25. Found: 76.55; N, 8.48; N, 4.11. So pl. 49-54oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 26

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-atilpirina

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-ethenylpyridine (example 22) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.15 (m,4H); 4.33(d, J=3.6 Hz, 2H); 3.41(Sept, J= 6.6 Hz. 1H); 3.26(Sept, J=6.6 Hz, 1H); 2.34(q, J=7.35,2 H); 1.33(d, J= 6.6 Hz, 6N); 1.31(d, J=6.6 Hz, 6N); 1.19(m, 1H); 0.93(t, J=7.35 Hz, 3H). The Belarusian library Association-MS: calculated for(C20H26FNO) 315, found 316 (M+H). Anal. Rasch. for C20H26FNO: 76.16; N, 8.31; N, 4.44. Found: 75.74; N, 8.50; N, 4.27. So pl. 126-129oC. Rf=0.4(20% ethylacetamide

The target compound is obtained from ethylisopropylamine, 4-forventelige and isobutyltrimethoxysilane by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.07 (m,4H); 5.92(d, J=10.7 Hz, 1H); 5.20(DD, J= 10.7, 11.4 Hz, 1H); 4.42(MS, 2H); 3.45(Sept, J=6.6 Hz, 1H); 3.30(Sept, J= 6.6 Hz, 1H); 2.06(m, 1H); 1.35(d, J=6.6 Hz, 6N); 1.31(m,1H); 1.24(m, 5H); 0.69(CL, 6N). The Belarusian library Association-MS: calculated for (C23H30FN) 355, found 356 (M+H). Anal. Rasch. for C23H30FNO: 77.71; N, 8.51; N, 3.94. Found: 77.94; N, 8.59; N, 3.79. So pl. 112oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 28

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-methyl-1-pentenyl)pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and islamicringtonesnokian by the method of example 1, stage A-G.

The product is obtained as a mixture of 6:4 TRANS:CIS isomers.

1H NMR (300 MHz, CDCl3): 7.11 (m,4H); 6.04(dt, J=1.5, 11 Hz, 0.4 H); 5.96(dt, J=1.5, 16 Hz, 0.6 H); 5.47(dt, J=7, 11 Hz, 0.4 H); 5.32(dt, J=7, 16 Hz, 0.6 H); 4.41(m, 2H); 3.44(m, 0.8 H); 3.38(Sept, J=6.6 Hz, 0.6 H); 3.24(Sept, J= 6.6 Hz, 0.6 H); 1.84(m, 1H); 1.45(m, 1H); 1.35(m, 6N); 1.24(m, 7H); 0.79(d, J= 6.6 Hz, 2.4 H); 0.73(d, J=6.6 Hz, 3.6 H). The Belarusian library Association-MS: calculated for (C24H32FNO) 369, found 370 (M+H). Anal. Rasch. for C23H32FNO: 78.01; N, 8.73; N, 3.79. Found: 78.13-hydroxymethyl-4-(4-forfinal)-5-(3-methylbutyl)pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(3-methyl-1-butenyl)pyridine (example 27) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.14 (m,4H); 4.33(d, J=5.5 Hz, 2H); 3.41(Sept, J= 6.6 Hz, 1H); 3.22(Sept, J=6.6 Hz, 1H); 2.27(m, 2H); 1.35(m, 1H); 1.33(d, J=7 Hz, 6N); 1.30(d, 5=7 Hz, 6N); 1.17 (m, 3H); 0.70(d, J=6.6 Hz, 6N). The Belarusian library Association-MS: calculated for (C23H32FN) 357, found 358 (M+H). Anal. Rasch. for C23H32FNO: 77.27; N, 9.02; N, 3.92. Found: 77.34; N, 9.15; N, 3.69. So pl. 43-45oC. Rf=0.2(20% ethyl acetate/hexane).

EXAMPLE 30

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-methylpentyl)pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-methyl-1-pentenyl)pyridine (example 28) by the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.14(m, 4H); 4.33(d, 1=5Hz, 2H);

3.41(Sept, J= 6.6 Hz, 1H); 3.22(Sept,J=6.6 Hz, 1H); 2.23(m, 2H); 1.38(m, 1H); 1.33(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.27(m, 1H); 1.17(m, 1H); 1.00(m, 3H); 0.76(d, 3=6.6 Hz, 6N). The Belarusian library Association-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Anal. Rasch. for C24H34FNO: C.59; N, 9.22; N, 3.77. Found: S.63; N, 9.39; N TO 3.58. So pl. 101-103oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 31

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-parentalguide and cyclopentadienylmanganese by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.13(m, 2H); 7.07(m, 2H); 5.88(s, 1H); 4.43(d, J= 5.5 Hz, 2H); 3.44(Sept, J=6.6 Hz, 1H); 3.21(Sept, J=6.6 Hz, 1H); 2.11(m, 2H); 1.75(m, 2H); 1.47(m,4H); 1.34(d, J=6.6 Hz, 6N); 1.29(m, 1H); 1.21(d, J= 6.6 Hz, 6N). The Belarusian library Association-MS: calculated for (C24H30FN) 367, found 368 (M+H). Anal. Rasch. for C24H30FN: 78.44; N, 8.23; N, 3.81. Found: 78.46; N, 8.18; N, 3.63. So pl. 97-98oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 32

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-heptenyl)pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and n-hexyltrichlorosilane by the method of example 1, stage A-G. the Product is obtained in the form of a 1:1 TRANS:CIS isomers; sticky oil.

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 5.99(m, 1H); 5.42(dt, J=7,11 Hz, 0.5 H); 5.30(dt, J= 7,16 Hz, 0.5 H); 4.41(d, J=5.5 Hz, 2H); 3.45(m, 1H); 3.37(Sept, J= 6.6 Hz, 0.5 H); 3.24(Sept, J=6.6 Hz, 0.5 H); 1.94(m, 1H); 1.35(m, 6N); 1.29(m, 1H); 1.26(d, J=6.6 Hz, 3H); 1.22(m, 6N); 1.15(m, 4H); 0.86(m, 3H). The Belarusian library Association-MS: calculated for (C25H34FNO) 383, found 384 (M+H). Anal. Rasch. for C25H34FNO: AT 78.29; N, 8.93; N, 3.65. Found: 78.37; N, 8.88; N, 3.57. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 33

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-octenyl)pyridine

The target connection poductive A-G. The product is obtained in the form of a 1:1 TRANS:CIS isomers; sticky oil.

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 5.98(m, 1H); 5.42(dt, J=7,11 Hz, 0.5 H); 5.30(dt, J= 7,16 Hz, 0.5 H); 4.41(d, J=5.5 Hz, 2H); 3.44(m, 1H); 3.37(Sept, J=6.6 Hz, 0.5 H); 3.24(Sept, J=6.6 Hz, 0.5 H); 1.94(m, 1H); 1.35(m, 6N); 1.30(m,1H); 1.26(d, J=6.6 Hz,6N); 1.22(m, 4H); 1.16(m, 5H); 0.87(m, 3H). The Belarusian library Association-MS: calculated for (C26H36FN) 397, found 398 (M+H). Anal. Rasch. for C26H36FN: 78.55; N, 9.13; N, 3.52. Found: 78.63; N, 9.16; N, 3.48. Rf= 0.4(20% ethyl acetate/hexane).

EXAMPLE 34

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-phenylethenyl] pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and benzyltriphenylphosphonium/sodium amide by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.21(m, N); 6.70(d, J=16.5 Hz, 1H); 6.26(d, J= 16.5 Hz, 1H); 4.45(d, J=5.5 Hz, 2H); 3.48(Sept, J=6.6 Hz, 2H); 1.37(d, J= 6.6 Hz, 6N); 1.31(d, J= 6.6 Hz, 6N); 1.29(m, 1H). The Belarusian library Association-MS: calculated for (C26H28FNO) 389, found 390 (M+H). Anal. Rasch. for C26H28FNO: C 80.17; N, 7.25; N, 3.60. Found: 79.89; N, 7.28; N, 3.49. So pl. 107-110oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 35

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-gatheredin

The target compound is obtained from 2,6-aminobutiramida 3-gemr (300 MHz, CDCl3): 7.13(m, 4H); 4.33(s, 2H); 3.41(Sept, J=6.6 Hz, 1H); 3.22(Sept, J= 6.6 Hz, 1H); 2.26(m, 2H); 1.33(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N);1.22(m, 3H); 1.11(m, 8H); 0.85(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H36FN) 385, found 386 (M+H). Anal. Rasch. for C25H36FNO: 77.88; N, 9.41; N, 3.63. Found: At 77.86; N, 9.66; N 3,59. So pl. 73-75oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 36

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-octylpyrimidine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-octenyl)pyridine (example 33) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.14(m, 4H); 4.33(d, J=5.5 Hz, 2H); 3.41(Sept, J= 6.6 Hz, 1H); 3.23(Sept, J=6.6 Hz, 1H); 2.26(m, 2H); 1.33(d, J= 6.6 Hz, 6N); 1.30(d, J=6.6.Hz, 6N); 1.25(m, 6N); 1.15(m, 10H); 0.87(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C26H38FNO) 399, found 400 (M+H). Anal. Rasch. for C26H38FN: 78.15; N, 9.59; N, 3.51. Found: 78.27; N, 9.81; N 3,43; sticky oil. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 37

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(2-phenylethyl)pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-phenylethenyl] pyridine (example 34) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7..5 Hz, 1H). The Belarusian library Association-MS: calculated for (C26H30FN) 391, found 392 (M+H). Anal. Rasch. for C26H30FNO: 79.76; N, 7.72; N, 3.58. Found: 79.57; N, 7.61; N 3,44. So pl. 158-159oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 38

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-phenyl-1-butenyl)pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and 3-phenylpropionaldehyde by the method of example 1, stage A-G. the Product is obtained in the form of a mixture 5:1 TRANS:CIS isomers; sticky oil.

1H NMR (300 MHz, CDCl3): 7.26(m, 2H); 7.19(m, 1H); 7.09(m, 6N); 6.05(d, J= 11 Hz, 0.2 H); 5.98(d, J=16 Hz, 0.8 H); 5.47(dt, J=7,11 Hz, 0.2 H); 5.33(dt, J= 7,16 Hz, 0.8 H); 4.40(d, J=5 Hz, 2H); 3.43(m, 1H); 3.26(Sept,J= 6.6 Hz, 2H); 2.51(m, 2H); 2.29(m,1.6 H); 2.05(m, 0.4 H); 1.34(m, 6N); 1.25(m, 1H); 1.22(d, J=6.6 Hz, 6N). The Belarusian library Association-MS: calculated for (C28H32FNO) 417, found 418 (M+H). Anal. Rasch. for C28H32FNO: 80.54; N, 7.72; N, 3.35. Found: 80.56; N, 7.56; N, 3.32. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 39

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-phenylbutyl)pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-phenyl-1-butenyl)pyridine (example 38) according to the method of example 1, stage N; sticky oil.

1Mr. YAM 1.47(m,2H); 1.32(d, J=6.6 Hz, 6N); 1.30(m, 2H); 1.27(d, J= 6.6 Hz, 6H); 1.15(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C28H34FN) 419, found 420 (M+H). Anal. Rasch. for C28H34FNO: 80.15; N, 8.17; N, 3.34. Found: 80.06; N, 7.94; N 3,28. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 40

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-(2-were)ethynyl]pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and 2-methylbenzenesulfonamide by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.22(m, 3H); 7.10(m, 5H); 6.62(d, J=17 Hz, 1H); 6.45(d, J=17 Hz, 1H); 4.45(d, J=5.5 Hz, 2H); 3.48(m, 2H); 2.12(s, 3H); 1.37(d, J= 6.6 Hz, 6H); 1.33(d, J=6.6 Hz, 6H); 1.31(m, 1H). The Belarusian library Association-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Rasch. for C27H30FNO: 80.36; N, 7.49; N, 3.47. Found: 80.23; N, 7.23; N, 3.44. So pl. 108-111oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 41

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-(3-were)ethynyl]pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and 3-methylbenzenesulfonamide by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.18(m, 3H); 7.11(m, 2H); 7.00(m, 3H); 6.68(d, J= 17 Hz, 1H); 6.23(d, J=17 Hz, 1H); 4.44(d, J=5.5 adeno 404 (M+H). Anal. Rasch. for C27H30FNO: 80.36; N, 7.49; N, 3.47. Found: 80.38; N, 7.45; N, 3.45. So pl. 97-99oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 42

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-(4-were)ethynyl]pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and 4-methylbenzenesulfonamide by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.18(m, 2H); 7.08(m, 6N); 6.63(d, J=17 Hz, 1H); 6.23(d, J= 17 Hz, 1H); 4.43(d, J=5 Hz, 2H); 3.47(Sept, J=6.6 Hz, 2H); 2.31(s, 3H); 1.36(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.26(m, 1H). The Belarusian library Association-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Rasch. for C27H30FNO: 80.36; N, 7.49; N, 3.47. Found: 79.93; N, 7.34; N, 3.47. So pl. 131-133oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 43

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(2-were)ethyl] pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-(2-were)ethynyl] pyridine (example 40) according to the method of example 1, stage N.1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 7.06(m, 3H); 6.81(m, 1H); 4.35(d, J= 4 Hz, 2H); 3.42(Sept, J=6.6 Hz, 2H); 2.57(m, 4H); 1.97(s, 3H); 1.36(d, J= 6.6 Hz, 6N); 1.35(d, J=6.6.Hz, 6N); 1.19(m, 1H). The Belarusian library Association-MS: calculated for (C27H32FNO) 405, SUB>=0.3(20% ethyl acetate/hexane).

EXAMPLE 44

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(3-were)ethyl] pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-(3-were)ethynyl] pyridine (example 41) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.18(d, J=7 Hz, 4H); 7.10(m, 1H); 6.97(m, 1H); 6.65(m, 2H); 4.36(s, 2H); 3.44(Sept, J=6.6 Hz, 1H); 3.35(d, J=6.6 Hz, 1H); 2.57(m, 4H); 2.28(s, 3H); 1.35(d, J=6.6 Hz, 6N); 1.34(d, J=6.6 Hz, 6N); 1.20(m, 1H). The Belarusian library Association-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Rasch. for C27H32FNO: 79.96; N, 7.95; N, 3.45. Found: 79.30; N, 8.10; N 3,36. So pl. 148-150oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 45

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(4-were)ethyl] pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[2-(E)-(4-were)ethynyl] pyridine (example 42) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.17(m, 4H); 7.02(d, J=7.7 Hz, 2H); 6.75(d, J= 7.7 Hz, 2H); 4.36(d, J=4 Hz, 2H); 3.43(Sept, J=6.6 Hz, 1H); 3.34(Sept, J= 6.6 Hz, 1H); 2.55(m, 4H); 2.29(s, 3H); 1.34(d, J=6.6 Hz, 6N); 1.33(d, J=6.6. Hz, 6H); 1.20(m, 1H). The Belarusian library Association-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Rasch. for C27H32FN IS 46

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[3-(1,3-dioxolane-2-yl)propyl]pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and [2-(1,3-dioxolane-2-yl)ethyl]triphenylphosphonium by the method of example 1, stage A-G.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 4.63(t, J=4 Hz, 1H); 4.33(d, J=5 Hz, 2H); 3.88(m, 2H); 3.77(m, 2H); 3.41(BL, 1H); 3.24(BL,1H); 2.34(m, 2H); 1.47(m, 4H); 1.32(m, N); 1.18(m, 1H). The Belarusian library Association-MS: calculated for (C24H32FN3) 401, found 402 (M+H). So pl. 90-91oC. Rf=0.2(20% ethyl acetate/hexane).

EXAMPLE 47

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(phenylthio)methyl] pyridine

Stage A. the Methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-hydroxymethyl-3-pyridineboronic acid

Receive from methylisobutylketone, 4-forventelige and ammonium acetate according to the method described in example 1, stage A-D.

Stage Century. Methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-methyl bromide-3-pyridineboronic acid

A solution of the intermediate obtained in stage A (20 g, 57.9 mmol) in acetonitrile (500 ml) is stirred at a temperature of 0oWith and portions treated with dibromothiophene (36.7 g, 86.9 mmol). The suspension is then warmed to room those who nd ether (400 ml) and water (350 ml). The ether layer was washed with brine (150 ml), dried (MgS4) and concentrate. Purification by chromatography on a column of silica gel (5% diethyl ether/hexane) to give white solid (20.6 g, 50.5 mmol, 87%).

1H NMR (300 MHz, CDCl3): 7.31 (m, 2H); 7.12(m, 2H); 4.29(s, 2H); 3.49(s, 3H); 3.41(Sept, J= 6.6 Hz, 1H); 3.06(Sept, J=6.6 Hz, 1H); 1.33(m, N). So pl. 109-111oC. Rf=0.6(50% CH2C12/hexane).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(phenylthio)methyl]pyridine

A solution of the intermediate obtained in stage (200 mg, 0.47 mmol) in anhydrous THF (5 ml), stirred in an argon atmosphere, is treated with bestiola (73 μl, 0.71 mmol) and N-methylmorpholine (0.26 ml, 2.4 mmol). The reaction mixture was stirred at reflux for 14 h, cooled to room temperature and treated with lydialydia (1.9 ml, 1.9 mmol, 1.0 M in THF). The reaction mixture is heated under reflux for 1 hour, then cooled to room temperature. The mixture was quenched by the sequential addition of water (80 μl), 20% NaOH (80 ml) and water (240 μl). The resulting suspension is filtered through a layer of celite and concentrate. Purification with flash chromatography on a column of silica gel (5% atilas is; .11(m, 4H); 4.36(d, J=5.5 Hz, 2H); 3.81(s, 2H); 3.45(Sept, J= 6.6 Hz, 1H); 3.43(Sept, J=6.6 Hz, 1H); 1.35(d, J=6.6 Hz, 6N); 1.33(d,J=6.6.Hz, 6N); 1.21 (t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C25H28FNOS) 409, found 410 (M+H). Anal. Rasch. for C25H28FNOS: 73.32; H 6.89; N, 3.42; p. 7.83. Found: At 73.24; N, 6.90; N 3,35; S 8.01. So pl. 119-121oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 48

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[((3-trifluoromethyl)phenyl)thio]methylpyridin

The target compound is obtained from 3-triptoreline by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.34(m, 2H); 7.24(m, 4H); 7.10(m, 2H); 4.36(d, J=5.5 Hz, 2H); 3.85(s, 2H); 3.45(Sept, J=6.6 Hz, 1H); 3.38(Sept, J= 6.6 Hz, 1H); 1.35(d, J=6.6 Hz, 6N); 1.34(d,J=6.6.Hz, 6N); 1.23(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C26H27F4NOS) 477, found 478 (M+H). Anal. Rasch. for C26H27F4NOS: 65.39; H 5.70; N, 2.93; S 6.71. Found: 65.39; H 5.76; N 2,88; S 6.62. So pl. 110-111oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 49

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-forfinal)thio] methylpyridin

The target compound is obtained from 4-portifino by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.24(m, 2H); 7.12(m, 4H); 6.93(m, 2H); 4.35(d, J=5.5 Hz, 2H); 3.76(s, 2H); 3.44(Sept, J=6.6 Hz, 1H); 3.40(Sept, J= 6.6, GTO 428 (M+H). Anal. Rasch. for C25H27F2NOS: 70.23; H 6.37; N, 3.28; S 7.50. Found: 70.22; H 6.41; N 3,22; S 7.39. So pl. 119-121oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 50

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[((4-methyl)phenyl)thio] methylpyridin.

The target compound is obtained from the pair-thiocresol by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.27(m, 2H); 7.13(m, 2H); 7.03(m, 4H); 4.35(d, J=5.5 Hz, 2H); 3.77(s, 2H); 3.44(m, 2H); 2.31(s, 3H); 1.34(d, J=6.6 Hz, 6N); 1.33(d,J=6.6.Hz, 6N); 1.22(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C26H30FNOS) 423, found 424 (M+H). Anal. Rasch. for C26H30FNOS: 73.72; N, 7.14; N, 3.31; S 7.57. Found: 74.00; N, 7.15; N 3,36; S 7.32. So pl. 90-91oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 51

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-naphthylthio)methylpyridin

The target compound is obtained from 1-naphthalenyl by the method of example 47.

1H NMR (300 MHz, CDCl3): 8.01(d, J=8.5 Hz, 1H); 7.82(d, J=8.5 Hz, 1H); 7.74(d, J= 8 Hz, 1H); 7.46(m, 3H); 7.34(m, 1H); 7.20(m, 2H); 7.06(m, 2H); 4.34(d, J=5.5 Hz, 2H); 3.82(s, 2H); 3.51(Sept, J=6.6 Hz, 1H); 3.45(Sept, J= 6.6 Hz, 1H); 1.36(d, J=6.6 Hz, 6N); 1.35(d, J=6.6 Hz, 6N); 1.19(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C29H30FNOS) 459, found 460 (M+H). Anal. Rasch. for C29H30FNOS: 75.78; N, 6.58; N, 3.05; < / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(2-naphthylthio)methylpyridin

The target compound is obtained from 2-naphthalenethiol by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.77(d, J=9 Hz, 1H); 7.68(d, J=9 Hz, 2H); 7.52(d, J=1.5 Hz, 1H); 7.45(m, 2H); 7.25(m, 2H); 7.17(DD, J=1.8,8.5 Hz, 1H); 7.07(m, 2H); 4.35(d, J=5.5 Hz, 2H); 3.91(s, 2H); 3.45(Sept, J=6.6 Hz, 2H); 1.35(d, J=6.6 Hz, 6N); 1.34(d, J=6.6.Hz, 6N); 1.21(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C29H30FNOS) 459, found 460 (M+H). Anal. Rasch. for C29H30FNOS: 75.78; N, 6.58; N, 3.05; S 6.98. Found: 75.55; H 6.60; N 2,95; S 6.91. So pl. 127-129oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 53

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(2,3,5,6-tetrafluorophenyl)thio]methylpyridin

The target compound is obtained from pentafluorothiophenol by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.27(m, 2H); 7.11(m, 2H); 6.99(m, 1H); 4.35(d, J=5.5 Hz, 2H); 3.84(s, 2H); 3.44(Sept, J=6.6 Hz, 1H); 3.43(Sept, J= 6.6 Hz, 1H); 1.34(d, J=6.6 Hz, 6N); 1.33(d, J=6.6.Hz, 6N); 1.23(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C25H24F5NOS) 481, found 482 (M+H). Anal. Rasch. for C25H24F5NOS: 62.36; N, 5.02; N, 2.91; S 6.66; F 19.73. Found: At 62.40; H 4.96; N 2,82; S 6.74; F 19.49. So pl. 109-110oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 54

< / BR>
2,6-Aminobutiramida 3-bestiole by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.24(m, 2H); 7.13(m, 3H); 6.72(m, 2H); 6.62(m, 1H); 4.35(d, J=5.5 Hz, 2H); 3.81(s, 2H); 3.75(s, 3H); 3.44(Sept, J= 6.6 Hz, 1H); 3.42(Sept, J=6.6 Hz, 1H); 1.34(d, J=6.6 Hz, 6N); 1.33(d, J=6.6 Hz, 6H); 1.23(t, J= 5.5 Hz, 1H).The Belarusian library Association-MS: calculated for (C26H30FNO2S) 339, found 440 (M+H). Anal. Rasch. for C26H30FNO2S: 71.04; N, 6.88; N, 3.19; S 7.29. Found: 70.94; H 6.77; N 2,96; S 7.41. So pl. 93-94oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 55

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-hydroxyphenyl)thio] methylpyridin

The target compound is obtained from 4-hydroxythiophenol by the method of example 47.

1H NMR (300 MHz, 5:1 CDCl3/CD3OD): 7.15(m, 2H); 7.06(m, 2H); 6.97(d, J=8.5 Hz, 2H); 6.64(d, J=8.5 Hz, 2H); 4.27(s, 2H); 3.66(s, 2H); 3.40(m, 2H); 1.29(d, J= 6.6 Hz, 6N); 1.28(d, J= 6.6 Hz, 6H). The Belarusian library Association-MS: calculated for (C25H28FNO2S) 425, found 426 (M+H). Anal. Rasch. for C25H28FNO2S: 70.56; H 6.63; N, 3.29; S 7.53. Found: 70.29; N, 6.34; N 3,12; S 7.44. So pl. 178-179oC. Rf=0.3(30% ethyl acetate/hexane).

EXAMPLE 56

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-methoxyphenyl)thio] methylpyridin

The target compound is obtained from 4-methoxybenzyl by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.23(m, 2H); 7.12(m, 4H);BA-MS: calculated for (C26H30FNO2S) 339, found 440 (M+H). Anal. Rasch. for C26H30FNO2S: 71.04; N, 6.88; N, 3.19; S 7.29. Found: C 70.96; N, 6.90; N 3,15; S 7.35. So pl. 92-93oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 57

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(3 - were)thio] methylpyridin

The target compound is obtained from m-thiocresol by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.25(m, 2H); 7.11(m, 3H); 7.00(m, 1H); 6.94(m, 2H); 4.36(d, J=5.5 Hz, 2H); 3.81(s, 2H); 3.45(Sept, J=6.6 Hz, 1H); 3.43(Sept, J=6.6 Hz, 1H); 2.28(s, 3H); 1.35(d, J=6.6 Hz, 6N); 1.34(d,J=6.6. Hz, 6N); 1.22(t, J= 5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C26H30FNOS) 423, found 424 (M+H). Anal. Rasch. for C26H30FNOS: 73.72; N, 7.14; N, 3.31; S 7.57. Found: 73.76; H 7.09; N 3,27; S 7.42. So pl. 92-93oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 58

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(2-were)thio] methylpyridin

The target compound is obtained from o-thiocresol by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.25(m, 2H); 7.11(m, 6N); 4.36(d, J=5.5 Hz, 2H); 3.74(s, 2H); 3.45(Sept, J=6.6 Hz, 2H); 2.26(s, 3H); 1.35(d, J=6.6 Hz, N); 1.21(t, J=5.5 Hz, 1H).The Belarusian library Association-MS: calculated for (C26H30FNOS) 423, found 424 (M+H). Anal. Rasch. for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S 7.57. Found: With the propyl-3-hydroxymethyl-4-(4-forfinal)-5-[(3-forfinal)thio] methylpyridin

The target compound is obtained from 3-portifino by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.27(m, 3H); 7.11(m, 2H); 6.87(m, 2H); 6.78(m, 1H); 4.36(d, J=5.5 Hz, 2H); 3.82(s, 2H); 3.45(Sept, J=6.6 Hz, 1H); 3.38(Sept, J= 6.6 Hz, 1H); 1.35(d, J=6.6 Hz, 6N); 1.33(d, J=6.6 Hz, 6N); 1.23(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C25H27F2NOS) 427 found 428 (M+H). Anal. Rasch. for C25H27F2NOS: 70.23; H 6.37; N, 3.28; S 7.50. Found: 70.22; H 6.31; N 3,20; S 7.41. So pl. 99-100oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 60

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(2-methoxyphenyl)thio] methylpyridin

The target compound is obtained from 2-methoxythiophene by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.22(m, 3H); 7.07(m, 3H); 6.83(m, 2H); 4.34(d, J= 5.5 Hz, 2H); 3.78(s, 3H); 3.75(s, 2H); 3.49(Sept, J=6.6 Hz, 1H); 3.43(Sept, J= 6.6 Hz, 1H); 1.34(d, J=6.6 Hz, N); 1.19(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C26H30FNO2S) 339, found 440 (M+H). Anal. Rasch. for C26H30FNO2S: 71.04; N, 6.88; N, 3.19; S 7.29. Found: 70.93; N, 6.67; N 3,12; S 7.48. So pl. 129-131oC. Rf=0.4(20% ethyl acetate/hexane).

EXAMPLE 61

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(3, 5dimethylphenyl)thio]methylpyridin

The target compound is obtained from 3,5-dimethylthiophene.5 Hz, 2H); 3.79(s, 2H); 3.44(Sept, J=6.6 Hz, 1H); 3.42(Sept, J=6.6 Hz, 1H); 2.23(s, 6N); 1.34(doctor J=6.6 Hz, 6N); 1.33(d, J=6.6 Hz, 6N); 1.21(t, J=5.5 Hz, 1 H). The Belarusian library Association-MS: calculated for (C27H32FNOS) 437 found 438 (M+H). Anal. Rasch. for C27H32FNOS: 74.11; N, 7.37; N, 3.20; S 7.33. Found: 74.18; N, 7.22; N 3,13; S 6.86. So pl. 109-110oC. Rf=0.5(20% ethyl acetate/hexane).

EXAMPLE 62

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-ethylphenyl)thio] methylpyridin

The target compound is obtained from 4-ethylthiophene by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.24(m, 2H); 7.05(m, 6N); 4.35(d, J=5.5 Hz, 2H); 3.77(s, 2H); 3.43(m, 2H); 2.60(q, J=7.7 Hz, 2H); 1.34(d, J=6.6 Hz, 6N); 1.32(d, J=6.6 Hz,6N); 1.21(m, 4H). The Belarusian library Association-MS: calculated for (C27H33FNOS) 437 found 438 (M+H). Anal. Rasch. for C27H32FNOS: 74.11; N, 7.37; N, 3.20; S 7.33. Found: 74.04; N, 7.23; N 3,09; S 7.23. So pl. 102-103oC. Rf=0.5(20% ethyl acetate/hexane).

EXAMPLE 63

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-isopropylphenyl)thio]methylpyridin

The target compound is obtained from 4-isopropylthiazole by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.25(m, 2H); 7.06(m, 6N); 4.35(d, J=5.5 Hz, 2H); 3.79(s, 2H); 3.43(m, 2H); 2.86 (Sept, J=7 Hz, 1H); 1.34(d, 3=6.6 Hz, 6N); 1.32(d, J= 6.6 Hz, 6N); 1.22(d, J=7 Hz, 6N); 1.20(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: caters is With 74.51; H 7.48; N, 3.04 FROM; S 6.85. So pl. 108-109oC. Rf=0.5(20% ethyl acetate/hexane).

EXAMPLE 64

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-benzyldimethylamine.

The target compound is obtained from benzylmercaptan by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.23(m, 5H); 7.08(m, 4H); 4.31(d, J=5.5 Hz, 2H); 3.55(s, 2H); 3.40(Sept, J=6.6 Hz, 1H); 3.24 (s, 2H); 3.19(Sept, J=6.6 Hz, 1H); 1.31(d, 3= 6.6 Hz, 6N); 1.24(d, J=6.6 Hz, 6N); 1.17(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C26H30FNOS) 423, found 424 (M+H). Anal. Rasch. for C26H30FNOS: 73,72; N, 7.14; N, 3.31; S 7.57. Found: 73.58; N, 7.25; N 3,05; S 7.45. So pl. 150-151oC. Rf=0.5(20% ethyl acetate/hexane).

EXAMPLE 65

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(phenethyl) thiomethyl] pyridine

The target compound is obtained from penicillata by the method of example 47.

1H NMR (300 MHz, CDCl3): 7.28(m, 5H); 7.11(m, 4H); 4.34(d, J=5.5 Hz, 2H); 3.39(m, 4H); 2.70(m, 2H); 2.61(m, 2H); 1.33(d, J=6.6 Hz, 6N); 1.32(d, J= 6.6 Hz, 6N); 1.20(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C27H32FNOS) 437 found 438 (M+H). Anal. Rasch. for C27H32FNOS: 74,11; N, 7.37; N, 3.20; S 7.33. Found:

With 73.99; N, 7.46; N 2,96; S 7.23; sticky oil. Rf=0.5(20% ethyl acetate/hexane).

EXAMPLE 66

< / BR>
2,6-Aminobutiramida 3-getmetadata of example 47.

1H NMR (300 MHz, CDCl3): 7.30(m, 2H); 7.14(m, 2H); 4.34(d, J=5.5 Hz, 2H); 3.41(m, 2H); 3.37 (m, 2H); 2.31(t, J=7.0 Hz, 2H); 1.31(m, 15 NM); 0.89(t, J= 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30NFOS) 375, found 376 (M+H). Anal. Rasch. for C22H30NOFS: C 70,36; H, 8.05; N, 3.73; F 5.06; S 8.54. Found: At 70.32; N, 7.97; N To 3.58; (F 4.76; S, 8.49. So pl. 98oC (decomp.). Rf= 0.3(10% ethyl acetate/hexane).

EXAMPLE 67

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(methylthio)methylpyridin.

The target compound is obtained from methylmercaptan by the method of example 47.

1H NMR (300 MHz, CDCl3) : 7.30(m, 2H); 7.16(m, 2H); 4.35(d, J=5.5 Hz, 2H); 3.43(m, 2H); 3.38 (m, 2H); 1.95(s, 3H); 1.30(m, N). The Belarusian library Association-MS: calculated for (C20H26NFOS) 347, found 348 (M+H). Anal. Rasch. for C20H26NFOS: 69,13; N, 7.54; N, 4.03; F 5.47. Found: 69.29; N, 7.54; N 3,91; F 5.45. So pl. 49oC (decomp.). Rf=0.2(10% ethyl acetate/hexane).

EXAMPLE 68

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-nitrophenyl)thio] methylpyridin

Stage A. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(tert-butyldimethylsiloxy)methyl]pyridine

A solution of 3 g (8.3 mmol) of the methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-hydroxymethyl-3-pyridineboronic acid (example 47, step A) in anhydrous DMF (75 ml) amrabat what metilsalicilata (1.4 g, 9.3 mmol). The reaction mixture was stirred at room temperature for 48 hours. The solution was diluted with diethyl ether (200 ml) and washed with water (2100 ml), 1 N. model HC1 (100 ml), saturated Panso3(50 ml) and brine (100 ml), dried (MgSO4) and concentrate to 4 g in the form of oil, Rf=0.4 (10% ethyl acetate/hexane).

This intermediate compound (4 g) dissolved in anhydrous THF (100 ml), stirred in an argon atmosphere and treated with lydialydia (17 ml, 17 mmol, 1.0 M in THF). The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The solution is quenched by the sequential adding dropwise water (0.6 ml), 20% NaOH (0.6 ml) and water (1.9 ml). The resulting suspension is filtered through a layer of celite and concentrate. Purification with flash chromatography on a column of silica gel (5% ethyl acetate/hexane) gives a colorless resin (1.8 g, 4.2 mmol, 51%).

1H NMR (300 MHz, CDCl3): 7.25(m, 2H); 7.12(m, 2H); 4.38(d, J=5 Hz, 2H); 4.28(s, 2H); 3.44(Sept, J= 6.6 Hz, 1H); 3.39(Sept, J=6.6 Hz, 1H); 1.33(t, J= 6.6 Hz, N); 1.24(t, J=5.5 Hz, 1H); 0.84(s, N); -0.08(C, 6N). The Belarusian library Association-MS: calculated for (C25H38FNSiO2) 431, found 432 (M+H). Anal. Rasch. for C25H38FNSiO2: 69,56; N, 8.87; N, 3.24. Found: 69.70; N, 8.82; N, 3.1 immissions)methyl]pyridine

The intermediate compound obtained in stage A (1.7 g, 3.9 mmol), dissolved in acetonitrile (50 ml) at a temperature ofoWith and handle portions of dibromothiophene (2.6 g, 6.2 mmol). The suspension is then warmed to room temperature and stirred for 2 hours. The solvent is removed in vacuum and the residue is divided between diethyl ether (150 ml) and water (100 ml). The ether layer was washed with brine (50 ml), dried (MgSO4) and concentrate. Purification by chromatography on a column of silica gel (5% diethyl ether/hexane) to give a viscous oil (1.4 g, 2.8 mmol, 72%) which slowly solidified upon maturation.

1H NMR (300 MHz, CDCl3): 7.28(m, 2H); 7.13(m, 2H); 4.23(m, 4H); 3.37(m, 2H); 1.34(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 0.83(s, N); -0.09(C, 6N). The Belarusian library Association-MS: calculated for (C27H37BrFSiNO) 493, found 494 (M+H). So pl. 72-73oC. Rf=0.5(10% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida-3 - hydroxymethyl-4-(4-forfinal)-5-[(4-nitrophenyl)thio]methylpyridin

The intermediate compound obtained in stage B (200 mg, 0.40 mmol), dissolved in anhydrous THF (5 ml), stirred under argon atmosphere at room temperature and treated with 4-nitrothiophene (118 mg, 0.6 mmol, 80%, technical purity) and N-methylmorpholine (0.2 ml, 1. the promote to room temperature. The mixture is treated with tetrabutylammonium (0.8 ml, 0.8 mmol, 1.0 M in THF) and stirred at room temperature for 24 hours. The solvent is removed in vacuum, the residue is dissolved in ethyl acetate (100 ml), washed with I called HC1 (50 ml), feast upon. Panso3(50 ml) and brine (50 ml), dried (MgSO4) and concentrate. Purification by chromatography on a column of silica (gradient of 5-10% ethyl acetate/hexane) gives the target compound in the form of easily colored solid (130 mg, 0.28 mmol, 70%).

1H NMR (300 MHz, CDCl3): 8.08(d, J=8.5 Hz, 2H);

7.27(m, 2H); 7.13(m, 4H); 4.37(d, J=5.5 Hz, 2H); 3.91(s, 2H); 3.46(Sept, J= 6.6 Hz, 1H); 3.33(Sept, J=6.6 Hz, 1H); 1.35(d, J=6.6 Hz, 6N); 1.34(d, J= 6.6 Hz, 6N); 1.27(t, J=5 Hz, 1H). The Belarusian library Association-MS: calculated for (C25H27FSN2O3) 454, found 455 (M+H). So PL/ 178-180oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 69

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(morpholinomethyl)pyridin

Stage A. the Methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(morpholino)methyl-3-pyridineboronic acid

A solution of methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-methyl bromide-3-pyridineboronic acid (example 47, step B) (500 mg, 1.22 mmol) in CH2CL2(20 ml) is treated with morpholine (0.14 ml, 1.61 her diluted with CH2CL2(70 ml), washed with saturated NaHCO3(240 ml), water (140 ml) and brine (140 ml). The organic layer is dried over MgSO4, filtered and concentrated to obtain a white solid (495 mg, 1.2 mmol, 98%).

1H NMR (300 MHz, CDCl3): 7.16(m, 2H); 7.07(m, 2H);

3.54(t, J=4.4 Hz, 4H); 3.49(m, 4H); 3.27(s, 2H); 2.98(septet, J=6.6 Hz, 1H); 2.19(t, J=4.8 Hz, 4H); 1.30(m, N). The Belarusian library Association-MS: calculated for (C24H31N2FO3) 414, found 415 (M+H). Anal. Rasch. for C24H31N2FO3: 69,54; N, 7.54; N, 6.76; F 4.58. Found: 69.55; N, 7.43; N 6,50; F 4.45. So pl. 132-134oC. Rf=0.2(20% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(morpholinomethyl)pyridin

The intermediate compound obtained in stage A (375 mg, 0.905 mmol), dissolved in dry THF (50 ml), treated dropwise with lydialydia (1M/THF, 1.81 ml) and the reaction mixture is stirred under reflux for 24 hours. The reaction mixture was quenched by the sequential adding dropwise water (0.1 ml), NaOH 20% (0.1 ml) and again water (0.3 ml). Concentration in vacuo gives a white residue, which is shared between CH2Cl2and water. The organic layer is dried over MgSO4filter and concentrate to obtain makenna hardens with obtaining the target compound as a white solid (295 mg, 0.76 mmol, 84%).

1H NMR (300 MHz, CDCl3): 7.14(m, 4H); 4.35(d, 2H); 3.53(t, J=4.8 Hz, 4H); 3.45(m, 2H); 3.18(s, 2H); 2.18(t, J=4.5 Hz, 4H); 1.26(m, 13H). The Belarusian library Association-MS: calculated for (C23H31N2FO2) 386, found 387 (M+H). Anal. Rasch. for C23H31N2O2F: 71,47; N, 8.08; N, 7.25; F 4.92. Found: 71.55; H,8.16; N 7,05; F 4.70. So pl. 93.5-95.5oC. Rf=0.4(40% diethyl ether/hexane).

EXAMPLE 70

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(piperidinomethyl)pyridine

The target compound is obtained from piperidine according to the method of example 69.

1H NMR (300 MHz, CDCl3): 7.05(m, 4H); 4.27(d, J=5.5 Hz, 2H); 3.38(m, 2H); 3.01(s, 2H); 2.02(m, 4H); 1.22(m, 24N). The Belarusian library Association-MS: calculated for (C24H33N2FO) 384, found 385 (M+H). Anal. Rasch. for C24H33N2OF: 74,96; N, 8.65; N, 7.28; F 4.94. Found: 75.13; N, 8.48; N 6,92; F 4.77; sticky oil. Rf=0.5(40% diethyl ether/hexane).

EXAMPLE 71

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(pyrrolidinyl)pyridine

The target compound is obtained from pyrrolidine by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.13(m, 4H); 4.34(d, J=4.8 Hz, 2H); 3.52(septet, J=6.6 Hz, 1H); 3.42(septet, J=6.6 Hz, 1H); 3.28(s, 2H); 2.22(t, J= 6.3 Hz, 4H); 1.60(t, J=3.3 Hz, 5H); 1.27(m, N). The Belarusian library Association-MS: calculated for (C< Found: 74.67; N, 8.72; N 7,35; F 5.01. So pl. 122-124oC. Rf=0.3(40% diethyl ether/hexane).

EXAMPLE 72

< / BR>
2,6-L-3-hydroxymethyl-4-(4-forfinal)-5-[(4-phenylpiperazin-1-yl)methyl]pyridine

The target compound is obtained from 4-phenylpiperidine by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.29(m, 2H); 7.15(m, 7H); 4.36(d, J=5.2 Hz, 2H); 3.48(m, 2H); 3.19(s, 2H); 2.71(d, J=11.0 Hz, 2H); 2.38(m, 1H); 1.86(m, 2H), 1.71(m, 2H); 1.58(m, 2H); 1.58(m, 13H). The Belarusian library Association-MS: calculated for (C30H31N2FO) 460, found 461 (M+H). Anal. Rasch. for C30H31N2OF: 78,22; N, 8.10; N, 6.08; F 4.12. Found: 78.01; N, 8.21; N 5,96; F 4.41. So pl. 66-68oC. Rf=0.5(40% diethyl ether/hexane).

EXAMPLE 73

< / BR>
Methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(4-piperidinophenyl-1-yl)methyl-3-pyridineboronic acid

The target compound is obtained from 4-piperidinylidene by the method of example 69 (stage A).

1H NMR (300 MHz, CDCl3): 7.16(m, 2H); 7.04(m, 2H); 3.51(septet, J=5.5 Hz, 1H); 3.47(s, 3H); 3.20(s, 2H); 2.98(septet, J=6.6 Hz, 1H); 2.65(d, J= 11.0 Hz, 2H); 2.44(m, 4H); 2.05(m, 1H); 1.62(m, 10H); 1.31(m, N). The Belarusian library Association-MS: calculated for (C30H42N3FO2) 495 found 496 (M+H). Anal. Rasch. for C30H42N3O2F: 72,69; N, 8.54; N, 8.48; F 3.83. Found: 72.43; N, 8.56; N Of 8.37; F 3.74. ropyl-3-hydroxymethyl-4-(4-forfinal)-5-[(4-piperidinophenyl-1-yl)methyl]pyridine

The target compound is obtained from 4-piperidinylidene by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.12(m, 4H); 4.34(d, J=3.7 Hz. 2H); 3.45(m, 2H); 3.10(m, 2H); 2.63(d, J=11.0 Hz, 2H); 2.44(m, 4H); 2.03(m, 1H); 1.44(m, 29N). The Belarusian library Association-MS: calculated for (C29H42N3FO) 467 found 468 (M+H). Anal. Rasch. for C29H42N3OF: 74,48; N, 9.05; N, 8.98; F 4.06. Found: 74.93; N, 9.35; N 8,39; F 3.83. So pl. 143-145oC. Rf=0.1(50% diethyl ether/hexane+2 drops Meon).

EXAMPLE 75

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(4-phenylpiperazin-1-yl)methyl]pyridine

The target compound is obtained from 4-phenylpiperazine by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.16(m, 6N); 6.85(m, 3H); 4.36(d, J=5.2 Hz, 2H); 3.47(m, 2H); 3.24(s, 2H); 3.04(t, J=4.8 Hz, 4H); 2.35(t, J=4.8 Hz, 4H); 1.29(m, 13H). The Belarusian library Association-MS: calculated for (C29H36N3FO) 461, found 462 (M+H). Anal. Rasch. for C29H36N3OF: 75,46; N, 7.86; N, 9.10; F 4.12. Found: 75.35; N, 7.82; N 8,80; F 3.99. So pl. 111-113oC. Rf=0.5(40% diethyl ether/hexane).

EXAMPLE 76

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(imidazol-1-yl)methylpyridin

The target compound is obtained from imidazole by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.01(m, 6N); 6.57(s, Kitano for (C22H26N3FO) 367, found 368 (M+H). Anal. Rasch. for C22H26N3OF: 71,91; N, 7.13; N, 11.43; F 5.17. Found: 71.26; N, 7.24; N 11,03; F 5.35. So pl. 184-186oC. Rf=0.1(50% diethyl ether/hexane +2 drops Meon).

EXAMPLE 77

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(cyclopropylamino)methylpyridin

The target compound is obtained from cyclopropylamine by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.04(m, 4H); 4.21(s, 2H); 3.35(s, 2H); 3.26(septet, J= 6.6 Hz, 2H); 1.78(m, 1H); 1.17(m, 13H); 0.153(m, 2H); -0.006(m, 2H). The Belarusian library Association-MS: calculated for (C22H29N2FO) 356, found 357 (M+H). Anal. Rasch. for C22H29N2OF: 74,12; N, 8.20; N, 7.86; F 5.33. Found: 74.29; N At 8.62; N 7,93; F 4.90. So pl. 81-83oC. Rf=0.3(40% diethyl ether/hexane).

EXAMPLE 78

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(cyclohexylamino)methylpyridin

The target compound is obtained from cyclohexylamine by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.25(m, 2H); 7.13(m, 2H); 4.34(s, 2H); 3.38(m, 4H); 2.16(m, 1H); 1.58(m, 5H); 1.23(m, N); 0.936(m, 2H). The Belarusian library Association-MS: calculated for (C25H35N2FO) 398, found 399 (M+H). Anal. Rasch. for C25H35N2OF: 4,12; N, 8.20; N, 7.86; F 5.33. Found: 74.29; N At 8.62; N 7 93; F , 4.90. So pl. 131-1334-forfinal)-5-(dimethylamino)methylpyridin

The target compound is obtained from dimethylamine hydrochloride according to the method of example 69.

1H NMR (300 MHz, CDCl3): 7.12(m, 4H); 4.25(m, 2H); 4.09(m, 1H); 3.68(septet, J=6.6 Hz, 1H); 3.41(septet, J=6.6 Hz, 1H); 2.18(m, 1H); 1.69(d, J=4.1 Hz, 1H); 1.26(m, N); 0.947(d, J=6.3 Hz, 3H); 0.555(d, J=7.0 Hz, 1H). The Belarusian library Association-MS: calculated for (C22H30NFO2) 359, found 360 (M+H). Anal. Rasch. for C22H30NO2F: 73,51; N, 8.41; N, 3.90; F 5.28. Found: AT 73.69;

N, 8.40; N 3,82; F 5.04. So pl. 77-79oC. Rf=0.2(40% diethyl ether/hexane).

EXAMPLE 80

< / BR>
2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(dibutylamino)methylpyridin

The target compound is obtained from dibutylamine by the method of example 69.

