Morpholine type cinnamide derivative

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

 

The technical field to which the invention relates.

The present invention relates to a derivative of Zinaida type of research and the pharmaceutical agent containing the compound as an active ingredient. More specifically the present invention relates to a dual-core ones derived Zinaida and inhibitor production of amyloid-β (hereinafter referred to as Aβ), which contains this compound as active ingredient and is particularly effective in the treatment of neurodegenerative disease caused by Aβ such as Alzheimer's disease or down's syndrome.

Background of invention

Alzheimer's is a disease characterized by degeneration and loss of neurons and the formation of senile plaques and neurofibrillary degeneration. Currently, Alzheimer's disease treated only by symptomatic therapy using tools to improve symptoms, a typical representative of which is an inhibitor of acetylcholinesterase and fundamental medicine, inhibiting the progression of the disease, is still not created. You must develop a way of monitoring the causes of pathology in order to create the fundamental remedy for the treatment of Alzheimer's disease.

It is believed that Aβ proteins as metabolites of amyloid protein precursor (hereinafter referred to as APP) are strongly involved in the processes of degeneration and loss of neurons and the onset of symptoms of dementia (see non-patent documents 1 and 2). Aβ protein contains as main ingredients Aβ40, consisting of 40 amino acids, and Aβ42, in which the number of amino acids at two more on the C-end. It is known that Aβ40 and Aβ42 have a high aggregation ability (see non-patent document 3) and are the main components of senile plaques (see non-patent documents 3, 4 and 5). It is also known that Aβ40 and Aβ42 are greater by a mutation in the genes APP and presenilin, which is observed in Alzheimer's disease family type (see non-patent documents 6, 7 and 8). Therefore, it is expected that the combination of lowering the production of Aβ40 and Aβ42, is an inhibitor of progression or prophylactic agent for Alzheimer's disease.

Aβ is produced in the cleavage of APP by β-secretases and then γ secretases. For this reason, attempts have been made to create inhibitors of β-secretase and γ-secretase to inhibit the production of Aβ. Many of these inhibitors secrets already known, for example peptides and mimetics of the peptides, such as L-685458 (see non-patent document 9) and LY-411575 (see non-patent documents 10, 11 and 12).

[Non-patent document 1] Klein WL, and seven others, Alzheimer's,'s disease-affected brain: Presence of oligomeric A(ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceding National Academy of Science USA 2003, Sep 2; 100(18), p.10417-10422;

[Non-patent document 2] Nitsch RM, and sixteen others, Antibodies against β-amyloid slow cognitive decline in Azheimer,'s disease, Neuron, 2003, May 22; 38, p.547-554;

[Non-patent document 3] Jarrett JT, and two others, The carboxy terminus of the (amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer,s disease, Biochemistry, 1993, 32(18), p.4693-4697;

[Non-patent document 4] Glenner GG, and one other, Alzheimer,s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and biophysical research communications, 1984, May 16, 120(3), p.885-890;

[Non-patent document 5] Masters CL, and five others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceding National Academy of Science USA, 1985, Jun, 82(12), p.4245-4249;

[Non-patent document 6] Gouras GK, and eleven others, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156(1), p.15-20;

[Non-patent document 7] Scheuner D, and twenty others, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer,s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer,s disease, Nature Medicine, 1996, Aug, 2(8), p.864-870;

[Non-patent document 8] Forman MS, and four others, Differential effects of the swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, The Journal of Biological Chemistry, 1997, Dec 19, 272(51), p.32247-32253;

[Non-patent document 9] Shearman MS, and nine others, L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity, Biochemistry, 2000, Aug 1, 39(30), p.8698-8704;

[Non-patent document 10] Shearman MS, and six others, Catalytic Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate Pharmacologically between Notch S3 and β-APP Cleavages, Biochemistry, 2003, Jun 24, 42(24), p.7580-7586;

[Non-patent document 11] Lanz TA, and three others, Studies of A(pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitor N2-[(2S)-2-(3,5-diluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575), The journal of pharmacology and experimental therapeutics, 2004, Apr, 309(1), p.49-55;

[Non-patent document 12] Wong GT, and twelve others, Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, The journal of biological chemistry, 2004, Mar 26, 279(13), p.12876-12882.

Disclosure of the invention

Objectives of the invention

As described above, the compound that inhibits the production of Aβ40 and Aβ42 from APP, it is assumed as a therapeutic or prophylactic agent for diseases caused by Aβ, a typical representative of which is Alzheimer's disease. However, ones connection with high efficacy in inhibiting the production of Aβ40 and Aβ42, is still not known. Therefore, there is a need for a new compound with low molecular weight, which will inhibit the production of Aβ40 and Aβ42.

Means to solve these problems,

As a result of extensive studies, the authors present invention discovered ones derived Zinaida type of research, which inhibits primarily the production of Aβ40 and Aβ42 from APP, and, thus, has developed a preventive or therapeutic agent for diseases caused by Aβ, a typical representative of which is Alzheimer's disease. This finding has led to the creation of the present invention.

In particular, in accordance with aseason invention include:

1), the Compound represented by formula (I):

[Formula 1]

or its pharmacologically acceptable salt, where

(a) R1, R2, R3and R4are the same or different, and each represents a hydrogen atom or C1-alkiline group;

X1represents a C1-alkylenes group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 hydroxyl groups; or a C3-tically group formed by two C1-alkylidyne groups together are attached to the same carbon atom in C1-alkalinous group;

Xarepresents a methoxy group or a fluorine atom;

Xbrepresents an oxygen atom or methylene group, provided that Xbrepresents only the oxygen atom when Xarepresents a methoxy group; and

Ar1represents an aryl group, pyridinyl group, alloctype or pyridyloxy, which may be substituted by 1-3 substituents selected from group A1 deputies;

(b) Ar1-X1represents a C3-cycloalkyl group condensed with a benzene ring, where one methylene group in the C3-cycloalkyl group may be substituted and the Ohm oxygen, C3-cycloalkyl group may be substituted by 1-3 hydroxy groups and/or C1-alkylidyne groups and the benzene ring may be substituted by 1-3 substituents selected from group A1 substituents, and R1, R2, R3, R4Xaand Xbare as defined in (a);

(c) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group; the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, and X1XaXband Ar1are as defined in (a) or (b);

(d) Ar1-X1and R4together with the nitrogen atom to which the group Ar1-X1is attached and the carbon atom to which R4attached, form a 4-8-membered nitrogen-containing heterocyclic group which may be substituted by an aryl group or pyridinoline group, where one methylene group in the 4-to 8-membered nitrogen-containing heterocyclic group may be substituted methylene group is substituted by 1 or 2 substituents selected from group A1 deputies, vanilinovoi what Ruppel, which may be substituted by 1 or 2 substituents selected from group A1 substituents, an oxygen atom or aminogroups, which can be substituted by the Deputy selected from the group A1 of the substituents, and the aryl or pyridinoline group may be substituted by 1-3 substituents selected from group A1 substituents, Xbrepresents an oxygen atom, and R1, R2, R3and Xaare as defined in (a) and (b);

(e) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3, R4X1XaXband Ar1are as defined in (a) and (b); or

(f) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1, R2X1XaXband Ar1are as defined in (a) and (b)

(group A1 deputies: (1) halogen atom, (2) hydroxyl group, (3) cyano, (4) C3-cycloalkyl group, (5) C3-cycloalkanes, (6) C1-alcalina group, C1-alcalina group may be substituted by 1-5 halogen atoms or one to three C1-alkoxygroup, (7) an amino group which may be substituted by one or two C1-alkylidyne groups, where C1-alkylene group may be substituted by 1-5 halogen atoms, (8) C1-alkoxygroup, where C1-alkoxyl the PAP may be substituted by 1-5 halogen atoms, and (9) carnemolla group which may be substituted by one or two C1-alkylidyne groups, where C1-alkylene group may be substituted by 1 to 3 halogen atoms);

2) the Compound or its pharmacologically acceptable salt according to item 1) above, where the compound represented by formula (I-a):

[Formula 2]

where R1, R2, R3, R4X1and Ar1are as defined above in paragraph (1);

3) the Compound or its pharmacologically acceptable salt according to item 1) above, where the compound represented by formula (II):

[Formula 3]

where R1, R2, R3, R4Xaand Xbare as defined above in paragraph (1), R5and R6are the same or different and each represents a hydrogen atom or C1-alkiline group, C1-alcalina group may be substituted by 1-3 hydroxyl groups, and Ar1-arepresents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 of the substituents defined above in paragraph (1);

4) the Compound or its pharmacologically acceptable salt according to paragraph 3) above, where the compound represented by formula (II-a):

[Formula 4]

where R1, R2, R3and R4JW is Auda such as defined above in paragraph (1), and R5, R6and Ar1-aare as defined above in paragraph 3);

5) the Compound or its pharmacologically acceptable salt according to paragraph 3) above, where the compound represented by formula (II-b):

[Formula 5]

where R1, R2, R3and R4are as defined above in paragraph (1), and R5, R6and Ar1-aare as defined above in paragraph 3);

6) the Compound or its pharmacologically acceptable salt according to paragraph 3) above, where the compound represented by formula (II-c):

[Formula 6]

where R1, R2, R3and R4are as defined above in paragraph (1), R7represents a hydrogen atom or C1-alkiline group and Ar1-ais as defined above in paragraph 3);

7) the Compound or its pharmacologically acceptable salt according to paragraph 3) above, where the compound represented by formula (II-d):

[Formula 7]

where R1, R2, R3and R4are as defined above in paragraph (1), and R5, R6and Ar1-aare as defined above in paragraph 3);