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 4.33(d, J=5.5 Hz, 2H); 3.62(septet, J=6.6 Hz, 1H); 3.62(septet, J=6.6 Hz, 1H); 3.24(s, 2H); 2.12(t, J= 7.0 Hz, 4H); 1.55(s, 1H); 1.33(t, J=6.6 Hz, 6N); 1.26(t, J=6.6 Hz, 6N); 1.16(m, 8H); 0.796(t, J= 6.6 Hz, 6N). The Belarusian library Association-MS: calculated for (C27H41N2FO) 428, found 429 (M+H). Anal. Rasch. for C27H41N2OF: 75,66; N, 9.64; N, 6.54; F 4.43. Found: 75.91; N, 9.83; N 6,26; F 4.33; sticky oil. Rf= 0.6(40% diethyl ether/hexane).

EXAMPLE 81

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-methylpyridin

A solution of methyl ester 2,b-aminobutiramida 4-(4-fervent in an argon atmosphere at room temperature and treated dropwise with lydialydia (2.1 ml, 1.0 M in THF, 2.1 mmol). The reaction mixture is heated under reflux for 1 hour, then cooled to room temperature. The reaction is quenched by the sequential addition dropwise at room temperature water (80 μl), 20% NaOH (80 ml) and water (240 μl). The resulting suspension is filtered through a layer of celite and concentrate. Purification by chromatography on a column of silica gel (5% ethyl acetate/hexane) to give the target compound as a white solid (182 mg, 0.6 mmol, 85%).

1H NMR (300 MHz, CDCl3): 7.15(d, J=Hz, 4H); 4.36(d, J=5.5 Hz, 2H); 3.42(Sept, J=6.6 Hz, 1H); 3.26(Sept, J=6.6 Hz, 1H); 1.94(s, 3H); 1.33(d, J= 6.6 Hz, 6N); 1.29(d, J=6.6 Hz, 6N); 1.19(t, J=5.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C19H24FNO) 301, 302 found (M+H). Anal. Rasch. for C19H24FNO: 75,72; N, 8.03; N, 4.65. Found: 75.62; N, 8.02; N Of 4.57. So pl. 127-128oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 82

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(3-phenyl-2-propenyl)pyridine

Stage A. the Methyl ester of 2,6-aminobutiramida-4-(4-propenyl)-5-(2-oxoethyl)-3-pyridineboronic acid

Ethoxymethylenemalononitrile (1.15 g, 3.35 mmol) is suspended in 25 ml of dry, distilled THF in an argon atmosphere and stirred at a temperature of -78oC. dropwise add Uchenie 1.0 hours. The solution is cooled again to -78oC, treated dropwise with a solution of 5-carboethoxy-2,6-aminobutiramida-4-(4-propenyl)-3-pyridinecarboxamide (example 1, step E) (1 g, 2.8 mmol) in 20 ml of dry THF, then warmed to room temperature and stirred over night. The reaction mixture was quenched with 2 ml of water and THF is evaporated in vacuum. Add diethyl ether and washed with water (2x40 ml), brine (g ml) and dried over MgSO4. The residue is dissolved in THF (20 ml), treated with a solution of concentrated Hcl and stirred at room temperature for 1 h, the Reaction mixture was diluted with diethyl ether (150 ml), washed with water (50 ml), brine (50 ml), dried over MgSO4and evaporated in vacuum. Flash chromatography (10% ethyl acetate/hexane) to give 335 mg (0.9 mmol, 32%) of product.

1H NMR (300 MHz, CDCl3): 9.62(s, 1H); 7.09(m, 4H); 3.97(q, J=7 Hz, 2H); 3.60(s, 2H); 3.06(Sept, J= 6.6 Hz, 1H); 3.00(Sept, J=6.6 Hz, 1H); 1.32(d, J= 6.6 Hz, 6N); 1.27(d, J=6.6 Hz, 6N); 0.97(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H26FN3) 371, found 372 (M+H). Anal. Rasch. for C22H26FNO3: 71,14; N, 7.06; N, 3.77. Found: At 70.91; N, 6.91; N 3,63. So pl. 69-71oC. Rf=0.3 (10% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-Floro on stage And, and benzyltriphenylphosphonium/ sodium amide by the method of example 1, stage F-G. the Product is obtained in the form of a mixture of 6:4 TRANS:CIS isomers.

1H NMR (300 MHz, CDCl3): 7.19(m, 8H); 6.96(m, 1H); 6.32(d, J=11 Hz, 0.4 H); 6.09(dt, J=5.5,16 Hz, 0.6 H); 5.96(d, J=16 Hz, 0.6 H); 5.45(dt, J= 7,11 Hz, 0.4 H); 4.37(d, J=5 Hz, 1.25 H); 4.33(d, J=5.5 Hz, 0.75 H); 3.41(m, 1.6 H); 3.25(m, 2H); 3.08(m, 0.4 H); 1.35(m, 5H); 1.30(d, J=6.6 Hz, 5H); 1.21(m, 3H). The Belarusian library Association-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Rasch. for C27H30FN: 80,36; N, 7.49; N , 3.47. Found: 80.15; N, 7.44; N 3,26. So pl. 72-73oC. Rf=0.3(20% ethyl acetate/hexane).

EXAMPLE 83

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(3-phenylpropyl)pyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(3-phenyl-2-propenyl)pyridine (example 82) according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.11(m, N); 4.31(s, 2H); 3.40(Sept, J=6.6, 1H); 3.12(Sept, J= 6.6, 1H); 2.46(t, J=7.35 Hz, 2H); 2.29(m, 2H); 1.62(m, 2H); 1.32(d, J= 6.6 Hz, 6N); 1.26(d, J=6.6 Hz, 6N); 1.16(BL, 1H). The Belarusian library Association-MS: calculated for (C27H32FNO) 405, found 406 (M+H). So pl. 137-140oC. Rf=0.3 (20% ethyl acetate/hexane).

EXAMPLE 84

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[3-(2-were)propyl]pyridine

The target connection get the 2-methylbenzenesulfonamide by the method of example 1, stage F-N.

1H NMR (300 MHz, CDCl3): 7.07(m, 7H); 6.90(m, 1H); 4.31 (s, 2H); 3.39(Sept, J= 6.6,1 H); 3.15(Sept, J=6.6,1 H); 2.43(t, J=7.5 Hz, 2H); 2.34(m, 2H); 2.17(s, 3H); 1.56(m, 2H); 1.31(d, J=6.6 Hz, 6N); 1.27(d, J=6.6 Hz, 6N); 1.15(m, 1H). The Belarusian library Association-MS: calculated for (C28H34FNO) 419, found 420 (M+H). Anal. Rasch. for C28H34FNO: 80,15; N, 8.17; N, 3.34. Found: 80.12; N, 8.01; N 3,25. So pl. 65-70oC. Rf=0.4 (20% ethyl acetate/hexane).

EXAMPLE 85

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[3-(3-were)propyl]pyridine

The target compound is obtained from the methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(2-oxoethyl)-3-pyridineboronic acid (example 82, step a) and 3-methylbenzenesulfonamide by the method of example 1, stage F-N.

1H NMR (300 MHz, CDCl3): 7.09(m, 5H); 6.98(m, 1H); 6.78(m, 2H); 4.31(s, 2H); 3.39(Sept, J=6.6, 1H); 3.12(Sept, J=6.6,1 H); 2.42(t, J=7 Hz, 2H); 2.30(s, 3H); 2.28(m, 2H); 1.58(m, 2H); 1.31(d, J=6.6 Hz, 6N); 1.26(d, J= 6.6 Hz, 6N); 1.15(m, 1H). The Belarusian library Association-MS: calculated for (C28H34FNO) 419, found 420 (M+H). Anal. Rasch. for C28H34FNO: 80,15; N, 8.17; N, 3.34. Found: 80.23 N, 8.17; N 3,23. So pl. 68-70oC. Rf=0.4 (20% ethyl acetate/hexane).

EXAMPLE 86

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[3-(4-were)propyl]pyridine

The target connection in the palladium (A) and 4-methylbenzenesulfonamide by the method of example 1, stage F-N.

1H NMR (300 MHz, CDCl3): 7.08(m, 4H); 7.01(d, J=8 Hz, 2H); 6.85(d, J= 8gts, 2H); 4.30(s, 2H); 3.39(Sept, J=6.6, 1H); 3.13(Sept, J=6.6,1 H); 2.41(t, J= 7 Hz, 2H); 2.31(s,3H); 2.27(m, 2H); 1.58(m, 2H); 1.31(d, J=6.6 Hz, 6N); 1.26(d, J=6.6 Hz, 6N); 1.15(m, 1H). The Belarusian library Association-MS: calculated for (C28H34FNO) 419, found 420 (M+H). Anal. Rasch. for C28H34FNO: 80,15; N, 8.17; N, 3.34. Found: At 80.33; N, 8.28; N 3,22. So pl. 79-80oC. Rf=0.4 (20% ethyl acetate/hexane).

EXAMPLE 87

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(2-propenyl)pyridine

The target compound is obtained from the methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(2-oxoethyl)-3-pyridylcarbinol islote (example 82, step a) and methyltriphenylphosphonium by the method of example 1, stage F-H.

1H NMR (300 MHz, CDCl3): 7.13(m, 4H); 5.73(m, 1H); 4.81(DD, J=4.8,1.8 Hz, 2H); 4.35(s, 2H); 3.43(septet, J=6.6, 1H); 3.21 (septet, J=6.6,1 H); 3.07(d, J=1.8 Hz, 2H); 1.24(m, 13H). The Belarusian library Association-MS: calculated for (C21H26FNO) 327, found 328 (M+H). Anal. Rasch. for C21H26FNO: 74,17; N, 7.71; N, 4.12; F 5.59+0.7 H2O. Found: 74.17; N, 7.57; N 3,94; F 5.26. So pl. 69-71oC. Rf= 0.35 (15% ethyl acetate/hexane).

EXAMPLE 88

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-hydroxybutyl)pyridine

To a solution of 2,6-aminobutiramida-3-hydroxymethyl-4-(4-ftor stirred for 17 h at room temperature. THF is removed in vacuo and the residual suspension is carefully neutralized to pH 7 feast upon. aq. Panso3. The aqueous phase is extracted with diethyl ether (3100 ml), the combined ether extract was washed with brine (50 ml), dried (MgSO4) and concentrate. Purification by chromatography on a column of silica gel (gradient of 10%-20% ethyl acetate/hexane) to give white solid (1.5 g, 4.2 mol, 83%).

1H NMR (300 MHz, CDCl3): 9.57(s, 1H); 7.16(m, 4H); 4.33(d, J=5 Hz, 2H); 3.42(m, 1H); 3.24(m, 1H); 2.33(m, 2H); 2.27(dt, J=1.8, 7.4 Hz, 2H); 1.61(m, 2H); 1.32(m, N); 1.20(m, 1H). The Belarusian library Association-MS: calculated for (C22H30FNO2) 359, found 340 (M+H). Rf=0.3 (20% ethyl acetate/hexane).

This intermediate compound (200 mg, 0.56 mmol) is dissolved in absolute ethanol (5 ml) and treated at room temperature with stirring with sodium borohydride (32 mg, 0.85 mmol). After stirring for 1 h the reaction mixture was quenched by adding dropwise 2 N. Hcl (3 ml). The solution is stirred for 5 min, then neutralized by careful addition of the feast upon. Panso3. The aqueous phase is extracted with diethyl ether (350 ml), the combined extracts dried (MgSO4) and concentrate. Purification by chromatography on a column of silica (20% ethyl acetate/hexane) gives C the ): 7.16(m, 4H); 4.33(d, J=5 Hz, 2H); 3.46(m, 2H); 3.41(m, 1H); 2.23(m, 1H); 2.32(m, 2H); 1.40(m, 4H); 1.32(m, N); 1.19(m, 1H); 1.09(m, 1H). The Belarusian library Association-MS: calculated for (C22H30FNO2) 359, found 360 (M+H). Anal. Rasch. for C22H30FNO2: 73,51; N, 8.41; N, 3.90. Found: 73.37; N, 8.41; N 3,72. So pl. 135-137oC. Rf=0.4 (50% ethyl acetate/hexane).

EXAMPLE 89

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(3-dimethylamino)propyl]pyridine

The target compound is obtained from 5-carboethoxy-2,6-aminobutiramida-4-(4-forfinal)-3-pyridinecarboxamide (example 1, step E) and (2-dimethylaminoethyl)triphenylphosphonium by the method of example 1, stage F-H.

1H NMR (300 MHz, CDCl3): 7.17(m, 4H); 4.33(s, 2H); 3.41(Sept, J=6.6, 1H); 3.21(Sept, J=6.6, 1H); 2.32(m, 2H); 2.16(m, 2H); 2.14(s, 6N); 1.49(m, 2H); 1.32(m, 13H). The Belarusian library Association-MS: calculated for (C23H33FN2O) 372 found 373 (M+H). So pl. 50-51oC. Rf=0.35 (20% ethanol/dichloromethane).

EXAMPLE 90

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(3-dimethylamino)heptyl] pyridine

Stage A. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(4-oxobutyl)pyridine

To a solution of 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[3-(1,3-dioxolane-2-yl)propyl]pyridine (example 46) (2 g, 5 mmol) in THF (50 ml) is added 2 n aq. HCl (10 ml). R is Orono neutralized to pH 7 feast upon. aq. Panso3. The aqueous phase is extracted with diethyl ether (3100 ml), the combined ether extract was washed with brine (50 ml), dried (MgSO4) and concentrate. Purification by chromatography on a column of silica (gradient of 10%-20% ethyl acetate/hexane) to give white solid (1.5 g, 4.2 mmol, 83%).

1H NMR (300 MHz, CDCl3): 9.57(s, 1H); 7.16(m, 4H); 4.33(d, J=5 Hz, 2H); 3.42(m, 1H); 3.24(m, 1H); 2.33(m, 2H); 2.27(dt, J=1.8, 7.4 Hz, 2H); 1.61(m, 2H); 1.32(m, N); 1.20(m, 1H). The Belarusian library Association-MS: calculated for (C22H28FNO2) 357, found 358 (M+H). Rf=0.3(20% ethyl acetate/hexane).

Stage C. 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(3-dimethylamino)heptyl]pyridine

The intermediate compound obtained in stage A, process (3-dimethylamino)propylthiophenethylamine according to the method described in example 1, stage F-H, to obtain the target compound in the form of a solid substance.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 4.32(s, 2H); 3.41(Sept, J=6.6 Hz, 1H); 3.22(Sept, J=6.6 Hz, 1H); 2.28(s, 6N); 2.26(m, 4H); 1.43(m, 2H); 1.33(d, J=6.6 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.27(m, 3H); 1.31(m, 6N). The Belarusian library Association-MS: calculated for (C27H41FN2O) 428, found 429 (M+H). So pl. 85-87oC. Rf= 0.1(20% tO/CH2CL2).

EXAMPLE 91

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2,6-Aminobutiramida-3-HYDR shall kemetyl-4-(4-forfinal)-5-(4-oxobutyl)pyridine (example 90, stage a) and (4-carboxybutyl)triphenylphosphonium bromide according to the method of example 90, step Century.

1H NMR (300 MHz, CD3OD): 7.17(m, 4H); 4.23(s, 2H); 3.44(Sept, J= 6.6,1 H); 3.23(Sept, J=6.6, 1H); 2.28(m, 2H); 2.14(t, J=7.5 Hz, 2H); 1.54(m, 2H); 1.28(d, J=6.6 Hz, 6N); 1.24(d, J=6.6 Hz, 6N); 1.22(m, 4H); 1.17(m, 2H); 1.10(m, 4H). EI-MS: calculated for (C27H38FN3) 443 found 443 (M+). So pl. 240oC (decomp.). Rf=0.3 (50% ethyl acetate/hexane).

EXAMPLE 92

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2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(3-carboxypropyl)pyridine

To a solution of 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[3-(1,3-dioxolane-2-yl)propyl]pyridine (example 46) (2 g, 5 mmol) in THF (50 ml) is added 2 n aq. Model HC1 (10 ml). The solution is stirred for 17 h at room temperature. THF is removed in vacuo and the residual suspension is carefully neutralized to pH 7 feast upon. NaHCO3. The aqueous phase is extracted with diethyl ether (3100 ml), the combined ether extract was washed with brine (50 ml), dried (MgSO4) and concentrate. Purification by chromatography on a column of silica (gradient of 10%-20% ethyl acetate/hexane) to give 1.5 g of the intermediate as a white solid. Rf=0.3(20% ethyl acetate/hexane).

280 mg of the intermediate solution of the anhydride (0.37 ml, 3.9 mmol). The reaction mixture was stirred at room temperature for 17 hours, the Pyridine is removed in vacuo and the residue is dissolved in diethyl ether (50 ml), washed feast upon. CuSO4(10 ml), water (20 ml), feast upon. NaHCO3(20 ml) and brine (10 ml), dried (MgSO4) and concentrate. Purification by chromatography on a column of silica (20% ethyl acetate/hexane) to give 220 mg in the form of a viscous yellow oil: Rf=0.6(50% ethyl acetate/hexane).

200 mg of the oil was dissolved in acetone (5 ml), stirred at room temperature and treated with Jones reagent (2 ml, obtained from 67 g SGAs3, 125 ml of N2O and 58 ml conc. H2SO4). The reaction mixture was stirred for 0.5 h, quenched by addition of 2-propanol, filtered through a thin layer of silicon dioxide and concentrate. The residue is dissolved in Meon (5 ml), treated with 20% NaOH (20 ml) and stirred for 14 h at room temperature. After neutralization to pH 7 aq. Model HC1 solution, saturated with NaCl and extracted with Snss (3h20 ml). The combined extract is dried (MgSO4) and concentrate. Purification by chromatography on a column of silica (1:1 ethyl acetate/hexane) to give the target compound as a white foam (22 mg).

1H NMR (300 MHz, CD3OD): 7.18(m, 4H is a matter for (C22H28FNO3) 373, found 374 (M+H). So pl. 160oC. Rf=0.3(50% ethyl acetate/hexane).

EXAMPLE 93

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-hydroxyethyl)pyridine

Stage A. () Ethyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(1-hydroxyethyl)-3-pyridineboronic acid

To 5-carboethoxy,6-aminobutiramida 4-(4-forfinal)-3-pyridine-carboxaldehyde (example 1, step E) (1 g, 2.91 mmol) in THF (30 ml) is added dropwise motility (1.4 M, 1.0 EQ., 2.08 ml) at a temperature of -78oC in argon atmosphere. The reaction mixture is stirred for 2 hours, then quenched with water and the THF is evaporated to obtain a white solid. The product is shared between diethyl ether and water. The organic layer is then dried over MgSO4, filtered and concentrated to obtain a white solid. The product is passed through a layer of silica (10% ethyl acetate/hexane) to give white solids (857 mg, 2.4 mmol, 82%).

1H NMR (300 MHz, CDCl3): 7.14(m, 4H); 4.86(DQC, J=3.7, J=6.6 Hz, 1H); 3.80(septet, J=6.6,1 H); 3.47 (s, 3H); 2.96(septet, J=6.6, 1H); 1.65(d, J=3.7 Hz, 1H); 1.46(d, J= 6.6 Hz, 3H); 1.27 (m, N). The Belarusian library Association-MS: calculated for (C21H26FNO3) 359, found 360 (M+H). Anal. Rasch. for C21H26NO3F: 69,54 the Diya Century ()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-hydroxyethyl)pyridine

The intermediate compound obtained in stage A (300 mg, 0.835 mmol), dissolved in 40 ml of dry THF, and then added dropwise a solution of LAG (1 M/THF, 1.67 ml, 2 EQ.). The reaction mixture was stirred at reflux for 24 hours, then cooled to room temperature and quenched with water (70 μl), 20% NaOH (70 ml) and water (140 ml). After filtration the solvent is evaporated to obtain white balance. The product is subjected to flash chromatography (20% ethyl acetate/hexane) to give the target compound as a white solid (84 mg, 0.25 mmol, 30%).

1H NMR (300 MHz, CDCl3): 7.15(m, 4H); 4.71(DQC, J=3.7, J=6.6 Hz, 1H); 4.30(m, 2H); 3.79(septet, J=6.6, 1H); 3.42(septet, J=6.6, 1H); 1.62(d, J= 3.68 Hz, 1H); 1.58(s, 1H); 1.43(d, J=6.6 Hz, 3H); 1.28 (m, N). The Belarusian library Association-MS: calculated for (C30H26FNO2) 331 found 332 (M+H). Anal. Rasch. for C20H26NO2F: 76,84; N, 8.69; N, 3.90. Found: At 76.67; N, 8.76; N 377. So pl. 184-186oC. Rf=0.2 (20% ethyl acetate/hexane).

EXAMPLE 94

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1 - hydroxypropyl)pyridine

The target compound is obtained from 5-carboethoxy-2,6-aminobutiramida-4-(4-forfinal)-3-pyridinecarboxylic is: 7.15(m, 4H); 4.40(DQC, J=3.7, J=5.2 Hz, 1H); 4.30(d, J= 5.5 Hz, 2H), 3.72(septet, J= 6.6,1 H); 3.42(septet, J=6.6, 1H); 1.88(m, 1H); 1.63(t, J=5.5 Hz, 1H); 1.27 (m, 14N); 0.804(t, J=7.36 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H28FNO2) 345, found 346 (M+H). Anal. Rasch. for C21H28NO2F: 76,84; N, 8.69; N, 3.90. Found: At 76.67; N, 8.76; N Of 3.77. So pl. 173-175oC. Rf=0.2 (20% ethyl acetate/hexane).

EXAMPLE 95

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-hydroxyphenyl)pyridine

The target compound is obtained from 5-carboethoxy-2,6-aminobutiramida-4-(4-forfinal)-3-pyridinecarboxamide (example 1, step E) and n-utillity by the method of example 93.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 4.49(m, 1H); 4.31(d, J=5.5 Hz, 2H), 3.74(septet, J=6.6, 1H); 3.42(septet, J=6.6, 1H); 1.88(m, 1H); 1.58(d, J=3.3 Hz, 1H); 1.18 (m, N); 0.821(t, J=4.1 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H32FNO2) 373, found 374 (M+H). Anal. Rasch. for C23H32NO2F: 78,96; N, 8.64; N, 3.75; F 5.09. Found: 73.81; N, 8.60; N To 3.58; (F 5.02. So pl. 166-168oC. Rf=0.3 (20% ethyl acetate/hexane).

EXAMPLE 96

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1 - hydroxyphenylethyl)pyridine

The target compound is obtained from 5-carboethoxy-2,6-aminobutiramida-4-(4-forfinal)-3-pyridinecarboxamide (example 1, step E) and finelite p, .47(septet, J=6.6,1 H); 3.12(septet,J=6.6, 1H); 2.12(d, J= 5.1 Hz, 1H); 1.57(c, 1H); 1.29 (m, 10H); 0.797(d, J=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H28FNO2) 393, found 394 (M+H). Anal. Rasch. for C25H28NO2F: 76,84; N, 8.69; N, 3.90. Found: At 76.67; N, 8.76; N Of 3.77. So pl. 202-204oC. Rf=0.2 (20% ethyl acetate/hexane).

EXAMPLE 97

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-[(1-hydroxy-2-methyl)propyl]pyridine

The target compound is obtained from 5-carboethoxy-2,6-aminobutiramida-4-(4-forfinal)-3-pyridinecarboxamide (example 1, step E) and isopropylacrylamide by the method of example 93.

1H NMR (300 MHz, CDCl3): 7.14(m, 4H); 4.35(d, 2H); 3.53(t, J=4.8 Hz, 4H), 3.45(m, 2H); 3.18(s, 2H); 2.18(t, J=4.5 Hz, 4H); 1.26 (m, 13H). The Belarusian library Association-MS: calculated for (C23H31N2FO2) 386, found 387 (M+H). Anal. Rasch. for C23H31N2O2F: 76,84; N, 8.69; N, 3.90. Found: At 76.67; N, 8.76; N Of 3.77. So pl. 139-140oC. Rf=0.3 (20% ethyl acetate/hexane).

EXAMPLE 98

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-methoxyethyl)pyridine stage A.

Methyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(2-methoxyethyl)-3-pyridineboronic acid

(A) ethyl ester of 2,6-aminobutiramida-4-(4-forfinal)-5-(1-hydroxyethyl)-3-pyridinecarboxamide argon, stirred for 15 min and treated with methyliodide (0.34 ml, 5.24 mmol). The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature, quenched with water and concentrated to obtain a whitish residue. The product is shared between diethyl ether and water, the organic layer dried over MgS4, filtered and concentrated to obtain a white solid. The product is passed through a layer of silica (5% ethyl acetate/hexane) to give white solid (495 mg, 1.33 mmol, 98%).

1H NMR (300 MHz, CDCl3): 7.13(m, 4H); 4.25(q, J=6.6 Hz, 1H); 3.80(septet, 3=6.6, 1H); 3.48(s, 3H); 3.10(s, 3H); 2.97(septet, J=6.6, 1H); 1.41(d, J= 6.6 Hz, 3H); 1.29 (m, N). The Belarusian library Association-MS: calculated for (C22H31FN3) 373, found 374 (M+H). Anal. Rasch. for C24H31N2O3F: 70,75; N, 7.56; N, 3.75; F 5.09. Found: 70.70; N, 7.63; N 3,59; F 4.77. So pl. 132-134oC. Rf=0.5 (10% ethyl acetate/hexane).

Stage Century. ()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-methoxyethyl)pyridine

The intermediate compound obtained in stage A (359 mg, 0.961 mmol), dissolved in 40 ml of dry THF, and then added dropwise a solution of LAG (1 M/THF, 1.92 ml, 2 EQ.). The reaction mixture was stirred p. the DOI (80 μl), 20% NaOH (80 ml) and water (160 ml). After filtration the solvent is evaporated to obtain a white residue, which was filtered through a layer of silica (10% ethyl acetate/hexane) to give the target compound as a white solid (281 mg, 0.72 mmol, 85%).

1H NMR (300 MHz, CDCl3): 7.13(m, 4H); 4.32(DQC, J=5.2, J=11.4 Hz, 1H); 4.1(q, J= 6.3 Hz, 1H); 3.77(septet, J=6.6, 1H); 3.42(septet, J=6.6,1 H); 3.10(s, 3H); 1.29 (m, N). The Belarusian library Association-MS: calculated for (C21H28FNO2) 345, found 346 (M+H). Anal. Rasch. for C21H28NO2F: 76,84; N, 8.69; N, 3.90. Found: At 76.67; N, 8.76; N Of 3.77. So pl. 151-153oC. Rf=0.4 (20% ethyl acetate/hexane).

EXAMPLE 99

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()-2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-methoxypropyl)pyridine

The target compound is obtained from ()-2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-hydroxypropyl)pyridine (example 94) according to the method of example 98.

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 4.32(m, 2H); 3.83(m, 1H); 3.74(septet, J=6.6, 1H); 3.41(septet, J=6.6, 1H); 3.12(s, 2H); 1.88(m, 1H); 1.56(m, 2H); 1.27 (m, 12 H); 0.776(t, J=3.7 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30FNO2) 359, found 360 (M+H). Anal. Rasch. for C22H30NO2F: 73,51; N, 8.41; N, 3.90; F 5.28. Found: At 73.55; N, 8.54; N 3,75; F 5.06. So pl. 147-149oC. Rf=0.5 (20% ethyl acetate/hexane).

1H NMR (300 MHz, CDCl3): 7.10(m, 4H); 4.32(m, 2H); 3.92(m, 1H); 3.76(septet, J=7.0, 1H); 3.42(septet, J=6.6, 1H); 3.12(s, 3H); 1.87(m, 1H); 1.52(m, 2H); 1.19 (m, 16 H); 0.821 (t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO2) 387 found 388 (M+H). Anal. Rasch. for C24H34NO2F: 74,38; N, 8.84; N, 3.61; F 4.90. Found: 74.38; N, 8.82; N 3,45; F 4.90. So pl. 121-123oC. Rf=0.5 (20% ethyl acetate/hexane).

EXAMPLE 101

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()-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

Stage A. ()-2,6-Aminobutiramida-4-(4-forfinal)-5-propyl-3-pyridinecarboxamide

To a solution of 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-propylpyridine (example 25) (5.7 g, 17 mmol) in dichloromethane (250 ml) is added a neutral alumina Brokman I (3.5 g, 34 mmol). The suspension is stirred at room temperature and treated with pyridylamino (PQQ) (7.5 g, 34 mmol). Stirring is continued at room temperature for 1 h, the Suspension is poured into 10% ethyl acetate/hexane (500 ml), filtered through a layer of silica and concentrated in vacuo to obtain (4.2 g/12.8 mmol, 74%) waxy solid.

1H NMR (300 MHz, CDCl3): 9.72(s, 1H); 7.15(m, 4H); 3.83(Sept, J= 6.6,1 H); 3.28(Sept, J=6.6,1 H); 2.31(m, 2H); 1.30(m, 14N); 0.78(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for C. ()-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

To the intermediate compound obtained in stage A (400 mg, 1.22 mmol) in THF (10 ml) at a temperature of -78oWith added dropwise MeLi (1.4 M, 1.2 equiv. , 1.05 ml). The reaction mixture was stirred for 20 min, then add another 0.5 EQ. MeLi, as yet there is source material. After 20 min the reaction is quenched with water (2 ml) and THF is evaporated in vacuum to obtain oil. The product is divided between water and CH2CL2(50 ml) and the organic layer is dried over MgSO4filter and concentrate to obtain a sticky solid. Flash chromatography on a column of silica gel (60% SN2CL2/hexane) gives an oil which slowly solidified to obtain the target compound as a solid (0.387 g,1.13 mmol, 92%).

1H NMR (300 MHz, CDCl3): 7.10(m, 4H); 4.66(DQC, J=3.3, J=6.6 Hz, 1H); 3.75(septet, J= 6.6,1 H); 3.20(septet, 3= 6.6,1 H); 2.17(t, J=1.5 Hz, 2H); 1.58(d, J=5.2 Hz, 1H); 1.41 (d, J=6.6 Hz, 3H), 1.29 (m, 14N); 0.74(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30FNO) 343, found 344 (M+H). Anal. Rasch. for C22H30FNO: 76,93; N, 8.80; N, 4.08; F 5.53. Found: 76.98; N, 8.73; N 3,93; F 5.80. So pl. 124,5-126,5oC. Rf=0.2 (60% CH2Cl2/hexane).

EXAMPLE 102

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(+)-proxetil)-4-(4-forfinal)-5-propylpyridine (example 101) share chiral GHUR on column Chiralpak AD, isocrates elution (99% hexane/methyl tert-butyl ether). First suirvey enantiomer get in 99% of ei. So pl. 103-104oC []D+40.4o.

EXAMPLE 103

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2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

The enantiomeric mixture of ()-2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine (example 101) share chiral GHUR on column Chiralpak AD, isocrates elution (99% hexane/methyl tert-butyl ether). Second suirvey enantiomer get 90% of ei. So pl. 95-97oC.

EXAMPLE 104

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()-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-butylpyrazine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-butylpyrazine (example 24) according to the method of example 101.

1H NMR (300 MHz, CDCl3): 7.1(m, 4H); 4.7(DQC, J=3 Hz, 1H); 3.7(septet, J=7,1 H); 3.2(septet, J=7, 1H); 2.2(t, J=1.5 Hz, 2H); 1.6(d, J=5 Hz, 1H); 1.4 (d, J= 7 Hz, 3H), 1.3 (m, N); 0.8(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H32F) 357, found 358 (M+H). So pl. 103-104oC. Rf= 0.2(60% SN2CL2/hexane).

EXAMPLE 105

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()-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-Fortini; .75(septet, J= 6.6, 1H); 3.20(septet, J=6.6, 1H); 2.19(t, J=8.1 Hz, 2H); 1.63(d, J=2.6 Hz, 1H); 1.40 (d, J=7.0 Hz, 3H), 1.31 (m, 14N); 1.11(m, 4H); 0.79(t, J=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Anal. Rasch. for C24H34FN: 77,59; N, 9.22; N, 3.77; F 5.11. Found: 77.59; N, 9.34; N 3,75; F 5.26. So pl. 99-101oC. Rf=0.2 (70% OF CH2CL2/hexane).

EXAMPLE 106

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2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine

The enantiomeric mixture of ()-2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine (example 105) share chiral GHUR on column Chiralpak AD, isocrates elution (99% hexane/methyl tert-butyl ether). First suirvey enantiomer get in 99% of ei. So pl. 83oC.

EXAMPLE 107

< / BR>
2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine

The enantiomeric mixture of ()-2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine (example 105) share chiral GHUR on column Chiralpak AD, isocrates elution (99% hexane/methyl tert-butyl ether). Second suirvey enantiomer get in 93% of ei. So pl. 84-86oC.

EXAMPLE 108

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()-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine

The target compound is obtained from 2,6-aminobutiramida 3-the CDCl3): 7.13(m, 4H); 7.04(m, 1H); 4.65(m, 1H); 3.73(septet, J=6.6, 1H); 3.19(septet, J=6.6,1 H); 2.18(m, 2H); 1.39 (doctor J=6.6 Hz, 3H), 1.30 (m, 13H); 1.18(m, 4H); 1.09(m, 4H); 0.81 (t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Rasch. for C25H36FNO: 77.88; N, 9.41; N, 3.63. Found: 77.84; N, 9.49; N 3,65. So pl. 96-99oC. Rf=0.3 (10% ethyl acetate/hexane).

EXAMPLE 109

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2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine

The enantiomeric mixture of ()-2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine (example 108) share chiral GHUR on column Chiralpak AD, isocrates elution (99% hexane/methyl tert-butyl ether). First suirvey enantiomer get 98% of ei. So pl. 75-77oC.

EXAMPLE 110

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2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine

The enantiomeric mixture of ()-2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine (example 108) share chiral GHUR on column Chiralpak AD, isocrates elution (99% hexane/methyl tert-butyl ether). Second suirvey enantiomer get in 88% of ei. So pl. 66-68oC.

EXAMPLE 111

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2,6-Aminobutiramida-3-[1-hydroxy-2-((S)-cellsurface)ethyl] -4-(4-forfinal)-5-pentylpyridine

The solution diisopropylamide littmoden tetrahydrofuran (50 ml) at a temperature of 0oC. To this solution is added dropwise a solution of (S)-(-)-methyl-para-tailslide (0.863 g, 5.60 mmol) in anhydrous tetrahydrofuran (10 ml) under stirring. The mixture is stirred at a temperature of 0oC for 2 h, then treated with a solution of 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step A) (1.0 g, 2.80 mmol) in anhydrous tetrahydrofuran (20 ml) dropwise with stirring. After stirring for 15 min at a temperature of 0oTo the reaction mixture was quenched by adding feast upon. NH4Cl (1 ml). The solvent is removed in vacuum and the residue is divided between SNS3(150 ml) and water (50 ml). The organic phase is washed feast upon. Panso3(100 ml), water (100 ml) and brine (50 ml), dried over MgSO4and concentrate. The crude product has a ratio of diastereomers 1.2:1. Flash chromatography (gradient of 5%-10%-20% ethyl acetate/hexane) to give 740 mg (52%) of the first lirovannomu of diastereoisomer.

1H NMR (300 MHz, CDCl3): 7.4(m, 4H); 7.0(m, 2H); 6.7(m, 2H); 5.1(m, 1H); 4.6(s, 1H); 3.8(m, 2H); 2.6(Sept, J=6.6, 1H); 2.5(s, 3H); 2.3(m, 1H); 2.1(m, 2H); 1.4 (m, N); 0.8(m, 3H). The Belarusian library Association-MS: calculated for (C31H40FNO2S) 509, found 510 (M+H). Anal. Rasch. for C31H40FNO2S: 73,05; N, 7.91; N, 2.75; S 6.29. Found: 72.88 ropyl-3-[1-hydroxy-2-(S)-tolilsulfonil] -4-(4-forfinal)-5-pentylpyridine

After the flash-chromatography described in example 111, the elution of the second diastereoisomer give 600 mg (42%) of target compound.

1H NMR (500 MHz, CDCl3): 7.4(m, 2H); 7.2(m, 2H);7.0(m, 3H); 6.8(m, 1H); 4.8(m, 1H); 3.8(m, 1H); 3.7(m, 1H); 3.2(Sept, J=6.6, 1H); 3.1(s, 1H); 2.7(m, 1H); 2.4(s, 3H); 2.1(m, 2H); 1.3 (m, N); 0.6(m, 3H). The Belarusian library Association-MS: calculated for (C31H40FNO2S) 509, found 510 (M+H). Anal. Rasch. for C31H40FNO2S: 73,05; N, 7.91; N, 2.75; S 6.29. Found: 72.90; N, 7.95; N, 2,50; S 6.54. So pl. 190oC. Rf=0.1 (20% ethyl acetate/hexane).

EXAMPLE 113

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()-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-penultimately

The target compound is obtained from 2,6-aminobutiramida-3-(1-hydroxymethyl)-4-(4-forfinal)-5-[(phenylthio)methyl] pyridine (example 47) according to the method of example 101.

1H NMR (300 MHz, CDCl3): 7.19(m, 4H); 7.09(m, 5H); 4.67(m, 1H); 3.74(m, 3H); 3.38(septet, J=6.6, 1H); 1.58(d, J=4 Hz, 1H); 1.41 (d, J=6.6 Hz, 3H), 1.31 (m, N). The Belarusian library Association-MS: calculated for (C26H30FNOS) 423, found 424 (M+H). Anal. Rasch. for C26H30FNOS: C 73,72; H, 7.14; N, 3.31; S 7.57. Found: 73.52; H 7.12; N 3,20; S 7.51. So pl. 125-128oC. Rf=0.5 (20% ethyl acetate/hexane).

EXAMPLE 114

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()-2,6-Aminobutiramida-3-(1-hydroxy-2-propenyl)-4-(4-forfinal)-5-pentylpyridine

Stage A. 2,6-Dipentylester (example 1) (2.30 g, 6.43 mmol) is dissolved in 175 ml of CH2Cl2in an argon atmosphere and treated with 2 EQ. aluminum oxide (neutral, 1.31 g, 12.87 mmol) followed by treatment with 2 EQ. pyridylamine (PQQ) (2.77 g, 12.87 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The suspension is added to 500 ml of a 1:1 hexane/diethyl ether, then filtered through a layer of silica (300 g). Layer was washed with 100 ml of diethyl ether and the filtrate are combined and concentrated in vacuo to obtain a solid substance. Flash chromatography (60:40, CH2CL2/hexane) on a column of silica give 1.84 g of a white solid (5.2 mmol, 80%).

1H NMR (300 MHz, CDCl3): 9.74(s, 1H); 7.17(m, 4H); 3.83(septet, J= 6.6,1 H); 3.30(septet, J= 6.6, 1H); 2.34(t, J=5.2 Hz, 2H); 1.30 (m, 14N); 1.15(m, 4H), 0.80(t, J=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H30FNO) 355, found 356. Anal. Rasch. for C23H30FN: 77,71; N, 8.51; N, 3.94; F 5.34. Found: 77.91; N, 8.47; N 3,83; F 5.42. So pl. 75.5-77.5oC. Rf=0.4 (50% CH2CL2/hexane).

Stage Century. ()-2,6-Aminobutiramida-3-(1-hydroxy-2-propenyl)-4-(4-forfinal)-5-pentylpyridine

To a solution of intermediate compound obtained in stage A (100 mg, 0.281 mmol) in THF (10 ml) at a temperature of -78o) And the aqueous phase extracted with diethyl ether. Adding NH4Cl a precipitate, which is filtered off. The ether layer is dried over MgSO4filter and concentrate to obtain a sticky oil. Flash chromatography (60% SN2CL2/hexane) to give the target compound as a white solid (38 mg, 0.1 mmol, 35%).

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 6.06(5, J=17.4 Hz, J=10.3 Hz, J= 4.0 Hz, 1H); 5.08(q, J=1.5 Hz, 1H); 5.00(m, 2H); 3.51(septet, J=6.6, 1H); 3.21(septet, J= 6.6,1 H); 2.21(t, J=4.4 Hz, 2H); 1.74(d, J=4.1 Hz, 1H); 1.27 (m, 14N); 1.11(m, 4H), 0.783(t, J= 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H34FNO) 383, found 384 (M+H). Anal. Rasch. for C25H34NOF: 78,29; N, 8.93; N, 3.65; F, 4.95. Found: 78.28; N, 8.97; N 3,53; F 5.04. So pl. 83-85oC. Rf=0.2 (50% CH2CL2hexane).

EXAMPLE 115

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()-2,6-Aminobutiramida-3-(1-hydroxyphenyl)-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine (example 1) and utility by the method of example 114.

1H NMR (300 MHz, CDCl3): 6.95(m, 4H); 4.33(m, 1H); 3.59(septet, J= 6.6,1 H);

3.09(septet, J= 6.6,1 H); 2.08(t, J=5.2 Hz, 2H); 1.75(m, 2H); 1.47 (m, 2H), 1.04 (m, 22N); 0.719(t, J=7.0 Hz, 3H); 0.674(t, J=7.0 Hz, 3H). The Belarusian library Association-MS: calculated for (C27H40FNO) 413 found 414 (M+H). Anal. Rasch. for C27H40FNO: 78,tx2">

EXAMPLE 116

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()-2,6-Aminobutiramida-3-(1-hydroxy-2-butenyl)-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine (example 1) and allylanisole by the method of example 114.

1H NMR (300 MHz, CDCl3): 7.09(m, 4H); 6.58(m, 1H); 5.06(s, 1H); 5.01(m, 1H); 4.47(m, 1H); 3.71(septet, J=6.6, 1H); 3.20(septet, J=6.6,1 H); 2.59(m, 1H); 2.35(m, 1H); 2.18(t, J=4.8 Hz, 2H); 1.72(d, J=2.9 Hz, 1H); 1.28 (m, 14N); 1.11(m, 4H); 0.783(t, J= 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C26H36FNO) 397, found 398 (M+H). Anal. Rasch. for C26H36FN: 77,88; N, 9.41; N, 3.63; F 4.93. Found: 78.10; N, 9.21; N 3,43; F 4.89. So pl. 70-72oC. Rf=0.2 (50% CH2CL2/hexane).

EXAMPLE 117

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()-2,6-Aminobutiramida-3-(1-hydroxy-2-propyl)-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine (example 1) and ethylmagnesium by the method of example 114.

1H NMR (300 MHz, CDCl3): 7.10(m, 4H); 4.35(DQC, J=3.7, 8.8 Hz, 1H); 3.68(septet, J= 6.3, 1H); 3.20(septet, J=6.6,1 H); 2.18(t, J=5.2 Hz, 2H); 1.86(septet, J= 5.5,1 H); 1.63(m, 2H); 1.28 (m, 14N); 1.09(m, 4H); 0.789(m, 6N). The Belarusian library Association-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Rasch. for C25H36FNO: 77,88; N, 9.41; N, 3.63; F 4.93. Found: 77.44; N 9. The isopropyl-3-(2,2,2-Cryptor-1-hydroxy)ethyl-4-(4-forfinal)-5-pentylpyridine

The stirred solution of 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step A) (190 mg, 0.53 mmol) in anhydrous THF (5 ml) in an argon atmosphere is treated with trimethyl(trifluoromethyl)silane (5.3 ml, 2.65 mmol, 0.5 M in THF) followed by treatment with tetrabutylammonium (100 μl, 1.0 M in THF). After stirring at a temperature of 22oC for 5 min add tetrabutylammonium (3 ml, 3 mmol, 1.0 M in THF) and the reaction mixture stirred for 17 hours, the Solvent is removed in vacuum, the residue is dissolved in diethyl ether (50 ml), washed with I called HC1 (50 ml), saturated NaHCO3(50 ml), water (50 ml), brine (20 ml), dried (MgSO4) and concentrate. Purification with flash chromatography on a column of silica gel (2% ethyl acetate/hexane) to obtain 153 mg (68%) of target compound as a white solid.

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 4.90(SHS, 1H); 3.64(SHS, 1H); 3.21(septet, J= 6.6, 1H); 2.35(m, 1H); 2.15(m, 2H); 1.30(d, J=6.6 Hz, 6N); 1.29(d, J=6.6 Hz, 6N); 1.26(m, 2H); 1.10 (m, 4H); 0.77(t, 1=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H31F4NO) 425, found 426 (M+H). Anal. Rasch. for C24H31F4NO: 67,75; N, 7.34; N, 3.29; F 17.86. Found: 67.82; N, 7.13; N 3,02; F 18.05. So pl. 88-89oC. Rf=0.35 (10% ethyl acetate/hexane).


Solution (methoxymethyl)triphenylmethylchloride (350 mg, 0.985 mmol) in THF (30 ml) is treated with butyllithium (1.6 M, 1.2 EQ., 0.74 ml) at a temperature of -78oC. the Reaction mixture is stirred at a temperature of 0oC for 1 h and then cooled again to -78oC. are added dropwise 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step A) (350 mg, 0.985 mmol) in THF (5 ml) and the reaction mixture is heated to room temperature. After 24 h the reaction mixture was quenched with water and the THF is evaporated in vacuum. The remainder is divided between ether and water. The organic layer is dried over MgSO4, filtered and concentrated to obtain oil. Flash chromatography (10% CH2CL2/hexane) gives the oil (172 mg).

Oil (172 mg) was placed in THF (15 ml) and treated with 4 ml conc. Model HC1. The solution is stirred for 1.5 hours and then diluted with ether (150 ml). The reaction mixture was washed with NaHCO3(G ml) and dried over MgSO4. Filtration and concentration gives a solid (20 mg, 0.054 mmol, 6%). The product is used directly in the next stage without further purification.

Stage C. 2,6-Aminobutiramida-3-(2-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine

To the intermediate compound obtained in peremeshivayte at reflux for 1 h The reaction mixture was quenched with water (3.9 ml), 20% NaOH (3.9 ml) and water (7.8 ml). Concentration gives a white solid. The product is passed through a layer of silica gel (CH2CL2) to obtain the target compound as a white solid (14 mg, 0.038 mmol, 70%).

1H NMR (300 MHz, CDCl3): 7.39(m, 2H); 7.12(m, 2H); 3.52(t, J=5.5,2 H); 3.23(m, 2H); 2.60(t, J= 2.9 Hz, 2H); 2.20(t, J=3.7 Hz, 2H); 1.30(m, 14N); 1.11(m, 4H); 0.771(t, J=6.3 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Anal. Rasch. for C24H34FNO: 77,59; N, 9.22; N, 3.77. Found: 77.57; N, 9.44; N 3,05. So pl. 81-83oC. Rf=0.6 (10% ether/hexane).

EXAMPLE 120

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2,6-Aminobutiramida 3-methylaminomethyl-4-(4-forfinal)-5-pentylpyridine

Matrimoniale (37.99 mg, 0.563 mmol) is added to a mixed solution of methylamine in methanol (2 M, 0.28 ml) in an argon atmosphere in a kiln dried round bottom flask equipped with a stirrer. Then add nutritionrelated (4 equiv. , 10.60 mg, 0.169 mmol) and added dropwise 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step A) (100 mg, 0.281 mmol) in solution in methanol (2 ml). The reaction mixture is heated under reflux for 18 h and then quenched with water. After concentration and addition of CH22Cl2gives the target compound as a white solid (21 mg, 0.057 mmol, 20%).

1H NMR (300 MHz, CDCl3): 7.13(m, 2H); 3.26(m, 4H); 2.24(m, 5H); 1.20(m, N); 0.783(t, J= 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H35FN2) 370, found 371 (M+H). So pl. 77-S. Rf=0.2 (20% ether/ CH2Cl2).

EXAMPLE 121

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2,6-Aminobutiramida 3-aminomethyl-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step a) and NH4OAc according to the method of example 120.

1H NMR (300 MHz, CDCl3): 7.10(m, 4H); 2.61(m, 4H); 2.20(t, J=5.5 Hz, 2H); 1.17(m, 20N); 0.776(t, J=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H33FN2) 356, found 357 (M+H). Anal. Rasch. for C23H33N2F: 77,48; N, 9.33; N, 7.86; F 5.33. Found: C,77.42; N, 9.12; N Of 7.64; F 5.51. So pl. 47-49oC. Rf=0.6 (50% CH2CL2/hexane).