8) the Compound or its pharmacologically acceptable salt according to paragraph 3) above, where the compound represented by formula (II-e):

[Formula 8]

where R1, R2, R3and R4are as defined above in paragraph (1), Ar1-ais as defined above in paragraph 3), and R7is as defined above in paragraph (6);

9) the Compound or its pharmacologically acceptable salt according to item 1) above, where the compound represented by formula (I-b):

[Formula 9]

where R1, R2, R3and R4are as defined above in paragraph (1), R13and R14are the same or different and each represents a hydrogen atom or a Deputy selected from the group A1 of the substituents defined above in paragraph (1), and Y represents a methylene group or an oxygen atom;

10) the Compound or its pharmacologically acceptable salt according to item 9) above, where R13and R14are the same or different and each represents a hydrogen atom, halogen atom or C1-alkoxygroup;

11) the Compound or its pharmacologically acceptable salt according to item 1) above, where the compound represented by formula (I-c):

[Formula 10]

where R1and R2are as defined above in paragraph (1), Ar1-crepresents a phenyl group or pyridinyl group which may be substituted by 1-3 mandated what teli, which are the same or different and selected from the group A1 substituents, Z1represents a methylene group or vanilinovoi group which may be substituted by 1 or 2 substituents selected from group A1 of the substituents defined above in paragraph (1), an oxygen atom or aminogroups, which can be substituted by the Deputy selected from the group A1 deputies,

and n and m are the same or different and each is an integer from 0 to 2;

12) the Compound or its pharmacologically acceptable salt according to item 11) above, where Z1represents a methylene group, a methylene group may be substituted by 1 or 2 substituents which are the same or different and selected from the group consisting of C1-alkiline group and hydroxyl group, and n and m are each equal to 1;

13) the Compound or its pharmacologically acceptable salt according to item 11) above, where Z1represents an oxygen atom, and n and m is an integer 1;

14) the Compound or its pharmacologically acceptable salt according to item 1) above, where Ar1represents an aryl group or pyridinyl group, or aryl group, or pyridinyl group substituted by 1-3 halogen atoms;

15) the Compound or its pharmacologically acceptable salt according to item 1) above, where Ar1represents f is niloy group or pyridinyl group, or phenyl group, or pyridinyl group substituted by 1-3 halogen atoms;

16) the Compound or its pharmacologically acceptable salt according to item 1) above, where the compound is selected from the following group including:

1) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(3,4,5-triptorelin)morpholine-3-one,

2) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(2,3,4-triptorelin)morpholine-3-one,

3) (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one,

4) (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one,

5) (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one,

6) (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one,

7) (Z)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

8) (Z)-(R)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

9) (Z)-(S)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

10) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,

11) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(R)-1-(3,4,5-Tr is forfinal)ethyl]morpholine-3-one,

12) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

13) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

14) (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

15) (Z)-(6S,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

16) (Z)-(6R,9aS)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

17) (Z)-(S)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

18) (Z)-(S)-4-[(R)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

19) (Z)-(S)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

20) (Z)-(S)-4-[(R)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

21) (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

22) (Z)-(S)-4-[(R)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

23) (Z)-(S)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-metalmorph the n-3-one,

24) (Z)-(S)-4-[(R)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

25) (Z)-(S)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

26) (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

27) (Z)-4-[(R)-1-(4-forfinal)-2-hydroxyethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

28) (Z)-(6R)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

29) (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one,

30) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one,

31) (Z)-(S)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

32) (Z)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

33) (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

34) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(Mei-1-yl)phenyl]metaled the n]-6,6-dimethylmorpholine-3-one,

35) (Z)-(S)-4-[(S)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

36) (Z)-(6S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,

37) (Z)-(6S)-4-[1-(4-forfinal)-1-methylethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

38) (Z)-(6S)-4-[1-(4-forfinal)cyclopropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

39) (Z)-(6S,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

40) (Z)-(6S,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

41) (Z)-(6S,9aR)-6-(2,6-differencein-3-yl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

42) (Z)-(S)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

43) (Z)-(S)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

44) (Z)-(S)-4-[(S)-1-(2-chloro-3-herperidin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

45) (Z)-(S)-4-[(S)-1-(2,6-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

46) (Z)-4-[(S)-1-(2-chloropyridin-4-yl)et the l]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

47) (Z)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

48) (Z)-4-[(S)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

49) (Z)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

50) (Z)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

51) (Z)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

52) (Z)-(R)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

53) (Z)-(S)-4-(4-terbisil)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

54) (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(4-tryptophanyl)ethyl]-6,6-dimethylmorpholine-3-one,

55) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

56) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

57) (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-3-one,

58) (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-ethylmorpholine-3-one,

59) (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-6-methylmorpholin-3-one,

60) (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6,6-dimethylmorpholine-3-one,

61) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

62) 1-[1-(2,4-differenl)ethyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}piperidine-2-it,

63) (E)-(S)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it,

64) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]piperidine-2-it,

65) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(2R,3R)-3-hydroxy-1,1-dietlinde-2-yl]piperidine-2-it,

66) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(S)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]piperidine-2-it,

67) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[1-(4-forfinal)-1-methylethyl]piperidine-2-it,

68) (E)-(R)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it,

69) (E)-(S)-1-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-5-methylpiperidin-2-it,

70) (Z)-(6S,8aR)-3-{1-[3-methoxy-4-(4-methyl-1H-shall midazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,

71) (6S,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

72) (6R,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}-6-(3,4,5-tryptophanyl)-tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one,

73) (6R,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one,

74) (6R,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one

75) (6R,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c]oxazin-4-one;

17) a Pharmaceutical agent containing the compound or its pharmacologically acceptable salt according to any one of items 1)to 16) above as an active ingredient;

18) the Pharmaceutical agent according to item 17) above for the prevention or treatment of disease caused by amyloid-β, and

19) the Pharmaceutical agent according to item 18) above, where the disease caused by amyloid-β is Alzheimer's disease, senile dementia, down's syndrome or amyloidosis.

The compound of General formula (I) or its pharmacologically acceptable salt according to the present invention and a preventive or therapeutic agent for diseases caused by Aβ, according to the present invention are new and are not described in which Aceh any publications.

Next explained is the application of values, terms and the like, used in this description, and the present invention is described in more detail.

In this specification, the structural formula of the compound may for convenience to represent any isomer. However, the present invention includes all isomers and isomeric mixture, such as geometric isomers, which may be formed in connection with the structure of the compound, optical isomers, the formation of which is based on asymmetric carbons, stereoisomers and tautomers. The present invention is not limited to the description chosen for reasons of convenience, chemical formulas, and can cover any of the isomers or a mixture thereof. Accordingly, the compound of the present invention may be of the molecule in the asymmetric carbon atom and can exist as optically active compound or racemate, and the present invention includes, but without limitation, as optically active compound, and the racemate. Although there may be crystalline polymorphs of the compound, this compound is not limited and may be in the form of single crystal or a mixture of single crystals. The connection can be UN-hydrated or hydrate.