EXAMPLE 122

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2,6-Aminobutiramida-3-(dimethylamino)methyl-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step a) and dimethylamine hydrochloride according to the method of example 120.

25H37FN2) 384, found 385 (M+H). Anal. Rasch. for C23H37N2F: 78,08; N, 9.70; N, 7.28; F 4.94. Found: 77.95; N, 9.66; N 7,12; F 5.25. So pl. 69-71oC. Rf=0.4 (20% ether/CH2CL2.

EXAMPLE 123

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2,6-Aminobutiramida-3-(ethylamino)methyl-4-(4-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, step A) and ethylamine by the procedure of example 120.

1H NMR (300 MHz, CDCl3): 7.06(m, 4H); 3.18(m, 4H); 2.32(q, J=7.4 Hz, 2H); 2.15(t, J=5.2 Hz, 2H); 1.13(m, N); 0.839(t, J=7.4 Hz, 3H); 0.698(t, J= 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H37FN2) 384, found 385 (M+H). Anal. Rasch. for C23H37N2F: 78,08; N, 9.70; N, 7.28; F 4.94. Found: 77.85; N, 9.50; N 6,99; F 4.79. So pl. 48-50oC. Rf=0.1 (20% ether/CH2Cl2.

EXAMPLE 124

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()-2,6-Aminobutiramida-3-(1,2-dihydroxyethyl)-4-(4-forfinal)-5-pentylpyridine

Stage A. 2,6-Aminobutiramida-3-ethynyl-4-(4-forfinal)-5-pentylpyridine

Methyltriphenylphosphonium suspended in 15 ml of dry THF in an argon atmosphere and stirred at -78oC. are added dropwise utility (1.6 M, 0.42 ml) over 2 min and then the reaction mixture peremeci solution of 2,6-aminobutiramida-4-(4-forfinal)-5-pentyl-3-pyridinecarboxamide (example 114, stage A) in 5 ml of dry THF and then stirred at a temperature of 0oC for 2.5 h, the Reaction mixture was quenched with water (10 ml) and THF is evaporated in vacuum. Add diethyl ether and the mixture washed with water (220 ml), brine (120 ml) and dried over MgSO4. Filtration, concentration and flash chromatography (30% CH2CL2/hexane) gives solid (0.132 g, 0.37 mmol, 66%).

1H NMR (300 MHz, CDCl3): 7.08(m, J=L1 Hz, 4H); 6.34, 6.28(d, J=11.4 Hz, J=11.4 Hz, 1H); 5.19(d, J=1.8 Hz, 1H); 4.96(d, J=1.8 Hz, 1H); 3.39(septet, J= 6.6 Hz, 1H); 3.24(septet, J=6.6 Hz, 1H); 2.30(t, J=5.2 Hz, 2H); 1.20(m, J=2.2 Hz, N); 0.979(t, J=6.0 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H32FN) 353, found 354 (M+H). Anal. Rasch. for C24H32NF: WITH 81,54; N, 9.12; N, 3.96; F 5.37. Found: 81.46; N, 9.06; N 3,78; F 5.59. So pl. 44-46oC. Rf=0.7 (30% CH2CL2/hexane).

Stage Century. ()-2,6-Aminobutiramida-3-( 1,2-dihydroxyethyl)-4-(4-forfinal)-5-pentylpyridine

In kiln dried round bottom flask, equipped with stirrer, add the intermediate compound obtained in stage A (150 mg, 0.424 mmol) in pyridine (10 ml) in an argon atmosphere. The solution is stirred and add OsO4(0.129 g, 0.509 mmol) in one portion. The reaction mixture turns black with prolonged stirring at room t NaHSO3(10 ml). The obtained heterogeneous solution is stirred very quickly within 18 hours. The layers are separated and the aqueous layer was extracted several times CH2CL2. The combined organic layers are dried (MgSO4), filtered and concentrated to obtain a white solid. The product is passed through a layer of silicon dioxide (65/35; CH2CL2/ether) to give a white solid (70 mg, 0.18 mmol, 43%).

1H NMR (300 MHz, CDCl3): 7.08(m, 4H); 4.57(d, J=1.5 Hz, 1H); 3.85(m, 1H); 3.65(septet, J= 6.6 Hz, 1H); 3.50(m, 1H); 3.20(septet, J=6.6 Hz, 1H); 2.19(m, 2H); 1.96(m, 1H); 1.24(m, 14N); 1.07(m, 4H); 0.780(t, J=6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO) 387 found 388 (M+H). Anal. Rasch. for C24H34NFO: 74,38; N, 8.84; N, 3.61; F 4.90. Found: 74.60; N, 9.03; N 3,83; F 5.04. So pl. 175-177oC. Rf=0.5 (65/35 CH2CL2/ether).

EXAMPLE 125

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-trifluoromethyl)phenyl] -5-(Penta-1-enyl)pyridine

Stage A. Diethyl ether 1,4-dihydro-2,6-aminobutiramida-4-[(4-trifluoromethyl)phenyl]pyridine-3.5-dicarboxylic acid

According to the method Chucholowski (U.S. patent 4950675) to a solution of 18.0 g (0.11 mol) of utilizability and 9.9 g (56.8 mmol) of 4-(trifluoromethyl)benzaldehyde in ethanol (25 ml) is added concentrated Ki is 12 o'clock After cooling to room temperature the reaction mixture was concentrated in vacuo to obtain a yellow oil. The crude product is taken directly to the next stage without purification.

Stage C. Diethyl ether 2,6-aminobutiramida-4-[(4-trifluoromethyl)phenyl]pyridine-3,5-dicarboxylic acid

Receive from the intermediate obtained in stage A, by the method of example 160, step Century.

1H NMR (300 MHz, CDCl3): 0.92(t, J=7.0 Hz, 6N); 1.33(d, J=6.6 Hz, N); 3.14(m, 4H); 4.0(q, J= 7.0 Hz, 4H); 7.42(d, J=8.0 Hz, 2H). So pl. 100-101oC.

Stage C. Ethyl ester of 2,6-aminobutiramida-4-[(4-trifluoromethyl)phenyl]-5-hydroxymethyluracil-3-carboxylic acid

Receive from the intermediate obtained in stage according to the method of example 1, step D.

1H NMR (300 MHz, CDCl3): 0.91 (t, J=7.0 Hz, 3H); 1.32(d, J=6.6 Hz, 6N); 1.35(d, J= 6.6 Hz, 6N); 3.08(m, 1H); 3.50(m, 1H); 3.96(q, J=7.0 Hz, 2H); 4.43(d, J=4.0 Hz, 2H); 7.44(d, J=8.0 Hz, 2H); 7.68(d, J=8.0 Hz, 2H). So pl. 102-103oC.

Stage D. 5-Etoxycarbonyl-2,6-aminobutiramida-4-[(4-trifluoromethyl)phenyl]pyridine-3-carboxaldehyde

To a solution of the intermediate obtained in stage C (1.9 g, 4.6 mmol), in dichloromethane (50 ml) was added celite (2.0 g). The suspension is stirred at room t is matney temperature for 1 h, then pour in a solution of 1:1 diethyl ether/hexane (250 ml), filtered through a layer of silicon dioxide, the layer is washed with diethyl ether (250 ml) and the combined eluent concentrate to obtain 1.7 g (93%) of product as a viscous oil which slowly solidified.

1H NMR (300 MHz, CDCl3): 0.94(t, J=7.0 Hz, 3H); 1.33(d, 3=6.6 Hz, 6N); 1.34(d, 3= 6.6 Hz, 6N); 3.14(m, 1H); 3.88(m, 1H); 4.0(q, J=7.0 Hz, 2H); 7.42(d, J=8.0 Hz, 2H); 7.71(d, J=8.0 Hz, 2H); 9.86(s, 1H). So pl. 105-106oC.

Stage E. Ethyl ester of 2,6-aminobutiramida-4-[(4-trifluoromethyl)phenyl]-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Receive from the intermediate obtained in stage D according to the method of example 1, step D.

1H NMR (300 MHz, CDCl3): 0.69(t, J=7.0 Hz, 3H), 0.90(t, J=7.0 Hz, 3H), 1.09-1.34(m, 14N); 1.92 (, J=14.0, 7.0, 1.5 Hz, 2H); 3.07(m, 1H); 3.38(m, 1H); 3.96(q, J= 7.0 Hz, 2H); 5.29(m, 1H); 6.05(m, 1H); 7.31(d, J=8.0 Hz, 2H); 7.59(d, J=8.0 Hz, 2H). So pl. 70-72oC.

Stage F. 2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-trifluoromethyl)phenyl]-5-(Penta-1-enyl)pyridine

The intermediate compound obtained in stage E (0.91 g, 2.04 mmol), dissolved in anhydrous THF (100 ml) in an argon atmosphere and treated at room temperature with lydialydia (1.0 M in THF, 10 ml, 10 mmol). The reaction mixture was stirred under heating Em H2About, 20% aqueous NaOH and H2O. the resulting suspension is filtered through a layer of celite and the filtrate is concentrated and purified flash chromatographia on a column of silica gel (5% ethyl acetate/n-hexane) to give 0.77 g (1.90 mmol, 93%) of target compound as a white foam.

1H NMR (300 MHz, CDCl3): 0.68(t, J=7.0 Hz, 3H); 1.05-1.40(m, 14N); 1.90(, J=14.0, 7.0,1.5 Hz, 2H); 3.34(m,1H); 3.45(m, 1H); 4.37(d, J=5.5 Hz, 2H); 5.26(m, 1H); 5.95(m, 1H); 7.30(d, J=8.0 Hz, 2H); 7.65(d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n-hexane). So pl. 77-78oC.

EXAMPLE 126

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-trifluoromethyl)phenyl] -5-pentylpyridine

0.59 g (1.46 mmol) of the compound 2,6-aminobutiramida-3-hydroxymethyl-4-[(4-trifluoromethyl)phenyl] -5-(Penta-1-enyl)pyridine (example 125) dissolved in absolute ethanol (50 ml) and treated with 10% palladium on coal (0.1 EQ.). The reaction flask is rinsed in aspiration vacuum and flushed with hydrogen (3). The reaction mixture is stirred in hydrogen atmosphere for 6 hours After the flush of the system with argon, the catalyst was removed by filtration through a layer of celite. The solvent is removed by concentration in vacuo and the crude product purified flash chromatography (10% ethyl acetate/n-hexane) to obtain 0.58 g (1.41 mmol, 97%) of target compound in the form of a white solid which 1H); 4.29(s, 2H); 7.34(d, J=8.0 Hz, 2H); 7.72(d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n-hexane). So pl. 99-100oC.

EXAMPLE 127

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-forfinal)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3-forfinal)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 3-forventelige, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): (Dan mixture of olefin isomers): 0.76(m, 3H); 0.97(t, J= 7.0 Hz, 3H); 1.13-1.37(m, 14N); 1.95(m, 2H); 3.07(m, 1H); 3.21-3.45(m, 1H); 4.0(m, 2H); 5.30-5.60(m, 1H); 6.06(m, 1H); 6.90-7.03(m, 3H); 7.27(m, 1H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3-forfinal)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.78(m, 3H); 1.13-1.37(m, 14N); 1.93(m, 2H); 3.41 (m, 2H); 4.40(s, 2H); 5.28-5.45(m, 1H); 6.0(m, 1H); 6.87-7.07(m, 3H); 7.34(m, 1H). Rf=0.36 (10% ethyl acetate/n-hexane). So pl. 117-118oC.

EXAMPLE 128

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(: 0.79(t, J=7.0 Hz, 3H); 1.10-1.35(m, N); 2.28(m, 2H); 3.24(m, 1H); 3.42(m, 1H); 4.33(s, 2H); 6.96(m, 2H);7.12(m, 1H); 7.40(m, 1H). So pl. 117-118oC. Rf= 0.36 (10% ethyl acetate/n-hexane).

EXAMPLE 129

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-were)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(4-were)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 4-methylbenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.75(t, 3=7.4 Hz, 3H); 0.95(t, J=7.4 Hz, 3H); 1.20-1.40(m, 14N); 1.95(TDD, 3=7.4, 7.4, 1.5, 2H); 2.35(s, 3H); 3.10(m, 1H); 3.40(m, 1H); 3.99(q, J=7.4 Hz, 2H); 5.30-5.40(m, 1H); 6.05(dt, J=16.2 Hz, 1H); 7.0-7.2(m, 4H). So pl. 74-77oC.

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-were)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3): 0.77(t, J=7.0 Hz, 3H); 1.1-1.3(m, 15 NM); 2.27(m, 2H); 2.42(s, 3H); 3.4(m, 2H); 4.34(d, J=6.0 Hz, 2H); 5.30-5.40(m, 1H); 5.90(d, J= 16.0 Hz, 1H), 7.0(d, J=8.0 Hz, 2H); 7.18(d, J=8.0 Hz, 2H). The Belarusian library Association-MS calculated for C24H33NO. 352, found 352 (M+H, 100%). Rf= 0.38 (10% ethyl acetate/n-hexane). So pl. 72-75oC.

EXAMPLE 130

< / BR>
2,6-Disoproxil-4-(4-were)-5-(Penta-1-enyl)pyridine (example 129) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.77(t, J=7.0 Hz, 3H); 1.10-1.40(m, N); 2.27(m, 2H);

2.42(s, 3H); 3.22(m, 1H); 3.41(m, 1H); 4.34(d, J=6.0 Hz, 2H); 7.10(d, J= 8.0 Hz, 2H); 7.20(d, J= 8.0 Hz, 2H). The Belarusian library Association-MS calculated for C24H35NO 354, found 354 (M+H, 100%). Rf= 0.38 (10% ethyl acetate/n-hexane). So pl. 92-94oC.

EXAMPLE 131

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-ethylphenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(4-ethylphenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 4-ethylbenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.78(t, J=7.4 Hz, 3H); 0.90(t, J=7.4 Hz, 3H); 1.10-1.40(m, 17H); 1.94(TDD, J= 7.0, 7.0, 1.5 Hz, 2H); 2.64(q, J=7.7 Hz, 2H); 3.0(m, 1H); 3.40(m, 1H); 3.96(q, J=7.4 Hz, 2H); 5.35(m, 1H); 6.08(dt, J=16.2,1.5 Hz, 1H); 7.10(m, 4H). So pl. 67-68oC.

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-ethylphenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.73(t, J= 7.0 Hz, 3H), 1.1-1.4(m, N); 1.91(TDD, J=7.0, 7.0, 1.0 Hz, 2H); 2.68(q, J= 7.4 Hz, 2H); 3.3-3.5(m, 2H); 4.41(d, J=5.5 Hz, 2H); 5.20-5.40(m, 1H); 6.0(dt, J= 16.0, 1.01 (10% the ethyl acetate/n-hexane).

EXAMPLE 132

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-ethylphenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-ethylphenyl)-5-(Penta-1-enyl)pyridine (example 131) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.77(t, J=7.0 Hz, 3H); 1.10-1.40(m, 22N); 2.28(m, 2H); 2.73(q, J=7.5 Hz, 2H); 3.35(m, 1H); 3.45(m, 1H); 4.35(s, 2H); 7.10(d, J= 8.0 Hz, 2H); 7.18-7.34(d, J=8.0 Hz, 2H). The Belarusian library Association-MS calculated for C25H37NO. 368, found 368 (M+H, 100%). Rf= 0.31 (10% ethyl acetate/n-hexane). So pl. 87-88oC.

EXAMPLE 133

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(4-isopropylphenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 4-isopropylbenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.70(t, J=7.7 Hz, 3H), 0.84(t, J=7.4 Hz, 3H); 1.10-1.40(m, 20N); 1.95(TDD, J=7.0, 7.0, 1.5, 2H); 2.80-3.10(m, 2H); 3.40(m, 1H); 3.94(q, J= 7.4 Hz, 2H); 5.30(m, 1H); 6.10(dt, J=15.8, 1.5 Hz, 1H); 7.0-7.20(m, 4H). So pl. 41-45oC.

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained is new): 0.68(t, J=7.4 Hz, 3H); 1.0-1.4(m, N); 1.90(TDD, J=7.0, 7.0, 1.5 Hz, 2H); 2.9(m, 1H); 3.3-3.5(m, 2H); 4.43(d, J=6.0 Hz, 2H); 5.20-5.35(m, 1H); 6.0(dt, J=16.0, 1.5 Hz, 1H); 7.0(d, J+8.0 Hz, 2H); 7.25(d, J=8.0 Hz, 2H). The Belarusian library Association-MS calculated for C26H37NO 380, found 380 (M+H, 100%). Rf= 0.40 (10% ethyl acetate/n-hexane).

EXAMPLE 134

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-isopropylphenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(Penta-1-enyl)pyridine (example 133) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.74(t, J=7.0 Hz, 3H); 1.10-1.40(m, 25N); 2.25(m, 2H); 2.95(m, 1H); 3.25(m, 1H); 3.40(m, 1H); 4.35(d, J=6.0 Hz, 2H); 7.1(d, J=8.5 Hz, 2H); 7.25(d, J=8.5 Hz, 2H). The Belarusian library Association-MS calculated for C29H39NO. 382, found 382 (M+H, 100%). Rf= 0.40 (10% ethyl acetate/n-hexane). So pl. 42-44oC.

EXAMPLE 135

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[4-(phenyl)phenyl] -5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-[4-(phenyl)phenyl]-5-(Penta-1-enyl)- pyridine-3-carboxylic acid

Obtained from 4-phenylbenzene, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.73(t, J=7.4 Hz, 3H); 0.93(t, J=7.0 Hz, 3H); 1.10-1.40(m, 14N); 1.97(TDD, J=7.0, 7.0, 1.1, 2H); 3.10(m, 1H); 3.45(m, 1H); 4.0(karacsonyi-4-[4-(phenyl)phenyl]-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.70(t, J= 7.0 Hz, 3H), 1.10-1.40(m, 15 NM); 1.90(TDD, J=7.0, 7.0, 1.5 Hz, 2H); 3.3-3.5(m, 2H); 4.40(d, J= 6.0 Hz, 2H); 5.35(m, 1H); 6.05(dt, J=16.0, 1.5 Hz, 1H); 7.20-7.24(m, 2H); 7.35-7.70(m, 7H). The Belarusian library Association-MS calculated for C29H35NO. 414, found 414 (M+H, 100%). Rf=0.15 (6% ethyl acetate/n-hexane). So pl. 50-52oC.

EXAMPLE 136

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[4-(phenyl)phenyl]-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-[4-(phenyl)phenyl]-5-(Penta-1-enyl)pyridine (example 135) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.76(t, J=7.0 Hz, 3H); 1.10-1.40(m, N); 2.31(m, 2H); 3.25(m, 1H); 3.44(m, 1H); 4.40(d, J=5.9 Hz, 2H); 7.22-7.70(m, N). The Belarusian library Association-MS calculated for C29H37NO 416, found 416 (M+H, 100%). Rf= 0.34 (10% ethyl acetate/n-hexane). So pl. 56-58oC.

EXAMPLE 137

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-forfinal)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(2-forfinal)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Is obtained from 2-forventelige, ethylisopropylamine and concentrated hydroxide and is of somerow): 0.70(m, 3H); 0.92(t, J= 7.0 Hz, 3H); 1.05-1.40(m, 14N); 1.90(m, 2H); 3.10(m, 1H); 3.35(m, 1H); 3.97(m, 2H); 5.29-5.50(m, 1H); 6.16(m, 1H); 7.08-7.32(m, 4H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(2-forfinal)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.69-0.82(m, 3H); 1.09-1.44(m, 14N); 1.90(m, 2H); 3.20-3.45(m, 2H); 4.40(m, 2H); 5.25-5.45(m, 1H); 6.08(m, 1H); , 7.08-7.41(m, 5H) Rf=0.24 (10% ethyl acetate/n-hexane).

EXAMPLE 138

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-forfinal)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(2-forfinal)-5-(Penta-1-enyl)pyridine (example 137) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.78(t, J=7.0 Hz, 3H); 1.07-1.40(m, N); 2.29(m, 2H); 3.26(m, 1H); 3.46(m, 1H); 4.34(m, 2H); 7.20(m, 3H); 7.42(m, 1H). Rf= 0.24 (10% ethyl acetate/n-hexane).

EXAMPLE 139

< / BR>
2,6-L-3-hydroxymethyl-4-(3-were)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3-were)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 3-methylbenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the method of application is, .0, 1.5, 2H); 2.32(s, 3H); 3.10(m, 1H); 3.40(m, 1H); 3.96(q, J=7.4 Hz, 2H); 5.40(m, 1H); 6.05(dt, J=16.2, 1.5 Hz, 1H); 6.90-7.20(m, 4H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3-were)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.73(t, J= 7.0 Hz, 3H); 1.0-1.4(m, 15 NM); 1.90(TDD, J=7.0, 7.0, 1.0 Hz, 2H); 2.36(s, 3H); 3.3-3.5(m, 2H); 4.40(d, J=4.0 Hz, 2H); 5.20-5.40(m, 1H); 5.95(dt, J= 16.0, 1.0 Hz, 1H); 6.90(m, 2H); 7.10-7.30(m, 2H). The Belarusian library Association-MS calculated for C24H33NO. 352, found 352 (M+H, 100%). Rf= 0.34 (10% ethyl acetate/n-hexane). So pl. 94-97oC.

EXAMPLE 140

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-were)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(3-were)-5-(Penta-1-enyl)pyridine (example 139) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.77(t, J=7.0 Hz, 3H); 1.10-1.40(m, N); 2.25(m, 2H); 2.39(s, 3H); 3.23(m, 1H); 3.44(m, 1H); 4.34(s, 2H); 6.97(m, 2H); 7.18-7.34(m, 2H). The Belarusian library Association-MS calculated for C24H35NO. 354, found 354 (M+H, 100%). Rf=0.34 (10% ethyl acetate/n-hexane). So pl. 88-90oC.

EXAMPLE 141

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-were)-5-(Penta-1-enyl)pyridine

1H NMR (300 MHz, CDCl3): 0.70(t, 3=7.4 Hz, 3H); 0.88(t, J=7.0 Hz,3H); 1.10-1.40(m, 14N); 1.90(dt, J=7.0, 7.0,2 H); 2.0(s, 3H); 3.10(m, 1H); 3.40(m, 1H); 3.90(m, 2H); 5.30-5.40(m, 1H); 6.0(m, 1H), 7.0-7.20(m, 4H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(2-were)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.70(t, J=7.5 Hz, 3H), 1.10-1.40(m, 15 NM); 1.87(TDD, J=7.5, 7.5, 1.5 Hz, 2H); 1.95(s, 3H); 3.3-3.5(m, 2H); 4.20(m, 1H); 4.45(m, 1H); 5.30(m, 1H); 5.93(m, 2H), 6.90-7.30(m, 4H). The Belarusian library Association-MS calculated for C24H33NO. 352, found 352 (M+H, 100%). Rf= 0.32 (10% ethyl acetate/n-hexane). So pl. 76-79oC.

EXAMPLE 142

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-were)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(2-were)-5-(Penta-1-enyl)pyridine (example 141) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.76(t, J=6.6 Hz, 3H); 1.10-1.40(m, N); 1.97(s, 3H); 2.0 (m, 1H); 2.35(m, 1H); 3.22(m, 1H); 3.42(m, 1H); 4.16(DD, J= 12.0, 5.0 Hz, 1H); 4.40(DD, J=12.0, 5.0 Hz, 1H); 7.0-7.10(m, 1H); 7.20-7.40(m, 3H). The Belarusian library Association-MS calculated for C 143

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(4-chlorophenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 4-chlorobenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.76(m, 3H); 0.98(m, 3H); 1.15-1.35(m, 14N); 1.95(m, 2H); 3.05(m, 1H); 3.39(m, 1H); 4.0(m, 2H); 5.29-5.48(m, 1H); 6.03(m, 1H); 7.11(m, 2H); 7.30(m, 2H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (given to a mixture of 6:1 of olefin isomers): 0.73-0.83(m, 3H); 1.10-1.40(m, 14N); 1.91(m, 2H); 3.93(m, 2H); 4.39(d, J=5.0 Hz, 2H); 5.25-5.45(m, 1H); 5.98(m, 1H); 7.11(m, 2H); 7.35(m, 2H). Rf=0.32 (10% ethyl acetate/n-hexane).

EXAMPLE 144

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-(Penta-1-enyl)pyridine (example 143) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.79(t, J=7.0 Hz, 3H); 1.08-1.38(m, N); 2.26(mn-hexane).

EXAMPLE 145

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-chlorophenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3-chlorophenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 3-chlorobenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.75(t, J=7.4 Hz, 3H); 0.98(t, J=7.0 Hz, 3H); 1.20-1.40(m, 14N); 1.96(TDD, J=7.0, 7.0, 1.5,2 H); 3.05(m, 1H); 3.40(m, 1H); 4.0(q, J= 7.0 Hz, 2H); 5.45(m, 1H); 6.05(dt, J=16.2, 1.5, 1H); 7.0-7.30(m, 4H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3-chlorophenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.75(t, J= 7.5 Hz, 3H), 1.0-1.4(m, 15 NM); 1.93(TDD, J=7.0. 7.0, 1.0 Hz, 2H); 3.3-3.5(m, 2H); 4.37(d, J= 12.0 Hz, 1H); 4.43(doctor J=12.0 Hz, 1H); 5.20-5.40(m, 1H); 5.9(dt. J= 16.0, 1.1 Hz, 1H), 7.0-7.40(m, 4H). The Belarusian library Association-MS calculated for C23H30NOCl 372, found 372 (M+H, 100%). Rf= 0.26 (10% ethyl acetate/n-hexane). So pl. 101-104oC.

EXAMPLE 146

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-chlorophenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(3-harfe Hz, 3H); 1.0-1.40(m, N); 2.26(m, 2H); 3.23(m, 1H); 3.41(m, 1H); 4.34(m, 2H); 7.05-7.45(m, 4H). The Belarusian library Association-MS: calculated for C23H32NOC1 374, found 374 (M+H, 100%). Rf=0.26 (10% ethyl acetate/n-hexane). So pl. 94-95oC.

EXAMPLE 147

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(2,4-dichlorophenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Derived from 2,4-dichlorobenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3) (Dan 1:1 mixture of olefin isomers): 0.79(m, 3H); 0.99(m, 3H); 1.12-1.38(m, 14N); 1.91(m, 2H); 3.12(m, 1H); 3.32(m, 1H); 4.0(m, 2H); 5.20-5.60(m, 1H); 6.09(m, 1H), 7.05-7.41(m, 3H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-(Penta-1-enyl)-pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan 1:1 mixture of olefin isomers): 0.75-0.87(m, 3H); 1.13-1.37(m, 14N); 1.65-2.0(m, 2H); 3.20-3.51(m, 2H); 4.30(m, 1H); 4.42(m, 1H); 5.31-5.50(m, 1H); 6.0(m, 1H), 7.05(m, 1H); 7.28(m, 1H); 7.47(m, 1H). Rf= 0.38 (10% ethyl acetate/n-hexane).

EXAMPLE 148

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2,4-dichlorophenyl-enyl)pyridine (example 147) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.80(t, J=7.0 Hz, 3H), 1.12-1.48(m, N); 2.12(m, 1H); 2.35(m, 1H); 3.26(m, 1H); 3.45(m, 1H); 4.31(AB, J=12.0 Hz, 2H); 7.16(d, J= 8.0 Hz, 1H); 7.36(DD, J=8.0, 2.0 Hz, 1H); 7.54(d, J=2.0,1 H). Rf= 0.38 (10% ethyl acetate/n-hexane).

EXAMPLE 149

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3,4-dichlorophenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3,4-dichlorophenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Derived from 3,4-dichlorobenzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the method of example 160, stages a-E.

1H NMR (300 MHz, CDCl3) (Dan 6:1 mixture of olefin isomers): 0.78(m, 3H); 1.04(m, 3H); 1.16-1.35(m, 14N); 1.98(m, 2H); 3.04(m, 1H); 3.57(m, 1H); 5.31-5.58(m, 1H); 6.02(m, 1H), 7.04(m, 1H); 7.28-7.42(m, 2H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3,4-dichlorophenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan 6:1 mixture of olefin isomers): 0.80(m, 3H), 1.16-1.57(m, 14N); 1.95(m, 2H); 3.40(m, 2H); 4.41(m, 2H); 5.28-5.42(m, 1H); 6.0(m, 1H), 7.05(s, 1H); 7.30(s, 1H); 7.45(m, 1H). So pl. 46-48oC. Rf= 0.38 (10% ethyl acetate/n-hexane).

EXAMPLE 150

< / BR>
2,6-Aminobutiramida 3-hydroxymethyl)pyridine-3-carboxylic acid

Derived from 2,4-diferentialglea, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.75(t, 3=7.4 Hz, 3H); 1.0(t, J=7.0 Hz, 3H); 1.10-1.40(m, 14N); 1.93(TDD, J=7.4, 7.4, 1.5 Hz, 2H); 3.10(m, 1H); 3.35(m, 1H); 4.0(q, J= 7.0 Hz, 2H); 5.30(dt, J=15.0, 7.0 Hz, 1H); 6.10(m, 1H); 6.80-7.20(m, 3H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(2,4-differenl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage a by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.75(t, J= 7.5 Hz, 3H); 1.10-1.40(m, 15 NM); 1.92(TDD, J=7.0, 7.0, 1.5 Hz, 2H); 3.30-3.60(m, 2H); 4.34(DD, J= 12.0, 6.0 Hz, 1H); 4.43(DD, J=12.0, 5.0 Hz, 1H); 5.3(m, 1H); 6.05(d, J=16.0 Hz, 1H); 6.80-7.20(m, 3H). The Belarusian library Association-MS: calculated for C23H29NOF2374, found 374 (M+H, 100%). Rf= 0.24 (10% ethyl acetate/n-hexane). So pl. 59-62oC.

EXAMPLE 151

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2,4-differenl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(2,4-differenl)-5-(Penta-1-enyl)pyridine (example 150) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.79(t, J=7.0 Hz, 3H), 1.10-1.40(m, N); 2.30(m, 2H); 3.20(m, 1H); 3.40(m, 1H); 4.30(d, J=12.0 UB>= 0.24 (10% ethyl acetate/n-hexane). So pl. 93-95oC.

EXAMPLE 152

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 3-benzyloxybenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the method of example 160, stages a-E.

1H NMR (300 MHz, CDCl3): 0.75(t, J=7.4 Hz, 3H); 0.93(t, J=7.2 Hz, 3H); 1.25(m, 14N); 1.93(TDD, J=7.4, 7.4, 1.1 Hz, 2H); 3.07(m, 1H); 3.40(m, 1H); 3.97(m, 2H); 5.04(MS, 2H); 5.35(m, 1H); 6.06(dt, J=16.2, 1.5 Hz, 1H), 6.79(m, 2H); 6.89(m, 1H); 7.31(m, 6N).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.74(t, J= 7.4 Hz, 3H); 1.25(m, 14N); 1.90(m, 2H); 3.39(m, 2H); 4.39(doctor J=6.0 Hz, 2H); 5.07(s, 2H); 5.32(m, 1H); 5.97(m, 1H), 6.74(m, 2H); 6.95(m, 1H); 7.35(m, 7H). The Belarusian library Association-MS: calculated for C30H37NO2444, found 444 (M+H, 100%). Elemental analysis: calculated for C30H37NO2: 81.22; N, 8.41; N, 3.16 found: 80.51; N, 8.41; N, 3.36. Rf= 0.5 (25% ethyl acetate/n-hexane).

1H NMR (300 MHz, Dl3): 0.78(t, J=7.0 Hz, 3H); 1.28(m, N); 2.28(m, 2H); 3.22(m, 1H); 3.39(m, 1H); 4.34(m, 2H); 5.52(s, 1H); 6.63(m, 1H); 6.71(d, J= 8.0 Hz, 1H); 6.81(m, 1H); 7.26(m, 1H). The Belarusian library Association-MS: calculated for C23H33NO2356, found 357 (M+H, 100%). Elemental analysis: calculated for C23H33NO2: 77.70; N, 9.36; N, 3.94 found: 76.51; N, 9.49; N, 3.85. Rf= 0.21 (10% ethyl acetate/n-hexane). So pl. 121-122oC.

EXAMPLE 154

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3-trifluoromethyl)phenyl-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Obtained from 3-(trifluoromethyl)benzaldehyde, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-E.

1H NMR (300 MHz, CDCl3) (listed for 6:1 mixture of olefin isomers): 0.72(m, 3H); 0.94(m, 3H); 1.10-1.40(m, 14N); 1.94(m, 2H); 3.07(m, 1H); 3.41(m, 1H); 3.97(m, 2H); 5.33(m, 1H); 6.05(m, 1H), 7.29-7.60(m, 4H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(Penta-1-enyl)-pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan 6:1 mixture of olefin isomers): 0.>the. Rf=0.36 (10% ethyl acetate/n-hexane).

EXAMPLE 155

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(Penta-1-enyl)pyridine (example 154) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.75(t, J=6.5 Hz, 3H); 1.07-1.39(m, N); 2.24(m, 2H); 3.24(m, 1H); 3.42(m, 1H); 4.31(arcs, J=12.0, 5.0 Hz, 2H); 7.42(d, J=8.0 Hz, 1H); 7.50(s, 1H); 7.57(t, J=8.0 Hz, 1H); 7.67(d, J=8.0 Hz, 1H). So pl. 96-97oC. Rf= 0.36 (10% ethyl acetate/n-hexane).

EXAMPLE 156

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(Penta-1-enyl)pyridine

Stage A. Diethyl ether 2,6-aminobutiramida-4-(2-itfinal)pyridine-3,5-dicarboxylic acid

Is obtained from 2-identilied, ethylisopropylamine and concentrated ammonium hydroxide by the procedure of example 125, stages a-C.

1H NMR (300 MHz, CDCl3): 0.94(t, J=7.0 Hz, 6N); 1.30(d, J=6.6 Hz, 6N); 1.34(d, J= 6.6 Hz, 6N); 3.19(septet, J=6.6 Hz, 2H); 4.0(q, J=7.0 Hz, 4H); 7.0-7.40(m, 3H), 7.85(m, 1H).

Stage C. Diethyl ether 2,6-aminobutiramida-4-[(2-trimethylsilylethynyl)phenyl]pyridine-3,5-dicarboxylic acid

A solution of 1.50 g (3 mmol) of the intermediate obtained in stage A, in toluene is treated with 1.48 g (15 m, .2 g (0.8 mmol) of triphenylphosphine, and 0.2 g (1.17 mmol) of copper iodide. This reaction mixture is stirred at room temperature for 1 h and heated at a temperature of 90oWith in an isolated reaction flask for 16 hours, the Reaction mixture was cooled to room temperature, filtered through celite and was stripped to obtain a dark oil, which when cleaning flash chromatography on a column of silica gel give 1.22 g (2.5 mmol) of the product.

1H NMR (300 MHz, CDCl3): 0.0(s, N); 0.93(t, J=7.0 Hz, 6N); 1.32(d, J= 6.6 Hz, 6N); 1.33(d, J=6.6 Hz, 6N); 3.18(septet, J=6.6 Hz, 2H); 3.90(q, J= 7.0 Hz, 4H); 7.20-7.50(m, 4H).

Stage C. Diethyl ether 2,6-aminobutiramida-4-(2-ethynylphenyl)pyridine-3,5-dicarboxylic acid

A solution of 5.68 g (11.9 mmol) of the intermediate obtained in stage b In 800 ml of ethanol, treated with 2.8 g (20.3 mmol) of potassium carbonate and the reaction mixture was stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, brine and separated. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material is purified flash chromatography on a column of silica gel, elwira 10% J=7.0 Hz, 6N); 1.32(m, N); 2.97(s, 1H); 3.21(septet, 3=6.6 Hz, 2H); 3.90(q, J=7.0 Hz, 4H); 7.2-7.6(m, 4H).

Stage D. Ethyl ester of 2,6-aminobutiramida-4-(2-ethynylphenyl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Receive from the intermediate obtained in stage C according to the method of example 125, stages a-E.

1H NMR (300 MHz, CDCl3): 0.68(t, J=7.4 Hz, 3H);, 0.88(dt, J=7.0, 2.4 Hz, 3H); 1.20-1.40(m, 14N); 1.88(TDD, J=7.0, 7.0, 1.1 Hz, 2H); 2.92(d, J=2.4 Hz, 1H); 3.0-3.40(m, 2H); 3.90(m, 2H); 5.28(dt, J= 16.2, 7.0 Hz, 1H); 6.15(dt, J=16.2, 1.5 Hz, 1H); 7.10-7.60(m, 4H).

Stage E. 2,6-Aminobutiramida-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage D, according to the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.81(t, J= 7.4 Hz, 3H); 1.0-1.40(m, 15 NM); 1.75(m, 2H); 2.98(d, J=3.3 Hz, 1H); 3.20-3.60(m, 2H); 4.20-4.50(m, 2H); 5.40(m, 1H); 6.0(m, 1H), 7.0-7.60(m, 4H). Rf= 0.23 (10% ethyl acetate/n-hexane).

EXAMPLE 157

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-ethenylene)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(Penta-1-enyl)pyridine-3-carboxylate by the procedure of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan for mixture Olaf is m, 1H); 7.0-7.70(m, 4H). The Belarusian library Association-MS: calculated for C25H33NO 363.5 found 364 (M+H, 100%). Rf=0.28 (10% ethyl acetate/n-hexane).

EXAMPLE 158

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3,4-differenl)-5-(Penta-1-enyl)pyridine

Stage A. Ethyl ester of 2,6-aminobutiramida-4-(3,4-differenl)-5-(Penta-1-enyl)pyridine-3-carboxylic acid

Derived from 3,4-diferentialglea, ethylisopropylamine and concentrated ammonium hydroxide by the method of example 1, stage a, that is,

1H NMR (300 MHz, CDCl3) (specified for a 8:1 mixture of olefin isomers): 0.78(m, 3H); 1.03(m, 3H); 1.18-1.33(m, 14N); 1.97(m, 2H); 3.04(m, 1H); 3.38(m, 1H); 4.04(m, 2H); 5.30-5.45(m, 1H); 6.02(m, 1H); 6.89-7.17(m, 3H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-(3,4-differenl-5-(Penta-1-enyl)pyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 125, step F.

1H NMR (300 MHz, CDCl3) (Dan mixture of olefin isomers): 0.75(m, 3H); 1.05-1.38(m, 14N); 1.90(m, 2H); 3.35(m, 2H); 4.35(m, 2H); 5.25(m, 1H); 5.91(m, 1H); 6.80-7.20(m, 4H). So pl. 105-106oC. Rf=0.30 (10% ethyl acetate/n-hexane).

EXAMPLE 159

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3,4-differenl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida 3-GI MHz, Dl3): 0.81(t, J=7.0 Hz, 3H); 1.12(m,4H); 1.30(m, 14N); 2.27(m, 2H); 3.24(m, 1H); 3.41(m, 1H); 4.32(d, J=4.0 Hz, 2H); 6.95(m, 1H); 7.06(m, 1H); 7.25(m, 1H). So pl. 106-107oC. Rf=0.30 (10% ethyl acetate/n-hexane).

EXAMPLE 160

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine

Stage A. Diethyl ether 1,4-dihydro-2,6-aminobutiramida-4-(4-benzyloxyphenyl)-3,5-pyridinedicarboxylic acid

To 4-benzyloxybenzaldehyde (24.3 g, 114 mmol) and utilizability (37.8 g, 239 mmol) are added ethanol (50 ml), acetic acid (1 ml) and piperidine (1.7 ml). The mixture is stirred in an argon atmosphere at a temperature of 25oWith in 12 hours. Then add a freshly prepared solution of ethoxide sodium in ethanol (15%, 15 ml) and the reaction mixture is stirred at a temperature of 25oC for 2 h To this mixture add a solution of ammonium acetate (13.1 g, 171 mmol) in acetic acid (100 ml). The reaction mixture is heated under reflux for 14 hours and then cooled to a temperature of 25oS, during which a white precipitate is formed. To this mixture is added 40% (V/V) solution of 2-propanol in water. The mixture is stirred for 0.5 h at a temperature of 25o, Then cooled to -20oC for 2 hours. White solid FDS is mol, 75%) as pure white solid (so pl. 140-141oC).

1H NMR (300 MHz, CDCl3): 1.14-1.29(m, N); 4.10(q, J=6.9 Hz, 4H); 4.19(Sept, J= 6.9 Hz, 2H); 4.95(s, 1H); 5.01(s, 2H); 6.12(s, 1H); 6.82(d,J= 8.7 Hz, 2H); 7.17(d, J=8.7 Hz, 2H); 7.27-7.45(m, 5H).

Stage C. Diethyl ether 2,6-aminobutiramida-4-(4-benzyloxyphenyl)-3,5-pyridinedicarboxylic acid

To the solution obtained in stage A (39.72 g, 81 mmol) in acetone (400 ml), stirred in an argon atmosphere at a temperature of 25oTo add an aqueous solution of cerium (IV) ammonium nitrate (CAM) (1 M, 162 ml). The mixture is stirred at a temperature of 25oC for 0.5 h and the acetone removed under reduced pressure. The resulting mixture was diluted with dichloromethane (400 ml) and poured into water (100 ml). The organic layer is preserved and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layer was washed with a saturated solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain product as a white powder (39.51 g, 100%) (so pl. 87oC).

1H NMR (300 MHz, CDCI3): 0.96(t, J=6.9 Hz, 6N); 1.31(d, J=6.6 Hz, N); 3.10(septet, J= 6.6 Hz, 2H); 4.01(q, J=7.5 Hz, 4H); 5.09(s, 2H); 6.95(d, J=8.7 Hz, 2H); 7.21 (d, J=8.7 Hz, 2H); 7.32-7.46(m, 5H).

Stage C. Ethyl ester 2,6 what soedineniya, retrieved on stage, according to the method of example 1, stage D-F.

1H NMR (300 MHz, CDCI3): 0.77(t, J=7.2 Hz, 3H); 0.95(t, J=7.2 Hz, 3H); 1.21-1.34(m, 14N); 1.96(q, J= 7.2 Hz, 2H); 3.05(septet, J=6.6 Hz, 1H); 3.42(septet, J=6.6 Hz, 1H); 3.94-4.03(m, 2H); 5.06-5.12(m, 2H); 5.32-5.42(m, 1H); 6.03-6.15(m, 1H); 6.94(d, J=9.0 Hz, 2H); 7.10(d, J=9.0 Hz, 2H); 7.34-7.47(m, 5H).

Stage D. 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine

The intermediate compound obtained in stage C (6 g, 12.35 mmol), dissolved in anhydrous tetrahydrofuran (THF) (130 ml) in an argon atmosphere and treated dropwise at room temperature lydialydia (LAS) (1.0 M in THF, 24.7 ml, 24.7 mmol). The reaction mixture was stirred at reflux for 3 h, cooled to room temperature and quenched by the addition of 0.9 ml of water, 0.9 ml of 20% aqueous NaOH and 2.7 ml of water. The resulting suspension is filtered through a layer of celite and the filtrate is concentrated and purified by chromatography on a column of silica (20% ethyl acetate/hexane) to give 4.76 g of the target compound as a colorless wax.

1H NMR (300 MHz, CDCl3): 0.73-0.83(m, 3H); 1.37-1.70(m, 14N); 1.56(s, 1H); 1.92(DQC, J=0.90, 6.90 Hz, 2H); 3.41(, J=6.60, 13.20, 24.60 Hz, 2H); 4.43(d, J= 5.1 Hz, 2H); 5.10(s, 2H); 5.27-5.37(m, 1H); 5.97(d, J=15.90 Hz, 1H), 6.97-7.69(m, 4H); 7.35-7.4 2,6-Aminobutiramida-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine (example 160) (500 mg, 1.13 mmol) dissolved in absolute ethanol (10 ml) in an argon atmosphere, and treated with 10% palladium on coal (15 mg), then stirred under hydrogen atmosphere for 14 hours After the flush of the system with argon, the catalyst was removed by filtration through a layer of celite. The solvent is removed and the residue is purified flash chromatography (5% methanol-methylene chloride) to give 371 mg of the target compound in the form of prapinabracni solids (I. pl. 158.5oC).

1H NMR (300 MHz, CDCl3): 0.79(t, J=6.6 Hz, 3H); 1.06-1.36(m, N); 2.24-2.31(m, 2H); 3.22(septet, J=6.6 Hz, 1H); 3.40(septet, J=6.6 Hz, 1H); 4.36(d, J=5.4 Hz, 2H); 4.85(s, 1H); 6.89(d, J=8.4 Hz, 1H), 7.05(d, J=8.7 Hz, 1H).

EXAMPLE 162

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine

The target connection will get prapinabracni solids from 2-benzyloxybenzaldehyde by the method of example 160.

1H NMR (300 MHz, CDCl3): 0.69-0.74(m, 3H); 1.07-1.38(m, 14N); 1.69-1.79(m, 1H); 1.84-1.99(m, 2H); 3.26-3.54(m, 2H); 4.28-4.46(m, 2H); 4.90-5.09(m, 2H); 5.26-5.47(m, 1H); 6.00(DD, J=15.9, 1.2 Hz, 1H), 7.05-7.10(m, 5H); 7.24-7.36(m, 4H).

EXAMPLE 163

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(2-benzyloxy who 3H); 1.09-1.15(m, 4H); 1.30-1.37(m, 14N); 1.70-1.73(m, 1H); 2.16-2.28(m, 1H); 2.32-2.42(m, 1H); 3.22-3.32(m, 1H); 3.39-3.51(m, 1H); 4.29-4.35(m, 1H); 4.48-4.54(m, 1H); 5.14(SHS, 1H); 7.02-7.05(m, 3H); 7.28-7.36(m, 1H). The Belarusian library Association-MS: calculated for (C23H33NO2) 355, found 356 (M+1). Anal. Rasch. for C23H33NO2: 77.70; N, 9.36; N, 3.94 found: 76.63; N 9.12 N 3.75. So pl. 125.5oC.

EXAMPLE 164

< / BR>
2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine

Stage A. 2,6-Aminobutiramida-(2-benzyloxyphenyl)-5-pentyl-3-pyridinecarboxamide

2,6-Aminobutiramida-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine (example 162) (680 mg, 1.53 mmol) was dissolved in 15 ml of methylene chloride in an argon atmosphere and treated with a mixture of celite (661 mg) and pyridylamine (PQQ) (661 mg, 2 EQ.). The reaction mixture was stirred at room temperature for 1.5 hours, the Suspension is filtered through a layer of silica, washed with 50 ml of dichloromethane,and the filtrate are combined and concentrated in vacuo to obtain 572.4 mg of product (84%). 1< / BR>
H NMR (300 MHz, CDCl3): 0.70(t, J=7.2 Hz, 3H); 1.08-1.35(m, 15 NM); 1.85-1.93(m, 1H); 3.26-3.45(m, 1H); 3.87-3.97(m, 1H); 4.97-5.06(m, 2H); 5.27-5.50(m, 1H); 6.01-6.10(m, 1H); 6.94-7.34(m, N); 9.82(d, J=3.6 Hz, 1H).

Stage C. 2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(2-benzyloxyphenyl)-5-(Penta-1-enyl)pyridine

Vet the method of example 101, stage Century. Two diastereoisomer share flash chromatography on a column of silica gel, elwira 10% ethyl acetate/hexane.

The diastereoisomer 1: colorless oil.1H NMR (300 MHz, CDCI3): 0.68-1.91(m, N); 3.19-3.40(m, 1H); 3.77(Sept, J=6.6 Hz, 1H); 4.69-4.79(m, 1H); 4.94(DD, J= 12.3, 3.9 Hz, 1H); 5.05(d, J=12.3 Hz, 1H); 5.20-5.43(m, 1H); 5.90-6.05(m, 1H), 6.94-7.38(m, N). The Belarusian library Association-MS: calculated for (C31H39NO2) 457, found 458 (M+1).

The diastereoisomer 2: colorless oil.

1H NMR (300 MHz, CDCl3): 0.69(t, J=7.2 Hz, 3H); 1.05-1.40(m, 17H), 1.67-1.73(m, 1H); 1.80-1.88(m, 2H); 3.18-3.41(m, 1H); 3.68-3.80(m, 1H); 4.84-5.08(m, 3H); 5.25-5.42(m, 1H); 5.86-6.08(m, 1H), 6.90-7.38(m, N). The Belarusian library Association-MS: calculated for (C31H39NO2) 457, found 458 (M+1).

Stage C. 2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine

Diastereomers the mixture of intermediate compounds obtained in stage (39 mg), dissolved in absolute ethanol (1.5 ml) in an argon atmosphere, and treated with 10% palladium on coal (4 mg), then stirred under an atmosphere of hydrogen for 8 hours After the flush of the system with argon, the catalyst was removed by filtration through a layer of celite. The solvent is removed and the product dried in vacuum to obtain 32 mg of the target compound as a colorless solid. Preparative it is diastereomer.

The diastereoisomer 1 (1)(11.2 mg).1H NMR (300 MHz, CDCl3); 0.68(t, J=7.30 Hz, 3H); 0.99-1.03(m,4H); 1.19-1.34(m, 17H); 1.62(d,1=3.60 Hz, 1H), 1.97-2.07(m, 1H); 2.16-2.2(m, 1H); 3.14(Sept, J=7.30 Hz, 1H); 3.67(Sept, J=7.30 Hz, 1H); 4.72(wide s, 1H); 4.83(DQC, J=4.20, 6.60 Hz, 1H); 6.89-6.97(m, 3H), 7.19-7.25(m, 1H). The Belarusian library Association-MS: calculated for (C24H35NO2) 369, found 370 (M+1).

The diastereoisomer 1 (D1) can be separated into the individual enantiomers as follows. System Waters Prep LC 2000 HPLC equipped with a column for chiral GHUR (BRB-9668A; 6 x 50 cm ID). System balance mobile phase consisting of 2% (1% acetic acid, 99% ethanol) and 98% hexane at a flow rate of 175 ml/min Sample dissolved in mobile phase (20 mg/ml) and inject 5 ml aliquots with 30 minute intervals. The outgoing flow control at 280 nm and two fractions (corresponding enantiomers) collect at (15-17 min, 100% of ei) and (19-26 min, > 99% of ei), respectively.

The diastereoisomer 2 (D2)(11.8 mg).1H NMR (300 MHz, CDCl3): 0.68(t, J=6.60 Hz, 3H); 0.99-1.03(m, 4H); 1.16-1.32(m, 17H); 1.86(Shir. s, 1H); 2.00-2.10(m, 1H); 2.19-2.29(m, 1H); 3.14(Sept, J=6.60 Hz, 1H); 3.67(Sept, J=6.60 Hz, 1H); 4.57(q, J= 6.60 Hz, 1H); 4.76(Shir. s, 1H); 6.84-6.93(m, 3H); 7.19-7.24(m, 1H). The Belarusian library Association-MS: calculated for (C24H35NO2) 369, found 370 (M+1).

EXAMPLE 165

< / BR>
2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(is karbonovoi acid

Is obtained from 2-benzyloxybenzaldehyde by the method of example 160, stage A-Century

1H NMR (300 MHz, CDCl3): 0.87(t, J=6.9 Hz, 6N); 1.32(d, J=6.6 Hz, 6N); 1.33(d, J= 6.6 Hz, 6N); 3.19(Sept, J=6.6 Hz, 2H); 3.97(q, J=7.2 Hz, 4H); 5.01 (s, 2H); 6.88(d, J=8.1 Hz, 1H); 6.94(dt, J=7.2, 0.6 Hz, 1H); 7.16(DD, J=7.8, 1.8 Hz, 1H); 7.14-7.30 (m,6N).

Stage Century. 5-Etoxycarbonyl-2,6-aminobutiramida-4-(2-benzyloxyphenyl)-3-pyridinecarboxamide

Receive from the intermediate obtained in stage A, by the method of example 1, stage D-E.

1H NMR (300 MHz, CDCl3): 0.91(t, J=6.6 Hz, 3H); 1.30-1.39(m, N); 3.18(Sept, J= 6.6 Hz, 2H); 3.91-4.03(m, 3H); 5.04(DD, J=6.6, 12.6 Hz, 2H), 6.96-7.05(m, 2H); 7.17-7.28(m, 6N); 7.34-7.40(m, 1H).

Stage C. 2,6-Aminobutiramida-4-(2-benzyloxyphenyl)-3-etoxycarbonyl-5-(prop-1-enyl)pyridine

Ethyltriphenylphosphonium (4.01 g, 10.8 mmol) suspended in anhydrous THF (130 ml) in an argon atmosphere and stirred at a temperature of -78oC. are added dropwise 1.6 M solution of n-utility in hexane (6.75 ml, 10.8 mmol). The reaction mixture is heated to a temperature of 0oAnd mmol). The reaction mixture is heated to a temperature of 0oC and stirred at this temperature for 1 h Obtained brightly coloured solution is cooled again to -78oC and treated dropwise with a solution at a temperature of 25oC for 3 h, then quenched by addition of water (5 ml). THF is removed in vacuo, the residue is divided between ethyl ether (200 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated. Flash chromatography on a column of silica gel (5% ethyl acetate/hexane) to give 4.1 g of the product (E, Z mixture) as a viscous oil.

1H NMR (300 MHz, CDCl3): 0.86-0.92(m, 3H); 1.40-1.21(m, 15 NM); 3.06-3.28(m, 2H); 3.91-4.01(m, 2H); 5.00(Shir. s, 2H); 5.29-5.56(m, 1H); 6.10-6.19(m, 1H); 6.89-6.97(m, 2H); 7.08-7.12(m, 1H); 7.15-7.19(m, 2H); 7.22-7.29(m, 4H).

Stage D. 2,6-Aminobutiramida-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(prop-1-enyl)pyridine

Receive from the intermediate obtained in stage C according to the method of example 160, step D.

1H NMR (300 MHz, CDCl3): 1.21-1.60(m, 15 NM); 1.90-1.95(m, 1H); 3.18-3.53(m, 2H); 4.26-4.58(m, 2H); 4.87-4.94(m, 1H); 5.06(d, J=12.3 Hz, 1H); 5.27-5.57(m, 1H); 5.95-6.05(m, 1H); 7.00-7.06(m, 5H); 7.22-7.37(m, 4H).

Stage E. 2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-propylpyridine

The intermediate compound obtained in stage D is converted into the target compound by the method of example 164, stages a-C. the Diastereomers separated radial tape chromatography using a gradient of element 100% hexane to 5% ethyl acetate/hexane.<, H); 1.96-2.06(m, 1H); 2.15-2.25(m, 1H); 3.15(Sept, J=6.60 Hz, 1H); 3.56(Sept, J=6.60 Hz, 1H); 4.70(Shir. s, 1H); 4.81-4.87(m, 1H); 6.90-6.97(m, 3H); 7.19-7.26(m, 1H). The Belarusian library Association-MS: calculated for (C22H31NO2) 341, found 342 (M+1).

The diastereoisomer 1 (D1) can be separated into the individual enantiomers as follows. System Waters Prep LC 2000 HPLC equipped with a column for chiral GHUR (BRB-9466AD; 6h50 cm ID). System balance mobile phase consisting of 25% hexane and 75% of the mixture (15% THF in heptane) at a flow rate of 150 ml/min Sample dissolved in mobile phase (10 mg/ml) and inject 5 ml aliquots with a 35-minute intervals. The outgoing flow control at 280 nm. The peaks were not clearly defined and thus leveled. Mixed fractions are then evaporated and re-injected. Collected enantiomers independently analyzed on an analytical column (BRB-9705A) at 1.5 ml/min with a mobile phase of 1% (1% acetic acid in ethanol) and 99% hexane. Lower Rtenantiomer on the preparative column was the top Rtthe enantiomer on the analytical column with Rt=8.80 min; 98.8% of ei. Top Rtenantiomer on the preparative column was lower Rtthe enantiomer on the analytical column with Rt=3.71 min; 81% of ei.

The Diastereoisomer 2 (D2).1the EPT, J=6.60 Hz, 1H); 4.56-4.63(DQC, J= 3.0, 6.0 Hz, 1H); 5.66(Shir. s, 1H); 6.88-6.99(m, 3H); 7.25-7.28(m, 1H). The Belarusian library Association-MS: calculated for (C22H31NO2) 341, found 342 (M+1).

EXAMPLE 166

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-2-hydroxy)phenyl] -5-pentylpyridine

Stage A. 2-Benzyloxy-4-ferramentas

To a solution containing 2-bromo-5-terfenol (50 g, 0.26 mol) in 500 ml of acetone, add potassium carbonate (54.2 g, 0.39 mmol) and benzylbromide (34.3 ml, 0.288 mol). The reaction mixture is heated under reflux in an argon atmosphere for 2 h and then cooled to 25oC. the Acetone is removed under reduced pressure and the residue is placed in ether (400 ml). The organic layer was washed with water (5100 ml) and saline solution (1100 ml) and then dried (magnesium sulfate). The solution is then concentrated under reduced pressure and subjected to flash chromatography using hexane as eluent. Thus obtained 2-benzyloxy-4-torbenson in the form of a white solid.

1H NMR (300 MHz, CDCI3): 5.14(s, 2H); 6.57-6.63(m, 1H); 6.69(DD, J= 2.7, 10.2 Hz, 1H); 7.32-7.52(m, 6N).

Stage C. 2-Benzyloxy-4-forbindelse

To a suspension of magnesium (9.52 g, 0.39 mol) in THF (25 ml) in a 1-liter round bottom flask equipped with a condenser, add what Hladilnika. To this heated under reflux the mixture add a solution of the intermediate obtained in stage A (109 g) with such speed that supports the boiling reaction mixture. After complete addition the reaction is allowed to proceed until the mixture is cooled to a temperature of 25oC, and then heated under reflux for 1 h, the Reaction mixture is cooled to 25oWith and portions add DMF (48 ml). The reaction mixture is cooled to 25oC and then filtered through a layer of celite. THF is removed under reduced pressure, the residue is dissolved in ethyl acetate (500 ml) and washed successively with water (100 ml), 10% Hcl (100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml). The organic layer is dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue is purified flash chromatography (10% ethyl acetate/hexane) to obtain 77.3 g of 2-benzyloxy-4-forventelige.

1H NMR (300 MHz, Dl3): 5.16(s, 2H); 6.70-6.76(m, 2H); 7.34-7.44(m, 5H); 7.87-7.92(m, 1H); 10.43 (s, 1H). The Belarusian library Association-MS: calculated for (C14H11O2F) 230, found 231 (M+1).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyl] -5-(Penta-1-enyl)pyridine

Get NMR (300 MHz, CDCl3): 0.73(t, J=7.4 Hz, 3H); 1.09-1.36(m, 14N); 1.63-1.73(m, 2H); 1.89(q, J=6.9 Hz, 1H); 3.25(septet, 3=6.6 Hz, 1H); 3.46(d septet, J=2.7, 6.6 Hz, 1H); 4.29-4.42(m, 2H); 4.89-5.06(m, 2H); 5.24-5.47(m, 1H); 5.95-6.00(m, 1H); 6.70-6.79(m, 3H); 7.00-7.07(m, 5H). The Belarusian library Association-MS: calculated for (C30H36NO2F) 461, found 462.

Stage D. 2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-2-hydroxy)phenyl] -5-pentylpyridine

The target connection receive in the form of a racemate of the intermediate compound obtained in stage C according to the methods of example 161.

1H NMR (300 MHz, CDCl3): 0.78(t, J=6.6 Hz, 3H); 1.09-1.35(m, N); 1.65(t, J= 5.0 Hz, 1H); 2.13-2.23(m, 1H); 2.28-2.38(m, 1H); 3.24(septet, J= 6.6 Hz, 1H); 3.39(septet, J= 6.6 Hz, 1H); 4.29(DD=11.1, 5.0 Hz, 1H); 4.52(DD, J= 11.1, 5.1 Hz, 1H); 5.45(SHS, 1H); 6.71-6.78(m, 2H); 6.95-7.00(m, 1H). The Belarusian library Association-MS: calculated for (C23H32NO2F) 373, found 374 (M+1). Rf=0.15(20% ether/hexane). So pl. 152oC.

EXAMPLE 167

< / BR>
2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-[(4-fluoro-2-hydroxy)phenyl] -5-pentylpyridine

The target connection receive in the form of two partial diastereomers of 2,6-aminobutiramida-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyl] -5-(Penta-1-enyl)pyridine (example 166, step C) according to the method of example 164, stages a-C. the Diastereomers separated radial tape chromatography using a gradient e); 1.10-1.42(m, N); 1.64(d, J= 3.6 Hz, 1H); 2.03-2.13(m, 1H); 2.21-2.31(m, 1H); 3.15-3.26(Sept, 1H); 3.54-3.65(Sept, 1H); 4.89-4.98(m, 1H); 4.99(SHS, 1H); 6.69-6.75(m, 2H), 6.94-6.99 (, J= 2.7, 6.5, 6.5 Hz, 1H). The Belarusian library Association-MS: calculated for (C24H34NO2F) 387 found 388 (M+1). Rf=0.41(40% ether/hexane). So pl. 124-126oC.

The diastereoisomer 1 (D1) can be separated into the individual enantiomers as follows. System Waters Prep LC 2000 HPLC equipped with a column for chiral GHUR (BRB-9668A; 6 x 50 cm ID). System balance mobile phase consisting of 2% (1% acetic acid, 99% ethanol) and 98% hexane at a flow rate of 175 ml/min Sample dissolved in mobile phase (50 mg/ml) and inject 5 ml aliquots at 30 minute intervals. The outgoing flow control at 280 nm and two fractions (corresponding to the two enantiomers) are collected by 13-18 min (100% of ei) and 18.5-27 min (>99% of ei), respectively.

The Diastereoisomer 2 (D2).1H NMR (300 MHz, CDCl3): 0.78(t, J=6.5 Hz, 3H); 1.06-1.40(m, N); 1.75(d, J= 3.6 Hz, 1H), 2.06-2.16(m, 1H); 2.26-2.37(m, 1H); 3.21(Sept, J=6.6 Hz, 1H); 3.74(Sept, J=6.6 Hz, 1H); 4.59-4.67(m, 1H); 4.83(Shir. C. 1H); 6.68-6.75(m, 2H); 6.86-6.91(, J=3.0, 6.6, 6.6. Hz, 1H). The Belarusian library Association-MS: calculated for (C24H34NO2F) 387 found 388 (M+1). Rf=0.24(40% ether/hexane). So pl. 157-159oC.

EXAMPLE 168

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-methoxy is 5.

1H NMR (300 MHz, CDCl3): 0.76 and 0.81(t, J=7.2 Hz, 3H); 1.12-1.39(m, 14N); 1.60-1.80(SHS. 1H); 1.86-1.97(m, 2H); 3.33-3.50(m, 2H); 3.85(s, 3H); 4.43(m, 2H); 5.27-5.48(m, 1H); 5.93-6.05(m, 1H); 6.92(d, J=8.4 Hz, 2H); 7.07(d, J= 8.4 Hz, 2H). The Belarusian library Association-MS: calculated for (C24H33NO2) 367, found 368 (M+1).

EXAMPLE 169

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-methoxyphenyl)-5-pentylpyridine

The target compound obtained as white solid from 2,6-aminobutiramida-3-hydroxymethyl-4-(4-methoxyphenyl)-5-(Penta-1-enyl)pyridine (example 168) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.80(t, J=6.6 Hz, 3H); 1.08-1.19(m, 4H); 1.24-1.38(m, 15 NM); 2.27-2.33(m, 2H); 3.24(Sept, J=6.6 Hz, 1H); 3.42(Sept, J= 6.6 Hz, 1H); 3.87(s, 3H); 4.35(d, J=5.7 Hz, 2H); 6.97(d, J=8.7 Hz, 2H); 7.11(d, J= 8.7 Hz, 2H). The Belarusian library Association-MS: calculated for (C24H35NO2) 369, found 370 (M+1). So pl. 47-49oC.

EXAMPLE 170

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-methoxyphenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from 3-methoxybenzaldehyde by the method of example 125.

1H NMR (300 MHz, CDCl3): 0.78(t, J=7.5 Hz, 3H); 1.17-1.41(m, 14N); 1.65(C. 1H); 1.97(8, J=14.0, 7.2, 1.5 Hz, 2H); 3.39-3.55(m, 2H); 3.81 (s, 3H); 4.45(s, 2H); 5.35-5.50(m, 1H); 6.01-6.09(m, 1H); 6.73-6.77(m, 2H); 6.89(, J= 8.1, 2.1, 0.9 Hz, 1H); 7.30(t, J=8.0 Hz, 1H). The Belarusian library Association-MS: calculated for (C24H33NO2) Phenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(3-methoxyphenyl)-5-(Penta-1-enyl)pyridine (example 170) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.79(t, J=6.6 Hz, 3H); 1.09-1.33(m, 7H); 1.30(d, J= 6.6 Hz, 6N); 1.33(d, J=6.6 Hz, 6N); 2.25-2.31(m, 2H); 3.23(Sept, J= 6.6 Hz, 1H); 3.42(Sept, J= 6.6 Hz, 1H); 3.82(s, 3H); 4.35(d, J=6.0 Hz, 2H); 6.73(DD, J=2.4, 1.5 Hz, 1H); 6.76(dt, J=7.5, 1.4 Hz); 6.93(, J=8.4, 3.6, 1.2 Hz, 1H); 7.34(d, J=8.1 Hz, 1H). The Belarusian library Association-MS: calculated for (C24H35NO2) 369, found 370 (M+1). So pl. 65-66oC.

EXAMPLE 172

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-methoxyphenyl)-5-(Penta-1-enyl)pyridine

The target compound is obtained from 2-methoxybenzaldehyde by the method of example 125.

1H NMR (300 MHz, CDCl3): 0.82 and 0.72(t, J=7 Hz, 3H); 1.05-1.47(m, 15 NM); 1.80-2.00(m, 1H); 2.06(SHS, 1H); 3.21-3.60(m, 2H); 3.75 and 3.76(s, 3H); 4.27(d, J= 11.4 Hz, 1H); 4.43(d, J=11.4 Hz, 1H); 5.25-5.44(m, 1H); 6.01-6.07(m, 1H); 6.93-7.03(m, 3H); 7.29-7.37(m, 1H).

EXAMPLE 173

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(2-methoxyphenyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(2-methoxyphenyl)-5-(Penta-1-enyl)pyridine (example 172) according to the method of example 126.

1H NMR (300 MHz, CDCl3): 0.77(t, J=6.6 Hz, 3H); 1.06-1.11 (m, 4H); 1.22-1.38(m, 14N); 1.87(DD, J=9.3, 3.3 Hz, 1H); 2.14-2.40(m, 2H); 3.25(septet, J=6.6 Hz, 1H); >/BR>< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-methylthio)phenyl] -5-(Penta-1-enyl)pyridine

The target compound obtained as a thick colorless oil from 4-(methylthio)benzaldehyde according to the procedure of example 125.

1H NMR (300 MHz, CDCl3): 0.66, and 0.72(t, J=7.5 Hz, 3H); 1.05-1.32(m, 14N); 1.51-1.70(SHS. 1H); 1.80-1.89(m, 2H); 2.43(s, 3H); 3.12-3.41(m, 2H); 4.32(MS, 2H); 5.17-5.40(m, 1H); 5.85-5.97(m, 1H); 6.99(d, J=8.1 Hz); 7.18(d, J=8.1 Hz, 2H).

EXAMPLE 175

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl] -5-(Penta-1-enyl)pyridine

2,6-Aminobutiramida-3-hydroxymethyl-4-[4-(methylthio)phenyl] -5-(Penta-1-enyl)pyridine (100 mg, 0.261 mmol) (example 174) dissolved in methylene chloride (1.5 ml) and stirred at a temperature of 0oC in argon atmosphere. To this mixture is added a solution containing 3-chloroperoxybenzoic acid (mjpbk) (85%, 53 mg, 0.261 mmol) in methylene chloride (1 ml). The mixture is stirred for 1.5 hours at a temperature of 0oC and quenched by adding saturated aqueous solution of NaHSO3(3 ml). The reaction mixture is then diluted by addition of water (5 ml) and then extracted with methylene chloride (310 ml). The combined organic layers washed successively with saturated aqueous sodium bicarbonate solution (10 ml) and brine (10 ml), dried (sodium sulfate) and the compound (52 mg, 50%) as a white solid, so pl. 133-135oC.

1H NMR (300 MHz, CDCl3): 0.77, and 0.69(t, J=7.5 Hz, 3H), 1.08-1.36(m, 14N); 1.70-1.92(m, 3H); 2.75 and 2.76(s, 3H); 3.19-3.51(m, 2H); 4.32-4.40(m, 2H); 5.20-5.45(m, 1H); 5.93-6.00(m, 1H); 7.31-7.38(m, 2H); 7.59-7.70(m, 2H). Anal. Rasch. for C24H33NO2S: 71.86; N, 8.29; N, 3.39; S 7.73 found: 72.14; H 8.32 3.51 N; S 8.02.

EXAMPLE 176

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[4-(methylsulphonyl)phenyl] -5-(Penta-1-enyl)pyridine

2,6-Aminobutiramida-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl] -5-(Penta-1-enyl)pyridine (100 mg, 0.261 mmol) (example 175) is dissolved in methylene chloride (1.5 ml) and stirred at a temperature of 0oC in argon atmosphere. To this mixture is added a solution containing 3-chloroperoxybenzoic acid (m-HPBC) (85%, 53 mg, 0.261 mmol) in methylene chloride (1 ml). The mixture is stirred for 1.5 hours at a temperature of 0oC and quenched by adding saturated aqueous solution of NaHSO3(3 ml). The reaction mixture is then diluted by addition of water (5 ml) and then extracted with methylene chloride (310 ml). The combined organic layers washed successively with saturated aqueous sodium bicarbonate solution (10 ml) and brine (10 ml), dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue is 3
): 0.69 and 0.79(t, J=7.2 Hz, 3H); 1.08-1.37 (m, 14N); 1.45 (t, J= 4.2 Hz, 1H); 1.86-1.93 (m, 2H); 3.10 and 3.11 (s, 3H); 3.25-3.50 (m, 2H); 4.34-4.36(m, 2H); 5.20-5.50 (m, 1H); 5.93-6.00(m, 1H); 7.41(d, J=8.4 Hz, 2H); 7.96(d, J=8.4 Hz, 2H). Anal. Rasch. for C24H33NO3S: 69.28; N, 7.91; N, 3.18; S 7.50 found: 69.36; H 8.00 N 3.37; S 7.71.

EXAMPLE 177

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-3-hydroxymethyl)phenyl] -5-pentylpyridine

Stage A. 2,6-Aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl] -4-(4-forfinal)-5-pentylpyridine

To a solution of 2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine (3.14 g, 8.78 mmol) (example 1, step H) in methylene chloride (45 ml) was added imidazole (0.9 g, 13.17 mmol, 1.5 EQ.) and tert-butyl-dimethylsilane (2.0 g, 13.17 mmol, 1.5 EQ.). Immediately begins to form a white precipitate. The mixture is stirred for 14 hours at a temperature of 25oC and then diluted with methylene chloride (100 ml) and washed sequentially with 10% hydrochloric acid (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml). The organic layer is concentrated under reduced pressure and the resulting residue is recrystallized from methanol to obtain the product (3.27 g, 79%) as a white crystalline solid.

1H NMR (300 MHz, Dl29H46NOFSi: 73.83; N, 9.83; N 2.97 found: 73.82; H 9.95 N 2.86.

Stage C. 2,6-Aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-hydroxymethyl)phenyl]-5-pentylpyridine

To a solution of intermediate compound obtained in stage A (5.4 g, 11.4 mmol) in THF (80 ml) add second-utility (1.3 M, 26.4 ml, 3 EQ. ) at a temperature of -78oC in argon atmosphere. The yellow solution is stirred for 1 h at a temperature of -78oC and quenched by addition of water (50 ml). The mixture is heated to 25oWith and extracted with ethyl acetate (350 ml) and the organic layer washed with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated under reduced pressure to get crude intermediate compound (6.41 g).

This intermediate compound (3.2 g) was dissolved in THF and stirred at a temperature of 0oWith the addition thereto of socialogical (LAS) (1M in THF, 25.7 ml, 25.7 mmol). The resulting mixture is stirred at a temperature of 0oC for 1.5 h and quenched with successive addition of water (1 ml), 1 N. aqueous sodium hydroxide solution (1 ml) and water (3 ml). The resulting mixture was filtered and the precipitate washed with ether (100 ml). The combined organic layer is washed with the hydrated residue is subjected to flash chromatography using a 10% mixture of ether/hexane as eluent. Thus obtained 1.1 g of the product.

1H NMR (300 MHz, CDCl3): -0.09(C, 6N); 0.83(s, N); 1.07-1.20(m, 4H); 1.29-1.33(m, 17H); 1.96-2.02(m, 1H); 2.22-2.31(m, 2H); 3.23(Sept, J=6.6 Hz, 1H); 3.36(Sept, J= 6.6 Hz, 1H); 4.22-4.32(m, 2H); 4.70-4.90(m, 2H); 7.09-7.12(m, 2H); 7.23-7.28(m, 1H).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-3-hydroxymethyl)phenyl]-5-pentylpyridine

To a solution of the intermediate from step B (123 mg, 0.245 mmol) in THF (3 ml) add tetrabutylammonium (1M in THF, 0.7 ml, 0.7 mmol) at a temperature of 25oC in argon atmosphere. The mixture is stirred for 14 hours at a temperature of 25oC and then diluted with water (5 ml) and extracted with methylene chloride (35 ml). The combined organic layer was washed with brine (5 ml), dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue is purified flash chromatography using 40% mixture of ethyl acetate/hexane as eluent. Thereby obtaining the target compound (79 mg, 83%) as a colourless oil.

1H NMR (300 MHz, CDCl3): 0.78(t, J=6.6 Hz, 3H); 1.10-1.17 (m, 4H); 1.24-1.35 (m, 14N); 2.10-2.40 (m, 2H); 2.73 (SHS, 1H); 3.22(Sept, J=6.6 Hz, 1H); 3.34 (Sept, J=6.6 Hz, 1H); 3.85 (SHS, 1H); 4.06(d, J=11.4 Hz, 1H); 4.35 (d, J= 11.4 Hz, 1H); 4.48 (d, J=14.1 Hz, 1H); 4.73(d, J= 14.1 Hz, 1H); 7.00-7.06(m, 2H); 7.25 (d, J=7.2 Hz, 1H).

NOTE is A. 2,6-Aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl] -4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine

To a solution of 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-hydroxymethyl)phenyl]-5-pentylpyridine (example 177, step A) (1.09 g, 2.18 mmol) in methylene chloride (100 ml) is added a mixture of PQQ (0.94 g, 4.35 mmol, 2 EQ.) and celite (0.94 g). The resulting mixture was stirred for 2 h at a temperature of 25oC and then filtered through a layer of silica gel. The layer of silica gel is washed with a 10% mixture of ethyl acetate/hexane (200 ml) and the combined organic layers concentrated to obtain the crude product (0.78 g) as a white prapinabracni solid.

Stage C. 2,6-Aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-methoxycarbonyl)phenyl]-5-pentylpyridine

To a solution of intermediate compound obtained in stage A (82 mg, 0.164 mmol), in methanol (3 ml) is added potassium cyanide (53 mg, 0.82 mmol) and activated manganese dioxide (71 mg, 5 EQ.). The mixture is stirred at a temperature of 25oC for 14 h and then filtered through a layer of celite. Layer celite washed with ethyl acetate (25 ml) and the combined organic layer was washed with brine (5 ml), dried (sodium sulfate) and concentrated under reduced SUP>1
H NMR (300 MHz, CDCl3): -0.13(C, 6N); 0.75(t, J=6.6 Hz, 3H); 1.06-1.40(m, N); 2.20-2.35(m, 2H); 3.20(Sept, J=6.6 Hz, 1H); 3.32(Sept, J=6.6 Hz, 1H); 4.15(d, J=10.8 Hz, 1H); 4.25(d, J=10.8 Hz, 1H); 7.15-7.25(m, 1H); 7.40-7.50(m, 1H); 7.69(DD, J= 6.6, 2.4 Hz, 1H); 10.41 (C. 1H). The Belarusian library Association-MS: calculated for (C30H46NO2FSi) 499, found 500 (M+1).

Stage C. 2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-3-methoxycarbonyl)phenyl]-5-pentylpyridine

The target compound is obtained from the intermediate obtained in stage B, by the method of example 177, step C.

1H NMR (300 MHz, CDCl3): 0.78(t, J=6.6 Hz, 3H); 1.08-1.16(m, 4H); 1.23-1.34(m, 15 NM); 2.20-2.30(m, 2H); 3.22(Sept, J=6.6 Hz, 1H); 3.40(Sept, J= 6.6 Hz, 1H); 3.93(s, 3H); 4.25-4.39(m, 2H); 7.12(DD, J=10.3, 8.5 Hz, 1H); 7.28(, J=8.5,4.8, 2.2 Hz, 1H); 7.69(DD, J=6.6, 2.2 Hz, 1H).

EXAMPLE 179

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-3-pentyl)phenyl] -5-pentylpyridine

Stage A. 2,6-Aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-(Penta-1-enyl))phenyl]-5-pentylpyridine

To a solution of 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl] -5-pentylpyridine (example 178, step A) (200 mg, 0.40 mmol) in THF (10 ml) is added a mixture of butyldiphenylchlorosilane/sodium amide (Fluka, 0.55 g, 3 EQ.) in an argon atmosphere. The reaction mixture is stirred at a temperature of 25o

1H NMR (300 MHz, CDCl3): -0.13(C, 6N); 0.75-1.47(m, N); 2.13-2.33(m, 4H); 3.21 (Sept, J= 6.6 Hz, 1H); 3.34(Sept, J=6.6 Hz, 1H); 3.93(s, 3H); 2.7(d, J= 2.7 Hz, 2H); 5.75-6.31(m,1H); 6.41-6.59(m, 1H); 6.98-7.09(m, 3H). The Belarusian library Association-MS: calculated for (C34H54NOFSi) 539, 540 (M+1).

Stage C. 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-pentyl)phenyl]-5-pentylpyridine

The intermediate compound obtained in stage A (200 mg), dissolved in ethanol (10 ml) and the mixture is blown with argon. Then to the mixture is added 10% Pd-C (20 mg) and the mixture is rinsed with hydrogen and stirred under hydrogen atmosphere at a temperature of 25oC for 16 h the Mixture was then filtered through a layer of silicon dioxide and a layer of silicon dioxide is washed with ethanol (25 ml). The organic layer is concentrated under reduced pressure and the resulting residue purified flash chromatography using hexane as eluent to obtain the intermediate (150 mg, 75%).

1H NMR (300 MHz, D13): -0.11(C, 6N); 0.76-1.65(m, N); 2.17-2.33(m, 2H); 2.51-2.78(m, 2H); 3.21(septet, J=6.6 Hz, 1H); 3.35(septet, J=6.6 Hz, 1H); 4.42(DD, J=10.2, 16.2 Hz, 2H); 6.92-7.05(m, 3H). The Belarusian library Association-MS: calculated for (C34H56NFSi) 541, nilavae compound obtained as a colorless oil from the intermediate connection retrieved on stage, according to the method of example 177, step C.

1H NMR (300 MHz, CDCl3): 0.77(t, J=6.9 Hz, 3H); 0.88(t, J=6.9 Hz, 3H); 1.08-1.34(m, 24N); 1.57-1.65(m, 1H); 2.22-2.29(m, 2H); 2.57-2.75(m, 2H); 3.21(Sept, J=6.6 Hz, 1H); 3.40(Sept, J=6.6 Hz, 1H); 4.33(DD, J=5.6, 1.4 Hz, 2H); 6.93-7.09(m, 3H). The Belarusian library Association-MS: calculated for (C28H42NOF) 427 found 428 (M+1). Rf=0.42(20% ether/hexane).

EXAMPLE 180

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[(4-fluoro-3-ethyl)phenyl]-5-pentylpyridine

The target compound obtained as a white wax 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (example 178, step A) (200 mg, 0.40 mmol) and ethyltriphenylphosphonium/sodium amide (Fluka) according to the method of example 179, stage I-n -

1H NMR (300 MHz, CDCl3): 0.77(t, J=6.9 Hz, 3H); 1.10-1.33(m, 22N); 2.17-2.33(m, 2H); 2.60-2.80(m, 2H); 3.21(Sept, J=6.6 Hz, 1H); 3.40(Sept, J= 6.6 Hz, 1H); 4.34(DD, J=5.7, 1.8 Hz, 2H); 6.94-7.09(m, 3H). The Belarusian library Association-MS: calculated for (C25H36NOF) 385, found 386 (M+1). Rf=0.38 (20% ether/hexane).

EXAMPLE 181

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[4-fluoro-3-(-hydroxy-4-terbisil)] -5-pentylpyridine

Stage A. 2,6-aminobutiramida-3-(tert-butyldimethylsiloxy)-4-[4-fluoro-3-(-hydroxy-4-terbisil)phenyl]-5-pentylpyridine

To a solution of 2,6-diisopropyl is A) in THF (10 ml) is added 4-performancebased (1.0 M in THF, 0.4 ml, 2.5 EQ. in an argon atmosphere at a temperature of 25oC. the Reaction mixture was stirred for 30 min and then quenched by adding dropwise water (5 ml). The mixture is extracted with ether (210 ml) and the combined organic layer was washed with brine, dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue is purified flash chromatography using a 10% mixture of ether/hexane as eluent to obtain 150 mg of the intermediate.

1H NMR (300 MHz, CDCl3): -0.19(d, 6.3 Hz, 3H); -0.10(d, J=7.2 Hz, 3H); 0.71-1.30(m, N); 2.17-2.28(m, 3H); 3.18(Sept, J=6.6 Hz, 1H); 3.25-3.40(m, 1H); 4.04-4.38(m, 2H); 6.14(DD, J= 4.4, 17.9 Hz, 1H); 6.97-7.38(m, 7H). The Belarusian library Association-MS: calculated for (C36H51NOF2Si) 595 found 596 (M+1).

Stage C. 2,6-aminobutiramida-3-hydroxymethyl-4-[4-fluoro-3-(-hydroxy-4-terbisil)phenyl]-5-pentylpyridine

The target compound is obtained from the intermediate obtained in stage a by the procedure of example 177, step C.

1H NMR (300 MHz, CDCl3): 0.72-1.45(m, 22N); 2.13-2.36(m, 2H); 2.65(d, J= 4.2 Hz, 1H); 3.21(Sept, J=6.6 Hz, 1H); 3.39(Sept, J=6.6 Hz, 1H); 4.21-4.39(m, 2H); 6.14-6.17(m, 1H); 6.98-7.12(m, 4H); 7.35-7.42(m, 3H). The Belarusian library Association-MS: calculated for (C30H37NO2F2) 481, found 482(M+1).Rf=0.21, 0.51(20%ether/hexane).T. sq. 118-120o
The target compound obtained as oil from 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl] -4-[(4-fluoro-3-formyl)phenyl] -5-pentylpyridine (example 178, step A) and methylacrylamide by the method of example 181, stages a-C.

1H NMR (300 MHz, CDCl3): 0.76(t, J=6.0 Hz, 3H); 1.09-1.53(m, N); 1.84(SHS, 1H); 2.18-2.27(m, 2H); 2.87(SHS. 1H); 3.20(Sept, J=6.6 Hz, 1H); 3.37(Sept, J= 6.6 Hz, 1H); 4.16(d, J=11.4 Hz, 1H); 4.28-4.35(m, 1H); 5.16-5.19(m, 1H), 7.01-7.07(m, 2H); 7.25-7.34(m, 1H). The Belarusian library Association-MS: calculated for (C25H36NO2F) 401, found 402 (M+1). Rf=0.32 and 0.20 (50% ether/hexane).

EXAMPLE 183

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-[4-fluoro-3-((N-((pyridin-2-yl)methyl)amino)methyl)]phenyl-5-pentylpyridine

Stage A. 2,6-Aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[4-fluoro-3-((N-((pyridin-2-yl)methyl)amino)methyl]phenyl-5-pentylpyridine

To a solution of 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl] -5-pentylpyridine (500 mg, 1 mmol) (example 178, step A) in methanol (10 ml) and ether (2 ml) is added 2-methylaminopropane (0.42 ml, 4 mmol, 4 EQ.) in an argon atmosphere at a temperature of 25oC. To this solution add ZnCl2(68.1 mg, 0.5 EQ.) and Lamborghini sodium (68.2 mg, 1 EQ.) in methanol (6 ml). The reaction mixture is stirred for 20 h and then quenched Appendix the comfort with ethyl acetate (330 ml). The organic layer was washed with water (10 ml) and brine (10 ml), dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue is purified flash chromatography using 60% of a mixture of ether/hexane as eluent to obtain the intermediate compound (260 mg, 44%).

1H NMR (300 MHz, CDCl3): -0.12(C, 6N); 0.72-0.81(m, N); 1.80(SHS, 1H); 1.07-1.15(m, 4H); 1.27-1.31(m, 14N); 2.23-2.29(m, 2H); 3.20(Sept, J=6.6 Hz, 1H); 3.34(Sept, J=6.6 Hz, 1H); 3.83-4.03(m, 4H); 4.25(DD, J=10.5, 27.6 Hz, 2H); 7.06-7.33(m, 5H); 7.64(, J=1.8, 7.5, 7.5 Hz, 1H); 8.54-8.56(m, 1H). The Belarusian library Association-MS: calculated for (C36H54N3OFSi) 591 found 592 (M+1).

Stage C. 2,6-aminobutiramida-3-hydroxymethyl-4-[4-fluoro-3-((N-((pyridin-2-yl)methyl)amino)methyl)]phenyl-5-pentylpyridine

The target compound obtained as a colorless oil from the intermediate obtained in stage A, by the method of example 177, step C.

1H NMR (300 MHz, CDCl3): 0.75(t, J=6.9 Hz, 3H); 1.07-1.36(m, N); 1.75(MS, 2H); 2.19-2.36(m, 2H); 3.20(Sept, J=6.6 Hz, 1H); 3.47(Sept, J=6.6 Hz, 1H); 3.74(d, J=14.1 Hz, 1H); 3.79(d, J=13.5 Hz, 1H); 3.89(d, J=13.5 Hz, 1H); 4.07(d, J= 14.1 Hz, 1H); 4.20(d, J=11.4 Hz, 1H); 4.41 (d, J=11.4 Hz. 1H); 7.02-7.25(m, 4H); 7.38(d, J=7.8 Hz, 1H); 7.66(, J=1.8, 7.5, 7.5 Hz, 1H); 8.47(m, 1H). The Belarusian library Association-MS: calculated for (C30H40N3OF) 477, found 478 (M+1). Rf=0.4(ethyl acetate).

R> The target compound is obtained from 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl] -4-[(4-fluoro-3-formyl)phenyl] -5-pentylpyridine (example 178, step A) according to the method of example 183, stages a-C.

1H NMR (300 MHz, CDCl3): 0.77(t, J=6.6 Hz, 3H); 1.05-1.31(m, N); 1-75-1.85(m, 5H); 2.23-2.29(m, 2H); 2.50-3.50(m, 4H); 3.20(Sept, J=6.6 Hz, 1H); 3.41(Sept, J= 6.6 Hz, 1H); 3.71(d, J=12.9 Hz, 1H); 3.82(d, J=12.9 Hz, 1H); 4.29(DD, J= 11.7,20.4 Hz, 2H); 7.03-7.13(m, 2H); 7.26-7.30(m, 1H). The Belarusian library Association-MS: calculated for (C28H41N2OF) 440, found 441 (M+1). Rf= 0.2(ethyl acetate).

EXAMPLE 185

< / BR>
2,6-aminobutiramida-3-hydroxymethyl-4-[4-fluoro-3-butylamino)methyl] phenyl-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-[(tert-butyldimethylsiloxy)methyl] -4-[(4-fluoro-3-formyl)phenyl] -5-pentylpyridine (example 178, step A) according to the method of example 183, stages a-C.

1H NMR (300 MHz, CDCl3): 0.79(t, J=6.8 Hz, 3H); 0.91(t, J=7.4 Hz, 3H); 1.10-1.61(m, 24N); 2.25-2.31(m, 2H); 2.62(t, J=7.2 Hz, 2H); 3.23(Sept, J=6.6 Hz, 1H); 3.42(Sept, J= 6.6 Hz, 1H); 3.89(c, 2H); 4.32(DD, J=11.7 Hz, 2H); 7.04-7.20(m, 3H). The Belarusian library Association-MS: calculated for (C28H43N2OF) 442, found 443 (M+1). Rf=0.33(ethyl acetate).

EXAMPLE 186

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(pyridin-3-yl)-5-pentylpyridine

The target compound obtained as oil from utilizou the A-MS: calculated for (C22H32N2O) 340, found 341 (M+1).1H NMR (300 MHz, CD3OD): 0.77(t, J=6.5 Hz, 3H); 1.08-1.32(m, N); 2.27-2.33(m, 2H); 3.28(Sept, J= 6.6 Hz, 1H); 3.48(septet. J=6.6 Hz, 1H); 4.25(s, 2H); 7.52-7.57(m, 1H); 7.73-7.76(m, 1H); 8.42-8.43(m, 2H); 8.59(DD, J=5.1, 1.5 Hz, 1H). Anal. Rasch. for C22H32N2O: 77.60; N, 9.47 N 8,23 found: 75.96; H 9.32 N 7.88.f=0.40 (diethyl ether).

EXAMPLE 187

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-furyl)-5-(Penta-1-enyl)pyridine

Substituting 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (DDH) cerium ammonium nitrate (CNA) by the oxidation of intermediate compounds of dihydropyridines to phenylpyridine obtain the target compound in the form of a mixture of E and Z isomers (4.5: 1, E:Z) from ethylisopropylamine, ammonium acetate and furan-3-carboxaldehyde with 10% yield by the procedure of example 125.

The Belarusian library Association-MS: calculated for (C21H29NO2) 327, found 328 (M+1). 1H NMR (300 MHz, CD3OD): 0.84(t, J=7.4 Hz, 3H); 1.17-1.38(m, 14N); 2.01-2.04(m, 2H); 3.39(Sept, J= 6.6 Hz, 1H); 3.47(Sept, J=6.6 Hz, 1H); 4.44(s, 2H); 5.40-5.58(m, 2H); 6.11-6.25(m, 1H); 6.38-6.40(m, 1H); 7.41-7.54(m, 2H).

EXAMPLE 188

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(3-furyl)-5-pentylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-(3-furyl)-5-(Penta-1-enyl)pyridine (example 187) with 6% yield by the method of example 1 OD): 0.83(t, J=6.8 Hz, 3H); 1.19-1.36(m, N); 2.42-2.48(m, 2H); 3.25(septet, J=6.6 Hz, 1H); 3.45(septet, J=6.6 Hz, 1H); 4.38(s, 2H); 6.42(m, 1H); 7.45-7.46(m, 1H); 7.61-7.62(t, J= 1.7 Hz, 1H). Anal. Rasch. for C21H31NO2: 76.55; H 9.48 N4,25, found: 76.41; N, 9.76 N 4.24. Rf=0.59 (20% tOA/hexane). So pl. 98-100oC.

EXAMPLE 189

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(thiophene-3-yl)-5-(Penta-1-enyl)pyridine

The target compound obtained as a mixture of E and Z isomers (5.5:1, E:Z) from ethylisopropylamine, ammonium acetate and thiophene-3-carboxaldehyde with 7% yield by the procedure of example 125.

The Belarusian library Association-MS: calculated for (C21H29NOS) 343, found 344 (M+1).1H NMR (300 MHz, CDCl3): 0.78-0.84(m, 3H); 1.22-1.37(m, 15 NM); 1.96-2.00(m, 2H); 3.37-3.50(m, 2H); 4.47(d, J=5.7 Hz, 2H); 5.32-5.43(m, 1H); 6.02-6.12(m, 1H); 6.95-6.97(m, 1H); 7.12-7.13(m, 1H), 7.35-7.38(m, 1H). Anal. Rasch. for C21H29NOS: 73.43; H 8.52 N4.08; S 9.32 found: 73.38; H 8.75 3.97 N; S 9.03. Rf=0.65 (20% tO AU/hexane). So pl. 85-87oC.

EXAMPLE 190

< / BR>
3,5-Aminobutiramida-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-bipheny

Stage A. 1-(2-Methoxyethoxy)methoxymethyl-2,4-aminobutiramida 5 - hydroxymethylbenzene.

A mixture of 1,5-bis-(hydroxymethyl)-2,4-diisopropylbenzene (0.947 g, 4.26 mol) (obtained by the method of Fey et al., U.S. patent 5138090), methoxyethoxymethyl (0.49 ml, 4.29 mmol) and deism) and extracted with dichloromethane (350 ml). Chromatography on a column of silica gel (67:33 hexane/ethyl acetate) to give colorless oil (0.679 g, 51%).

1H NMR (300 MHz, CDCl3): 7.31 (s, 1H); 7.29(s, 1H); 4.83(s, 2H); 4.72(s, 2H); 4.66(s, 2H); 3.76(m, 2H); 3.60(m, 2H); 3.43(s, 3H); 3.26(m, 2H); 1.27(d, 7.0 Hz, N). EA-MS: calculated for (C18H30O4) 310, found 292 (M-H2O, 24%), 221 (100%).

Stage C. 3-(2-Methoxyethoxy)methoxymethyl-4,6-diisopropylbenzamide

Receive from the intermediate obtained in stage A, by the method of example 1, step E.

1H NMR (300 MHz, CDCl3): 10.29(s, 1H); 7.80(s,1H); 7.39(s, 1H); 4.83(s, 2H); 4.70(s, 2H); 3.98(Sept, 6.8 Hz, 1H); 3.76(m, 2H); 3.59(m, 2H); 3.42(s, 3H); 3.26(Sept. 6.8 Hz, 1H); 1.30(d, 7.0 Hz, 6N); 1.28(d, 7.0 Hz, 6N). The Belarusian library Association-MS: calculated for (C18H28O4) 308, found 309 (M+H).

Stage C. N-Phenyl - 3-(2-methoxyethoxy)methoxymethyl-4,6-diisopropylbenzene

A mixture of the intermediate from step B (2.35 g, 7.62 mmol), aniline (700 ml, 7.68 mmol), p-toluenesulfonic acid (58.8 mg, 309 mmol) and molecular sieves (20.7 g) in toluene is heated under reflux during the night. The mixture is cooled to room temperature and filtered. The filtrate is diluted with ethyl acetate (65 ml) and washed with saturated aqueous Panso3(50 ml) and water (50 ml), dried (with whom without further purification.

1H NMR (300 MHz,6D6): 8.70(s, 1H); 8.48(s, 1H); 7.31(s, 1H); 7.17(m, 4H); 7.00(m, 1H); 4.61(s, 2H); 4.60(C. 2H); 3.56(m, 2H); 3.46(Sept, 6.8 Hz, 1H); 3.29(m, 2H); 3.20(Sept. 6.8 Hz, 1H); 3.07(s, 3H); 1.17(d, 7.0 Hz, 6N); 1.12(d, 7.0 Hz, 6N).