“The disease caused by Aβ” refers to a wide range of diseases, such as disease Alzheimer is a (see, for example, Klein WL, and seven others, Alzheimer's disease-affected brain: Presence of oligomeric A(ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceding National Academy of Science USA, 2003, Sep 2, 100(18), p.10417-10422; Nitsch RM, and sixteen others, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22, 38(4), p.547-554; Jarrett JT, and two others, The carboxy terminus of the (amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, May 11, 32(18), p.4693-4697; Glenner GG, and one other, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and biophysical research communications, 1984, May 16, 120(3), p.885-890; Masters CL, and six others, Amyloid plaque core protein in Alzheimer's disease and Down syndrome, Proceding National Academy of Science USA, 1985, June, 82(12), p.4245-4249; Gouras GK, and eleven others, Intraneuronal Aβ42 accumulation in human brain, American journal of pathology, 2000, Jan, 156(1), p.15-20; Scheuner D, and twenty others, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2(8), p.864-870; and Forman MS, and four others, Differential effects of the swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, The journal of biological chemistry, 1997, Dec 19, 272(51), p.32247-32253), senile dementia (see, for example, Blass JP, Brain metabolism and brain disease: Is metabolic deficiency = MKD the proximate cause of Alzheimer dementia? Journal of Neuroscience Research, 2001, Dec 1, 66(5), p.851-856), fronto-temporal dementia (see, for example, Evin G, and eleven others, Alternative transcripts of presenilin-1 associated with frontotemporal dementia, Neuroreport, 2002, Apr 16, 13(5), p.719-723), the disease Peak (see, for example, Yasuhara O, and three others, Accumulation of amyloid precursor protein in brain lesions of patients with Pick disease, Neuroscience Letters, 1994, Apr 25, 171(1-2), p.63-66), Ingram down (see, for example, Teller JK, and ten others, Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down''s syndrome, Nature Medicine, 1996, Jan, 2(1), p.93-95; and Tokuda T, and six others, Plasma levels of amyloid (proteins Aβ1-40 and Aβ1-42(43) are elevated in Down''s syndrome, Annals of Neurology, 1997, Feb, 41(2), p.271-273), cerebral angiopathy (see, for example, Hayashi Y, and nine others, Evidence for presenilin-1 involvement in amyloid angiopathy in the Alzheimer's disease-affected brain, Brain Research, 1998, Apr 13, 789(2), p.307-314; Barelli H, and fifteen others, Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid (peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases, Molecular Medicine, 1997, Oct, 3(10), p.695-707; Calhoun ME, and ten others, Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid, Proceding National Academy of Science USA, 1999, Nov 23, 96(24), p.14088-14093; and Dermaut B, and ten others, Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's Disease due to a novel presenilin-1 mutation, Brain, 2001, Dec, 124(12), p.2383-2392), hereditary cerebral hemorrhage with amyloidosis (Dutch type), (see, for example, Cras P, and nine others, Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala -->Gly mutation, Acta Neuropathologica (Berl), 1998, Sep, 96(3), p. 253-260; Herzig MC, and fourteen others, A is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis, Nature Neuroscience, 2004, Sep, 7(9), p.954-960; van Duinen SG, and five others, Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer's disease, Proceding National Academy of Science USA, 1987, Aug, 84(16), p.5991-5994; and Levy E, and eight others, Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science, 1990, Jun 1, 248(4959), p.1124-1126), cognitive disturbance (see, for example, Laws SM, andseven others, Association between the presenilin-1 mutation Glu318Gly and complaints of his or her memory, Neurobiology of Aging, 2002, Jan-Feb, 23(1), p.55-58), memory impairment and learning disability (see, for example, Vaucher E, and five others, Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes, Experimental Neurology, 2002 Jun, 175(2), p.398-406; Morgan D, and fourteen others, A(peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, Nature, 2000 Dec 21-28, 408(6815), p.982-985; and Moran PM, and three others, Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human β-amyloid precursor protein, Proceding National Academy of Science USA, 1995, June 6, 92(12), p.5341-5345), amyloidosis, cerebral ischemia (see, for example, Laws SM, and seven others, Association between the presenilin-1 mutation Glu318Gly and complaints of memory his or her, Neurobiology of Aging, 2002, Jan-Feb, 23(1), p.55-58; Koistinaho M, and ten others, β-amyloid precursor protein transgenic mice that harbor diffuse A(deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation, Proceding National Academy of Science USA, 2002, Feb 5, 99(3), p.1610-1615; and Zhang F, and four others, Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein, The journal of neuroscience, 1997, Oct 15, 17(20), p.7655-7661), vascular dementia (see, for example, Sadowski M, and six others, Links between the pathology of Alzheimer's disease and vascular dementia, Neurochemical Research, 2004, Jun, 29(6), p.1257-1266), ophthalmoplegia (see, for example, O'riordan S, and seven others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology, 2002, Oct 8, 59(7), p.1108-1110), multiple sclerosis (see, for example, Gehrmann J, and four others, Amyloid precursor protein (APP) expression in multiple sclerosis lesions, Glia, 1995, Oct, 15(2), p.141-51; and Reynolds WF, and six others, Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease, Experimental Neurology, 1999, Jan, 155(1), p.31-41, head trauma, cranial trauma (see, for example, Smith DH, and four others, Protein accumulation in traumatic brain injury, NeuroMolecular Medicine, 2003, 4(1-2), p.59-72), apraxia (see, for example, Matsubara-Tsutsui M, and seven others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American journal of Medical Genetics, 2002, Apr 8, 114(3), p.292-298), primary disease, familial amyloid neuropathy, a disease of repeating triplets (see, for example, Kirkitadze MD, and two others, Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies, Journal of Neuroscience Research, 2002, Sep 1, 