Stage D. Bis[(2-N-phenylethylamine)-3,5-aminobutiramida-6-(2 - methoxyethoxy)methoxymethyl]dipalladium

A mixture of intermediate stages (2.78 g, 7.27 mmol) and Pd(OAc)2(1.63 g, 7.26 mmol) in acetic acid (34 ml) is heated under reflux for 1 h the Mixture is cooled to room temperature, poured into water (135 ml) and filtered through fittowindow funnel with medium porosity. The filtrate lyophilizer. The residue is dissolved in ethyl acetate (100 ml) and washed with saturated aqueous NaHCO3(50 ml) and saturated aqueous NaCl (50 ml), dried (magnesium sulfate) and concentrate to obtain brown solid. The solid is mixed with a mixture of 50:50 petroleum ether/ethyl acetate (17 ml) and cooled in the refrigerator. The precipitate is collected and dried to obtain brown solid (0.951 g, 27%).

1H NMR (300 MHz,6D6): 7.70(s,1H); 7.65(s, 1H); 7.63(s, 1H); 7.11(s, 1H); 7.08(s, 1H); 6.99(m, 1H); 6.73(s, 1H); 5.33(s, 2H); 5.08(s, 2H); 4.19(m, 2H); 3.35(m, 2H); 3.04(s, 3H); 2.68(Sept, 6.8 Hz, 1H); 2.15(Sept, 6.8 Hz, 1H); 1.01(d, 7.0 Hz, 6N); 0.96(d, 7 the I E. 3,5-Aminobutiramida 2-formyl-6-(2-methoxyethoxy)methoxymethyl-4'-fluoro-1,1'-biphenyl

A mixture of 1,2-dibromethane (80 ml) and magnesium turnings (0.349 g, 14.4 mmol) in diethyl ether (1 ml) is heated under reflux for several minutes. The mixture is diluted with diethyl ether and a solution of 1-bromo-4-fervently (950 ml, 8.65 mmol) and after a few minutes add 1,2-dibromethane (160 ml) in diethyl ether (30 ml). The reflux continued for 1 h, then the mixture is cooled to room temperature. The cannula add pop-up fluid to a solution of the intermediate obtained in stage D (0.951 g, 973 mmol), and triphenylphosphine (2.02 g, 7.71 mmol) in benzene (19 ml) and the mixture is stirred over night. Add an aqueous solution of 6 N. model HC1 (6 ml) and the mixture is stirred for 2 hours the Mixture is filtered and the solid washed with di-ethyl ether (75 ml). The combined filtrates are washed with saturated aqueous sodium chloride (50 ml). Chromatography on a column of silica gel gives a colourless solid (0.413 g, 53%).

1H NMR (300 MHz, CDCl3): 9.70(s, 1H); 7.50(s,1H); 7.26(m, 2H); 7.11(m, 2H); 4.59(s, 2H); 4.30(s, 2H); 3.89(Sept, 6.8 Hz, 2H); 3.55(m, 2H); 3.44(m, 2H); 3.37(s, 3H); 1.33(d, 6.6 Hz, 6N); 0.96(d, 7.0 Hz, 6N). The Belarusian library Association-MS: calculated for (
Receive from the intermediate obtained in stage E, according to the method of example 1, step F. the Olefin is a mixture of CIS and TRANS isomers in a ratio of 9:91.

1H NMR (300 MHz, CDCl3): 7.32(s,1H); 7.12(m, 2H); 7.01(m, 2H); 5.95(d, 16.2 Hz, 1H); 5.23(dt, 16.2 Hz, 7.0 Hz, 1H); 4.57(s, 2H); 4.29(s, 2H); 3.53(m, 2H); 3.43(m, 2H); 3.37(s, 3H); 3.31(m, 2H); 1.89(m, 2H); 1.32(d, 6.6 Hz, 6N); 1.23(d, 7.0 Hz, 6N); 1.2(m, 2H); 0.74(t, 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C28H39FO3) 442, found 442 (M+).

Stage G. of 3,5-Aminobutiramida-2-(2-methoxyethoxy)ethoxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl

Receive from the intermediate obtained in stage F, according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.29(s,1H); 7.19(m, 2H); 7.07(m, 2H); 4.52(s, 2H); 4.21 (s, 2H); 3.51 (m, 2H); 3.41(m, 2H); 3.37(s, 3H); 3.27(Sept, 6.8 Hz, 1H); 3.16(Sept, 6.8 Hz, 1H); 2.27(m, 2H); 1.30(d, 7.0 Hz, 6N); 1.27(m, 2H); 1.23(d, 7.0, 6N); 1.10(m, 4H); 0.77(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C28H41FO3) 444, found 445 (M+H).

Stage N. 3,5-Aminobutiramida 2-acetoxymethyl-6-pentyl-4'-fluoro-1,1'-bipheny

Chlorotrimethylsilane (110 ml, 867 mmol) are added to a chilled (0o(C) a mixture of the intermediate from step G (62.4 mg, 140 mmol) and NaI (132 mg, 880 mmol) in CH3CN (1.4 ml). After 25 min the mixture is filtered through silica gel (5:1 g is (2.3 ml) is heated to a temperature of 80oWith during the night. The solvent is removed and the residue dissolved in water (15 ml) and extracted with dichloromethane (315 ml). Chromatography on a column of silica gel (95:5 hexane/ethyl acetate) to give colorless oil (38.2 mg, 69%).

1H NMR (300 MHz, CDCl3): 7.31(s,1H); 7.15(m, 2H); 7.07(m, 2H); 4.76(s, 2H); 3.18(Sept, 6.8 Hz, 1H); 3.12(Sept, 6.8 Hz, 1H); 2.28(m, 2H); 1.97(s, 3H); 1.29(d, 6.6 Hz, 6N); 1.29(m, 2H); 1.29(d, 6.6, 6N);1.14-1.07(m, 4H); 0.78(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C26H35FO2) 398, found 338 (M-Asón).

Stage I. 3,5-Aminobutiramida-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-bipheny

A solution of the intermediate obtained in stage H (11.2 g, 28.1 mmol), and potassium hydroxide (109 mg, 1.65 mmol) in methanol (2 ml) is heated at a temperature of 50oC for 3 hours the Solvent is removed and the residue is dissolved in saturated aqueous ammonium chloride (15 ml) and extracted with diethyl ether (315 ml). Chromatography on a column of silica gel (5:1 hexane/ethyl acetate) to give the target compound as a colourless crystalline solid (12.0 mg, 120%).

1H NMR (300 MHz, CDCl3): 7.30(s,1H); 7.19(m, 2H); 7.11(m, 2H); 4.32(s, 2H); 3.37(Sept, 6.9 Hz, 1H); 3.16(Sept, 6.9 Hz, 1H); 2.26(m, 2H); 1.31(d, 6.6 Hz, 6N); 1.29(m, 2H); 1.28(d, 7.0, 6N); 1.17-1.03(m, 4H); 0.77(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C24o
C.

EXAMPLE 191

< / BR>
3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

Stage A. 3,5-Aminobutiramida 2-formyl-6-pentyl-4'-fluoro-1,1'-biphenyl

Derived from 3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl (example 190) according to the method of example 1, step E.

1H NMR (300 MHz, CDCl3): 9.70(s, 1H); 7.42(s,1H); 7.23-7.10(m, 4H); 3.8(Sept, 6.8 Hz, 1H); 3.23(Sept, 6.8 Hz, 1H); 2.34(m, 2H); 1.31(d, 6.6 Hz, 6N); 1.29(d, 7.0, 6N); 1.28(m, 2H); 1.14(m, 4H); 0.79(t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H31FO) 354 found 355 (M+H).

Stage C. 3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

The target compound is obtained from the intermediate obtained in stage A, by the method of example 101, step Century.

1H NMR (300 MHz, CDCl3): 7.32(s,1H); 7.19-7.06(m, 4H); 4.70(DQC, 7.0 Hz, 2.9 Hz, 1H); 3.88(Sept, 6.8 Hz, 1H); 3.13(Sept, 6.8 Hz, 1H); 2.20(m, 2H); 1.63(d, 2.9 Hz, 1H); 1.40(d, 6.6 Hz, 3H); 1.30(d, 7.0 Hz, 6N); 1.3(m, 2H); 1.27(d, 7.0 Hz, 6N), 1.08(m, 4H); 0.78(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H35FO) 370, found 370 (M+). Rf=0.36(83:17 hexane/ethyl acetate). So pl. 126oC.

EXAMPLE 192

< / BR>
3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

In a separate experiment, the target link is 3H), 2.17-2.22(m, 2H); 3.11-3.16(m, 1H); 3.86-3.90(m, 1H); 4.66-4.73(m, 1H); 7.06-7.22(m, 4H); 7.32(s, 1H).13With NMR (75 MHz, CDCl3): 13.87, 22.01, 23.37, 24.22, 24.55, 24.61, 25.08, 28.66, 28.94, 29.91, 31.02, 32.22. 68.89, 114.65-115.15 (2D, 2C), 124.25, 130.33-131.28(2D, 2C), 135.51, 136.96, 137.72, 139.00, 145,80 (2C), 161.67(d, J=245.7 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H35FO) 370, found 370 (M+). Anal. Rasch. for C25H35FO: 81.03; N, 9.52 found: 81.05; N, 9.70. Rf=0.37 (9:l hexane/ethyl acetate). GHUR: (C-18, A= 0.05% aqueous triperoxonane acid,=CH3SP; linear gradient: 75%-100% over 30 min; 254 nm, 1 ml/min): R. T. 20-0 min (91.1 area %); (Daicel Hiracel OD-H; isocratic 99:1 hexane:methyl tert-butyl ether; 254 nm, 1.5 ml/min); R. T.=5.83 min (49.0 square, %), 7.67 min (51 area %). So pl. 124.0-125.0oC.

EXAMPLE 193

< / BR>
(+)-3,5-Aminobutiramida-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

Stage A. Polyether 3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyldiol acid

A solution of 1.90 g (5.36 mmol) of 3,5-aminobutiramida-2-formyl-6-pentyl-4'-fluoro-1,1'-biphenyl (example 191, step A) in 36 ml of tetrahydrofuran at a temperature of -78oC in an atmosphere of argon is treated by the addition dropwise of 4.6 ml (6.43 mmol) of a 1.4 M solution metallice in the air. The reaction mixture is heated to room temperature over one hour. Then added 1.03 g (6.97 mmol) of f the th mixture was quenched with 30 ml saturated aqueous ammonium chloride and extracted with 60 ml ethyl acetate. The separated organic phase is washed again with 30 ml of saturated aqueous ammonium chloride. The combined aqueous phase is extracted with 20 ml of ethyl acetate is added in several portions. The combined organic phases are dried (sodium sulfate) and concentrated in vacuo. The crude mixture is purified by chromatography on a column of silica, using hexane: ethyl acetate: acetic acid (75:24:1) as eluent to obtain 2.55 mg (4.94 mmol, 97%) of product.

The Belarusian library Association-MS: calculated for C33H39O4F 518; found 519(M+H).1H NMR (300 MHz, CDCl3): 0.77(t, J=7.0 Hz, 3H); 1.03-1.30(m, N); 1.53(d, J=7.0 Hz, 3H), 2.16-2.22(m, 2H); 3.05-3.20(m, 1H); 3.53-3.65(m, 1H); 5.87-5.93(m, 1H); 7.05-7.37(m, 4H); 7.54-8.06(m, 5H).f=0.47(75:24:l hexane:ethyl acetate:acetic acid).

Stage C. (+)-3,5-Aminobutiramida-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

A solution of 2.54 g (4.90 mmol) of Palmyra phthalic acid from the stage And 50 ml of hexane and 0.5 ml of methanol at reflux treated with 0.63 ml (4.90 mmol) of (R)-(+)-a-methylbenzylamine. The reflux continued until, until you begin to precipitate a solid. At this point, the flask is removed from the hot plate and allowed to cool. Further cooling is carried out by placing the flask in holdingcompany in hexane and add methanol at reflux to dissolve the crystals. The reflux continued until, until you begin to precipitate a solid. At this point, the flask is removed from the plate and allow it to cool. Further cooling is not necessary and the salt crystals are harvested as described above. Salt crystallized third time on the second describes the methodology and the collected crystals are placed in a vacuum overnight at a temperature of 50oWith obtain 0.57 g (0.89 mmol, 18%) crystalline amine salt. A solution of 0.57 g (0.89 mmol) of the amine salt in 5 ml of dioxane is treated with 20% solution (V/V) NaOH/H2O and then aged by heating under reflux for 3.5 hours After cooling to room temperature the reaction mixture was diluted with 20 ml of ethyl acetate. The separated aqueous phase is extracted with ethyl acetate (210 ml). The combined organic extracts are dried (sodium sulfate) and concentrated in vacuo. The crude oil is purified flash chromatography on a column of silica using hexane:ethyl acetate (19:1) and the compound obtained is placed in a vacuum overnight (at a temperature of 50o(C) to obtain 0.26 g (0.70 mmol, 79%) of target compound as a white solid.

1H NMR (300 MHz, CDCl3): 0.75-0.80(m, 3H); 1.02-1.31(m, N); 1.40(d.02, 23.38, 24.23, 24.56, 24.63, 25.09, 28.68, 28.96, 29.92, 31.04, 32.23, 68.91, 114.66-115.16 (2D, 2C), 124.27, 130.34-131.30(2D, 2C), 135.53, 136.98, 137.74, 139.02, 145.82 (2C), 161.68(d, J=245.4 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H35OF) 370, found 370 (M+). Anal. Rasch. for C25H35FO: 81.03; N, 9.52 found: 81.15; N, 9.68. Rf=0.36 (9:1 hexane:ethyl acetate). GHUR: (C-18, A= 0.05% aqueous triperoxonane acid, B=CH3CN; linear gradient: 75%-100% over 30 min; 254 nm, 1 ml/min): R. T. 20.0 min (93.9 area %); (Daicel Hiracel OD-H; isocratic 99:1 hexane:methyl tert-butyl ether; 254 nm, 1.5 ml/min); R. T.=5.23 min (98.0 area%), 8.37 min (0.89 square. %); 98.2% of ei. []D=+26.9o(C=0.00196 g/ml, dichloromethane). So pl. 95.0-96.0oC.

EXAMPLE 194

< / BR>
3,5-Aminobutiramida-2-hydroxymethyl-6-(Penta-1-enyl)-4'-fluoro-1,1'-biphenyl

The target compound is obtained from the intermediate obtained in example 190, step F by the procedure of example 190, stage H and I. the Olefin is a mixture of CIS and TRANS isomers in a ratio of 17:83.

1H NMR (300 MHz, CDCl3): 7.33(s, 3H); 7.15-7.02(m, 4H); 5.95(d, 16.2 Hz, 1H); 5.24 (dt, 16.2 Hz, 7.0 Hz, 1H); 4.40(C. 2H); 3.41 (Sept, 6.8 Hz. 1H); 3 30(Sept, 6.8 Hz, 1H); 1.89 (dt, 7.2 Hz, 7.2 Hz, 2H); 1.33(D. 6.6 Hz, 6N); 1.24(d, 7.0 Hz, 6N); 1.2 (m, 2H); 0.74 (t, 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H31OF) 354 found 354 (M+). Rf=0.36(83:17 hexane/ethyl acetate). Anatometal-2-(1-hydroxyethyl-6-propyl-4'-fluoro-1,1'-biphenyl

< / BR>
Stage A. 2 Allyloxy-4,6-dimethylacetophenone

A solution of 2-hydroxy-4,6-dimethylacetophenone (4.99 g, 30.4 mmol) in dimethylformamide (31 ml) is added to a chilled (0o(C) suspension of sodium hydride (0.772 g, 32.1 mmol) in dimethylformamide (8 ml). The mixture is heated to room temperature for 2.5 hours the Mixture was re-cooled to 0oWith and add allylbromide (5.4 ml, 62.4 mmol). The mixture is heated to room temperature and stirred for 25 hours the Mixture is diluted with saturated aqueous sodium chloride (150 ml) and extracted with diethyl ether (250 ml+2125 ml). The combined organic phases are washed with 1 n KOH (2125 ml) and saturated aqueous sodium chloride. Chromatography on a column of silicagel gives colorless oil (5.74 g, 92%).

1H NMR (300 MHz, CDCl3): 6.64(s, 1H); 6.56(s, 1H); 6.03(DDT, 17.3 Hz, 10.7 Hz, 5.2 Hz, 1H), 5.38 (d, 17.3 Hz, 1H); 5.27(d, 10.7 Hz, 1H); 4.55(D. 5.0 Hz, 2H); 2.51(s, 3H); 2.31(s, 3H); 2.22 (s, 3H).

Stage C. 2-Hydroxy-3-(prop-2-enyl)-4,6-dimethylacetophenone

A solution of the intermediate obtained in stage A (6.30 g, 30.8 mmol) and 2,6-di-tert-butyl-4-METHYLPHENOL (71.9 mg, 326 mmol) in xylene Tegaserod in three cycles of freeze-pumping-thawing. The mixture is heated on a water bath at the temperature afia on a column of silica gel gives a yellow oil (5.47 g, 87%).

1H NMR (300 MHz, CDCl3): 13.09(c, 1H); 6.56(c, 1H); 5.93(m, 1H); 4.95(m, 2H); 3.42(d, 6.0 Hz, 2H), 2.65 (s, 3H); 2.55(s, 3H); and 2.27(s, 3H). EI MS: 204 (M+, 70), 189(100).

Stage C. 2-Acetyl-3,5-dimethyl-6-(prop-2-enyl)fenestrated

The solution trifluoro anhydride (1.10 ml, 6.54 mmol) in dichloromethane (3.8 ml) is added to a chilled (-10o(C) to a solution of pyridine (0.58 ml, 6.54 mmol) in dichloromethane (9.6 ml). After 35 min, add a solution of the intermediate obtained in stage (0.271 g, 1.33 mmol), in dichloromethane (6.4 ml) and the mixture is heated to room temperature. After 5 h the mixture was poured into ice water and extracted with dichloromethane (215 ml). Chromatography on a column of silica gel gives a yellow oil (0.426 g, 95%).

1H NMR (300 MHz, CDCl3): 7.09(s, 1H); 5.86(m, 1H); 5.09(d, 10.3 Hz, 1H); 4.93(D. 17.1 Hz, 1H); 3.51(d, 5.6 Hz, 2H), 2.52 (s, 3H); 2.34(s, 3H); 2,30(s, 3H).

Stage D. 3,5-Dimethyl-2-acetyl-6-(prop-2-enyl)-4'-fluoro-1,1'-biphenyl

A mixture of intermediate compound obtained in stage C (3.25 g, 9.68 mmol), 4-ftorpolimernoj acid (2.06 g, 14.7 mmol), PD(h3)4(1.13 g, 976 mmol), K3RHO4(4.10 g, 19.3 mmol) and KBR (1.97 g, 16.6 mmol) in 1,4-dioxane (50 ml) is heated at a temperature of 85oC for 16.5 hours the Mixture is poured into a saturated aqueous solution of chlorine is of Xan/ethyl acetate) to give a yellow oil (1.03 g, 38%).

1H NMR (300 MHz, CDCl3): 7.18(m, 2H); 7.07(m, 3H); 5.76(m, 1H); 4.97(d, 10.2 Hz, 1H); 4.72(D. 17.0 Hz, 1H); 3.15(d, 5.5 Hz, 2H); 2.32 (s, 3H); 2.24(s,3H); 1.91 a(s,3H).

Stage E. 3,5-Dimethyl-2-acetyl-6-propyl-4'-fluoro-1,1'-biphenyl

Receive from the intermediate obtained in stage D, according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.19(m, 2H); 7.07(m, 3H); 2.36(m, 5H); 2.22 (s, 3H); 1.91(s, 3H); 1.32 to(m, 2H); 0.75(t, 7.2 Hz, 3H). The Belarusian library Association-MS: calculated for (C19H21OF) 384, found 385 (M+H).

Stage F. 3,5-Dimethyl-2-(1-hydroxyethyl)-6-propyl-4'-fluoro-1,1'-biphenyl

A mixture of intermediate compound obtained in stage E (21.0 mg, 73.8 mmol), and socialogical (31.0 mg, 0.818 mmol) in tetrahydrofuran (2 ml) is heated under reflux during the night. Add aqueous hydrochloric acid (5%, 1 ml) and the mixture stirred for 1 h the Mixture is diluted with 5% aqueous hydrochloric acid (25 ml) and extracted with diethyl ether (315 ml). Chromatography on a column of silica gel gives the target compound as a colourless crystalline solid (15.7 mg, 74%).

1H NMR (300 MHz, CDCl3): 7.19-7.01(m, 5H); 4.71(DQC, 6.7 Hz, 3.2 Hz, 1H); 2.56(C. 3H); 2.32(C. 3H); 2.20(m, 2H); 1.52(d, 3.3 Hz, 1H); 1.38(d, 7.0 Hz, 3H); 1.28 (m, 2H); 0.73 (t, 7.2 Hz). EI-MS: calculated for (SUB>FO: 79.68; H 8.10, found: 79.46; H 7.95. So pl. 98-99oC.

EXAMPLE 196

< / BR>
3,5-Dimethyl-2-(1-hydroxyethyl)-6-(prop-2-enyl)-4'-fluoro-1,1'-biphenyl

The target compound is obtained from the intermediate obtained in example 195, step D, by the method of example 195, step F.

1H NMR (300 MHz, CDCl3): 7.16-7.02(m, 5H); 5.66(m, 1H); 4.90(d, 10.2 Hz, 1H); 4.75-4.62(m, 2H); 2.99(d, 5.5 Hz, 2H), 2.57(C. 3H); 2.28(C. 3H); 1.50(d, 3.7 Hz, 1H); 1.38(d, 7.0 Hz, 3H). Rf=0.27 (83:17 hexane/ethyl acetate). Anal. Rasch. for C19H21FO: 80.25; N, 7.44 found: 80.14; N, 7.36. So pl. 92oC.

EXAMPLE 197

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-methylpyridin

Stage A. 2-Isopropyl-3-carboethoxy-4-(4-forfinal)-5-carbomethoxy-6-methyl-1,4-dihydropyridines

A mixture of methyl-3-aminocrotonate (13 g, 114 mmol) and 4-carboethoxy-5-(4-forfinal)-3-methylpent-4-EN-2-it (30 g, 114 mmol) (obtained according to the method Angerbauer et al., U.S. patent 5169857) in absolute ethanol (300 ml) is heated under reflux during the night. The mixture was concentrated in vacuo and the crude product is taken directly to the next stage without purification.

Stage C. 2-Isopropyl-3-carboethoxy-4-(4-forfinal)-5-(Penta-1-enyl)-6-methylpyridin

Obtained from intermediate compounds,the rate of 34:66.

1H NMR (300 MHz, CDCl3): 7.16(m, 2H); 7.04(m, 2H); 6.02(m, 1H); 5.46(m, 1H); 4.01(m, 2H); 3.06(m, 1H); 2.61(s, 3H, major isomer); 2.50(s, 3H), not the main isomer); 1.99(m, 1H); 1.67 (m, 1H); 1.4-1.15(m, 8H); 0.98(m, 3H); 0.79(m, 3H).

Stage C. 2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-(Penta-1-enyl)-6-methylpyridin

A mixture of 1.25 g (3.38 mmol) of the intermediate obtained in stage B, and socialogical (0.28 g, 6.8 mmol) in tetrahydrofuran (50 ml) is heated under reflux for 2.5 hours the Mixture was quenched with water (10 ml) and extracted with ethyl acetate to obtain colorless crystalline solid (1.0 g, 90%). Olefin obtained as a mixture of CIS and TRANS isomers in a ratio of 19:81.

1H NMR (300 MHz, CDCl3): 7.10(m, 4H); 5.88(d, 16.2 Hz, 1H); 5.39(dt, 16.2 Hz, 7.0 Hz, 1H); 4.39(d, 5.5 Hz, 2H); 3.44(Sept, 7.0 Hz, 1H); 2.57(s, 3H, major isomer), 2.46(s, 3H), not the main isomer); 1.92(m, 2H); 1.4-1.15(m, 4H); 1.33(d, 6.6 Hz, 6N); 0.75(t, 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H26FNO) 310, found 326 (M-H)+). Rf=0.44(80:20 hexane/ethyl acetate). Anal. Rasch. for C21H26FNO: 77.03; H 8.00; F 5.80; N, 4.28 found: 77.02; H 8,14; F 5.99; N, 4.22. So pl. 106-108oC.

Stage D. 2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-methylpyridin

A mixture of intermediate compound obtained n is filtered through a layer of silica gel and a layer washed with ethyl acetate. Chromatography on a column of silica gel (80:20 hexane/ethyl acetate) followed by recrystallization from ethyl acetate gives the target compound as colorless crystals (650 mg, 50%).

1H NMR (300 MHz, CDCl3): 7.25(C. 2H); 7.23(s, 2H); 4.43(doctor 5.5 Hz, 2H); 3.53(cept, 7.0 Hz, 1H); 2.69(s, 3H); 2.35(m, 2H); 1.44(d, 6.6 Hz, 6N); 1.4(m, 2H); 1.2(m, 4H); 0.88(t 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H28FNO) 310, found 328 (M-H)+). Rf=0.43 (80:20 hexane/ethyl acetate). Anal. Rasch. for C21H28FNO: 76.56; N, 8.57; F 5.77; N, 4.25, found: 76.71; H 8,60; F 6.04; N, 4.21.T. sq.83-85oC.

EXAMPLE 198

< / BR>
2-Isopropyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-methylpyridin

Stage A. 2-Isopropyl-3-carboethoxy-4-(4-forfinal)-5-hydroxymethyl-6-methylpyridin

Receive from the intermediate obtained in example 197, step A, according to the method of example 1, stage C and D.

1H NMR (300 MHz, CDCl3): 7.25(m, 2H); 7.09(m, 2H); 4.44(D. 5.1 Hz, 2H); 3.97(q, 7.1 Hz, 2H); 3.04(Sept, 6.8 Hz, 1H); 2.71 (s, 3H), 1.53(t, 5.2 Hz, 1H); 1.30(D. 6.6 Hz, 6N); 0.96(t 7.2 Hz, 3H). EI-MS: calculated for (C19H22FNO3) 331 found 331.

Stage C. 2-Isopropyl-3-carboethoxy-4-(4-forfinal)-5-(tert-butyldimethylsiloxy)methyl-6-methylpyridin

A solution of the intermediate obtained n the Ministry of foreign Affairs (6 ml) is stirred over night. The mixture is diluted with water and extracted with ethyl acetate. Chromatography on a column of silica gel (95: 5 hexane/ethyl acetate) to give a colorless solid (3.5 g, 76%).

1H NMR (300 MHz, CDCl3): 7.30(m, 2H); 7.20(m, 2H); 4.49(C. 2H); 4.03(q, 7 Hz, 2H); 3.1(Sept, 1H); 2.72(s, 3H), 1.34(d, 7.0 Hz, 6N); 1.01(t 7.0 Hz, 3H); 0.90(s, N); 0.00(C. 6N). The Belarusian library Association-MS: calculated for (C25H36FNO3Si) 331 found 446 (M+H).

Stage C. 2-Isopropyl-3-(Penta-1-enyl)-4-(4-forfinal)-5-(tert-butyldimethylsiloxy)methyl-6-methylpyridin

Receive from the intermediate obtained in stage B, by the method of example 1, stage D, E, and f

1H NMR (300 MHz, CDCl3): 7.2-7.0(m, 4H); 5.99(d, 16.2 Hz, 1H); 5.28(dt, 15.6 Hz, 7.2 Hz, 1H); 4.30(C. 2H); 3.38(m, 1H); 2.67(m, 3H); 1.92(m, 2H); 1.4-1.2(m, 8H); 0.85(s, N); 0.75(t, 7.4 Hz, 3H); -0.06(C, 6N).

Stage D. 2-Isopropyl-3-(Penta-1-enyl)-4-(4-forfinal)-5-hydroxymethyl-6-methylpyridin

Tetrabutylammonium (1 ml, 1.0 M solution in tetrahydrofuran, 2.5 EQ. ) are added to a solution of the intermediate obtained in stage C (200 mg, 0.45 mmol) in tetrahydrofuran (10 ml). After 2 h the mixture was concentrated in vacuo. The residue is dissolved in water and extragere with ethyl acetate. Chromatography on a column of silicagel (80: 20 hexane/ethyl acetate) gives going to be the 1
H NMR (300 MHz, CDCl3): 7.09(m, 4H); 5.96(d, 16.2 Hz, 1H); 5.27(dt. 16.2 Hz. 1H); 4.38(d, 5.5 Hz, 2H); 3.36(Sept, 1H); 2.69(s, 3H); 1.90(m, 2H); 1.4-1.1(m, 4H); 1.25(d, 6.6 Hz, 6N); 0.73(t, 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H26FNO) 327 found 327 (M+). Rf=0.23 (80:20 hexane/ethyl acetate). Anal. Rasch. for C21H26FNO: 77.03; H 8.00; F 5.80; N, 4.28 found: At 76.92; H 8,07; F 5.92; N, 4.15. So pl. 119-120oC.

Stage E. 2-Isopropyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-methylpyridin

The target compound obtained as a colorless solid (86% yield from intermediate compounds obtained in stage D, according to the method of example 1, stage N.

1H NMR (300 MHz, CDCL3): 7.2(m, 4H); 4.29(d, 5.5 Hz, 1H); 3.24(Sept, 6.6 Hz, 1H); 2.65(s, 3H); 2.26(m, 2H); 1.29(d, 6.6 Hz, 6N); 1.25(m, 4H); 1.1 (m, 4H); 0.76(t, 7.0 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H28FNO) 329, found 328 (M-H)+). Rf= 0.20(80: 20 hexane/ethyl acetate). Anal. Rasch. for C21H28FNO: 76.56; N, 8.57; F 5.77; N, 4.25, found: 76.49; N 8,55; F 5.78; N, 4.21. So pl. 110-112oC.

EXAMPLE 199

< / BR>
2-Morpholinomethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-Isopropyl-3-(tert-butyldiphenylsilyl)methyl-4-(4-forfinal)-5-pentyl-6-methylpyridin

A solution of the intermediate from example 197, Stadel) is stirred for 2 hours The mixture is diluted with water and extracted with ethyl acetate. Chromatography on a column of silica gel (95:5 hexane/ethyl acetate) to give a colorless solid (64 mg, 75%).

1H NMR (300 MHz, CD3D): 7.41(m 6N); 7.33(m, 4H); 7.05(m, 4H); 4.25(C. 2H); 3.13(Sept, 6.8 Hz, 1H); 2.57(s, 3H); 2.23(m, 2H); 1.3(m, 2H); 1.17(d, 6.6 Hz, 6N); 1.15(m, 4H); 0.99(s, N); 0.78(t 6.4 Hz, 3H).

Stage C. 2-Isopropyl-3-(tert-butyldiphenylsilyl)methyl-4-(4-forfinal)-5-pentyl-6-methylpyridine N-oxide

A mixture of the intermediate from step A (60 mg, 0.11 mmol) and 3-chloroperoxybenzoic acid (52 mg, 1.4 EQ.) in chloroform (5 ml) is heated under reflux for 15 minutes the Mixture is diluted with ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (325 ml). The organic phase is filtered through a layer of silica gel at room temperature and concentrated to obtain yellow solid (54 mg, 84%).

1H NMR (300 MHz, CDCl3): 7.31(m, 6N); 7.24(m, 4H); 6.96(m, 4H); 4.13(C. 2H); 3.16(SHS, 1H); 2.47(s, 3H); 2.18(m, 2H); 1.33(d, 6.6 Hz, 6N); 1.25(m, 2H); 1.05(m, 4H); 0.93(s, N); 0.70(i.e 6.4 Hz, 3H).

Stage C. 2-Chloromethyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

The phosphorus oxychloride (9.5 g) and triethylamine (8.6 ml) are added simultaneously to load the dichloromethane (30 ml). After 3 h the mixture was diluted with dichloromethane (100 ml) and washed with saturated aqueous sodium bicarbonate (3100 ml). Chromatography on a column of silica gel (90:10 hexane/ethyl acetate) gives solid (9.4 g, 61%).

1H NMR (300 MHz, CDCl3): 7.41 (m 6N); 7.32(m, 4H); 7.06(m, 4H); 4.75(C. 2H); 4.27(C. 2H); 3.15(Sept. 6.8 Hz, 1H); 2.39(m, 2H); 1.35(m, 2H); 1.18(d, 6.6 Hz, 6N); 1.12(m, 4H); 1.00(s, N); 0.79(t 6.6 Hz, 3H).

Stage D. 2-Morpholinomethyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound obtained in stage C (0.5 g, 0.83 mmol), research (0.108 g, 1.5 EQ.) and 4-dimethylaminopyridine (0.172 g, 1.7 EQ. ) in dichloromethane (15 ml) is heated under reflux for 2 hours the Mixture was washed with saturated aqueous sodium chloride. Chromatography on a column of silica gel (90:10 hexane/ethyl acetate) to give a yellow oil (170 mg, 30%).

1H NMR (300 MHz. CDCl3): 7.41(m 6N); 7.34(m, 4H); 7.05(m, 4H); 4.26(C. 2H); 3.71(m, 4H); 3.67(s, 2H); 3.13(Sept, 6.8 Hz, 1H); 2.61(m, 4H); 2.35(m, 2H); 1.15(d, 6.6 Hz, 6N); 1.1(m, 4H); 0.99(s, N); 0.9(m, 2H); 0.78(t, 7.0 Hz, 3H).

Stage E. 2-Morpholinomethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in stage(Sept, 6.6 Hz, 1H); 2.59(m, 4H); 2.39(m, 2H); 1.32(d, 6.6 Hz, 6N); 1.25(m, 2H); 1.1 (m, 4H); 0.78(t 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H35FN2O2) 414, found 415 (M+H). Anal. Rasch. for C25H35FN2O2: 72.43; N, 8.51; F 4.58; N, 6.76 found: 72.49; H 8,42; F 4.71; N, 7.05.

EXAMPLE 200

< / BR>
2,5-Bis-(hydroxymethyl)-3-pentyl-4-(4-forfinal)-6-isopropylpyridine

Stage A. 2-Acetoxymethyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound obtained in example 199, step In (4.8 g, 7.97 mmol), and acetic anhydride (20 ml) is heated to a temperature of 100oFor 20 minutes the Mixture is poured into ice and the aqueous phase extracted with ethyl acetate (330 ml). The combined organic phases are washed with saturated aqueous sodium bicarbonate (350 ml) and saturated aqueous sodium chloride (350 ml). Chromatography on a column of silica gel gives a yellow oil (4.4 g, 90%).

1H NMR (300 MHz, CDCl3): 7.40(m, 6N); 7.31(m, 4H); 7.06(m, 4H); 5.29(C. 2H); 4.26(s, 2H); 3.14(Sept, 6.8 Hz, 1H); 2.2(m, 2H); 2.18(s, 3H); 1.2(m, 2H); 1.16(d, 6.6 Hz, 6N); 1.05(m, 4H); 0.99(s, N); 0.77(t, 6.8 Hz, 3H).

Stage C. 2-Hydroxymethyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate is grebaut under reflux for 1.5 hours The mixture is diluted with ethyl acetate and washed with saturated aqueous sodium chloride. Concentration of the organic phase gives a colourless solid (60 mg, 100%), which is used in the next stage without purification.

1H NMR (300 MHz, CDCl3): 7.4-7.2(m, 10H); 7.11(m, 4H); 4.90(s, 2H); 4.39(s, 2H); 3.34(cept, 7.0 Hz, 1H); 2.34(m, 2H); 1.25(d, 7.0 Hz, 6N); 1.2(m, 2H); 1.04(m, 4H); 0.90(s, N); 0.68(t, 7.0 Hz, 3H).

Stage C. 2,5-Bis-(hydroxymethyl)-3-pentyl-4-(4-forfinal)-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in stage B, by the method of example 198, step D.

1H NMR (300 MHz, CD3OD): 7.21(m, 4H); 4.70(s, 2H); 4.30(C. 2H); 3.54(cept, 6.6 Hz, 1H); 2.28(m, 2H); 1.32(d, 6.6 Hz, 6N); 1.25(m, 2H); 1.1 (m, 4H); 0.75(t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C21H28FNO2) 345, found 346 (M+H). Anal. Rasch. for C21H28FNO2: 73.01; N, 8.17; F 5.50; N, 4.05, found: At 72.89; H 8.25; F 5.21; N, 4.41. So pl. 135-136oC.

EXAMPLE 201

< / BR>
2-Methoxymethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-Methoxymethyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound obtained in example 200, step B (0.1 g, 0.17 mmol), methyliodide the t in the 40oC for 3 hours the Mixture is diluted with water and extracted with ethyl acetate (310 ml). The combined organic phases are washed with saturated aqueous sodium chloride (310 ml). Chromatography on a column of silica gel gives a colourless solid (40 mg, 40%).

1H NMR (300 MHz, CDCl3): 7.41 (m, 6N); 7.32(m, 4H); 7.06(m, 4H); 4.62(s, 2H); 4.27(C. 2H); 3.48(s, 3H); 3.15(Sept, 6.6 Hz, 1H); 2.36(m, 2H), 1.27(m, 2H); 1.18(d, 6.6 Hz, 6N); 1.12(m, 2H); 1.00(C. N); 0.87(m, 2H); 0.78(t, 6.6 Hz, 3H).

Stage C. 2-Methoxymethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.14(m, 4H); 4.62(s, 2H); 4.36(D. 5.2 Hz, 2H); 3.46(s, 3H); 3.44(Sept, 6.6 Hz, 1H); 2.38(m, 2H), 1.34(d, 7.0 Hz, 6N); 1.23(m, 2H); 1.12(m, 4H); 0.77(t 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30FNO2) 359, found 360 (M+H). Anal. Rasch. for C22H30FNO2: 73.51; H 8.41; F 5.28; N, 3.90, found: 73.40; H Of 8.47; F 5.19; N, 3.91.

EXAMPLE 202

< / BR>
2-Ethoxymethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 200 by stage, according to the method of example 201, step a, and CA is, .6 Hz, 1H); 2.40(m, 2H); 1.4(m, 2H); 1.34(d, 6.6 Hz, 6N); 1.26(t 7.0 Hz, 3H); 1.13(m, 4H); 0.78(t 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H32FNO2) 373, found 374 (M+H). Anal. Rasch. for C23H32FNO2: S.96; N, 8.64; F 5.09; N, 3.75, found: 73.97; H 8,83; F 5.33; N, 3.52.

EXAMPLE 203

< / BR>
2-(Prop-2-enyloxy)methyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 200 by stage, according to the method of example 201, step a and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.15(m, 4H); 5.97(DDT, 17.1 Hz, 10.5 Hz, 6 Hz, 2H); 5.33(d, 17.3 Hz, 1H); 5.21(d, 10.3 Hz, 1H); 4.68(s, 2H); 4.34(C. 2H); 4.12(doctor 5.5 Hz, 2H); 3.44(Sept, 6.8 Hz, 1H); 2.39(m, 2H); 1.33(d, 6.6 Hz, 6N); 1.29(m, 2H); 1.10(m, 4H); 0.77(t 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H32FNO2) 385, found 386 (M+H). Anal. Rasch. for C24H32FNO2: 74.8; N, 8.37; F 4.93; N, 3.63 found: 75.20; H 8,54; F 4.90; N, 3.52.

EXAMPLE 204

< / BR>
2-Benzoyloxymethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 200 by stage, according to the method of example 201, step a and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.43-7.30(m, 5H); 7.17(m, 4H); 4.73(s, 2H); 4.66(24H32FNO2) 435, found 436 (M+H). Anal. Rasch. for C28H34FNO2: 77.21; H 7.87; F 4.36; N, 3.22, found: 77.26; H 7,84; F 4.42; N, 3.1. So pl. 110-112oC.

EXAMPLE 205

< / BR>
2-(1-Hydroxymet-3-enyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-Formyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropyl

Is obtained from 2-hydroxymethyl-3-pentyl-4-(4-forfinal)-5-[(tert-butyldiphenylsilyl)methyl] -6-isopropylpyridine (example 200, step B) according to the method of example 1, step E.

1H NMR (300 MHz, CDCl3): 10.20(C. 1H); 7.41(m 6N); 7.33(m, 4H); 7.04(m, 4H); 4.33(s, 2H); 3.23(Sept, 6.6 Hz, 1H); 2.66(m, 2H); 1.3-1.1(m 6N); 1.22(d, 6.6 Hz, 6N); 1.01(C. N); 0.79(t 7.0 Hz, 3H). The Belarusian library Association-MS: calculated for (C37H44FNO2Si) 581 found 582 (M+H).

Stage C. 2-(1-Hydroxymet-3-enyl)-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound obtained in stage A (0.2 g, 0.34 mmol) and allylanisole (1 ml of 1.0 M solution in tetrahydrofuran, 3 EQ.) in tetrahydrofuran (10 ml) is heated under reflux for 1.5 hours the Mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate and washed with saturated aqueous sodium chloride. Chroma MHz, CDCl3): 7.42(m 6N); 7.2(m, 4H); 7.06(m, 4H); 5.94(m, 1H); 5.14-5.08(m, 2H); 4.99-4.90(m, 2H); 4.28(d, 2.2 Hz, 2H); 3.16(Sept, 6.8 Hz, 1H); 2.55(m, 1H); 2.45-2.15(m, 3H); 1.3(m, 2H); 1.20(d, 6.6 Hz, 3H); 1.15(D. 6.6 Hz, 3H); 1.1(m, 4H); 0.76(i.e 6.6 Hz, 3H).

Stage C. 2-(1-hydroxymet-3-enyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in stage B, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 5.94(m, 1H); 5.13(d, 7.7 Hz, 1H); 5.08(s, 1H); 4.92(s, 2H); 4.38(m, 2H); 3.47(cept, 6.7 Hz, 1H); 2.51(m, 1H), 2.4-2.1(m, 3H); 1.35(d, 6.6 Hz, 3H); 1.34(d, 6.6 Hz, 3H); 1.29(m, 2H); 1.10(m, 4H); 0.77(t 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H32FNO2) 385, found 386 (M+H). Rf= 0.15(85: 15 hexane/ethyl acetate). Anal. Rasch. for C24H32FNO2: At 74.77; N, 8.37; F 4.93; N, 3.63 found: 74.85; H 8,53; F 4.99; N, 3.50.

EXAMPLE 206

< / BR>
2-(1-Hydroxyprop-2-enyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 205 on stage And, according to the method of example 205, step B, and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 5.89(DDT, 17.0 Hz, 10.0 Hz, 7.1 Hz, 1H); 5.66(d, 5.5 Hz, 1H); 5.37(d, 16.9 Hz. 1H); 5.26(t, 5.7 Hz, 1H); 5.20(d, 9.9 Hz, 1H); 4.38(d, 4.8 Hz, 2H); 3.49(cept 23H30FNO2) 371, found 372 (M+H). Rf=0.15(85:15 hexane/ethyl acetate). So pl.=113-115oC. Anal. Rasch. for C23H30FNO2: 74.36; H 8.14; F 5.11; N, 3.77 found: 74.16; H 8,28; F 5.11; N, 3.60.

EXAMPLE 207

< / BR>
Hydrochloride of 2-(hydroxy-p-tolyl)methyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 205 on stage And, according to the method of example 205, step B, and example 198, step D.

1H NMR (300 MHz, CD3OD): 7.28(m 6N); 7.21(m, 2H); 6.90(d, 7.7 Hz, 1H); 6.43(s, 1H); 4.48(q, j 11.8 Hz, 1H); 4.41(q, j 11.8 Hz, 1H); 3.96(Sept, 6.8 Hz, 1H); 2.46(s, 3H); 2.19(m, 2H); 1.61(d, 7.0 Hz, 3H); 1.58(d, 7.0 Hz, 3H); 1.0-0.6(m, 5H); 0.57(t, 7.0 Hz, 3H); 0.3(m, 1H). The Belarusian library Association-MS: calculated for (C28H34FNO2) 435, found 436 (M+H). Anal. Rasch. for C28H34FNO2HCl: At 71.25; H 7.47; C1 7.51; F 4.02; N, 2.97 found: 71.43; H 7,49; Cl 7.48; F 4.10; N, 2.87. So pl. 178-180oC.

EXAMPLE 208

< / BR>
2-(a-Hydroxy)benzyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 205 on stage And, according to the method of example 205, step b and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.30(m, 5H); 7.17(m, 4H); 6.43(d, 6.6 Hz, 1H); 5.79(D. 6. the Chicano for (C27H32FNO2) 421 found 422 (M+H). Rf= 0.10(85: 15 hexane/ethyl acetate). Anal. Rasch. for C27H32FNO2: 76.93; N, 7.65; F 4.51; N, 3.32, found: 76.70; H 7,86; F 4.45; N, 3.14.

EXAMPLE 209

< / BR>
2-(4-Forfinal)hydroxymethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in example 205 on stage And, according to the method of example 205, step B, and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.24(m, 2H); 7.15(m, 4H); 6.98(m, 2H); 6.40(d, 5.9 Hz, 1H); 5.77(doctor 5.5 Hz, 1H); 4.40(m, 2H); 3.55(cept, 6.6 Hz, 1H); 2.13(m, 2H); 1.43(d, 6.3 Hz, 3H); 1.41(d, 6.6 Hz, 3H); 1.08(m, 1H); 0.99(m 6N); 0.69(i.e 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C27H31F2NO2) 439 found 440 (M+H). Rf= 0.15(85: 15 hexane/ethyl acetate). Anal. Rasch. for C27H31F2NO2: 73.78; H 7.11; F 8.64; N, 3.19, found: 73.49; H 7.23 Percent; F 8.45; N, 3.01.

EXAMPLE 210

< / BR>
2-(1-Hydroxyethyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-(1-Hydroxyethyl)-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

Receive from the intermediate obtained in example 205 on stage And, according to the method of example 205, step Century.

1H NMR (300 MHz, CD.6 Hz, 3H); 1.16(D. 6.6 Hz, 3H); 1.10(m 6N); 0.76(i.e 6.8 Hz, 3H).

Stage C. 2-(1-hydroxyethyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.19-7.15(m, 4H); 5.12(d, 7.0 Hz, 1H); 4.99(t, 1H); 4.38(d, 5 Hz, 2H); 3.48(Sept, 6.8 Hz, 1H); 2.27(m, 2H); 1.43(d, 6.3 Hz, 1H); 1.35(d, 6.6 Hz, 6N); 1.30(m, 2H); 1.09(m, 7H); 0.76(i.e 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30FNO2) 359, found 360 (M+H). Rf=0.15(85: 15 hexane/ethyl acetate). Anal. Rasch. for C22H30FNO2: 73.51; H 8.41; F 5.28; N, 3.90, found: At 73.24; H 8,40; F 5.41; N, 3.85. So pl. 125-127oC.

EXAMPLE 211

< / BR>
2-(1-Hydroxybutyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in example 205, according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.17(m, 4H); 4.92(MS, 2H); 4.85(MS, 2H); 4.37(d, 5.2 Hz, 2H); 3.47(cept, 6.6 Hz, 1H); 2.29-2.23(m, 2H); 1.62-1.53(m, 5H); 1.35(d, 6.6 Hz, 3H); 1.34(d, 6.6 Hz, 3H); 1.3(m, 1H); 1.11(m, 5H); 0.94(t 7.0 Hz, 3H); 0.77(t 6.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO2) 387 found 388 (M+H). Anal. Rasch. for C24H34FNO2: 74,38; N, 8.84; F 4.90; N, 3.61 found: 74.11; H 8,93; F 4. the ridin

The target compound is obtained from the compound obtained in example 206, according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.18(m, 4H); 4.94(SHS, 1H); 4.82(SHS, 1H); 4.39(d, 4.8 Hz, 2H); 3.48(cept, 6.6 Hz. 1H); 2.3-2.1(m, 2H); 1.82(m, 1H); 1.36(d, 5.5 Hz, 3H); 1.34(d, 6.3 Hz, 3H); 1.11(m, 8H); 1.02(t 7.4 Hz, 3H); 0.78(t 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H32FNO2) 373, found 374 (M+H). Rf= 0.15(85: 15 hexane/ethyl acetate). Anal. Rasch. for C23H32FNO2: 73,96; N, 8.64; F 5.09; N, 3.75, found: 73.88; H 8,57; F 5.17; N, 3.53. So pl. 89-90oC.

EXAMPLE 213

< / BR>
2-N-(2-Methoxyphenyl)aminomethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-N-(2-Methoxyphenyl)aminomethyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound of example 205, step A (60 mg, 0.10 mmol) and m-anisidine (50 mg, 4 equiv.) in methanol (10 ml) is treated with a mixture of zinc chloride (7 mg, 0.5 EQ.) and laborgerate sodium (6 mg, 1 EQ.) in methanol (15 ml). After stirring at room temperature overnight, the mixture was quenched with water and extracted with ethyl acetate (315 ml). The combined organic phases are washed with saturated aqueous sodium chloride (315 ml). Chromatography on a column with silicagel); 7.06(m, 4H); 6.43(m, 1H); 6.32(m, 2H); 5.98(SHS, 1H); 4.38(s, 2H); 4.29(s, 2H); 3.83(C. 3H); 3.19(Sept, 6.6 Hz, 1H); 2.28(m, 2H), 1.25(m, 2H); 1.22(D. 6.6 Hz, 6N); 1.14(m, 2H); 0.99(C. N); 0.80(t 6.8 Hz, 3H).

Stage C. 2-N-(2-Methoxyphenyl)aminomethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.16(m, 5H); 6.43(m, 1H); 6.32(m, 2H); 4.40(C. 2H); 4.39(s, 2H); 3.83(s, 3H); 3.50(Sept, 6.6 Hz, 1H); 2.32(m, 2H); 1.39(d, 6.6 Hz, 6N); 1.31(m, 2H); 1.16(m, 4H); 0.80(so 6.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C28H35FN2O2) 450 found 451 (M+H). Anal. Rasch. for C28H33FN2O2: 74,64; N, 7.83; N, 6.22, found: 74.44; H Of 7.75; N, 6.03. So pl. 109-110oC.

EXAMPLE 214

< / BR>
2-Ethynyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-Ethynyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

n-Utility (0.03 ml, 1.6 M solution in hexane) are added to a chilled (0oC) the solution methyltriphenylphosphonium (10 mg) in tetrahydrofuran (3 ml) After 2 h, add a solution of 2-formyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine (example 205, step A) in tetrahydrofuran (1 ml) is ografia on a column of silica gel (95: 5 hexane/ethyl acetate) to give a colorless solid (20 mg).

1H NMR (300 MHz, CDCl3): 7.44-7.36(m 6N); 7.34-7.27(m, 4H); 7.08-6.98(m, 5H); 6.59(DD, 16.7 Hz, 2.7 Hz, 1H); 5.48(DD, 10.5 Hz, 2.8 Hz, 1H); 4.26(s, 2H); 3.16(Sept, 6.6 Hz, 1H); 2.29(m, 2H), 1.4-1.2(m, 2H); 1.19(d, 6.6 Hz, 6N); 1.15(m, 4H); 0.98(C. N); 0.78(t 6.8 Hz, 3H).

Stage C. 2-Ethynyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.17(s, 2H); 7.14(C. 2H); 7.04(DD, 16.7 Hz, 10.5 Hz, 1H); 6.61 (DD, 16.7 Hz, 2.8 Hz, 1H); 5.51(DD, 10.5 Hz, 2.8 Hz, 1H); 4.36(s, 2H); 3.45(Sept, 6.7 Hz, 1H); 2.32(m, 2H), 1.37(d, 6.6 Hz, 6N); 1.34(m, 2H); 1.15(m, 4H); 0.80(i.e 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H28FNO) 341, found 342 (M+H). Anal. Rasch. for C22H28FNO: 77,38; N, 8.27; N, 4.10, found: 77.15; N 7,98; N, 4.06.

EXAMPLE 215

< / BR>
2-(2-Carbomethoxyamino)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-(2-Carbomethoxyamino)-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound obtained in example 205, step A (50 mg, 85 mmol), and methyl(triphenylphosphonium)acetate (31 mg, 1.1 EQ.) in toluene (5 ml) is heated under reflux for 5 hours the Mixture is cooled to room temperature and to the R (300 MHz, CDCl3): 7.96(D. 15.1 Hz, 1H); 7.42(m 6N); 7.34-7.21 (m, 5H); 7.05(C. 2H); 7.03(s, 2H); 4.28(s, 2H); 3.84(s, 3H); 3.17(Sept, 6.8 Hz, 1H); 2.38(m, 2H), 1.31(m, 2H); 1.19(d, 6.6 Hz, 6N); 1.14(m, 4H); 1.00(C. N); 0.79(i.e 6.6 Hz, 3H).

Stage C. 2-(2-Carbomethoxyamino)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.95(d, 15.1 Hz, 1H); 7.25(d, 15.1 Hz, 1H); 7.17(s, 2H); 7.15(C. 2H); 4.37(d, 3.7 Hz, 2H); 3.84(s, 3H); 3.45(Sept, 6.6 Hz, 1H); 2.40(m, 2H); 1.35(d, 6.6 Hz, 6N); 1.3(m, 4H); 1.14(m, 4H); 1.00 (s, N); 0.79(i.e 6.6 Hz, 3H). EI-MS: calculated for (C24H30FNO3) 399, found

399 (M+). Anal. Rasch. for C24H30FNO3: 72,16; N, 7.57; N, 3.51, found: 71.79; H 7,50; N, 3.32. So pl. 82-83oC.

EXAMPLE 216

< / BR>
2-(1-Methoxyethyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in example 210, step A, according to the method of example 201, step A, and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.15(m, 4H); 4.75(kV, 6.3 Hz, 1H); 4.35(d, 3.7 Hz, 2H); 3.44(Sept, 6.4 Hz, 1H); 3.31(s, 3H); 2.4-2.2(m, 2H); 1.58(d, 6.3 Hz, 3H); 1.35(d, 6.3 Hz, 3H); 1.34(d, 6.6 Hz, 3H); 1.27(m, 2H); 1.11(m, 4H); 0.78(t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H32FNO2

EXAMPLE 217

< / BR>
2-(1-Ethoxyethyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in example 210, step A, according to the method of example 201, step A, and example 198, step D.

1H NMR (300 MHz, CDCl3) 7.16(m, 4H); 4.83(kV, 6.5 Hz, 1H); 4.34(d, 4.4 Hz, 2H); 3.5-3.2(m, 3H); 2.4-2.2(m, 2H), 1.57(d, 6.6 Hz, 3H); 1.34(d, 6.6 Hz, 3H); 1.33(d, 6.6 Hz, 3H); 1.27(m, 2H); 1.10(m, 4H); 1.20(t, 7.2 Hz, 3H); 0.77(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO2) 387 found 388 (M+H). Anal. Rasch. for C24H34FNO2: 74,38; N, 8.84; F 4.90; N, 3.61 found: 74.67; H 9,00; F 5.14; N, 3.27.

EXAMPLE 218

< / BR>
2-Acetyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-Acetyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of intermediate compound obtained in example 210, step A (210 mg, 0.35 mmol), pyridylamine (113 mg, 1.5 EQ.) and celite (110 mg) in dichloromethane (13 ml) is stirred over night. The mixture is filtered through a thin layer of silica gel. Chromatography on a column of silica gel (95:5 hexane/ethyl acetate) to give a colorless solid (120 mg, 57%).

1H NMR (300 MHz, CDCl3): 7.41(m, 6N); 7.34(m, 4H); 7.06(s, 2H); 7.03(s, 2H); 4.29(s, 2H); 3.18(Seil-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.17(s, 2H); 7.15(s, 2H); 4.39(d, 5.2 Hz, 2H); 3.48(Sept, 6.8 Hz, 3H); 2.74(s, 3H); 2.55(m, 2H); 1.35(d, 6.6 Hz, 6N); 1.3(m, 2H); 1.1(m, 4H); 0.77(t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H28FNO2) 357, found 358 (M+H). Anal. Rasch. for C22H28FNO2: 73,92; N, 7.90; N, 3.92 found: 73.89; N 8,14; N, 3.88. So pl. 69-70oC.

EXAMPLE 219

< / BR>
2-(1-Hydroxy-1-methylethyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

Stage A. 2-(1-Hydroxy-1-methylethyl)-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

Receive from the intermediate obtained in example 218, step A, according to the method of example 205, step Century.

1H NMR (300 MHz, Dl3): 7.41(m, 6N); 7.32(m, 4H); 7.08(m, 4H); 4.25(s, 2H); 3.13(Sept, 6.8 Hz, 1H); 2.44(m, 2H); 1.62(s, 6N); 1.2(m, 2H); 1.17(d, 6.6 Hz, 6N); 1.03(m, 4H); 1.01 (s, N); 0.72(t, 6.8 Hz, 3H).

Stage C. 2-(1-Hydroxy-1-methylethyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in stage A, by the method of example 198, step D.

1H NMR (300 MHz, CDCl3): 7.19(m, 4H); 4.36(d, 5.5 Hz, 2H); 3.486(C2
FNO2) 373, found 374 (M+H). Anal. Rasch. for C23H32FNO2: 73,96; N, 8.63; F 5.09; N, 3.75, found: 73.88; H 8,64; F 4.81; N, 3.59. So pl. 180-182oC.

EXAMPLE 220

< / BR>
2-(1-Methoxy-1-methyl)ethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in example 219, step A, according to the method of example 201, step A, and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.26-7.12(m, 4H); 4.34(d, 5.5 Hz, 2H); 3.40(cept, 6.5 Hz, 1H); 3.12(s, 3H); 2.76(m, 2H); 1.67(s, 6N); 1.31(d, 6.6 Hz, 6N); 1.3-0.9(m, 6N); 0.72(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO2) 387 found 388 (M+H). Anal. Rasch. for C24H34FNO2: 74,38; N, 8.84; N, 3.61 found: 74.64; H 8,97; N, 3.61. So pl. 57-59oC.

EXAMPLE 221

< / BR>
2-(1-Ethoxy-1-methyl)ethyl-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the compound obtained in example 219, step A, according to the method of example 201, step A, and example 198, step D.

1H NMR (300 MHz, CDCl3): 7.23-7.11(m, 4H); 4.33(d, 5.1 Hz, 2H); 3.39(cept, 6.6 Hz, 1H); 3.28(q, 7.0 Hz, 2H); 2.80(m, 2H); 1.67(s, 6N); 1.30(d, 6.6 Hz, 6N); 1.15(t, 7.0 Hz, 3H); 1.15-0.9(m, 6N); 0.71 (t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H36FNO2) 401, found 402 (M+H). Anal. Rasch-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

Stage A. ()-2,6-Aminobutiramida-3-[1-hydroxy-2-(S)-tolilsulfonil]-4-(4-forfinal)-5-propylpyridine

The solution sitedisability prepared by adding n-utility (15 ml, 23 mmol, 1.6 M/hexane) to a solution of Diisopropylamine (3 ml, 23 mmol) in anhydrous tetrahydrofuran (100 ml) at a temperature of 0oC. To this solution is added dropwise a solution of (S)-(-)-methyl-para-tailslide (3.6 g, 23 mmol) in anhydrous tetrahydrofuran (20 ml) under stirring. The mixture is stirred at a temperature of 0oC for 2 h, then treated dropwise with a solution of 2,6-aminobutiramida-4-(4-forfinal)-5-propyl-3-pyridinecarboxamide (example 101, step A) (3.8 g, 11 mmol) in anhydrous tetrahydrofuran (50 ml) under stirring. After stirring for 15 min at a temperature of 0oTo the reaction mixture was quenched by adding saturated ammonium chloride (5 ml). The solvent is removed in vacuum and the residue is divided between Snss (300 ml) and water (100 ml). The organic phase is washed with saturated NaHCO3(100 ml), water (100 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. The crude product is a mixture of diastereomers in a ratio of 1.3:1, which is shared by flash chromatography (gradient of 5%-15%-20% ethyl acetate/Gex what shanna faction. The diastereoisomer II recrystallized once from ethanol/hexane to obtain fine white needle-shaped crystals (1.7 g, 3.5 mmol, 30% yield).

I. T. pl. 225-227oC. Rf=0.4(30% ethyl acetate/hexane).

1H NMR (500 MHz, CDCl3): 7.23(m, 4H); 6.95(m, 2H); 6.63(m, 1H); 6.55(m, 1H); 5.03(d, J=11.0 Hz, 1H); 4.53(s, 1H); 3.79(m, 2H); 3.11(Sept, J= 6.6 Hz, 1H); 2.46(s, 3H); 2.30(DD, J=1.9, 14.1 Hz, 1H); 2.01(m, 2H); 1.25(m, N); 1.16(m, 2H); 0.64(t, J=7.3 Hz, 3H). The Belarusian library Association-MS: calculated for (C29H36FNO2S) 481, found 482 (M+H).

II. So pl. 205-206oC. Rf=0.2(30% ethyl acetate/hexane).

1H NMR (500 MHz, CDCl3): 7.38(d, J=8.2 Hz, 2H); 7.24(m, 2H); 7.05(m, 1H); 7.03(m, 1H); 6.97(m, 1H); 6.87(m, 1H); 4.84(dt, J=2.7, 10.8 Hz, 1H); 3.69(Sept, J= 6.6 Hz, 1H); 3.49(DD, J=10.8, 13.1 Hz, 1H); 3.14(Sept, J=6.6 Hz, 1H); 3.00(d, J=2.5 Hz, 1H); 2.68(DD, J=2.5, 13.1 Hz, 1H); 2.41(s, 3H); 2.10(m, 2H); 1.23(m, 14N); 0.69(t, J=7.3 Hz, 3H). The Belarusian library Association-MS: calculated for (C29H36FNO2S) 481, found 482 (M+H).

Stage C. (+)-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

A suspension of Raney Nickel (20 g) in methanol (50 ml) is stirred under hydrogen atmosphere for 1 h, the Suspension is cooled to 0oC and treated with a solution of the intermediate compound (II) obtained in stage A (1.6 g, 3.3 mmol) in methanol (50 ml). The suspension is vigorously methanol decanted from the catalyst, the catalyst was washed and decanted another 3 times with methanol. The combined decanted solution is filtered through celite and concentrated. Flash chromatography on a column of silica (10% ethyl acetate/hexane) gives the target compound (99% of ei) as a white solid (1.1 g, 3.2 mmol, 96%).

1H NMR (300 MHz, CDCl3): 7.11(m, 3H); 7.04(m, 1H); 4.64(DQC, J=3.7, 6.6 Hz, 1H); 3.73(Sept, J=6.6 Hz, 1H); 3.18(Sept, J=6.6 Hz, 1H); 2.15(m, 2H); 1.56(d, J=3.7 Hz, 1H); 1.39(d, J=6.6 Hz, 3H); 1.28(m, 14N); 0.73(t, J= 7.35 Hz, 3H), of the Belarusian library Association-MS: calculated for (C22H30FNO) 343, found 344 (M+H). Anal. Rasch. for C22H30FNO: 76,93; N, 8.80; N, 4.08; F 5.53 found: 76.98; H 8,71; N, 3.76; F 5.73. []D=+41.5o(SNS3). So pl. 101-103oC; Rf= 0.3(10% ethyl acetate/hexane).

EXAMPLE 223

< / BR>
(+)-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

Stage A. 2,6-Aminobutiramida-4-(4-forfinal)-5-propyl-3-[(1-oxo-2-cellsurface)ethyl]pyridine

To a solution of Diisopropylamine (4.8 ml, 36.7 mmol) in anhydrous tetrahydrofuran (160 ml) is added n-utility (23 ml, 33.4 mmol, 1.45 M/THF) at a temperature of 0oC. To the reaction mixture add a solution of (S)-(-)-methyl-para-tailslide (5.65 g, 36.7 mmol) in anhydrous tetrahydrofuran (30 ml). The mixture is stirred for 1 is pushing A) (8.0 g, 24.4 mmol) in anhydrous tetrahydrofuran (100 ml) at a temperature of 0oC. After stirring for 15 min at a temperature of 0oTo the reaction mixture was quenched by adding a saturated solution of ammonium chloride (8 ml). The solvent is removed in vacuum and the residue is dissolved in chloroform (480 ml). The organic phase is washed with water (2160 ml) and brine (160 ml), dried over magnesium sulfate and concentrated. The residue is dissolved in dichloromethane (800 ml) and add manganese dioxide (IV) (40 g, 464 mmol). The suspension is vigorously stirred using a mechanical stirrer and heated under reflux for 16 hours Dioxide manganese (IV) is removed by filtration through celite, washed with dichloromethane (100 ml) and the solvent is removed in vacuum. Filtration through a layer of silica gel (7.5% diethyl ether/dichloromethane) to give white solid (10.2 g, 21.3 mmol, 87%).

1H NMR (300 MHz, CDCl3): 7.39(m, 2H); 7.26(m, 2H); 7.05(m, 4H); 3.72(d, J= 16 Hz, 1H); 3.38(d, J= 16 Hz, 1H); 3.24(Sept, J=6.6 Hz, 1H); 2.59(Sept, J= 6.6 Hz. 1H); 2.42(s, 3H); 2.32(m, 2H); 1.27(m, 8H); 1.20(m, 8H); 0.75(t, J= 7.35 Hz, 3H). The Belarusian library Association-MS: calculated for (C29H34FNO2S) 479 found 480 (M+H). So pl. 140-142oC. Rf=0.2(20% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida-3-(1-hydroxy-2-(S)-tailcall) in anhydrous tetrahydrofuran (145 ml) at a temperature of -78oTo quickly add a solution of socialogical (169 ml, 169 mmol, 1.0 M/THF). After 15 min, the reaction mixture becomes turbid and slowly quenched at a temperature of -78oWater (6 ml), 20% aqueous sodium hydroxide solution (6 ml) and water (18 ml). The reaction mixture is heated to room temperature and the resulting suspension is filtered through a layer of celite. The solvent is evaporated and the residue purified by chromatography on a column of silica gel (10% diethyl ether/dichloromethane) to give a white solid (4.8 g, 10 mmol, 83%).

1H NMR (300 MHz, CDCl3): 7.41 (d, J=8.5 Hz, 2H); 7.27(m, 2H); 7.06(d, J=7.Hz, 2H); 7.00(m, 1H); 6.89(m, 1H); 4.85(dt, J=2.2, 11 Hz, 1H); 3.71(Sept, J= 6.6 Hz, 1H); 3.51(DD, J=11,13 Hz, 1H); 3.16(Sept, J=6.6 Hz, 1H); 3.02(d, J=2.2 Hz, 1H); 2.70(DD, J=2.2, 13 Hz, 1H); 2.43(s, 3H); 2.12(m, 2H); 1.25(m, 14N); 0.71(t, J=7.35 Hz, 3H). The Belarusian library Association-MS: calculated for (C29H36FNO2S) 481, found 482 (M+H). So pl. 204-206oC. Rf=0.2(30% ethyl acetate/hexane).

Stage C. (+)-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

A suspension of Raney Nickel (40 g, washed 3100 ml ethanol) in ethanol (80 ml) is stirred under hydrogen atmosphere for 1.5 hours, the Suspension is treated with a solution of the intermediate obtained in stage (4.1 g, 8.5 mmol) in ethanol (80 m and concentrate. Filtration through silica gel (dichloromethane) to give the target compound (99% of ei) as a white solid (2.74 g, 8 mmol, 94%).

1H NMR (300 MHz, CDCl3): 7.11(m, 3H); 7.04(m, 1H); 4.64(DQC, J=3.7, 6.6 Hz, 1H); 3.73(Sept, J=6.6 Hz, 1H); 3.18(Sept, J=6.6 Hz, 1H); 2.15(m, 2H); 1.56(d, J=3.7 Hz, 1H); 1.39(d, J=6.6 Hz, 3H); 1.28(m, 14N); 0.73(t, J= 7.35 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H31FNO, M+N) 344, found 344. Anal. Rasch. for C22H30FNO: 76,93; N, 8.80; N, 4.08; F 5.53 found: At 77.20; N 8,97; N, 4.01; F 5.60. []D= +39.40(CH2CL2). So pl. 104-106oC. Rf=0.4(dichloromethane).

EXAMPLE 224

< / BR>
(+)-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

Stage A. 2,6-Aminobutiramida-3-(1-oxoethyl)-4-(4-forfinal)-5-propylpyridine

K ()-2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine (example 101) (8.03 g, 23.4 mmol) in dichloromethane (600 ml) is added pyridineboronic (10.08 g, 46.76 mmol) and celite (10.1 g) in an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was added to a 1:1 mixture of diethyl ether/hexane (1 l), then filtered through a layer of silicon dioxide. Layer was washed with 150 ml of diethyl ether and the combined filtrates concentrated in vacuo to obtain a white solid= 6.6 Hz, 1H); 2.36(m, 2H); 1.97(s, 3H); 1.33(m, 14N); 0.774(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H28FNO) 341, found 342 (M+H). So pl. 131-133oC. Rf=0.5(50% dichloromethane/hexane).

Stage C. (+)-2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine

To a solution of (1S,2R)-(+)-N-methylpyridine (31.1 g, 0.174 mol) in ether (208 ml) was added dropwise socialogical (lM/diethyl ether, 1.5 EQ., 174 ml) at a temperature of 0oC in argon atmosphere. The reaction mixture is heated under reflux for 1.5 hours, transforming from a pure solution in the solution a milky color. The reaction mixture is cooled to room temperature and then to a temperature of -78oC. the Intermediate compound obtained in stage A (39.53 g, 0.116 mmol), dissolved in 400 ml of dry diethyl ether and cooled to 0oIn order dropwise adding to the reaction mixture (about 2 ml/min, the temperature should not rise above -60oC). The reaction mixture stand at a temperature of -78oC for 4.0 h and then allowed to warm during the night. The reaction mixture is quenched at a temperature of 0oWith isopropanol (70 ml) and diluted with ether (700 ml), washed with water (4500 ml), 10% Hcl (2500 ml), saline solution (2500 ml) and dried over magnesium sulfate. Shown is an) to obtain the target compound (97% of ei) as a white solid (36.67 g, 107 mmol, 92%).

1H NMR (300 MHz, CDCl3): 7.11(m, 4H); 4.67(DQC, J=3.3, 6.6 Hz, 1H); 3.74(septet, J=6.6 Hz, 1H); 3.20(septet, J=6.6 Hz, 1H); 2.17(m, 2H); 1.61(d, J= 2.9 Hz, 1H); 1.40(d, J=7.0 Hz, 3H); 1.30(m, 14N); 0.741(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H30FNO) 343, found 344 (M+H). So pl. 102-104oC. Rf=0.2(60% dichloromethane/hexane).

EXAMPLE 225

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-(2-TRANS-phenylethyl)pyridine

Stage A. 2-methyl bromide-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

Receive from the intermediate obtained in example 200, step B, by the method of example 47, step Century.

1H NMR (300 MHz, CDCl3): 7.40(m, 6N); 7.32(m, 4H); 7.04(m, 4H); 4.64(s, 2H); 4.26(s, 2H); 3.14(Sept, 6.8 Hz, 1H); 2.38(m, 2H); 1.34(m, 2H); 1.17(d, 7.0 Hz, 6N); 1.12(m, 4H); 1.00(s, N); 0.78(t, 6.6 Hz, 3H).

Stage C. 2-(diethylphosphino)methyl-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

A mixture of diethylphosphate (280 mg) and metal sodium (50 mg) in benzene (5 ml) is stirred over night. The mixture solution diethylphosphate sodium (1 ml) and intermediate compounds obtained in stage A (100 mg, 0.17 mmol) in benzene (5 ml) is heated under reflux for 2 hours the Mixture is concentrated in Chromatography on a column of silica gel (70: 30 hexane/ethyl acetate) to give a yellow oil (80 mg, 67%).

1H NMR (300 MHz, CDCl3): 7.41(m, 6N); 7.32(m, 4H); 7.04(m, 4H); 4.25(s, 2H); 4.15(DQC, 7.2 Hz, 4H); 3.49(d, 22.4 Hz, 2H); 3.14(Sept, 6.8 Hz, 1H); 2.38(m, 2H); 1.30(t, 7.2 Hz, 6N); 1.25(m, 2H); 1.16(d, 6.6 Hz, 6N); 1.10(m, 4H); 0.99(s, N); 0.77(t, 6.8 Hz, 3H).

Stage C. 2-(TRANS-2-Phenylethenyl)-3-pentyl-4-(4-forfinal)-5-(tert-butyldiphenylsilyl)methyl-6-isopropylpyridine

Sodium hydride (8 mg) is added to a mixture of intermediate compound obtained in stage B (90 mg, 128 μmol), and benzaldehyde (20 mg) in THF (2.7 ml). After 15 min the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride. Chromatography on a column of silica gel (97:3 hexane/ethyl acetate) to give a yellow oil (100 mg).

1H NMR (300 MHz, CDCl3): 8.00( d, 15.4 Hz, 1H); 7.61(m, 2H); 7.45-7.27(m, 14N); 7.04(m, 4H); 4.29(s, 2H); 3.20(Sept, 6.4 Hz, 1H); 2.38(m, 2H); 1.40(m, 2H); 1.25(d, 6.6 Hz, 6N); 1.18(m, 4H); 1.00(s, N); 0.81(m, 3H).

Stage D. 2-(TRANS-2-Phenylethenyl)-3-pentyl-4-(4-forfinal)-5-hydroxymethyl-6-isopropylpyridine

The target compound is obtained from the intermediate obtained in stage C according to the method described in example 198, step D. Chromatography on a column of silica gel (94: 6 hexane/ethyl acetate) to give a yellow oil (24 mg, 38%).

1H NMR (300 MHz, CDCl3): 8.02( d, 15.5 Hz, 1H); 7.63(m, nitro for (C28H32FNO) 417, found 418(M+H). Rf=0.13 (90:10 hexane/ethyl acetate). Anal. Rasch. for C28H32FN: C, 80,54; H, 7.72; N, 3.35, found: 80.34; N 7,79; N, 3.10. So pl. 98-100oC.

EXAMPLE 226

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-(2-methylpropenyl)pyridine

The target compound obtained as yellow oil from the intermediate obtained in example 225, step In, according to the method of example 225, step C and example 198, step D. the Product is obtained in the form of an undivided mixture of the target compounds and the corresponding desplazando of olefin in the ratio of 84:16.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 6.43(s, 1H); 4.82(s, 1H, not the main isomer); 4.60(s, 1H, not the main isomer); 4.36(s, 2H); 3.58(s, 2H, not the main isomer); 3.46(cept, 6.6 Hz, 1H); 2.26(m, 2H); 2.07(s, 3H); 1.99(s, 3H); 1.82(s, 3H), not the main isomer); 1.35(d, 7.0 Hz, 6N); 1.28(m, 2H); 1.13(m, 4H); 0.79(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H32FNO) 369, found 370 (M+H). Rf= 0.16 (90: 10 hexane/ethyl acetate). Anal. Rasch. for C24H32FNO: 78,01; N, 8.73; N, 3.79 found: 77.73; N 8,86; N, 3.97.

EXAMPLE 227

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-(2-phenylethyl)pyridine

The target compound obtained as yellow oil from the intermediate connections, 9-7.19(m, 5H); 7.14(s, 2H); 7.12(s, 2H); 4.34(s, 2H); 3.44(Sept, 6.6 Hz, 1H); 3.18-3.10(m, 4H); 2.20(m, 2H); 1.35(d, 6.6 Hz, 6N); 1.22(m, 2H); 1.08(m, 4H); 0.76(t, 6.8 Hz, 3H). The Belarusian library Association-MS: calculated for (C28H34FNO) 419, found 420 (M+H). Rf=0.21 (90:10 hexane/ethyl acetate). Anal. Rasch. for C28H34FNO: 80,18; N, 8.17; N, 3.34, found: 80.12; N 8,15; N, 3.24.

EXAMPLE 228

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-(2-methylpropyl " pyridine

The target compound obtained as a colorless crystalline solid from intermediate compounds obtained in example 226, according to the method of example 1, stage N.

1H NMR (300 MHz, CDCl3): 7.15(m, 4H); 4.33(d, 5.2 Hz, 2H); 3.41(Sept, 6.6 Hz, 1H); 2.67(d, 7.0 Hz, 2H); 2.34(m, 2H); 2.25(m, 2H); 1.32(d, 6.6 Hz, 6N); 1.20(m, 2H); 1.12(m, 4H); 0.99(d, 6.6 Hz, 6N); 0.78(t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Rf=0.77 (90:10 hexane/ethyl acetate). Anal. Rasch. for C24H34FNO: 77,59; N, 9.22; N, 3.77 found: 77.49; H 9,20; N, 3.73.

EXAMPLE 229

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5-pentyl-6-(3-methylbutyl)pyridine

The target compound obtained as yellow oil from the intermediate obtained in example 225, step In, according to the method of example 225, stage C and D, and example 1, step H.1H NMR (300 MHz, 6.3 Hz, 6N); 0.79 (t, 6.6 Hz, 3H). The Belarusian library Association-MS: calculated for (C25H36FN) 385, found 386 (M+H). Rf=0.15 (90:10 hexane/ethyl acetate). Anal. Rasch. for C25H36FN: 77,88; N, 9.41; N, 3.63 found: 77.62; N 9,13; N, 3.42.

EXAMPLE 230

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylphenol

Stage A. 2-[(4-Forfinal)methylene]-4-methyl-3-oxopentanoic acid

To a solution of utilizability (30 g, 0.190 mol) in ethanol (75 ml) was added cyclohexane (120 ml), acetic acid (0.6 ml), piperidine (0.6 ml) and 4-forbindelse (20.35 ml, 0.190 mol). The reaction mixture is heated under reflux with trap Dean-stark for 5 hours the Mixture is poured into 200 ml of diethyl ether and washed with saline solution (175 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated to obtain an orange oil. The product is taken directly to the next stage without further purification. Rf=0.1 (50% dichloromethane/hexane).

Stage C. 2-Isopropyl-3-carboethoxy-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylphenol

To a solution of lithium bis(trimethylsilyl)amide (1.0 M/THF, 2 EQ., 13.6 ml) in THF (15 ml) is added 2,2-dimethylcyclohexanone (1.88 ml, 13.6 mmol) at a temperature of -78oC. the Reaction mixture is re the ol). The reaction mixture was stirred overnight and warmed to room temperature. To the crude product add acetic acid (19.4 ml), ammonium acetate (2.62 g, 34.0 mmol) and copper acetate (5.14 g, 28.3 mmol). The reaction mixture is heated to a temperature of 100oWith and THF is removed by distillation. The reaction mixture is heated to a temperature of 130oC and refluxed for 24 hours Add ethyl acetate (100 ml) and washed with sodium bicarbonate (230 ml), water (220 ml), brine (220 ml), dried over magnesium sulfate, filtered and concentrated to obtain oil. Flash chromatography (5% ethyl acetate/hexane) to give white solid (1.36 g, 3.7 mmol, 32%).

1H NMR (300 MHz, CDCl3): 7.17(m, 2H); 7.08(m, 2H); 3.98 (q, J=7.4 Hz, 2H); 3.03(septet, J=7.0 Hz, 1H); 2.35(t, J=5.9 Hz, 2H); 1.70(m, 4H); 1.36(s, 6N); 1.31(d, J=4.1 Hz, 6N); 0.965(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H28FNO) 369, found 370 (M+H). So pl. 124-126oC. Rf=0.6 (50% dichloromethane/hexane).

Stage C. 2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylphenol

To the intermediate compound obtained in stage (1.32 g, 3.6 mmol) in THF (35 ml) was added dropwise socialogical (1M/THF, 2 EQ., 7.2 ml). The reaction mixture is heated OBR is more. The remainder is divided between diethyl ether (150 ml) and water (100 ml). The organic layer was washed with saline solution (1100 ml), dried over magnesium sulfate, filtered and concentrated to obtain a solid substance. Flash chromatography (40% dichloromethane/hexane)to give the target compound as a white solid (808 mg, 2.5 mmol, 70%).

1H NMR (300 MHz, CDCl3): 7.13(d, J=7.0 Hz, 4H); 4.36(d, J=5.5 Hz, 2H); 3.42(septet, J= 6.6 Hz, 1H); 2.24(t, J=5.5 Hz, 2H); 1.67(m, 4H); 1.32(m, 13H). The Belarusian library Association-MS: calculated for (C21H26FNO) 327, found 328(M+H). So pl. 146-149oC. Rf=0.2(50%dichloromethane/hexane).

EXAMPLE 231

< / BR>
2-Isopropyl-3-(1-hydroxyethyl)-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylphenol

Stage A. 2-Isopropyl-3-carboxaldehyde-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylphenol

To a solution of 2-isopropyl-3-hydroxymethyl-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylaniline (example 230) (765 mg, 2.34 mmol) in dichloromethane (30 ml) was added celite (1.01 g) and pyridineboronic (1.01 g, 4.69 mmol). The reaction mixture was stirred at room temperature for 2 h and then added 1:1 solution of diethyl ether/hexane (500 ml). The solution is passed through a layer of silica and washed several times with diethyl ether. The concentration of dapat, J=6.6 Hz, 1H); 2.31(t, J= 5.9 Hz, 2H); 1.70(m, 4H); 1.37(s, 6N); 1.30(m, 6N). The Belarusian library Association-MS: calculated for (C21H24FNO) 325, found 326 (M+H). So pl. 94-96oC. Rf=0.7 (50% dichloromethane/hexane).

Stage C. 2-Isopropyl-3-(1-hydroxyethyl)-4-(4-forfinal)-5,6,7,8-tetrahydro-8,8-dimethylphenol

To the intermediate compound obtained in stage A (508 mg, 1.56 mmol) in THF (20 ml) added dropwise methylmagnesium (0.57 ml, 3.0 M/ether, 1.1 EQ.) at a temperature of -78oC. After 2 hours the reaction mixture was quenched with a saturated solution of ammonium chloride (30 ml) and diluted with dichloromethane (100 ml). The solid is filtered off and mother liquor was washed with water (150 ml), brine (150 ml), dried over magnesium sulfate, filtered and concentrated to obtain a white solid. Flash chromatography (50% dichloromethane/hexane) to give white solid (205 mg, 0.6 mmol, 39%).

1H NMR (300 MHz, CDCl3): 7.13(m, 3H); 7.01(m, 1H); 4.73, 4.71(DQC, J= 3.7, 6.6 Hz, 1H); 3.74(septet, J= 6.6 Hz, 1H); 2.13(q, J=4.4 Hz, 2H); 1.64(m, 3H); 1.31(m, 17H). The Belarusian library Association-MS: calculated for (C22H27FNO) 341, found 342 (M+H). So pl. 56.5-58.5oC. Rf=0.2 (50% dichloromethane/hexane).

EXAMPLE 232

< / BR>
2,6-Aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-(1-butenyl)pyridine

Target sulfur 230.

1H NMR (300 MHz, CDCl3): 7.16(m, 3H); 6.91(m, 6N); 4.45(d, J=5.1 Hz, 2H); 3.52(septet, J= 6.6 Hz, 1H); 2.86(septet, J=6.6 Hz, 1H); 1.55(s, 1H); 1.36(m, 6N); 1.17(d, J=6.6 Hz, 1H). The Belarusian library Association-MS: calculated for (C24H26FNO) 363, found 364 (M+H). So pl. 115-117oC. Rf=0.3 (60% dichloromethane/hexane).

EXAMPLE 233

< / BR>
2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-vinylpyridin

The target connection receive according to the method of example 231.

1H NMR (300 MHz, CDCl3): 7.14(m, 3H); 6.88(m, 6N); 4.80(DQC, J=7.0, 3.7 Hz, 1H); 3.84(Sept, J=6.6 Hz, 1H); 2.79(Sept, J=6.6 Hz, 1H); 1.66(d, J= 3.7 Hz, 1H); 1.48(d, J= 7.0 Hz, 3H); 1.39(m, 6N). The Belarusian library Association-MS: calculated for (C25H28FNO) 377 found 378 (M+H). So pl. 155-157oC. Rf=0.4 (60% dichloromethane/hexane).

EXAMPLE 234

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-7,7-dimethyl-5H-cyclopent[b] pyridine

The target compound is obtained from ethylisopropylamine, 4-forventelige and 2,2-dimethylcyclopentane by the method of example 230.

1H NMR (300 MHz, CDCl3): 7.29(m, 2H); 7.14(m, 2H); 4.49(d, J=5.2 Hz, 2H); 3.46(Sept, J=6.6 Hz, 1H); 2.56(t, J=7.0 Hz, 2H); 1.90(t, J=7.0 Hz, 2H); 1.34(m, 13H). The Belarusian library Association-MS: calculated for (C20H24FNO) 313, found 314 (M+H). So pl. 141-143oC. Rf=0.1 (60% dichloromethane/hexane).

EXAMPLE 235

< / BR>
2-Isopropyi example 231.

1H NMR (300 MHz, CDCl3): 7.15(m, 4H); 4.95(DQC, J=6.6, 3.7 Hz, 1H); 3.77(Sept, J=6.6 Hz, 1H); 2.44(m, 2H); 1.88(t, J=7.4 Hz, 2H); 1.62(d, J=3.7 Hz, 1H); 1.48(d, J= 7.0 Hz, 3H); 1.32(m, N). The Belarusian library Association-MS: calculated for (C21H26FNO) 327, found 328 (M+H). So pl. 90-92oC. Rf=0.1 (60%dichloromethane/hexane).

EXAMPLE 236

< / BR>
2-Isopropyl-3-hydroxymethyl-4-(4-forfinal)-5,6-dihydro-6,6,8-trimethylquinoline

The target compound is obtained from ethylisopropylamine, 4-forventelige and 2,4,4-trimethyl-2-cyclohexen-1-it is by the method of example 230.

1H NMR (300 MHz, CDCl3): 7.16(m, 4H); 5.81(s, 1H); 4.41(d, J=5.2 Hz, 2H); 3.45(Sept, J= 6.6 Hz, 1H); 2.29(s, 2H); 2.16(s, 3H); 1.58(s, 1H); 1.35(d, J=6.6 Hz, 6N); 0.95(s, 6N). The Belarusian library Association-MS: calculated for (C22H26FNO) 339, found 340 (M+H). So pl. 112-114oC. Rf=0.2 (60% dichloromethane/hexane).

EXAMPLE 237

< / BR>
2-Isopropyl-3-(1-hydroxyethyl)-4-(4-forfinal)-5,6-dihydro-6,6,8-trimethylquinoline

The target connection receive according to the method of example 231.

1H NMR (300 MHz, CDCl3): 7.14(m, 3H); 7.00(m, 1H); 5.78(s, 1H); 4.77(DQC, J=6.6, 3.7 Hz, 1H); 3.76(Sept, J=6.6 Hz, 1H); 2.18(s, 2H); 2.14(s, 3H); 1.61(d, J= 3.7 Hz, 1H); 1.43(d, J=6.6 Hz, 3H); 1.33(m, 6N); 0.91 (s, 6N). The Belarusian library Association-MS: calculated for (C23H28FNO) 353, found 354 (M+H). So pl. 117-119oC. Rf=0.3 (60% dichloromethane/hexane).


Receive from the intermediate obtained in example 166, step In, according to the method of example 160, stages A-D.

1H NMR (300 MHz, CDCl3): 1.20-1.34(m, N); 1.56-1.59(m, 3H); 1.68-1.74(m, 1H); 3.13-3.50(m, 2H); 4.23-4.42(m, 2H); 4.87-5.05(m, 2H); 5.25-5.56(m, 1H); 5.23-6.03(m, 1H); 6.69-6.77(m, 2H); 6.95-7.08(m, 3H); 7.22-7.27(m, 3H). The Belarusian library Association-MS: calculated for (C28H32NO2F) 433 found 434 (M+1). Rf= 0.3 (10% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-fluoro-2-hydroxyphenyl)-5-propylpyridine

The target connection receive in the form of two partial diastereomers of the intermediate compound obtained in stage A, by the method of example 164, stages a-C. the Diastereomers separated radial tape chromatography using a gradient eluent of 100% hexane to 20% ether-hexane.

The diastereoisomer 1.1H NMR (300 MHz, CDCl3): 0.75(t, J=7.2 Hz, 3H); 1.27-1.40(m, 17H); 1.66(SHS, 1H); 2.02-2.12(m, 1H); 2.20-2.31(m, 1H); 3.21(Sept, J= 6.6 Hz, 1H); 3.60(Sept, J=6.6 Hz, 1H); 4.94(m, 1H); 5.03(SHS, 1H); 6.70-6.76(m, 2H); 6.94-7.00(m, 1H). The Belarusian library Association-MS: calculated for (C22H30NO2F) 359, found 360 (M+1). Rf=0.29 (20% ethyl acetate/hexane). So pl. 152-153oC.

The diastereoisomer 1 share at cost-9668A, 650 cm ID). System balance mobile phase consisting of 1% (1% acetic acid, 99% ethanol) and 99% hexane at a flow rate of 150 ml/min, the Sample was dissolved in chloroform (50 mg/ml) and inject 5 ml aliquots with an interval of 40 minutes Outgoing flow control at 280 nm and two fractions (corresponding to the two enantiomers) collect at (17-23 min, 100% of ei) and (23-32 min, 98% of ei), respectively.

The diastereoisomer 2. 1H NMR (300 MHz, CDCl3): 0.75(t, J=7.2 Hz, 3H); 1.26-1.31(m, 14N); 1.38(d, J= 6.9 Hz, 3H); 1.84-1.87(m, 1H); 2.05-2.14(m, 1H); 2.24-2.34(m, 1H); 3.20(septet, J=6.6 Hz, 1H); 3.72(septet, J=6.6 Hz, 1H); 4.58-4.65(m, 1H); 5.06(CL, 1H); 6.67-6.74(m, 2H); 6.85-6.90(m, 1H). The Belarusian library Association-MS: calculated for (C22H30NO2F) 359, found 360 (M+1). Rf=0.19 (20% ethyl acetate/hexane). So pl. 157-159oC.

EXAMPLE 239

< / BR>
2,6-Aminobutiramida-3-(1-hydroxymethyl)-4-(4-fluoro-2-hydroxyphenyl)-5-propylpyridine

The target compound is obtained from 2,6-aminobutiramida-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyl] -5-(prop-1-enyl)pyridine (example 238, step A) according to the methods of example 161, step A (so pl. 138-141oC).

1H NMR (300 MHz, CDCl3): 0.76(t, J=7.2 Hz, 3H); 1.24-1.35(m, 14N); 1.82(SHS, 1H); 2.12-2.22(m, 1H); 2.27-2.37(m, 1H); 3.24(Sept, J=6.6 Hz, 1H); 3.39(Sept, J= 6.6 Hz, 1H); 4.29(d, J=11.4 Hz, 1H); 4.52(d, J=10.8 Hz, 1H); 5.72(CL, 1H); 7.70-6.77(m, 2H); 6.94-7.00(m, 1H).2">

The racemate is separated into its constituent enantiomers as follows. Waters Prep LC 2000 HPLC system equipped with a column for chiral GHUR (BRB-9668A, 6h50 cm ID). System balance mobile phase consisting of 1% (1% acetic acid, 99% ethanol) and 99% hexane at a flow rate of 100 ml/min Sample dissolved in mobile phase (5 mg/ml) and inject 3 ml aliquots every 30 minutes Outgoing flow control at 280 nm, and two fractions (corresponding to the two enantiomers) are picked at 24-36 min (100% of ei) and 26-30 min (95.5% of ei), respectively.

EXAMPLE 240

< / BR>
2,6-Aminobutiramida-3-(1-hydroxyethyl)-4-(4-fluoro-2-hydroxyphenyl)-5-eilperin

Stage A. 2,6-Aminobutiramida-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyl] -5-ethenylpyridine

Receive from the intermediate obtained in example 166, step In, according to the method of example 160, stages A-D.

1H NMR (300 MHz, CDCl3): 1.25-1.33(m, N); 1.66-1.70(m, 1H); 3.34-3.50(m, 2H); 4.28-4.41(m, 2H); 4.89-5.18(m, 4H); 6.29-6.39(m, 1H); 6.67-6.78(m, 2H); 7.23-7.25(m, 3H). The Belarusian library Association-MS: calculated for (C27H30NO2F) 419, found 420 (M+1). Rf=0.29 (10% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida 3-carboxaldehyde-4-[(2-benzyloxy-4-fluoro)phenyl]-5-ethenylpyridine

Obtained from intermediate compounds, PA.24(Sept, J=6.6 Hz, 1H); 3.89(Sept, 1H, J=6.6 Hz); 4.93-5.04(m, 3H); 5.23(DD, J=1.5, 11.4 Hz, 1H); 6.40(DD, J= 11.4, 17.7 Hz, 1H); 6.70-7.04(m, 2H); 6.99-7.04(m, 1H); 7.10-7.14(m, 2H); 7.24-7.29(m, 3H); 9.82(s, 1H). The Belarusian library Association-MS: calculated for (C27H28NO2F) 417, found 418 (M+1). Rf=0.68 (10% ethyl acetate/hexane).

Stage C. 2,6-Aminobutiramida-3-(2-hydroxyethyl)-4-[(2-hydroxy-4-fluoro)phenyl]-5-ethylpyridine

In kiln dried 250-ml three-neck round bottom flask equipped with a thermometer, was placed a copper iodide (I) (3.21 g, 16.9 mmol) and toluene (40 ml) in an argon atmosphere. The suspension is cooled to an internal temperature of 0oC. Add motility (1.4 M in ether, 25 ml, 0.03314 mol) with such a rate as to maintain the temperature of the reaction mixture <5C. the Reaction mixture was then stirred at a temperature of 0oWith over 50 minutes By the end of this period of time add an intermediate stage In connection with (1.33 g, 3.19 mmol) in 10 ml of toluene via syringe at such a speed as to maintain the temperature of the reaction mixture <5C. the Syringe is washed with an additional 4 ml of toluene and the toluene is added to the reaction mixture with such a rate as to maintain the temperature of the reaction mixture <5C. the Reaction mixture is stirred at a temperature of 0oWith W for 36 hours at a temperature of 25oC. the Reaction mixture is poured into a separating funnel and extracted with ethyl acetate (350 ml). The combined organic layer is then concentrated to obtain the crude intermediate compound (1.4 g, yellow oil, the ratio of diastereomers 9:1). The crude intermediate compound dissolved in a mixture of ethanol (30 ml) and tetrahydrofuran (10 ml) in an argon atmosphere, and treated with 10% palladium on coal (140 mg) and then stirred in an atmosphere of hydrogen for 14 hours After the flush of the system with argon, the catalyst was removed by filtration through a layer of celite. The solvent is removed and the residue purified flash chromatography (12-15% ethyl acetate/hexane) to give 1.0 g of the target compound in the form of two partial diastereomers.

The diastereoisomer 1.1H NMR (300 MHz, CDCl3): 0.91(t, J=7.4 Hz, 3H); 1.28-1.40(m, 15 NM); 1.70(d, J=3.9, 1H); 2.12-2.24(m, 1H); 2.29-2.41(m, 1H); 3.24(Sept, J= 6.6 Hz, 1H); 3.61(Sept, J= 6.6 Hz, 1H); 4.89-5.00(m, 1H); 5.10(SHS, 1H); 6.70-6.76(m, 2H); 6.96-7.01(m, 1H). The Belarusian library Association-MS: calculated for (C21H28NO2F) 345, found 346 (M+1). Rf=0.43 (30% ethyl acetate/hexane). So pl. 190-191oC.