69(5), p.567-577; Evert BO, and eight others, Inflammatory genes are upreglulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains, The Journal of Neuroscience, 2001, Aug 1, 21(15), p.5389-5396; and Mann DM, and one other, Deposition of amyloid(A4) protein within the brains of persons with dementing disorders other than Alzheimer's disease and Down''s syndrome, Neuroscience Letters, 1990, Feb 5, 109(1-2), p.68-75), Parkinson's disease (see, for example, Primavera J, and four others, Brain accumulation of amyloid-(in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p.183-193), dementia with calves Levi (see, for example, Giasson BI, and two others, Interactions of amyloidogenic proteins. NeuroMolecular Medicine, 2003, 4(1-2), p.49-58; Masliah E, and six others, β-amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a trancgenic mouse model linking Alzheimer's disease and PA's disease, Proceding National Academy of Science USA, 2001, Oct 9, 98(21), p.12245-12250; Barrachina M, and six others, Amyloid-(deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46(3), p. 253-260; and Primavera J, and four others, Brain accumulation of amyloid-(in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p.183-193), the complex parks shall aNISM-dementia (see, for example, Schmidt ML, and six others, Amyloid plaques in Guam amyotrophic lateral sclerosis/ parkinsonism-dementia complex contain species of A(similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging, Acta Neuropathologica (Berl), 1998, Feb, 95(2), p.117-122; and Ito H, and three others, Demonstration of amyloid protein-containing neurofibrillary tangles in parkinsonism-dementia complex on Guam, Neuropathology and applied neurobiology, 1991, Oct, 17(5), p.365-373), fronto-temporal dementia and parkinsonism associated with chromosome 17 (see, for example, Rosso SM, and three others, Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations, Annals of the New York academy of sciences, 2000, 920, p.115-119), dementia with argyrophyllum grains (see, for example, Tolnay M, and four others, Low amyloid (Aβ) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease, Neuropathology and applied neurobiology, 1999, Aug, 25(4), p.295-305), Niemann-pick disease (see, for example, Jin LW, and three others, Intracellular accumulation of amyloidogenic fragments of amyloid-(a precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities, American Journal of Pathology, 2004, Mar, 164(3), p.975-985), amyotrophic lateral sclerosis (see, for example, Sasaki S, and one other, Immunoreactivity of β-amyloid precursor protein in amyotrophic lateral sclerosis, Acta Neuropathologica(Berl), 1999, May, 97(5), p.463-468; Tamaoka A, and four others, Increased amyloid (protein in the skin of patients with amyotrophic lateral sclerosis, Journal of neurology, 2000, Aug, 247(8), p.633-635; Hamilton RL, and one other, Alzheimer's disease pathology in amyotrophic lateral sclerosis, Acta Neuropathologica, 2004, Jun, 107(6), p.515-522; and Turner BJ, and six others, Brain β-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1, Neurochemical Research, 2004, Dec, 29(12), p.2281-2286), hydrocephalus (see, for example, Weller RO, Pathology of cerebrospinal fluid and interstitial fluid of the CNS: Significance for Alzheimr disease, prior disorders and multiple sclerosis, Journal of Neuropathology and Experimental Neurology, 1998, Oct, 57(10), p.885-894; Silverberg GD, and four others, Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory discrimination: a hypothesis, Lancet neurology, 2003, Aug, 2(8), p.506-511; Weller RO, and three others, Cerebral amyloid angiopathy: Accumulation of A(in interstitial fluid drainage pathways in Alzheimer's disease, Annals of the New York academy of sciences, 2000, Apr, 903, p.110-117; Yow HY, and one other, A role for cerebrovascular disease in determining the pattern of β-amyloid deposition in Alzheimer's disease, Neurology and applied neurobiology, 2002, 28, p.149; and Weller RO, and four others, Cerebrovasculardisease is a major factor in the failure of elimination of A(from the aging human brain, Annals of the New York academy of sciences, 2002, Nov, 977, p.162-168), prepares (see for example, O'riordan S, and seven others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology, 2002, Oct 8, 59(7), p.1108-1110; Matsubara-Tsutsui M, and seven others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American journal of Medical Genetics, 2002, Apr 8, 114(3), p.292-298; Smith MJ, and eleven others, Variable phenotype of Alzheimer's disease with spastic paraparesis, Annals of Neurology, 2001, 49(1), p.125-129; and Crook R, and seventeen others, A variant of Alzheimer's disease with spastic pararesis and unusual plaques due to deletion of exon 9 of presenilin 1, " Nature Medicine, 1998, Apr; 4(4), p.452-455), progressive supranuclear paralysis (see, for example, Barrachina M, and six others, Amyloid-(deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46(3), p. 253-260; and Primavera J, and four others, Brain accumulation of amyloid-(in Non-Alzheimer Neurodegeneration, Jornal of Alzheimer's Disease, 1999, Oct, 1(3), p.183-193), intracerebral hemorrhage (see, for example, Atwood CS, and three others, Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow fr the maintenance of vascular integrity and blood supply, Brain Research Reviews, 2003, Sep, 43(1), p.164-78; and Lowenson JD, and two others, Protein aging: increasing interest among amyloid formation and intracellular repair, Trends in cardiovascular medicine, 1994, 4(1), p.3-8), convulsion (see, for example, Singleton AB, and thirteen others, Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation, Brain, 2000, Dec, 123(Pt12), p.2467-2474), mild cognitive disorder (see, for example, Gattaz WF, and four others, Platelet phospholipase A2 activity in Alzheimer's disease and mild his or her cognitive, Journal of Neural Transmission, 2004, May, 111(5), p.591-601; and Assini A, and fourteen others, Plasma levels of amyloid β-protein 42 are increased in women with mild cognitive impariment, Neurology, 2004, Sep 14, 63(5), p.828-831) and arteriosclerosis (see, for example, De Meyer GR, and eight others, Platelet phagocytosis and processing of β-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis, Circulation Reserach, 2002, Jun 14, 90(11), p.1197-1204).