The diastereoisomer 1 is separated into its constituent enantiomers as follows. Waters Prep LC 2000 HPLC system equipped with a column for chiral GHUR (BRB-9668A, 6h50 cm ID). The system is AC 100 ml/min Sample (1 g) dissolved in a mixture of dichloromethane (40 ml), ethanol (1 ml) and 10 ml of mobile phase. The mixture is injected, and the outgoing flow control at 280 nm and two fractions (corresponding to the two enantiomers) are picked at 27-29 min (99.8% of ei) and 37-57 min (99.4% of ei), respectively. Fraction 1 (27-29 min): []25D+4.7o(C=0.54, dichloromethane).

The diastereoisomer 2.1H NMR (300 MHz, CDCl3): 0.89(t, J=7.5 Hz, 3H); 1.26-1.38(m, 15 NM); 1.92(d, J=3 Hz, 1H); 2.12-2.25(m, 1H); 2.31-2.43(m, 1H); 3.23(septet, J= 6.6 Hz, 1H); 3.72(septet, J=6.6 Hz, 1H); 4.56-4.63(m, 1H); 5.14(SHS, 1H); 6.68-6.74(m, 2H); 6.85-6.91(m, 1H). The Belarusian library Association-MS: calculated for (C21H28NO2F) 345, found 346 (M+1). Rf=0.27 (30% ethyl acetate/hexane). So pl. 201-202oC.

EXAMPLE 241

< / BR>
3,5-Aminobutiramida-2-hydroxymethyl-6-propyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

Stage A. Dimethyl ether 4,6-diethyl-2-hydroxy-1,3-benzylcarbamoyl acid

A mixture of dimethyl ether 1,3-aacondicionado acid (200 g, 1.15 mol), 3,5-heptanedione (140 g, 1.09 mol) and sodium methoxide (70 g, 1.25 mol) in methanol (1.5 l) was heated under reflux overnight. The methanol is removed on a rotary evaporator and the resulting orange slurry is shared between diethyl ether (1 l) and 10% aqueous hydrochloric acid (1 liter). The separated aqueous layer was EXTA (0.1 l), dried over sodium sulfate, filtered through a layer of silicon dioxide (40mm x 100mm) and concentrated in vacuo. The crude oil is purified by distillation in vacuum at 0.25 Torr to obtain the pure product in the form of translucent yellow oil (so Kip. 125-145oWith, 202 g, 70%).

1H NMR (300 MHz, Dl3): 1.20(t, J=7.4 Hz, 6N); 2.71-2.80(m, 4H); 3.95(s, 6N); 6.64(s, 1H); 11.67(s, 1H).13H NMR (75 MHz, Dl3): 15.42, 28.31, 52.27, 115.22, 121.91, 148.63, 159.71, 169.86. EI-MS: calculated for (C14H18O5) 266, found 266 (M+). Anal. Rasch. for C14H18O5: 63.15; H 6.81. Found: 63.23; N, 6.92. Rf=0.38 (9:1 hexane:ethyl acetate). GHUR: (C-18, A= 0.05% aqueous triperoxonane acid,=CH3SP; linear gradient: 50%-100% over 30 min; 254 nm, 1 ml/min): R. T. 14.4 min (100.0 area %).

Stage C. Dimethyl ether 4,6-diethyl-2-methoxy-1,3-benzylcarbamoyl acid

A mixture of crude intermediate compound from step A (241.6 g, 0.91 mol), potassium carbonate (204 g, 1.48 mol) and dimethylsulfate (129 ml, 1.37 mol) in acetone (1 l) and vigorously stirred overnight. After 6 hours of heating under reflux, the reaction mixture was cooled to room temperature, add the additional amount of dimethylsulfate (43 ml, 0.46 mol) and nagrevaniya use diethyl ether (1 l) and the combined filtrates concentrated in vacuo. The crude oil is purified by vacuum distillation to obtain the pure product in the form of translucent yellow oil (so Kip. 180-190oWith, 178.1 g, 58% (stage 2)).

1H NMR (300 MHz, Dl3): 1.16-1.25(m, 6N); 2.55-2.66(m, 4H); 3.81(s, 3H); 3.91(s, 6N); 6.89(s, 1H). Rf=0.34 (9:1 hexane:ethyl acetate).

Stage C. Dimethyl ether 4,6-aminobutiramida-2-methoxy-1,3-benzylcarbamoyl acid

The solution Diisopropylamine (26.7 ml, 0.20 mol) in dry tetrahydrofuran (0.2 l) at a temperature of -78oC in an atmosphere of argon is treated by slow addition of the

n-utility (2.4 M in hexane, 85.0 ml, 0.20 mol). After stirring the reaction mixture for 15 min a solution of the intermediate from step B (58.0 g, 0.16 mol) in dry tetrahydrofuran (0.2 l) was added to a solution of LDA over 45 minutes, the Stirring is continued for another 80 minutes, until the internal temperature will not -76oC. To the reaction mixture add the undiluted logmean (13.2 ml, 0.21 mol) via syringe; first transfer two-thirds of the load and the reaction mixture was stirred for 30 min, then add the remaining third of the load and the reaction mixture is stirred for a further 30 minutes the Second portion of LDA (0.2 mol) in dry tetrahydrofuran (0.2 l) get the try for 80 min at a temperature of -76oSince, then, to the reaction mixture add the second portion of undiluted iodomethane (13.2 ml, 0.21 mol) in the above-described sequence. The cooling bath removed and the reaction quenched with saturated aqueous ammonium chloride (0.4 l). The mixture is extracted with diethyl ether (30.4 l) and the combined organic phases are dried over magnesium sulfate, filtered through a layer of silica gel and concentrated in vacuo to obtain pure product as a white solid (60.2 g, 98%).

1H NMR (300 MHz, Dl3): 1.24(t, J=6.6 Hz, N); 2.84-2.96(m, 2H); 3.82(s, 3H); 3.92(C. 6N); 7.04(C. 1H).13With NMR (75 MHz, CDCl3): 23.72, 31.36, 52.30,63.56,117.95, 125.66,148.68, 153.76,168.36. The Belarusian library Association-MS: calculated for (C17H24O5) 308, found 309 (M+H)+). Anal. Rasch. for C17H24O5: 66.21; H 7.84. Found: 66.22; N, 7.94. Rf=0.3(9:1 hexane:ethyl acetate). GHUR: (C-18, A= 0.05% aqueous triperoxonane acid,=CH3SP; linear gradient: 50%-100% over 30 min; 254 nm, 1 ml/min): R. T. 16.2 min (97.6 area %). So pl. 70.5-71.5oC.

Stage D. Diisopropyl ether 4,6-aminobutiramida-2-methoxy-1,3-benzylcarbamoyl acid

Isopropanol (50 ml) was carefully added to the flask loaded with sodium hydride (95%, 0.33 g, 13.8 mmol). Add a solution of intermediate compound A night. To expedite completion of the reaction add an additional amount of sodium hydride (95%, 0.33 g, 13.8 mmol) and isopropanol (50 ml). The reflux continued for 5 h, then the reaction mixture was cooled to ambient temperature and quenched with 10% aqueous hydrochloric acid (60 ml). The isopropanol is removed in vacuum and the residual aqueous layer was extracted with diethyl ether (2150 ml). The combined ether extracts are dried over magnesium sulfate, concentrated in vacuo and subjected to chromatography on a column of silica (300 g) using dichloromethane:hexane (1:1) as eluent to obtain the pure product as a colourless crystalline solid (8.5 g, 85%).

1H NMR (300 MHz, CDCl3): 1.25(t, J=7.0 Hz, N); 1.37(d, J=6.3 Hz, N); 2.90-2.98(m, 2H); 3.85(s, 3H); 5.30(septet, J=6.3 Hz, 2H); 7.02(C. 1H).13With NMR (75 MHz, Dl3), 21.77,23.74, 31.12, 63.59, 68,92, 117.78, 126.44, 148.08, 153.20, 167.40. The Belarusian library Association-MS: calculated for (C21H32ABOUT5) 364, found 365 (M+H)+). Anal. Rasch. for C21H32ABOUT5: 69.20; N, 8.85. Found: 69.23; N, 8.86. Rf=0.42(9:1 hexane:ethyl acetate). GHUR: (C-18, A=0.05% aqueous triperoxonane acid, B= CH3CN; linear gradient: 50%-100% over 30 min; 254 nm, 1 ml/min): R. T. 24.4 min (96.6 area %). the 6-dicarboxylic acid

A dry flask containing sieroty magnesium (2.88 g, 120 mmol) and a crystal of iodine is heated to form a dark purple atmosphere of iodine. The flask was cooled to ambient temperature and add a solution of 2-bromo-5-forgenerations ether (33.8 g, 120 mmol, example 166, step A) in dry tetrahydrofuran (60 ml) in several portions over 40 min at a rate sufficient to maintain the boil under reflux. The reflux continued for 45 min, then the reaction mixture is cooled to room temperature. The solution of Grignard reagent is transferred via syringe into the second flask containing a solution of the intermediate from step D (11.0 g, 30.2 mmol) in dry benzene (66 ml). The reaction mixture is heated under reflux for 1 h, quenched with 10% aqueous hydrochloric acid (300 ml) and extracted with diethyl ether (3300 ml). The combined extracts are dried over magnesium sulfate and concentrated in vacuo to obtain a brown oil, which was subjected to flash chromatography on a column of silica (80 mm x 19.5") using a step gradient elution with dichloromethane:hexane(1:3, 1:2, 1:1, 4 l each). The fractions containing the product are pooled the Institute about 1: 1 in the form of a pale yellow gum (5.3 g, 33 wt.% the balance). This material does not have full features and used in the next stage without further purification.

Stage F. Isopropyl ester of 3,5-aminobutiramida-6-hydroxymethyl-2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2-carboxylic acid.

A mixture of the intermediate from step E (5.83 g, 10.9 mmol) and Red-Al (3.3 ml, 10.9 mmol) in dry tetrahydrofuran (100 ml) is heated under reflux for 2.5 hours Add an additional number of Red-Al (3.3 ml aliquots) and reflux continued until, until there is no longer lower Rfspot (21 h, the total volume of Red-Al 8 EQ. , i.e. a by-product from the previous stage reacts faster than the desired ether). The reaction mixture was cooled to 0oWith carefully quenched with water (14 ml) and vigorously stirred for 2 hours the Precipitated solid is removed by filtration under vacuum through the paper and the collected solid washed with ethyl acetate (3100 ml) and again filtered. The combined filtrates are washed with a mixture 1:1 of water and saturated aqueous sodium chloride (100 ml) followed by washing with water (75 ml) and saturated aqueous sodium chloride (50 ml). The organic phase is separated, dried over sodium sulfate and concentrated in vacuo:1) as eluent gives pure diisopropyl ether 3,5-aminobutiramida 2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2,6-dicarboxylic acid (2.63 g, 9.92 mmol). This ester is subjected to interaction with Red-Al (2.95 ml, 9.84 mmol) in dry tetrahydrofuran (45 ml). Add an additional number of Red-Al (2.95 ml aliquots) and reflux continued until completion of the reaction (30 h, the total number of Red-Al 12 EQ.). Process, as described above, and the crude product is subjected to chromatography on a column of silica (40 mm x 7") using hexane:ethyl acetate (19:1) as eluent to give the desired product in the form of a translucent colorless oil (1.25 g, 55%).

1H NMR (300 MHz, CDCl3)^ 0.91(d, J=6.6 Hz, 3H); 1.09(d, J=6.3 Hz, 3H); 1.20-1.33(m N); 1.35(d, J= 7.0 Hz, 3H); 1.91-2.00(SHS, 1H); 2.94-3.07(m, 1H); 3.37-3.50(m, 1H); 4.24-4.46(m, 2H); 4.84-5.06(m, 3H); 6.73-6.87(m, 2H); 7.01-7.08(m, 2H); 7.14-7.29(m, 4H); 7.39(C. 1H). The Belarusian library Association-MS: calculated for (C30H35ABOUT4F) 478 found 479 (M+H)+). Rf=0.23(9:1 hexane:ethyl acetate).

Stage G. Isopropyl ester of 3,5-aminobutiramida-6-formyl-2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2-carboxylic acid

Chilled (0o(C) a mixture of the intermediate from step F (0.73 g, 1.52 mmol), celite (1.46 g) and pyridylamine (0.61 g, 2.84 mmol) in dry dichloromethane (30 ml) is stirred for 5 h, warming to room temperature. The mixture is diluted with ethylacetophenone (a mixture of 1:1, 2120 ml). The combined filtrates concentrated in vacuo to give the desired product as a pure colorless oil (0.72 g, 99%).

1H NMR (300 MHz, Dl3)^ 0.90(d, J=6.3 Hz, 3H); 1.07(d, J=6.3 Hz, 3H); 1.23-1.36(m N); 2.99-3.10(m, 1H); 3.92-4.02(m, 1H); 4.85-5.06(m, 3H); 6.65-6.76(m, 2H); 7.15-7.30(m 6N); 7.46(C. 1H); 9.84(s, 1H). The Belarusian library Association-MS: calculated for (C30H34ABOUT4F) 476 found 477 (M+H)+). Rf=0.47(9:l hexane: ethyl acetate).

Stage N. Isopropyl ester of 3,5-aminobutiramida-6-(prop-1-enyl)-2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2-carboxylic acid

Chilled (-70o(C) suspension (ethyl)triphenylphosphonium (0.88 g, 2.37 mmol) in dry tetrahydrofuran (6 ml) is treated with added dropwise n-utility (2.47 M in hexane, 1.04 ml, 2.56 mmol). The mixture was immediately warmed to 0oC, stirred for 90 minutes at a temperature of 0oWith and re-cooled to -70oC. To a solution of ilide add a solution of the intermediate from step G (0.94 g, 1.97 mmol) in dry tetrahydrofuran (6 ml) for several minutes, the reaction mixture is heated again to 0oC and stirred for 1 h the Reaction is quenched with water (3 ml) and diluted with ethyl acetate (25 ml). The organic phase is washed with saturated aqueous sodium chloride (215 ml). the sodium sulfate and concentrated in vacuo to obtain the crude solids, which is subjected to flash chromatography on a column of silica (30 mm x 6") using hexane:ethyl acetate (19:1) as eluent. Pure fractions are combined and concentrated in vacuo to give the desired product as a pale yellow oil (0.81 g, 84%).

1H NMR (300 MHz, CDCl3): 0.84-0.92(m, 3H); 1.02-1.59(m N); 2.96-3.31(m, 2H); 4.82-4.97(m, 1H); 4.98(s, 2H); 5.19-5.52(m, 1H); 6.07-6.19(m, 1H); 6.57-6.69(m, 2H); 7.05-7.31(m, 7H). The Belarusian library Association-MS: calculated for (C32H37ABOUT3F) 488 found 489 (M+H)+. Rf=0.58(9:l hexane:ethyl acetate).

Stage I. 3,5-Aminobutiramida-2-hydroxymethyl-6-(prop-1-enyl)-2'-benzyloxy-4'-fluoro-1,1'-biphenyl

The reaction flask is charged with a slurry of socialogical (95%, 0.14 g, 3.3 mmol) in dry tetrahydrofuran (5 ml) and heated under reflux. To the heated mixture is added dropwise a solution of the intermediate from step H (0.80 g, 1.64 mmol) in dry tetrahydrofuran (10 ml) via syringe. The reaction mixture is heated under reflux for 23 hours, cooled to ambient temperature and quenched with a saturated aqueous solution of sodium sulfate, which is added dropwise until gas evolution stops. The mixture was then diluted with ethyl acetate (15 ml), stirred for several military filtrate was concentrated in vacuo and subjected to flash chromatography on a column of silica (30 m x 3") to obtain the pure product in the form of pure oil (0.53 g, 75%).

1H NMR (300 MHz, CDCl3): 1.05-1.46(m, 15 NM); 1.68-1.78(SHS, 1H); 3.07-3.49(m, 2H); 4.27-4.47(m, 2H); 4.85-5.05(m, 2H); 5.25-5.52(m, 1H); 5.92-6.08(m, 1H); 6.68-6.76(m, 2H); 6.98-7.13(m, 3H); 7.18-7.29(m, 3H); 7.35(s, 1H). The Belarusian library Association-MS: calculated for (C29H33ABOUT2F) 432, found 432 (M)+. Rf=0.29(9:1 hexane:ethyl acetate).

Stage J. 3,5-Aminobutiramida-2-hydroxymethyl-6-propyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

A mixture of intermediate compound with stage I (0.53 g, 1.23 mmol) and 10% palladium on coal (53 mg) in methanol (12 ml) is stirred under hydrogen atmosphere for 18 hours the Reaction mixture was then filtered through a layer of celite layer and thoroughly washed with methanol (100 ml). The combined filtrates concentrated in vacuo and subjected to flash chromatography on a column of silica (20 mm x 4"), using hexane:ethyl acetate (9:1) as eluent. So get pure product in the form of pure oil, which slowly solidified to obtain the target compound as a white solid (0.37 g, 87%).

1H NMR (300 MHz, Dl3): 0.76(t, J=7.4 Hz, 3H); 1.16-1.36(m, 15 NM); 2.11-2.42(m, 2H); 3.12-3.25(m, 1H); 3.30-3.43(m, 1H); 4.29-4.47(m, 2H); 6.69-6.80(m, 2H); 7.00-7.07(m, 1H); 7.36(s, 1H).13With NMR (75 MHz, Dl3): 14.65, 24.29, 24.34. 24,50, 24.58, 29.21, 32.18, 59.61, 103.6 (d, J=24.4 Hz), 107,6(d, J=22.0 Hz), 123.50, 123.67(d, J=2.4 Hz), 13UB>F) 344, found 344 (M)+. Anal. Rasch. for C22H29ABOUT2F: C, 76.71; H, 8.49. Found: 76.66; N, 8.34. Rf= 0.41(4: 1 hexane: ethyl acetate). GHUR: (C-18, A=0.05% aqueous triperoxonane acid,= CH3SP; linear gradient: 50%-100% over 30 min; 254 nm, 1 ml/min): R. T. 17.1 min (97.5 area %). So pl. 127.5-129.oC.

EXAMPLE 242

< / BR>
3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

Stage A. 3,5-Aminobutiramida-2-hydroxymethyl-6-propyl-4'-fluoro-2'-benzyloxy-1,1'-biphenyl

The racemic mixture of the compound obtained in example 241 (293 mg, 851 µmol), benzylbromide (110 μl, 925 mmol) and potassium carbonate (303 mg, 2.19 mmol) in acetone (29 ml) is heated under reflux for 3 hours the Mixture is diluted with saturated aqueous ammonium chloride (50 ml) and extracted with Et2O (350 ml). Chromatography on a column of silica gel (90:10 hexane/ethyl acetate) to give colorless oil (0.369 g, 100%).

1H NMR (300 MHz, Dl3): 7.34(C. 1H); 7.23(m, 3H); 7.12(m, 1H); 7.03(m, 2H); 6.84-6.75(m, 2H); 5.04(V. 12.1 Hz, 1H); 4.94(V. 12.1 Hz, 1H); 4.38(DD, 11.4.Hz, 8.5 Hz, 1H); 4.25(DD, 11.4.Hz, 3.3 Hz, 1H); 3.39(cept, 6.9 Hz, 1H); 3.18(Sept, 6.9 Hz, 1H); 2.30-2.40(m, 1H); 2.09-2.20(m, 1H); 1.65(DD. 8.5 Hz, 3.3 Hz, 1H); 1.26-1.34(m 14N); 0.72(t, 7.4 Hz, 3H).

Stage C. 3,5-Aminobutiramida 2-formyl-6-propyl-4'-fluoro-2'-benzo is 8, stage A. Chromatography on a column of silica gel (95:5 hexane/ethyl acetate) gives a colorless crystalline solid (0.323 g, 88%).

1H NMR (300 MHz, CDCl3): 9.74(s, 1H); 7.41(C. 1H); 7.22-7.28(m, 3H); 7.06-7.13(m, 3H); 6.72-6.80(m, 2H); 5.00(C. 2H); 3.91(Sept, 6.8 Hz. 1H); 3.23(Sept, 6.7 Hz, 1H); 2.37-2.46(m, 1H); 2.17-2.27(m, 1H); 1.20-1.36(m 14N); 0.73(t, 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C29H33FO2) 432, found 433 (M+H).

Stage C. 3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-fluoro-2'-benzyloxy-1,1'-biphenyl

Motility (2.7 ml of a 1.4 M solution in Et2Oh, 3.78 mmol) is added dropwise over 5 min to a cooled (ice-water bath) suspension of Cul (715 mg, 3.75 mmol, purified by attrakzia THF) in toluene (10.8 ml), so that the internal temperature of the mixture was 3oC. adding receive the first yellow-orange suspension, then colourless solution. After 25 min the mixture again becomes yellow-orange suspension. Added dropwise a solution of the intermediate from step B (306 mg, 707 mmol) in toluene (1 ml) for 4 min so that the internal temperature of the mixture was 2oC. After 30 minutes add 1/3 of a saturated aqueous solution of NH4OH (40 ml). After 60 min the mixture was diluted with saturated aqueous ammonium chloride (40 ml) and actorthe substance (0.290 g, 91%). The product is a mixture of diastereomers in a ratio of 93:7, as shown GHUR.

1H NMR (300 MHz, Dl3only the main peak corresponds visible diastereoisomer): 7.35(C. 1H); 7.22-7.24(m, 3H); 7.11(DD 8.1 Hz, 7.0 Hz, 1H); 7.04(m, 2H); 6.70-6.78(m, 2H); 4.99(D. 2.6 Hz, 2H); 4.83(arcs, J= 6.8 Hz, J= 2.8 Hz, 1H); 3.84(Sept, 6.8 Hz, 1H); 3.14(Sept, 6.9 Hz, 1H); 2.29(m, 1H); 2.07(m, 1H); 1.74(d, 2.9 Hz, 1H); 1.25-1.35(m, 17H); 0.70(t, 7.4 Hz, 3H). EI-MS: calculated for (C30H37FO2) 448 found 448 (M+).

Stage D. 3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

The target compound is obtained from the intermediate stage To the method of example 1, step H. Chromatography on a column of silica gel (83:17 hexane/ethyl acetate) gives two colorless solid (0.229 g, 99%).

The diastereoisomer 1 obtained as a colorless crystalline solid (0.214 g, 92%).1H NMR (300 MHz, CDCl3): 7.37(C. 1H); 7.03(m, 1H); 6.72(m, 2H); 4.80-4.89(m, 2H); 3.79(Sept, 6.8 Hz, 1H); 3.14(Sept, 6.8 Hz, 1H); 2.31(m, 1H); 2.08(m, 1H); 1.64(d, 3.3 Hz, 1H); 1.41(d, 7.0 Hz, 3H); 1.26-1.31(m 14N); 0.74(t, 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H31FO2) 358, found 341 (M-OH). So pl. 149-150oC. Rf=0.25 (83:17 hexane:ethyl acetate).

The diastereoisomer 1 (212 mg) divided into pillar 6 x 50 cm ID). System balance mobile phase consisting of 1% butanol and 99% heptane at a flow rate of 100 ml/min Sample dissolved in dichloromethane (70 mg/ml) and inject 1 ml aliquots at intervals of 40 minutes Outgoing flow control at 285 nm, and two fractions (corresponding to the two enantiomers) are picked at 19-23 min (100% of ei) and 30-37 min (98% of ei), respectively.

Enantiomer 1 obtained as a colorless solid (78 mg).1H NMR (300 MHz, Dl3): 7.37(C. 1H); 7.02(m, 1H); 6.71(m, 2H); 4.77-4.89(m, 2H); 3.77(m, 1H); 3.14(Sept, 6.8 Hz, 1H); 2.31(m, 1H); 2.08(m, 1H); 1.63(d, 2.9 Hz, 1H); 1.41(d, 6.6 Hz, 3H); 1.26-1.31(m 14N); 0.74(t, 7.2 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H31FO2) 358, found 341 (M-IT).

Enantiomer 2 obtained as a colorless solid (74 mg).1H NMR (300 MHz, CDCl3): 7.38(C. 1H); 7.03(m, 1H); 6.72(m, 2H); 4.80-4.90(m, 2H); 3.79(cept, 6.6 Hz, 1H); 3.14(Sept, 6.7 Hz, 1H); 2.30(m, 1H); 2.07(m, 1H); 1.63(d, 3.3 Hz, 1H); 1.41(d, 6.6 Hz, 3H); 1.26-1.31(m 14N); 0.74(t, 7.2 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H31FO2) 358, found 341 (M-IT).

The diastereoisomer 2 obtained as a colorless crystalline solid (15.3 mg, 7%).1H NMR (300 MHz. Dl3)^ 7.37(C. 1H); 6.92(m, 1H); 6.70(m, 2H); 5.1(SHS, 1H); 4.64(square 6.7 Hz, 1H); 3.85(cept, 6.7 Hz, 1H); 3.14(Sept, 6.8 Hz, 1H); 2.32(m, 1H); 2.09(m, 1H); 1.8(SHS, 1H); 1.37 square 179-180oC.

EXAMPLE 243

< / BR>
(+)-3,5-Aminobutiramida-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

Stage A. 3,5-Diisopropyl-2-(1-oxoethyl)-6-pentyl-4'-fluoro-1,1'-bipheny

A mixture of 3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl (example 192, 13.7 g, 37.1 mmol), celite (26 g) and pyridylamine (14.9 g, 69.3 mmol) in dichloromethane (750 ml) is stirred for 45 minutes the Mixture is diluted with ethyl acetate (750 ml) and hexane (1.5 l) and filtered through a layer of silicon dioxide (100 mm x 2") covered by alicom (100 mm x 0.5"). Elution continue with ethyl acetate: hexane (mixture of 1:1, 3 l 2). The combined filtrates concentrated in vacuo to give the desired product as a white solid (13.5 g, 99%).

1H NMR (300 MHz, CDCl3): 0.75-0.80(m, 3H); 1.06-1.31(m, N); 1.95(C. 3H); 2.33-2.39(m, 2H); 2.78(septet. J=7.0 Hz, 1H); 3.18(septet, J=7.0 Hz, 1H); 7.03-7.09(m, 2H); 7.17-7.22(m, 2H); 7.26(s, 1H).13With NMR (75 MHz, CDCl3): 13.75, 22.02, 24.32, 24.37, 28.99, 29.10, 29.28, 30.60, 31.04, 32.06, 33.03, 114.85(D. J= 20.8 Hz, 2C), 122.06, 132.03(d, J=7.3 Hz, 2C), 135.52(d, J= 2.4 Hz, 1C), 135.58, 135.76, 140.13, 140.85, 147.66, 161.99(d, J= 246.6 Hz, 1C), 208.23. EI-MS: calculated for (C25H33OF) 368, found 368 (M)+. Anal. Rasch. for C25H33OF: 80.86; N, 8.96. Found: 81.04; N, 9.06. Rf=0.65 (9:1 hexane:ethyl acetate). GHUR: (C-18, A=0.05% aqueous triflorum. 123.5-124.oC.

Stage C. (+)-3,5-Aminobutiramida-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl

A mixture of (1S, 2R)-(+)-N-methylephedrine (13.9 g, 77.3 mmol) in diethyl ether (225 ml) at a temperature of 0oC in an atmosphere of argon is treated by slow addition of socialogical (1M in diethyl ether, 77.3 ml, 77.3 mmol). The mixture is heated under reflux for one hour and then cooled to a temperature of -75oC. Then, to the reaction mixture add a solution of the intermediate from step A (13.5 g, 36.7 mmol) in diethyl ether (500 ml, 50 ml washing) so that the internal temperature does not rise above -68oC. the Reaction mixture is stirred for 3 hours at a temperature of -75oC and then heated to ambient temperature over night. The reaction mixture was cooled to 0oC. Quenched by addition of water (500 ml) and diluted with diethyl ether (750 ml). The aqueous phase is separated and re-extracted with diethyl ether (200 ml). The combined organic phases are washed with water (2500 ml), 10% aqueous hydrochloric acid (500 ml) and saturated aqueous sodium chloride (2500 ml), dried over sodium sulfate, filtered through a layer of celite (80 mm x 1.25") and concentrated in vacuo. The obtained solid target compound in the form of a crystalline powder (11.08 g, 82%).

1H NMR (300 MHz, CDCl3): 0.75-0.80(m, 3H); 1.02-1.31(m, N); 1.40(d, J= 6.6 Hz, 3H); 2.17-2.22(m, 2H); 3.08-3.18(m, 1H); 3.83-3.92(m, 1H); 4.66-4.73(m, 1H); 7.05-7.23(m, 4H); 7.32(s, 1H).13With NMR (75 MHz, CDCl3): 13.88, 22.02, 23.38, 24.23, 24.56, 24.63, 25.09, 28.68, 28.96, 29.92, 31.04, 32.23, 68.91, 114.80(d, J=20.8 Hz, 1C), 115.02(d, J=20.8 Hz, 1C), 124.27, 130.40(d, J=8.5 Hz, 1C). 131.25(d, J=7.3 Hz, 1C). 135.53, 136.98, 137.73(d, J= 2.4 Hz, 1C), at 139.02, 145.82(2C), 161.68(d, J=245.4 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H33OF) 370, found 370 (M)+. Anal. Rasch. for C25H35OF: 81.03; N, 9.52. Found: 81.15; N, 9.68. Rf=0.36(9:1 hexane:ethyl acetate). GHUR: (C-18, A= 0.05% aqueous triperoxonane acid,=CH3SP; linear gradient: 75%-100% over 30 min; 254 nm, 1 ml/min): R. T. 22.6 min (98.3 area %). (Daicel Hiralcel OD-H; isocratic 99:1 hexane:methyl tert-butyl ether; 254 nm, 1.5 ml/min); R. T. 6.20 min (97.2, area, %), 8.37 min (0.36 square, %); 99.5% of ei. []D=26.9o(C=0.00196 g/ml, dichloromethane). So pl. 108.5-109.5oC.

EXAMPLE 244

< / BR>
(+)-3,5-Aminobutiramida-2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl

Stage A. Dimethyl ether 4,6-diethyl-2-tripterocalyx-1,3-benzylcarbamoyl acid

A solution of 90 g (338 mmol) of dimethyl ether 4,6-diethyl-2-hydroxy-1,3-benzylcarbamoyl acid (example 241, step (A) in dichloromethane (1 l) was treated with pyridine (109 ml, 1.35 m is dream (83 ml, 507 mmol). The reaction mixture is heated to room temperature and stirred for 3 hours. The mixture is then washed with 5% Hcl (1.5 l), water (1 l), saturated sodium bicarbonate (2500 ml) and dried over magnesium sulfate. Filtration and concentration gives a dark oil (129.7 g, 326 mmol, 96%). Rf= 0.4(10% ethyl acetate/hexane).

1H NMR (300 MHz, CDCl3): 7.20(s, 1H); 3.93(C. 6N); 2.74(q, J=7.4 Hz, 4H); 1.22(t, J=4.8 Hz, 6N). The Belarusian library Association-MS: calculated for (C15H27F3O7) 398, found 399 (M+H).

Stage C. 3,5-Diethyl-2,6-dicarboxylate-4'-fluoro-1,1'-biphenyl

To a solution of the intermediate from step A (129.7 g, 326 mmol) in dioxane (2.5 l) is added 4-ferbinteanu acid (68.4 g, 492 mmol), potassium phosphate (145 g, 683 mmol), potassium bromide (58.1 g, 488 mmol), tetrakis(triphenylphosphine)palladium (18.8 g, 16.3 mmol) and water (20 ml). The reaction mixture is stirred in an argon atmosphere by heating under reflux for 24 hours, the Reaction mixture was filtered through celite and concentrated in vacuo. The oily residue is twice filtered through a layer of silicon dioxide (700 g, 40% dichloromethane/hexane) to give yellow solid. Recrystallization from hexane gives white solid (52.6 g, 153 mmol, 47%). So pl. 98-99oC. Rthe in, J=7.7 Hz, 4H); 1.25(t, J=7.7 Hz, 6N). The Belarusian library Association-MS: calculated for (C20H21FO4) 344, found 345 (M+H).

Stage C. 3,5-Aminobutiramida 2,6-dicarboxylate-4'-fluoro-1,1'-biphenyl

The solution Diisopropylamine (22.7 ml, 0.174 mol) in dry tetrahydrofuran (0.2 l) at a temperature of -78oC in an atmosphere of argon is treated by slow addition of n-utility (2.5 M in hexane, 70 ml, 0.174 mol). After stirring the reaction mixture for 15 min to a solution of LDA add a solution of the intermediate from step B (46.0 g, 0.133 mol) in dry tetrahydrofuran (0.2 l) for 15 minutes Stirring is continued for 30 min, keeping the temperature at -78oC. To the reaction mixture add the undiluted logmean (11.2 ml, 0.180 mol) via syringe; first, add 2/3 of the load, the reaction mixture was stirred for 20 min, then add the remaining third of the load and the mixture is stirred for 10 minutes the Second portion of LDA (0.174 mol) in dry tetrahydrofuran (0.2 l) are obtained by the above method and are added to the reaction mixture via cannula over 15 min Stirring is continued for 30 min at a temperature of -78oWith, then add the second portion of undiluted iodomethane (11.2 ml, 0.180 mol) in the same placenta is camping extracted with diethyl ether (30.4 l) and the combined organic phases are dried over magnesium sulfate and concentrated in vacuo to obtain an oil, which crystallizes upon maturation. White solid washed with a small amount of hexane (41.7 g, 84%). So pl. 128-130oC. Rf=0.5(10% ethyl acetate/hexane).

1H NMR (300 MHz, CDCl3): 7.33(s, 1H); 7.26(m, 2H); 7.03(m, 2H); 3.49(C. 6N); 2.97(Sept, J= 6.6 Hz, 2H); 1.29(d, J=7.0 Hz, 6N). The Belarusian library Association-MS: calculated for (C22H25FO4) 372 found 373 (M+H).

Stage D. 3,5-Aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl

To a solution of the intermediate from step C (37.3 g, 100 mmol) in anhydrous tetrahydrofuran (350 ml), stirred in an argon atmosphere at a temperature of 0oTo add a solution of 3.4 M sodium bis-(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (105 ml, 204 mmol, 65 wt.% in toluene) via syringe over 20 minutes the Reaction mixture was stirred at room temperature for 24 h, then cooled again to a temperature of 0oC and carefully quenched by adding dropwise water. The solution is decanted from the resulting solids and the solvent is removed in vacuum. The residue is purified flash chromatography (500 g silica) through a stepped gradient. Elution with 5% diethyl ether/hexane gives 9.8 g (26.3 mmol, 28%) selected the parent compound and elution of 40% Dipl. 124-126oC. Rf=0.2(10% ethyl acetate/hexane).

1H NMR (300 MHz, CDCl3): 7.35(s, 1H); 7.27(m, 2H); 7.08(m, 2H); 4.44(d, J= 5.5 Hz, 2H); 3.43(m, 4H); 2.92(Sept, J=6.6 Hz, 1H); 1.59(C. 1H); 1.28(m, N). The Belarusian library Association-MS: calculated for (C21H25FO3) 344, found 345 (M+H).

Stage E. 3,5-Aminobutiramida 2-carboxaldehyde-6-carboxymethyl-4'-fluoro-1,1'-biphenyl

To a solution of the intermediate obtained in stage D (26.8 g, 77.8 mmol) in dichloromethane (400 ml) was added celite (33.6 g). The suspension is stirred at room temperature and treated with pyridylamino (PQQ) (33.6 g, 15.6 mmol) in three portions. The suspension is stirred at room temperature for 2 h, then poured into 1:1 diethyl ether/hexane (1 l), filtered through a layer of silicon dioxide, the layer is washed with diethyl ether (600 ml) and the combined eluent concentrate with getting sticky oil (23.3 g, 68.1 mmol, 87%). Rf=0.4(10% ethyl acetate/hexane).

1H NMR (300 MHz, CDCl3): 9.87(C. 1H); 7.36(s, 1H); 7.28(m, 2H); 7.15(m, 2H); 3.48(C. 3H); 3.89(Sept, J=6.6 Hz, 1H); 3.10(Sept, J=6.6 Hz, 1H); 1.35(m, N). The Belarusian library Association-MS: calculated for (C21H23FO3) 342, found 343 (M+H).

Stage F. 3,5-Aminobutiramida 2-carboxymethyl-6-ethynyl-4'-fluoro-1,1'-bipheny

Methyltriphenylphosphonium (15.5 g, 43.4 MSM added 1.6 M solution of n-utility in hexane (25 ml, 40.2 mmol). The reaction mixture is heated to 0oC and stirred at this temperature for 1.5 hours Obtained brightly coloured solution is again cooled to -78oC and treated dropwise with a solution of the intermediate from step E (11.4 g, 33.3 mmol) in THF (100 ml). The reaction mixture is stirred at a temperature of 0oC for 1 h, then quenched by addition of water (30 ml). THF is removed in vacuo, the residue is divided between diethyl ether (400 ml) and water (400 ml). The organic layer was washed with brine (100 ml), dried over magnesium sulfate and concentrated. Flash chromatography on a column of silica (5% diethyl ether/hexane) gives solid (10.3 g, 30.3 mmol, 91%) of (E, Z mixture).

1H NMR (300 MHz, CDCl3): 7.31 (s, 1H); 7.16(m, 2H); 7.02(m, 2H); 6.10(DD, J=6.3, 11.4 Hz. 1H); 6.04(DD, J=1.8, 13.6 Hz, 1H); 5.48(DD, J=1.8, 19.9 Hz, 1H); 3.46(s, 3H); 3.35(Sept, J=6.6 Hz, 1H); 2.93(Sept, J=6.6 Hz, 1H); 1.29(m, N). The Belarusian library Association-MS: calculated for (C22H25FO2) 340, found 340 (M+). So pl. 58-61oC. Rf=0.6(10% ethyl acetate/hexane).

Stage G. of 3,5-Aminobutiramida-2-hydroxymethyl-6-ethynyl-4'-fluoro-1,1'-bipheny

The intermediate compound obtained in stage F (10.0 g, 29.4 mmol), dissolved in anhydrous THF (150 ml) in an argon atmosphere and treated with n the Ute when heated under reflux for 2 h, cooled to room temperature and quenched by adding 30 ml of water. THF is removed in vacuo, the residue is divided between diethyl ether (400 ml) and water (3 x 400 ml). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and concentrated. Flash chromatography on a column of silica (5% diethyl ether/hexane) gives solid (7.7 g, 24.7 mmol, 84%).

1H NMR (300 MHz, CDCl3): 7.38(C. 1H); 7.14(m, 4H); 6.35(DD, J=6.3, 11.4 Hz, 1H); 5.20(DD, J=1.8, 13.6 Hz, 1H); 4.98(DD, J=1.8, 19.9 Hz, 1H); 4.40(d, J= 5.5 Hz, 2H); 3.39(m, 2H); 1.29(m N). The Belarusian library Association-MS: calculated for (C21H25FO) 312, found 312 (M+). So pl. 97-99oC. Rf=0.1(50% dichloromethane/hexane).

Stage N. 3,5-Aminobutiramida-2-hydroxymethyl-6-ethyl-4'-fluoro-1,1'-biphenyl

The intermediate compound obtained in stage G (77.7 g, 24.7 mmol), dissolved in absolute ethanol (200 ml) and argon atmosphere, and treated with 10% palladium on coal (610 mg, 0.1 EQ), then stirred under an atmosphere of hydrogen for 2 hours After the flush of the system with argon, the catalyst was removed by filtration through a layer of celite. The solvent is removed and the product dried in vacuum to obtain the target compound as a white solid (7.7 g, 25 mmol, 99%).

1H NMR (300 MHz, Dl3): 7.32(s, ngle (C21H27FO) 314, found 314 (M+). So pl. 106-108oC. Rf=0.1(50% dichloromethane/hexane).

Stage I. 3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl

The intermediate compound obtained in stage N (7.65 g, 24.3 mmol), dissolved in dichloromethane (250 ml), treated with telicom (10.5 g). The suspension is stirred at room temperature and treated with pyridylamino (PQQ) (10.5 g, 48.7 mmol). Stirring is continued at room temperature for 2 hours, the Suspension is poured into 1:1 diethyl ether/hexane (1 l), filtered through a layer of silicon dioxide, the layer is washed with diethyl ether (600 ml) and the combined eluent concentrated to obtain a solid (7.25 g, 23.2 mmol, 95%).

The intermediate compound (7.25 g, 23.2 mmol) was dissolved in THF (75 ml) at a temperature of 0oC in an atmosphere of argon and treated dropwise Metalmania bromide (3 M, 1.3 EQ., 10.1 ml). The reaction mixture was stirred for 1 h, the Reaction mixture was quenched with saturated ammonium chloride (7 ml) and THF is evaporated in vacuum to obtain oil. The product is divided between water (100 ml) and diethyl ether (250 ml) and the organic layer is dried over magnesium sulfate, filtered and concentrated to obtain a white solid. Flash is square 138-140oC. Rf=0.1(50% dichloromethane/hexane).

1H NMR (300 MHz, Dl3): 7.34(s, 1H); 7.15(m, 4H); 4.69(DQC, J=2.9, 7 Hz, 1H); 3.88(Sept, J=7 Hz, 1H); 3.17(Sept, J=6.6 Hz, 1H); 2.28(q, J=7.4 Hz, 2H); 1.64(d, J=2.9 Hz, 1H); 1.39(d, J=6.6 Hz, 3H); 1.27(m, N); 0.89(t, J=7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H29FO) 328, found 328 (M+).

Stage J. 3,5-Aminobutiramida 2-(1-oxoethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl

To the intermediate compound obtained in stage I (7.23 g, 22 mmol), in dichloromethane (100 ml) is added pyridine chlorproma (9.49 g, 44 mmol) and celite (9.49 g) in an argon atmosphere. The reaction mixture was stirred at room temperature for 24 h the Reaction mixture was added to a 1:1 mixture of diethyl ether/hexane (1 l), then filtered through a layer of silicon dioxide. Layer was washed with 650 ml of diethyl ether and the combined filtrates concentrated in vacuo to obtain white solids (7.18 g, 22 mmol, 99%). So pl. 121-123oC. Rf=0.3(50% dichloromethane/hexane).

1H NMR (300 MHz, CDCl3): 7.27(s, 1H); 7.21(m, 2H); 7.07(m, 2H); 3.22(septet, J= 7 Hz, 1H); 2.78(Sept, J=7 Hz, 1H); 2.43(q, J=7.4 Hz, 2H); 1.96(C. 3H); 1.28(m, N); 0.930(so J=7.7 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H27FO) 326, found 327 (M+H).

Stage K. (+)-3,5-aminobutiramida-2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-shall etiological (lM/diethyl ether, 1.5 EQ. , 35 ml) at a temperature of 0oC. the Reaction mixture is heated under reflux for 1.5 hours, transforming from a pure solution in the solution a milky color. The reaction mixture is cooled to room temperature and then to -78oC. To the reaction mixture are added dropwise intermediate compound from step J (6.64 g, 20.3 mmol), dissolved in 60 ml of dry diethyl ether (about 2 ml/min, the temperature should not rise above -60oC). The reaction mixture stand at a temperature of -78oC for 2.0 h and then allowed to warm during the night. The reaction is quenched at a temperature of 0oWith water (30 ml) and diluted with diethyl ether (250 ml), washed with water (3 200 ml), brine (100 ml) and dried over magnesium sulfate. Filtration and concentration gives a residue which is filtered through a layer of silica (400 g, 80% dichloromethane/hexane) to give the target compound (99% of ei) as a white solid (5.85 g, 17.8 mmol, 88%). So pl. 143-145oC. Rf= 0.1(50% dichloromethane/hexane).

1H NMR (300 MHz, CDCl3): 7.34(s, 1H); 7.15(m, 4H); J=7 Hz, 1H); 3.18(Sept, J= 7 Hz, 1H); 2.29(q, J=7.7 Hz, 2H); 1.68(C. 1H); 1.37(d, J=4.8 Hz. 3H); 1.26(m, N); 0.890(t, J= 7.4 Hz, 3H). The Belarusian library Association-MS: calculated for (C22H29FO) 328, found 328 (M+). Anal. R>< / BR>
(+)-3,5-Aminobutiramida-2-(1-hydroxyethyl)-6-propyl-4'-fluoro-1,1'-biphenyl

The target compound (99% of ei) is obtained from the intermediate obtained in stage E, example 244, and ethyltriphenylphosphonium by the method of example 244, stage F-K.

1H NMR (300 MHz, CDCl3): 7.33(s, 1H); 7.14(m, 4H); 4.70(DQC, J=2.9, 7 Hz, 1H); 3.88(septet, J= 6.62 Hz, 1H); 3.14(Sept, J=6.62 Hz, 1H); 2.18(m, 2H); 1.67(d, J=2.9 Hz, 1H); 1.37(d, J=7.Hz, 3H); 1.29(m, 14N); 0.719(t, J=7 Hz, 3H). The Belarusian library Association-MS: calculated for (C23H31FO) 342, found 342 (M+). Anal. Rasch. for C23H31FO: C, 80.66; N, 9.12; F, 5.55. Found: 80.71; N, 8.99; F 5.34. []22=+23.8o. So pl. 114-116oC. Rf=0.1(50% dichloromethane/hexane).

EXAMPLE 246

< / BR>
3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

Stage A. Di-tert-butyl ether 4,6-diethyl-2-hydroxy-1,3-benzylcarbamoyl acid

A mixture of di-tert-butyl ether 1,3-aacondicionado acid (10 g, 38.7 mmol), 3,5-heptanedione (6.5 g, 50.3 mmol) and sodium methoxide (2.7 g, 50.3 mmol) in methanol (100 ml) was stirred at room temperature overnight. The methanol is removed on a rotary evaporator and the resulting orange slurry is shared between diethyl ether (100 ml) and 10% aqueous hydrochloric acid (100 ml). The separated aqueous layer was ex is rija (20 ml), dried over sodium sulfate, filtered through a layer of silicon dioxide (20 mm x 40 mm) and concentrated in vacuo to obtain a yellow oil (13.23 g, 97%).

1H NMR (300 MHz, CDCl3): 1.20(t, 6N); 1.60(s, N); 2.74(q, 4H); 6.55(C. 1H); 11.73(s,1H).

Stage C. Di-tert-butyl ester 3,5-aminobutiramida 2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2,6-dicarboxylic acid

The target compound is obtained from the intermediate obtained in stage A, by the method of example 241, steps In, and that is

1H NMR (300 MHz, CDCl3): 1.15(s, N); 1.27(DD, J=5.15, 1.65 Hz, N); 3.06(m, 2H); 4.95(s, 2H); 6.65(m, 2H); 7.27(m, 7H).

Stage C. 3,5-Diisopropyl ether 2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2,6-dicarboxylic acid

To a solution 14.37 g (25.53 mmol) of the intermediate stage In dichloromethane (150 ml) at a temperature of 0oTo add triperoxonane acid (20 ml, 259.6 mmol). This reaction mixture is warmed to room temperature over night. The reaction mixture is concentrated until dry and the residue is divided between diethyl ether and aqueous sodium hydroxide. The organic layer is removed, washed with aqueous sodium hydroxide and two water layers combined. The combined aqueous layers washed with diethyl ether (1x), stead magnesium sulfate, filter and concentrate to obtain a whitish solid. The crude product is taken in the next stage without further purification.

Stage D. Dimethyl 3,5-aminobutiramida 2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2,6-dicarboxylic acid.

To a suspension of 7.17 g (15.93 mmol) of the intermediate from step C in dichloromethane (200 ml) at a temperature of 0oWith added solid potassium carbonate (10.05 g, 72.71 mmol) followed by the addition of iodomethane (5.0 ml, 80.31 mmol). The mixture is heated to room temperature. After stirring for 1 day, the mixture is diluted with water and extracted with diethyl ether (3x). The combined extracts washed with brine (1x), dried over magnesium sulfate, filtered and concentrated to obtain a whitish solid.

1H NMR (300 MHz, Dl3): 1.22(DD, J=4.41, 2.4 Hz, N); 2.94(m, 2H); 3.39(s, 6N); 4.93(s, 2H); 6.55(m, 2H); 7.05(m, 1H); 7.18(m, 6N).

Stage E. 3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

The target compound is obtained from the intermediate obtained in stage D, according to the method of example 241, stage F-I (using ethyltriphenylphosphonium at stage N) and then by the method of example 242, stage B-D. Chromatography diastereomer 1 obtained as a colorless crystalline solid (1.029 g, 97%).1H NMR (300 MHz, CDCl3): 0.89(t, J=7.36 Hz, 3H); 1.28(m N); 1.40(d, J=6.62 Hz, 3H);1.63(SHS, 1H); 2.29(m, 2H); 3.17(m, 1H); 3.78(m, 1H); 4.84(m, 1H); 6.70(m, 2H); 7.03(m, 1H); 7.38(C. 1H). The Belarusian library Association-MS: calculated for (C22H29ABOUT2F) 344, found 367 (M+Na). So pl. 174-175oC.

The diastereoisomer 1 (1.029 mg) is separated into its constituent enantiomers as follows. Waters Prep LC 4000 HPLC system equipped with a column for chiral GHUR (BRB-9668A, 6h50 cm ID). The system balances the mobile phase, consisting of 0.75% butanol and 99.25% hexane at a flow rate of 100 ml/min Sample dissolved in dichloromethane (20 mg/ml) and sample inject a single injection. The outgoing flow control at 285 nm and two fractions (corresponding to the two enantiomers) are collected by 26-32 min 98% of ei) and 34-48 min (99% of ei), respectively.

Enantiomer 1 obtained as a colorless solid (480 mg).

1H NMR (300 MHz, Dl3): 0.89(t, J=7.54 Hz. 3H); 1.28(m N); 1.40(d, J=5.14 Hz, 3H); 1.65(SHS, 1H); 2.19(m, 1H); 2.35(m, 1H); 3.17(m, 1H); 3.78(m, 1H); 4.85(m, 1H); 6.71(m, 2H); 7.03(m, 1H); 7.38(C. 1H). So pl. 57-59oC.

Enantiomer 2 obtained as a colorless solid (483 mg).

1H NMR (300 MHz, CDCl3): 0.89(t, J=7.36 Hz, 3H); 1.28(m N); 1.39(d, J= 6.99 Hz, 3H);1.63(SHS, 1H); 2.29(m, 2H); 3.17(m, 1H); 3.78(m, 1H); 4.84(m, 1H); 6.70(m, SS="ptx2">

The diastereoisomer 2 obtained as a colorless crystalline solid (100 mg, 7%).1H NMR (300 MHz, CDCl3) 0.88(t, J=7.54 Hz, 3H); 1.27(m N); 1.36(d, J=6.62 Hz, 3H); 1.8(SHS, 1H); 2.19(m, 1H); 2.39(m, 1H); 3.16(m, 1H); 3.84(m, 1H); 4.63(sq J=6.62 Hz, 1H); 5.09(SHS, 1H); 6.69(m, 2H); 6.92(t, J=7.35 Hz. 1H); 7.37(C. 1H). So pl. 183-184oC.

EXAMPLE 247

< / BR>
3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

Stage A. 3,5-Aminobutiramida-2-hydroxymethyl-6-(Penta-1-enyl)-2'-benzyloxy-4'-fluoro-1,1'-biphenyl

The desired compound is obtained from the dimethyl ester of 3,5-aminobutiramida 2'-benzyloxy-4'-fluoro-1,1'-biphenyl-2,6-dicarboxylic acid (example 246, step D) using the procedure of example 241, stage F-I (using pentyltrichlorosilane at stage N). The pure product is obtained as a transparent oil (4.73 g, 52% after 4 stages).

1H NMR (300 MHz, CDCl3): 0.67-0.78(m, 3H); 1.09-1.34(m, 14N); 1.66-1.88(m, 3H); 3.16-3.46(m, 2H); 4.29-4.44(m, 2H); 4.88-5.04(m, 2H); 5.27-5.41(m, 1H); 5.94-6.01(m, 1H); 6.69-6.78(m, 2H); 7.00-7.06(m, 3H); 7.22-7.26(m, 3H); 7.35(s, 1H).13With NMR (75 MHz, CDCl3): 14.18, 14.52, 22.89, 23.05, 24.39, 24.64, 24.94, 25.11, 25.38, 29.73, 30.50, 30.66, 31.68, 35.85, 60.78, 71.07, 71.45, 102.25, 102.59, 108.08, 108.37, 122.33, 122.54, 127.11, 127.22, 127.92, 128.11, 128.51, 129.16, 132.70, 132.83, 133.39, 134.06, 135.96, 136.96, 137.29, 137.35, 147.48, 147.63, 147.79, 156.90, 156.93, 163.26(d, J= 246.6 Hz, 1C). The Belarusian library Association-MS: calculated for (C31f=0.34(9:1 hexane:ethyl acetate). GHUR: (C-18, A=0.05% aqueous triperoxonane acid,=CH3SP; linear gradient: 80%-100% over 20 min; 254 nm, 1 ml/min): R. T. 14.8 min (37.7 square,%), 15.2 min (56.0 area%); 93.7% purity (CIS and TRANS).

Stage C. 3,5-Aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-2'-hydroxy-1,1'-biphenyl

The target compound is obtained from the intermediate stage And the method of example 242, stage B-D. the Crude product subjected to flash chromatography on a column of silica (50 mm x 6") using hexane:ethyl acetate (19:1 and 9:1) as eluent to separate the diastereomers (2.19 g, 90%, 75% after 3 stages).

The diastereoisomer 1 are in the form of a white solid (2.03 g, 83%).

1H NMR (300 MHz, CDCl3): 0.78(t, J=6.6 Hz, 3H); 0.96-1.23(m, N); 1.41(d, J=7.0 Hz, 3H); 2.04-2.37(m, 2H); 3.09-3.19(m, 1H); 3.74-3.84(m, 1H); 4.81-4.90(m, 2H); 6.68-6.75(m, 2H); 6.99-7.06(m, 1H); 7.37(s, 1H).13With NMR (75 MHz, Dl3): 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70. 29.05, 29.80, 30.76, 32.20. 68.21, 102.98(d, J=24.4 Hz. 1C), 107.33(d, J= 20.8 Hz, 1C), 123.58(d, J= 2.4 Hz, 1C), 125.45. 130.70(d, J=9.8 Hz, 1C), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29(d, J=6.1 Hz, 1C), 163.04(d, J= 244.2 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H35O2F) 386. found 409 (M+Na)+. Anal. Rasch. for C25H35O2F: 77.68; N, 9.13. Found:Nany gradient: 70%-100% more than 30 min; 254 nm, 1 ml/min): R. T. 12.9 min (91.3 area%). (silicon dioxide, A=hexane, B=isopropanol; isocratic rate of 3% over 30 min; 254 nm, 1.5 ml/min); R. T. 5.1 min(100 area%). So pl. 122.5-124.0oC.

The diastereoisomer 1 (1.92 g) is separated into its constituent enantiomers as follows. Waters Prep LC 4000 HPLC system equipped with a column for chiral GHUR (BRB-9668A, 6 x 50 cm ID). The system balances the mobile phase, consisting of 0.75% butanol and 99.25% hexane at a flow rate of 100 ml/min Sample dissolved in dichloromethane (40 mg/ml) and sample inject two injections. The outgoing flow control at 285 nm, and two fractions (corresponding to the two enantiomers) are collected.

Enantiomer 1 are in the form of a white crystalline solid (0.78 g)1H NMR (300 MHz, CDCl3): 0.78(t, J=6.6 Hz, 3H); 0.96-1.23(m, N); 1.41(d, J= 7.0 Hz, 3H); 2.04-2.37(m, 2H); 3.09-3.19(m, 1H); 3.74-3.84(m, 1H); 4.81-4.90(m, 2H); 6.B8-6.75(m, 2H); 6.99-7.06(m, 1H); 7.37(s, 1H).13With NMR (75 MHz, CDCl3): 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80. 30.76, 32.20, 68.21. 102.98(d, J=24.4 Hz, 1C), 107.33(d, J= 20.8 Hz, 1C), 123.58(d, J=2.4 Hz, 1C), 125.45, 130.70(d, J=9.8 Hz, 1C), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29(d, J=6.1 Hz, 1C), 163.04(d, J= 244.2 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H35ABOUT2F) 386, found 409 (M+Na)+. Anal. Rasch. for C25H35ABOUT2F: 77= CH3SP; linear gradient: 70%-100% over 30 min; 254 nm, 1 ml/min): R. T. 12.8 min (94.9 area%).(BRB-9668, 99% (1% butanol in hexane), 5 min, 285 nm, 2 ml/min); R. T. 2.6 min(100 area% 100% ei). []D=-14.3o(C=0.00200 g/ml dichloromethane). So pl. 105.0-106.5oC.

Enantiomer 2 get in the form of a white flocculent solid (0.73 g).1H NMR (300 MHz, CDCl3): 0.78(t, J=6.6 Hz, 3H); 0.96-1.23(m, N); 1.41(d, J= 7.0 Hz, 3H); 2.04-2.37(m, 2H); 3.09-3.19(m, 1H); 3.74-3.84(m, 1H); 4.81-4.90(m, 2H); 6.68-6.75(m, 2H); 6.99-7.06(m, 1H); 7.37(s, 1H).13With NMR (75 MHz, CDCl3): 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76, 32.20, 68.21, 102.98(d, J=24.4 Hz, 1C), 107.33(d, J= 20.8 Hz, 1C), 123.58(d, J=2.4 Hz, 1C), 125.45, 130.70(d, J=9.8 Hz, 1C), 131.78, 137.45, 138.55, 146.48, 146.94. 154.29(d, J=6.1 Hz, 1C), 163.04(d, J= 244.2 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H35ABOUT2F) 386, found 409 (M+Na)+. Anal. Rasch. for C25H35ABOUT2F: 77.68; N, 9.13. Found: 77.64; H 9.06. Rf= 0.30(9:1 hexane:ethyl acetate). GHUR: (C-18, A=0.05% aqueous triperoxonane acid, B= CH3CN; linear gradient: 70%-100% over 30 min; 254 nm, 1 ml/min): R. T. 12.8 min (94.7 area%).(BRB-9668, 99% (1% butanol in hexane), 5 min, 285 nm, 2 ml/min); R. T. 1.7 min(0.51, area,%), 2.9 min(0.97 square, %), 4.0 min (98.5 area %, 98% ei, []D=+16.0o(C=0.00200 g/ml dichloromethane). So pl. 103.5-105.5oC.

The diastereoisomer 2 get in the form of a white who 2H); 3.09-3.19(m, 1H); 3.80-3.89(m, 1H); 4.61-4.68(m, 1H); 4.75-5.25(SHS, 1H); 6.6-6.74(m, 2H); 6.90-B. 9b(m, 1H); 7.37(s, 1H).13With NMR (75 MHz, Dl3): 13.83, 21.94, 23.43, 24.08, 24.48, 24.56, 24.98, 28.70, 29.04, 29.80, 30.76, 32.19, 68.89, 102.80(d, J=24.4 Hz, 1C), 107.3(d, J= 22.0 Hz, 1C), 123.24(d, J=2.4 Hz, 1C), 125.64, 131.25(d, J=9.8 Hz, 1C), 131.56, 137.08, 138.44, 146.81, 146.84, 154.37(d, J=12.2 Hz, 1C), 163.03(d, J= 244.2 Hz, 1C). The Belarusian library Association-MS: calculated for (C25H35ABOUT2F) 386, found 409 (M+Na)+. Anal. Rasch. for C25H35ABOUT2F: C, 77.68; N, 9.13. Found: C, 77.70; H, 9.12. Rf=0.17(9:1 hexane:ethyl acetate). GHUR: (C-18, A=0.05% aqueous triperoxonane acid,= CH3SP; linear gradient: 70%-100% over 30 min; 254 nm, 1 ml/min): R. T. 17.6 min (86.9 area%).(silicon dioxide, A= hexane, B= isopropanol, ; isocratic rate of 3% over 15 min; 254 nm, 1.5 ml/min); R. T. 4.9 min(100 area%). So pl. 148.0-150.0oC.

EXAMPLE 248

< / BR>
(+)-3,5-L-2-[(para-methylbenzylamine)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl

Stage A. 3,5-Aminobutiramida-2-[(para-methylbenzylamine)methyl]-6-hydroxymethyl-4'-fluoro-1,1'-biphenyl

To a solution of 3,5-aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) (4.09 g, 11.9 mmol) in THF (70 ml) is added at room temperature sodium hydride (0.85 g, 35.4 mmol) in portions. The reaction mixture was stirred for 10 min and satkania 24 h and then cooled to room temperature and quenched with water (30 ml). The solvent is removed in vacuum and the residue is divided between diethyl ether (300 ml)and water (200 ml). The ether layer is dried (magnesium sulfate) and concentrated, the residue is purified through silica (70% dichloromethane/hexane) to give white solid (4.5 g, 10.3 mmol, 84%), the Product is dissolved in THF (40 ml) and treated with lydialydia (19.8 ml, 19.8 mmol, 1.0 M in THF). The reaction mixture is heated under reflux for 2 h and then cooled to room temperature. The mixture was quenched with water (6 ml) and the solvent is removed in vacuum. The remainder is divided between diethyl ether (200 ml) and water (300 ml). The organic layer was washed with water (3300 ml), brine (100 ml), dried (magnesium sulfate), filtered and concentrated. The residue is filtered through a layer of silica (dichloromethane, 1 l) and evaporated to obtain a white solid (3.26 g, 7.7 mmol, 78%). So pl. 99-101oC. Rf=0.07(80% dichloromethane/hexane).

1H NMR (300 MHz, Dl3): 7.38(s, 1H); 7.24(m, 2H); 7.09(m 6N); 4.36(d, J=5.5 Hz, 2H); 4.27(C. 2H); 4.11(s, 2H); 3.42(septet, J=6.6 Hz, 1H); 3.32(Sept, J= 6.6 Hz, 1H); 2.35(s, 3H); 1.60(s, 1H); 1.22(m, N). The Belarusian library Association-MS: calculated for (C28H33FO2) 420, found 403 (M-IT).

Stage C. (+)-3,5-Aminobutiramida-2-[(para-methylbenzylamine)methyl] -6-(1 is about the method of example 244, stage I-K. T. pl. 84-86oC. Rf=0.1(80% dichloromethane/hexane.

1H NMR (300 MHz, CDCl3)^ 7.39(s, 1H); 7.27(m, 2H); 7.09(m 6N); 4.76(DQC, J=1.5,7 Hz, 1H); 4.22(C. 2H); 4.03(s, 2H); 3.89(septet, J=6.6 Hz, 1H); 3.26(Sept, J=6.6 Hz, 1H); 2.35(s, 3H); 1.66(s, 1H); 1.40(d, J=6.6 Hz, 3H); 1.26(m, N). The Belarusian library Association-MS: calculated for (C29H35FO2) 434, found 417 (M-OH). Anal. Rasch. for C29H35FO2: 80.15; N, 8.12; F 4.37. Found: 80.10; N, 8.30; F 4.24. []22=+30.7.

EXAMPLE 249

< / BR>
(+)-3,5-L-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl

The target compound is obtained from the pair-thiocresol and 3.5-aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) according to the method of example 47, steps In and With and then for example 244, stage I-K Rf= 0.36(70% dichloromethane/hexane).

1H NMR (300 MHz, CDCl3): 7.40(s, 1H); 7.28(m, 2H); 7.11(m 6N); 4.76(DQC, J= 1.8,7 Hz, 1H); 3.92(septet, J= 6.6 Hz, 1H); 3.78(s, 2H); 3.26(Sept, J= 6.6 Hz, 1H); 2.36(s, 3H); 1.66(s, 1H); 1.40(d, J=6.6 Hz, 3H); 1.28(m, N). The Belarusian library Association-MS: calculated for (C23H33FOS) 436, found 436 (M+). Anal. Rasch. for C29H35FOS: 77.02; H 7.62; S 7.34; F 4.35. Found: 76.90; N, 7.77; S 7.30; F, 4.37. []22=+32.2.

EXAMPLE 250

< / BR>
(+)-3,5-Aminobutiramida-2-[(4-methoxythiophene)methyl-6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl
f
=0.23 (70% dichloromethane/hexane). So pl. 14-2oC.

1H NMR (300 MHz, CDCl3): 7.36(s, 1H); 7.30(m, 2H); 7.08(m, 4H); 6.75(m, 2H); 4.72(q, J=7 Hz, 1H); 3.89(septet, J=7 Hz, 1H); 3.78(s, 3H); 3.68(m, 2H); 3.38(Sept, J= 7 Hz, 1H); 1.57(m, 1H); 1.40(d, J=6.6 Hz, MN); 1.31(m, N). The Belarusian library Association-MS: calculated for (C28H33FO2S) 452, found 452 (M+). Anal. Rasch. for C28H33FO2S: 74.30; H 7.35; S 7.08; F 4.20. Found: 74.06; H 7.46; S, 6.87; F 4.09. []22=+24.5.

EXAMPLE 251

< / BR>
(+)-3,5-Aminobutiramida-2-[(4-dimethylthiophenol)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl

The target compound is obtained from 4-(methylthio)phenol and 3,5-aminobutiramida-2-hydroxymethyl-b-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) according to the method of example 47, steps In, and With, and to the method of example 244, stage I-K Rf=0.52(90% dichloromethane/hexane). So pl. 157-159oC.

1H NMR (300 MHz, CDCl3): 7.37(s, 1H); 7.30(m, 2H); for 7.12(m 6N); 4.71(q, J= 7 Hz, 1H); 3.90(septet, J= 7 Hz, 1H); 3.75(d, J=11 Hz, 1H); 3.70(d, 1= 11. Hz, 1H); 3.33(Sept, J=7 Hz, 1H); 2.46(C. 3H); 1.58(s, 1H); 1.40(d, J=6.6 Hz, 3H); 1.29(m, N). EI-MS: calculated for (C28H33FOS2) 468 found 468 (M+). Anal. Rasch. for C28H33FOS2: 71.76; N, 7.10; S 13.68; F, 4.05. Found: 71.54; H 7.22; S 13.26; F 4.17, []
The target compound is obtained from 4-(trifluoromethyl)bentolila and 3.5-aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) according to the method of example 47, steps In, and With, and to the method of example 244, stage I-K Rf=0.39(80% dichloromethane/hexane). So pl. 171-173oC.

1H NMR (300 MHz, CDCl3): 7.45(s, 1H); 7.42(s, 1H); 7.39(s, 1H); 7.30(m, 1H); 7.09(m, 5H); 4.72(q, J=7 Hz, 1H); 3.91(septet, J=7 Hz, 1H); 3.83(d, J=11 Hz, 1H); 3.78(d, J=11 Hz, 1H); 3.28(Sept, J=7 Hz, 1H); 1.60(s, 1H); 1.41(d, J=6.6 Hz, 3H); 1.29(m, N). The Belarusian library Association-MS: calculated for (C28H30F4OS) 490, found 490 (M+). Anal. Rasch. for C28H30F4OS: 68.55; N, 6.16; S 6.53; F 15.49. Found: 68.67; H 6.15; S 6.56; F 15.33. []22= +25.6.

EXAMPLE 253

< / BR>
(+)-3,5-Aminobutiramida-2-[(4-trifloromethyl)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl

The target compound is obtained from 4-(triptoreline)bentolila and 3.5-aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) according to the method of example 47, steps In, and With, and to the method of example 244, stage I-K Rf=0.39 (80% dichloromethane/hexane). So pl. 124-126oC.

1H NMR (300 MHz, CDCl3): 7.38(s, 1H); 7.30(m, 2H); 7.09(m, 6N); 4.73(q, J= 7 Hz, 1H); 3.91(septet, J= 7 Hz, 1H); 3.78(d, J=11 Hz, 1H); 3.73(d, J= 11 Hz, 1H); 3.31(Sept, J=7 Hz, 1H); 1.60(s, 1H); 1.41(d, J=7 Hz, 3H); 1.2 SUB>30F4ABOUT2S: 66.39; H 5.97; S 6.33; F 15.00. Found: 66.71; H 6.06; S 6.22; F 15.24. []22+25.8.

EXAMPLE 254

< / BR>
(+)-3,5-Aminobutiramida-2-[(4-fortifier)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl

The target compound is obtained from 4-portifino and 3.5-aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) according to the method of example 47, steps In, and With, and to the method of example 244, stage I-K Rf=0.35 (70% dichloromethane/hexane). So pl. 138-140oC.

1H NMR (300 MHz, Dl3): 7.37(s, 1H); 7.30(m, 2H); 7.05(m, 4H); 6.90(m, 2H); 4.71(q, J=7 Hz, 1H); 3.90(septet, J=6.6 Hz, 1H); 3.72(m, 2H); 3.33(Sept, J=6.6 Hz. 1H); 1.52(s, 1H); 1.39(d, J=6.6 Hz, 3H); 1.27(m, N). The Belarusian library Association-MS: calculated for (C28H30FO2S) 506, found 506 (M+). Anal. Rasch. for C28H33FO2S: 74.30; H 7.35; S 7.08; F 4.20. Found: 74.06; H, 7.46; S 6.87; F 4.09. []22=+17.6.

EXAMPLE 255

< / BR>
3,5-Aminobutiramida 2-(thienylmethyl)-6-(hydroxymethyl)-4'-fluoro-1,1'-biphenyl

A suspension of Wang resin (100 g, 1.09 mmol/g, gidrauxilirovaniu) are suspended in 1 l solution of 4 N. Hcl in dioxane and gently stirred at room temperature for two days. After filtration of the chlorinated resin is washed 6 times with the following solvent: dioxane, isopropanol and finally THF. The resin is dried at temperature is entnum analysis) are suspended in DMF (25 ml) and stirred at room temperature for 5 min, then DMF decanted to add a solution of 3,5-aminobutiramida-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1'-biphenyl (example 244, step D) (1.13 g, 3.3 mmol) in DMF (25 ml) followed by the addition of sodium hydride (60% in mineral oil, 170 mg, 3.3 mmol) in DMF (12.5 ml). The suspension is stirred at room temperature for 2 days in an atmosphere of argon. The suspension is then filtered and the resulting resin was sequentially washed with 10 times following solvents: DMF, a mixture of THF/water (1:1), THF and finally dichloromethane.

The resinous residue is then treated with a solution of socialogical (1M in THF, 15 ml, 15 mmol) and heated under reflux for 2 days. The suspension is filtered and the obtained residue is washed successively 10 times the following solvents: THF, a mixture of THF/water (1:1), mixture of THF/water (2:1), THF and dichloromethane.

The residue is suspended in THF (25 ml) and slowly treated with RVG3(835 μl, 8.7 mmol) at room temperature. The resin is filtered and washed 10 times with the following solvents: THF, a mixture of THF/1 N. sodium bicarbonate (1: 1), THF/water (1:1), THF and dichloromethane, and then dried at a temperature of 60oWith over night to obtain 2.25 g of resin (0.62 mmol/g with respect to the content of bromine, opredeleayut thiophenol (26.4 mg, 0.24 mmol) in dry THF (500 μl) and N-methylmorpholine (26 μl, 0.24 mmol), then the suspension is heated under reflux for 8 hours After filtration the resin was washed sequentially with the following solvents: THF, a mixture of THF/water (1:1), and THF. The resin is then suspended in a mixture of TN and dichloromethane (1:1) and stirred at room temperature for 1 hour. The resin was filtered and the solvent is separated and evaporated. The residue is dissolved in a mixture of methanol and acetonitrile (1:1) and one drop of diisopropylethylamine, then stirred for one hour; GHUR: 12.5 min (persil BDS C-18, 5 μm, h mm/Hewlett Packard, flow 0.5 ml, 0-13 min 30-90%, 13-15 min 90%, solvent A:water/0.1% TN; solvent b: acetonitrile). After evaporation of the solvent, the remaining residue is transferred into a microtiter plate for testing.

Compounds shown in table 1 as examples 256-288, receive according to the method of example 255.

The degree of purity is determined by comparison with the peaks, not standards. Pharmaceutical use of the compounds of this invention are shown in the following study of the activity of the glucagon receptor.

The similarity of the glucagon receptor compounds of the present invention determined using islaptop glucagon (CHO-HGR) by scraping cells in hypotonic litany buffer (10 mm, pH 7.4, 2mm etc, 5mm MgCl2and 1 mm PMSF) and subjecting the material homogenization transmitter station. Cores removed at the stage of centrifugation 15 min at 800 x g, carried out at a temperature of 4oC. the Membranes containing the receptor, collected by centrifugation at 15,000 x g for 15 min at a temperature of 4oC. the Membrane is washed once Lisinym buffer and suspended in 0.25 M sucrose, 10 mm Tris, 5 mm add, pH 7.4. Membranes used in stage ligand binding, as indicated in (Yoo-Warren, H., A. G. Willse, Hancock, N., Hull, J., M. McCaleb and Livingston, J. Regulation of the Rat Glucagon Receptor Expression. Biochem. Biophysycal Res. Commun. 1994, 205, 347-353). Briefly, 10 mg of membrane protein incubated in 130 μl of binding buffer consisting of 20 mm Tris, pH 7.4, 1 mm add, 1 mg/ml anti-lock brakes and 1 mg/ml bacitracin. Suspension of membranes placed in each well of 96-aceace tablet to filter (fiberglass, type, micropores) In each cell add 20 ál of the test compound to obtain the final concentrations of 2 nm to 20 μm. Then in each cell add additional test compound, 50 μl of125I-glucagon (9 fluid. mol) (NAN). Control cells contain membrane, 0.5% DMSO (solvent for test compounds), radioactively labeled glucagon and without abundant natural glucagon filtered in a vacuum apparatus illir. Followed by washing of ice-cold physiologic solution with phosphate buffer/0.1% ABS, air filters placed in test tubes to test and determine the radioactivity of the membrane relations. For each connection count value IC50(the concentration of test compound required to reduce the binding membranes radioactive glucagon 50%). If 20 μm compound does not reduce the binding of glucagon to 50%% reduction at 20 μm instead give the values of the IC50. Characteristics of the binding of the compounds of this invention are presented in table I(C).

Preferred compounds phenylpyridine General formula (IC), and especially of General formula 1B shown in the following list:

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-propylpyridine;

2,6-dies piperidin;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl]-4-phenyl-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-forfinal)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-chlorophenyl)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-were)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxyphenyl)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxy-4-forfinal)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-phenyl-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-forfinal)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-chlorophenyl)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-were)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxyphenyl)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxy-4-forfinal)-5-hydroxymethyluracil;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-INF;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-phenyl-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-forfinal)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-chlorophenyl)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-were)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxy-4-forfinal)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-phenyl-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-forfinal)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-chlorophenyl)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[((4-Fortini is phenyl)-5-(1-hydroxyethyl)pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxy-4-forfinal)-5-(1-hydroxyethyl)pyridine;

Preferred compounds of biphenyl General formula (IC), and especially the General formula ID are presented in the following list:

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-4'-methyl-1,1'-biphenyl

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-4'-fluoro-1,1'-biphenyl

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-4'-chloro-1,1'-biphenyl

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-4'-METI is methyl-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl]-6-hydroxymethyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)METI,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-disop is 3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)isopropyl-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

Other variants of this invention are obvious to the person skilled in the art from this specification or from practice of the present invention described herein. It is assumed that the description and examples are only exemplary and the scope of the present invention, presented in the claims.

1. Substituted burilnye compounds with antagonistic activity against glucagon receptor having the General formula (IC)

< / BR>
where X is N or CR8; R8is hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6-alkoxycarbonyl, carboxy, formyl or-NR4R5and the substituents of the substituted phenyl or substituted alkyl groups, R8, which can be from 1 to 3 are, for example, hydroxy, fluorine, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6-alkoxycarbonyl, carboxy, formyl or-NR4R5; R4and R5independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl, wherein the substituents of the substituted phenyl or substituted naphthyl groups, R4and R5are from 1 to 3, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl or (C1-C4-alkoxygroup;

R4and R5can be objr>6
, NR6, O or S(O)nin which n is 0, 1 or 2; R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl;

R1aand R1bindependently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkenyl or (C1-C6-alkanoyl, and substituents of the substituted alkyl, substituted alkenyl and substituted quinil groups R1aand R1bindependently of one another, are from 1 to 3, for example, OR4, -C(O)R4, -CO2R4, -C(O)NR4R5, -NR4R5or phenyl, which is optionally substituted from 1 to 3, for example, halogen, (C1-C4)-alkyl or (C1-C4-alkoxygroup;

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6<-alkyl, moreover, the substituents of the substituted alkyl, substituted alkenyl, substituted quinil and substituted cycloalkyl group, R2independently of one another, are from 1 to 3 halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7in which m is 0,1 or 2, and the substituents of the substituted phenyl substituents of the group R2are from 1 to 3, for example, halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl, wherein the substituents of the substituted phenyl, substituted pyridyl or substituted naphthyl groups, R7are from 1 to 5, for example, halogen, three - vermeil, (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano or hydroxy; R2and R1bcan be combined, forming Allenby bridge containing from 3 to 5 carbon atoms, between tommila, (C1-C6-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6-alkenyl-, the substituents of the substituted alkyl and substituted alkenyl group, R3are from 1 to 3 hydroxy or triptoreline group;

AG is an optionally substituted aromatic or heteroaromatic ring, for example, phenyl, naphthyl, pyridium, TuranAlem, titaniam, pirrallo, imidazolium, pyrazolyl, triazolyl, tetrazolyl, oxazole-scrap, isoxazolyl, thiazolyl, isothiazolines, and if necessary, the Deputy group AG independently from each other represent 1 to 3, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3WITH7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5or-S(O)mR7the substituents of the substituted alkyl, substituted alkenyl and substituted quinil substituted group AG are from 1 to 3, for example, halogen, hydroxy, -NR4R5, Fe4)-alkyl or (C1-C4-alkoxygroup,

and their pharmaceutically acceptable salts.

2. Substituted pyridine, which has antagonistic activity against glucagon receptor, having the structural formula 1A

< / BR>
in which R1aand R1bindependently from each other are trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl or (C3-C7-cycloalkenyl, or (C1-C6-alkanoyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl; the substituents on the substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2groups independently from 1 to 3 times are galore who or 2; R4and R5independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R4and R5not necessarily together to form -(CH2)rA(CH2)s-, in which r and s are independently 1, 2 or 3, a is O, S(O)n, CHR6or NR6where n is 0, 1 or 2; R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R2and R1bnot necessarily together education is uedineny R2and R1b;

R3is hydroxy, TRIFLUOROACETYL, (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl, and substituents of the substituted alkyl and substituted alkenylphenol groups R3are from 1 to 3 times a hydroxyl or triptoreline group;

AG' is optionally mono-, di - or tri-substituted heteroaromatic ring selected from the group comprising pyridil, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazoline, in which the optional substituents are independently from 1 to 3 times are halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5-C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2, and their pharmaceutically acceptable salts.

3. Substituted pyridine under item 2, where the structural formula 1A R1aand R1b2
-C10-alkenyl, substituted (C2-C10-alkenyl, (C3-C7-cycloalkyl or (C3-C7-cycloalkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl; the substituents of the substituted alkyl and substituted alkenyl R2groups is independently from 1 to 3 times are halogen, phenyl, substituted phenyl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2; R4and R5independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R6is hydrogen, (C1-C6)-alkyl, phenyl or phenyl-(C1-C6)-alkyl; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, substituted pyridi-scrap, pyridyl-(C1-Cwill is formed Allenby bridge, containing 3 to 4 carbon atoms between the ring carbon atoms to which are attached R2and R1b; R3is (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl, in which the substituents are from 1 to 3 times with hydroxyl groups; AG' are selected from the group including pyridil, furanyl, thiophenyl, pyrazolyl, triazolyl, oxazolyl and thiazolyl, in which the substituents on Ar' is optionally independently from 1 to 3 times are, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl. 4. Substituted pyridine under item 2, in which the structural formula 1A R1aand R1bindependently are (C1-C6)-alkyl or (C2-C6-alkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl, in which the substituents of substituted alkyl and zames the P> is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl; R3is replaced by (C1-C6) alkyl or substituted (C3-C6-alkenyl, in which the substituents are from 1 to 2 hydroxyl groups; AG' are selected from the group including pyridil, furanyl and thiophenyl, in which the optional substituents are independently from 1 to 3 times are halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4or-OC(O)R4where R4is hydrogen or (C1-C6) alkyl.

5. The pharmaceutical composition exhibiting antagonistic activity against glucagon receptor containing substituted pyridine on p. 2 and a pharmaceutically acceptable carrier.

6. Substituted pyridine, which has antagonistic activity against glucagon receptor and having the structural formula 1B

< / BR>
in which R1aand R1bindependently from each other are trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2THE7-cycloalkenyl, or (C1-C6-alkanoyl;

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl, where the substituents of substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2groups is independently from 1 to 3 times are halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2; R4and R5independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R4and R5optional m is tsya About, S(O)n, CHR6, NR6where n is 0,1 or 2; R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R2and R1btogether optionally form Allenby bridge containing from 3 to 5 carbon atoms between the ring carbon atoms to which are attached R2and R1b< / BR>
R3is hydroxy, TRIFLUOROACETYL, (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl; the substituents on the substituted alkyl and substituted alkenylphenol R3the groups are from 1 to 3 times a hydroxyl or triptoreline groups;

AG is optionally mono-, di - or tri-substituted aromatic ring, which is selected from a group comprising finely and NAF6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, NR4R5, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2;

and their pharmaceutically acceptable salts.

7. Substituted pyridine under item 6, in which the structural formula 1B R1aand R1bindependently from each other are trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C3-C7-cycloalkyl, or (C3-C7-cycloalkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl, in which the substituents on the substituted alkyl and substituted alkenyl groups independently from 1 to 3 times are halogen, phenyl, substituted phenyl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2; R4and R5independently from drucilla, the phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R6is hydrogen, (C1-C6)-alkyl, phenyl or phenyl-(C1-C6)-alkyl; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl; R2and R1btogether optionally form Allenby bridge containing 3 to 4 carbon atoms between the ring carbon atoms to which are attached R2and R1b; R3is (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl, in which the substituents are from 1 to 3 times with hydroxyl groups; AG is a phenyl ring, and optional substituents on AG independently from 1 to 3 times are halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, (C6)-alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6)-alkyl.

8. Substituted pyridine under item 6, in which the structural formula 1B R1aand R1bindependently of one another are (C1-C6)-alkyl or (C2-C6-alkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl, in which the substituents on the substituted alkyl and substituted alkenyl groups independently from 1 to 3 times are halogen or-S(O)mR7where m is 0; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl; R3is replaced by (C1-C6) alkyl or substituted (C3-C6-alkenyl, in which the substituents are from 1 to 3 times with hydroxyl groups; AG is a phenyl ring, and the optional substituents are independently from 1 to 3 times are halogen, (C1-C6)-alkyl, (C2-C6-alkenyl, -OR4-or-OC(O)R4where R4is hydrogen or (C1-C6)-alkyl.

enyl-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-pentile is 4-(4-chlorophenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-phenyl-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-chlorophenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(4-were)-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-hydroxymethyl-4-(2-hydroxy-4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-phenyl-5-hydroxymethyluracil;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-forfinal)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-chlorophenyl)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-were)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxyphenyl)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxy-4-forfinal)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-phenyl-5-hydroxymethyl-pyridi(4-forfinal)thio)methyl] -4-(4-chlorophenyl)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-were)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxyphenyl)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxy-4-forfinal)-5-hydroxymethyl-pyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-ethylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-propylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-Buti is Teal)-4-(4-were)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-butylpyrazine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-phenyl-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(4-were)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-hexylpyridine;

2,6-aminobutiramida-3-(1-hydroxyethyl)-4-(2-hydroxy-4-forfinal)-5-hexylpyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-phenyl-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-forfinal)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(4-chlorophenyl)-5-(1-guide 2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[(para-tolylthio)methyl] -4-(2-hydroxy-4-forfinal)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-phenyl-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-forfinal)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-chlorophenyl)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(4-were)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)-pyridine;

2,6-aminobutiramida-3-[((4-forfinal)thio)methyl] -4-(2-hydroxy-4-forfinal)-5-(1-hydroxyethyl)-pyridine.

10. The pharmaceutical composition exhibiting antagonistic activity against glucagon receptor containing substituted pyridine on p. 6 and a pharmaceutically acceptable carrier.

11. Substituted burilnye compounds with antagonistic activity against glucagon receptor and having the structural formula 1C

< / BR>
in which R8is hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycle is anilam, carboxy, formyl or-NR4R5; R4and R5independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R4and R5not necessarily together to form -(CH2)rA(CH2)s-, in which r and s are independently equal to 1, 2 or 3 and a is O, S(O)n, CHR6, NR6; where n is 0, 1 or 2; R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl;

R1aand R1bindependently from each other are trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl or (C3-C7-cycloalkenyl, or (C1-C6)-A2
-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl; the substituents on the substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2groups independently from 1 to 3 times are halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R2and R1bnot necessarily together form Allenby bridge containing from 3 to 5 carbon atoms between the ring carbon atoms to which are attached R2and R1b;

R3is hydroxy, TRIFLUOROACETYL, (C1-C3
are from 1 to 3 times a hydroxyl or triptoreline groups;

AG' is optionally mono-, di - or tri-substituted heteroaromatic ring selected from the group comprising pyridil, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazoline, in which the substituents are independently from 1 to 3 times are, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C1-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5or-C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2;

and their pharmaceutically acceptable salts.

12. Substituted burilnye connection on p. 11, in which the structural formula 1C R8is hydrogen, halogen, trifluoromethyl or (C1-C10)-alkyl; R1aand R1bindependently is trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (the UP> is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl, in which the substituents on the substituted alkyl and substituted alkenyl groups independently from 1 to 3 times are halogen, phenyl, substituted phenyl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2; R4and R5independently are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R6is hydrogen, (C1-C6)-alkyl, phenyl or phenyl-(C1-C6)-alkyl; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl; R2and R1bnot necessarily together form Allenby bridge containing from 3 which is (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl; where the substituents are from 1 to 3 times with hydroxyl groups; AG' is selected from a group comprising pyridil, furanyl, thiophenyl, pyrazolyl, triazolyl, oxazolyl and thiazolyl, in which the optional substituents on AG' is independently from 1 to 3 times are halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl. 13. Substituted burilnye connection on p. 11, in which the structural formula 1C R8is hydrogen; R1aand R1bindependently of one another are (C1-C6)-alkyl or (C2-C6-alkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl, in which the substituents on the substituted alkyl and substituted alkenyl groups independently from 1 to 3 times are halogen or-S(O)mR7, DG is )-alkyl or substituted phenyl-(C1-C6)-alkyl; R3is replaced by (C1-C6) alkyl or substituted (C3-C6-alkenyl; where the substituents are from 1 to 2 hydroxyl groups; AG' is selected from a group comprising pyridil, furanyl and thiophenyl, in which the optional substituents are independently from 1 to 3 times are halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4or-OC(O)R4where R4is hydrogen or (C1-C6) alkyl.

14. The pharmaceutical composition exhibiting antagonistic activity against glucagon receptor containing substituted burilnye connection on p. 11 and a pharmaceutically acceptable carrier.

15. Substituted burilnye compounds with antagonistic activity against glucagon receptor with structural forum ID

< / BR>
in which R8is hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl the1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R4and R5not necessarily together to form -(CH2)rA(CH2)s-, in which r and s are independently equal to 1, 2 or 3; a is O, S(O)n, CHR6or NR6where n is 0, 1 or 2; R6is hydrogen, (C1-C6)-alkyl, piperidine-1-yl, phenyl or phenyl-(C1-C6)-alkyl;

R1aand R1bindependently from each other are trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C2-C10-quinil, substituted (C2-C10-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkenyl, or (C1-C6-alkanoyl;

R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C22-C10-quinil, (C3-C6-cycloalkyl-(C1-C6) alkyl or substituted (C3-C6-cycloalkyl-(C1-C6)-alkyl; the substituents on the substituted alkyl, substituted alkenyl, substituted etkinlik and substituted cycloalkyl R2groups independently from 1 to 3 times are halogen, phenyl, substituted phenyl, 1,3-dioxolane-2-yl, -C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R2and R1bnot necessarily together form Allenby bridge containing from 3 to 5 carbon atoms between the ring carbon atoms to which are attached R2and R1b;

R3is hydroxy, TRIFLUOROACETYL, (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl; cover is whether triptoreline groups;

AG is optionally mono-, di - tri-substituted aromatic ring, which is selected from a group comprising finely and nattily, in which the substituents are independently from 1 to 3 times are halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-quinil, substituted (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5-C(O)NR4R5or-S(O)mR7where m is 0, 1 or 2;

and their pharmaceutically acceptable salts.

16. Substituted burilnye connection on p. 15, in which the structural formula 1D R8is hydrogen, halogen, trifluoromethyl or (C1-C10)-alkyl; R1aand R1bindependently from each other are trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl, substituted (C2-C10-alkenyl, (C3-C7-cycloalkyl or (C3-C7-cycloalkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C104
R5or-S(O)mR7where m is 0, 1 or 2; R4and R5independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C6-alkenyl, (C3-C7-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl or substituted naphthyl-(C1-C6)-alkyl; R6is hydrogen, (C1-C6)-alkyl, phenyl or phenyl-(C1-C6)-alkyl; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridium, replaced by pyridium, pyridyl-(C1-C6)-alkyl or substituted pyridyl-(C1-C6)-alkyl; R2and R1bnot necessarily together form Allenby bridge containing 3 to 4 carbon atoms between the ring carbon atoms to which are attached R2and R1b; R3is (C1-C6-alkanoyl, substituted (C1-C6) alkyl or substituted (C3-C6-alkenyl; the substituents are from 1 1 to 3 times are halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C3-C7-cycloalkyl, cyano, -OR4or-OC(O)R4where R4is hydrogen, (C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl.

17. Substituted burilnye connection on p. 15, in which the structural formula 1D R8is hydrogen; R1aand R1bindependently of one another are (C1-C6)-alkyl or (C2-C6-alkenyl; R2is (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10-alkenyl or substituted (C2-C10-alkenyl, in which the substituents on the substituted alkyl and substituted alkenyl groups independently from 1 to 3 times are halogen, or-S(O)mR7where m is 0; R7is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl or substituted phenyl-(C1-C6)-alkyl;

R3is replaced by (C1-C6) alkyl or substituted (C3-C6-alkenyl; the substituents are from 1 to 2 hydroxyl groups; AG is phenyl>-alkyl, (C2-C6)-alkenyl, -OR4or-OC(O)R4where R4is hydrogen or (C1-C6)-alkyl.

18. Substituted burilnye connection on p. 15, selected from the following group of compounds:

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-4'-methyl-1,1'-biphenyl

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-4'-fluoro-1,1'-biphenyl

3,5-aminobutiramida-2-hydroxymethyl-6-butyl-4'-chloro-1,1'-biphenyl

3,5-aminobutiramida-2-hydroxymethyl-6-BU-2-hydroxymethyl-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-hydroxymethyl-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)met the -1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-hydroxymethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-disop is 3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida 2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)isopropyl-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[(para-tolylthio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-4'-chloro-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-4'-methyl-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;

3,5-aminobutiramida-2-[((4-forfinal)thio)methyl] -6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl.

19. The pharmaceutical composition exhibiting antagonistic activity against glucagon receptor containing substituted burilnye connection on p. 15 and a pharmaceutically acceptable carrier.

20. Substituted burilnye connection PP. 2, 6, 11 or 15, in which the Deputy, shown as R3is hydroxyethylene group having the following stereochemistry



 

Same patents:

The invention relates to new compounds of the formula I

< / BR>
where n is 0, 1 or 2; R1is hydrogen, C1-C4linear or branched alkyl or benzyl; Q is formula II

< / BR>
where R2, R3and R4individually is hydrogen, alkyl, alkoxy, alkylthio, alkoxycarbonyl, halogen, trihalomethyl, cyano, acetyl, formyl, benzoyl, nitro, alkoxymethyl, phenyl or phenylenecarbonyl, where the proportion of the alkyl or alkoxy, C1-C4linear or branched, provided that at least one of R2, R3or R4must not be hydrogen; or formula III

< / BR>
where R5, R6and R7individually is hydrogen, C1-C4alkoxy, C1-C4alkylthiomethyl, halogen, trihalomethyl, cyano, acetyl, formyl, benzoyl, nitro, phenyl-, or phenylenecarbonyl, provided that at least one of R5, R6or R7must not be hydrogen; or formula IV

< / BR>
where R8, R9and R10separately - hydroxyl-, UB>1-C5-alkylthio - tetrahydropyranyloxy, phenoxy, (C1-C4-alkyl)carbonyl-, phenylcarbinol-, C1-C4-alkylsulfonyl-, C1-C4-alkylsulfonyl-, carboxy -, or salt of an alkali metal, (C1-C4-alkoxy)carbonyl-, (C1-C4alkyl), aminocarbonyl, phenylenecarbonyl, triaminobenzene, morpholinomethyl-, amino-, nitro-, cyano-, DIOXOLANYL-, or (C1-C4alkoxy)iminomethyl-, or formula (V),

< / BR>
where X is oxygen or sulfur; V is nitrogen, CH, or C1-C4alkoxy)- ; R" is hydrogen or C1-C4alkyl

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, in which R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl) amino and di(C1-4alkyl)amino group; or a group of formula (a) Z means a hydrogen atom or a C1-4alkoxygroup, R0means a group of the formula Alk-NR4R5where Alk is alkalinous group having a straight or branched C1-6chain, one of R2and R3is amino and the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atom(s) of nitrogen and/or oxygen and attached via its nitrogen atom, and the specified heterocyclic group may be substituted WITH1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula - SR

The invention relates to the use as a medicinal substance medications for the treatment of diseases associated with impaired venous function and/or inflammatory edema tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and its new compounds of General formula I, where a is either a sulfur atom, oxygen or the radical R3N, where R3is a hydrogen atom, a C1-C5-alkyl; R1is either1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted group selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, methyl, phenyl; R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, and methoxy; and pharmaceutically acceptable salts

The invention relates to new isoxazol derivative of General formula I, where R1denotes optionally substituted C6-C14airgroup or 5-6-membered heterocyclic group containing one heteroatom selected from nitrogen, oxygen, sulfur; R2denotes a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl group, a C2-C6alkenylphenol group2-C6alkylamino group3-C10cycloalkyl group3-C10cycloalkenyl group, cyano, carboxitherapy,1-C7alkanoglu,2-C7alkoxycarbonyl group or optionally substituted carbamoyl; R3denotes optionally substituted by an amino group or a saturated 5-6-membered heterocyclic group containing a nitrogen atom; X represents an oxygen atom or a sulfur atom; n denotes an integer from 2 to 6, and their pharmaceutically acceptable salts

The invention relates to new heterocyclic compounds with valuable biological properties, in particular derived dioxide benzothiazine, the pharmaceutical compositions based on them having inhibitory receptor endothelin activity, and to a method of inhibiting endothelin receptor

The invention relates to the field of organic chemistry and oil industry, specifically to the new derived contrasena-2-trimethylammoniumchloride-4-methoxy-6-morpholyl-1,3,5-triazine, which is an intermediate in the synthesis of active additives, inhibiting the oxidation of vegetable oils (antioxidant)

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7

The invention relates to the use as a medicinal substance medications for the treatment of diseases associated with impaired venous function and/or inflammatory edema tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and its new compounds of General formula I, where a is either a sulfur atom, oxygen or the radical R3N, where R3is a hydrogen atom, a C1-C5-alkyl; R1is either1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted group selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, methyl, phenyl; R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, and methoxy; and pharmaceutically acceptable salts

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new chemical compound is 2-(N-morpholin)-4-methylpyridine, which can be used as inhibitors of acid corrosion of steel by acid treatment of wells or refineries

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl
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