"C1-Allenova group" refers to alkalinous group containing 1-6 carbon atoms. Preferred examples of the group include methylene group, ethylene group, propylene group, butylene group and Panteleeva group.

“C1-alcalina group" refers to an alkyl group containing 1-6 carbon atoms. Preferred examples of the group include unbranched or branched alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, n-pencilina group, isopentyl group, neopentyl group, n-exilda group, 1-methylpropyl groups who, 1,2-dimethylpropylene group, 1-ethylpropyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group and 3-methylpentyl group.

“C3-tically group” refers to a cyclic alkyl group containing 3-13 carbon atoms. Preferred examples of the group include cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, cycloneuralia group, cyclodecyl group, cyclohexadienyl group, cyclododecyl group and cyclotrimethylene group.

“Aryl group” refers to "6-14-membered cyclic aromatic hydrocarbon group or 5 to 14-membered aromatic heterocyclic group". "6-14-Membered cyclic aromatic hydrocarbon group", as used herein, refers to monocyclic, bicyclic or tricyclic aromatic hydrocarbon group containing 6-14 carbon atoms. Preferred examples of the group include 6-14-membered monocyclic, bicyclic or tricyclic aromatic uglevodorodno the e group, such as phenyl group, angenlina group, naftalina group, atulananda group, heptylaniline group, biphenylene group, fluoroaniline group, phenylaniline group, phenanthroline group and antarctilyne group. "5 to 14-Membered aromatic heterocyclic group" refers to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing 5-14 carbon atoms. Preferred examples of the group include (1) nitrogen-containing aromatic heterocyclic groups such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, piratininga group, imidazolidinyl group, indayla group, isoindolyl group, indolizinyl group, polylina group, indazolinone group, kinolinna group, izochinolina group, hyalinella group, phthalazinone group, naphthyridinone group, khinoksalinona group, chinadaily group, indolenine group, pteridinyl group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, pyrimidinyl group, phenanthroline group and group penicilina, (2) sulfur-containing aromatic heterocyclic groups such as thienyl group is a and benzothiazoline group, (3) oxygen-containing aromatic heterocyclic groups such as furilla group, Pernilla group, cyclopentadienyl group, benzofuranyl group and isobenzofuranyl group, and (4) aromatic heterocyclic groups containing two or more heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, such as thiazolidine group, isothiazolinone group, benzothiazolyl group, benzothiadiazole group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxypyridine group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group and pyridoxamine group.

“Alloctype" refers to a group in which a hydrogen atom in an aromatic hydrocarbon ring 6-14-membered cyclic aromatic hydrocarbon group or a hydrogen atom in the aromatic heterocycle "5 to 14-membered aromatic heterocyclic group substituted by an oxygen atom.

“C3-cycloalkyl group condensed with a benzene ring" may be, for example, a group of the formula:

[Formula 11]

The benzene ring may be substituted by 1-3 substituents selected from group A1 deputies, one methylene group in the C3-cycloalkyl group which may be substituted by an oxygen atom and a C3-cycloalkyl group may be substituted by 1-3 hydroxy groups and/or C1-alkylidyne groups.

"4-to 8-Membered nitrogen-containing heterocyclic group formed by a group Ar1-X1and R4together with the nitrogen atom to which Ar1-X1is attached and the carbon atom to which R4attached" may be, for example, a group of the formula:

[Formula 12]

4-8-Membered nitrogen-containing heterocyclic group may be substituted by an aryl group or pyridinoline group, where aryl group or pyridinoline group may be substituted by 1-3 substituents selected from group A1 deputies. In addition, one methylene group in the 4-to 8-membered nitrogen-containing heterocyclic group may be substituted methylene group is substituted by 1 or 2 substituents selected from group A1 deputies, vanilinovoi group which may be substituted by 1 or 2 substituents selected from group A1 substituents, an oxygen atom or aminogroups, which can be substituted by the Deputy selected from the group A1 deputies.

4-8-Membered nitrogen-containing heterocyclic group containing one methylene group which may be substituted methylene group is substituted by 1 or 2 substituents selected from group A1 deputies, vanilinovoi group which may be substituted by 1 or 2 substituents selected from group A1 deputies, atom sour the kind or aminogroups, which may be substituted by the Deputy selected from the group A1 of the substituents may be, for example, a group specifically represented by the formula:

[Formula 13]

“C1-Allina group", as used herein, refers to an acyl group containing 1-6 carbon atoms. Preferred examples of the group include formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, pentanoyl group and hexanoyl group.

“C3-cycloalkyl group formed by R1and R2together with the carbon atom to which they are attached", or “C3-cycloalkyl group formed by R3and R4together with the carbon atom to which they are attached, can be, for example, a group specifically represented by the formula:

[Formula 14]

“C1-Allenova group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 hydroxyl groups, or C3-tically group formed by two C1-alkylidyne groups together are attached to the same carbon atom in C1-alkalinous group"may be, for example, a group, a specific is on is represented by the formula:

[Formula 15]

Group A1 substituents refers to the following groups.

Group A1 deputies: (1) halogen atom, (2) hydroxyl group, (3) cyano, (4) C3-cycloalkyl group, (5) C3-cycloalkanes, (6) C1-alkiline group, C1-alcalina group may be substituted by 1-5 halogen atoms or one to three C1-alkoxygroup, (7) an amino group which may be substituted by one or two C1-alkylidyne groups, where C1-alkylene group may be substituted by 1-5 halogen atoms, (8) C1-alkoxygroup where C1-alkoxygroup may be substituted by 1-5 halogen atoms, and (9) carnemolla group which may be substituted by one or two C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 halogen atoms.

"Halogen atom" as used in this description refers to a fluorine atom, chlorine atom, bromine atom, iodine atom or the like and is preferably a fluorine atom, a chlorine atom or a bromine atom.

“C3-cycloalkyl group” refers to a cyclic alkyl group containing 3-8 carbon atoms. Preferred examples of the group include cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group.

“C3-cycloalkanes" relation is seeking to cyclic alkyl group, containing 3-8 carbon atoms, in which one hydrogen atom is substituted by an oxygen atom. Preferred examples of the group include cyclopropane, cyclobutanes, cyclopentamine, cyclohexamide, cycloheptylamine and cyclooctylamine.

“C1-alcalina group” is the same as defined above, and specific examples of the groups described above.

“C1-alkoxygroup" refers to an alkyl group containing 1-6 carbon atoms in which a hydrogen atom is substituted by an oxygen atom. Preferred examples of the group include a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, n-phenoxypropan, isobutoxy, sec-phenoxypropan, tert-phenoxypropan, n-hexachrome, isohexadecane, 1,2-DIMETHYLPROPANE, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1,1-Dimethylbutane, 2,2-Dimethylbutane, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylphenoxy, 3-methylphenoxy and hexyloxy.

"Amino group which may be substituted by one or two C1-alkylidyne groups”refers to an amino group in which one or two hydrogen atoms replaced by one or two who skillname groups, containing 1-6 carbon atoms. Preferred examples of the group include methylaminopropyl, dimethylaminopropyl, ethylamino, diethylaminopropyl, n-propylamino and di-n-propylamino.

“Carnemolla group which may be substituted by one or two C1-alkylidyne groups”refers to carbamoyl group in which one or two hydrogen atoms replaced by one or two alkyl groups containing 1-6 carbon atoms. Preferred examples of the group include methylcarbamoyl group, dimethylcarbamoyl group, ethylcarbitol group, diethylcarbamoyl group, n-profilirovannuju group, and di-n-profilirovannuju group.

In this description, there is no special limitation on the "pharmacologically acceptable salt", only that she was pharmacologically acceptable salt formed with the compound of General formula (I), there was a preventive or therapeutic agent for diseases caused by Aβ. Preferred specific examples of the salt include hydrogenogenic (such as hydrohloride, hydrochloride, hydrobromide and hydroiodide), inorganic salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates, and bicarbonates), organic carboxylates (such as acetates, oxalates, maleate, tartratami, fumarate and citrate), organic with libonati (such as methanesulfonate, triftoratsetata, econsultancy, bansilalpet, toluensulfonate and camphorsulfonate), salt, amino acids (such as aspartate and glutamate), salt, Quaternary amine, alkali metal salts (such as sodium salts and potassium salts), and salts of alkaline earth metals (such as magnesium salt and calcium salt).

The following compound of formula (I) according to the present invention.

In the compound of formula (I) or its pharmacologically acceptable salt is preferable:

(a) R1, R2, R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group;

X1represents a C1-alkylenes group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 hydroxyl groups; or a C3-tically group formed by two C1-alkylidyne groups together are attached to the same carbon atom in C1-alkalinous group;

Xarepresents a methoxy group or a fluorine atom;

Xbrepresents an oxygen atom or methylene group, provided that Xbrepresents only the oxygen atom when Xarepresents a methoxy group; and

Ar1represents an aryl group, ridinlow group, alloctype or pyridyloxy, which may be substituted by 1-3 substituents selected from group A1 deputies;

(b) Ar1-X1represents a C3-cycloalkyl group condensed with a benzene ring, where one methylene group in the C3-cycloalkyl group may be substituted by oxygen atom, C3-cycloalkyl group may be substituted by 1-3 hydroxy groups and/or C1-alkylidyne groups and the benzene ring may be substituted by 1-3 substituents selected from group A1 substituents, and R1, R2, R3, R4Xaand Xbare as defined in (a);

(c) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, and X1XaXband Ar1are as defined in (a) or (b);

(d) Ar1-X1and R4together with the nitrogen atom to which Ar1-X1is attached and the carbon atom to which R4attached, form a 4-8-membered and odderade heterocyclic group, which may be substituted by an aryl group or pyridinoline group, where one methylene group in the 4-to 8-membered nitrogen-containing heterocyclic group may be substituted methylene group is substituted by 1 or 2 substituents selected from group A1 deputies, vanilinovoi group which may be substituted by 1-3 substituents selected from group A1 substituents, an oxygen atom or aminogroups, which can be substituted by the Deputy selected from the group A1 of the substituents, and the aryl or pyridinoline group may be substituted by 1-3 substituents selected from group A1 substituents, Xbrepresents an oxygen atom, and R1, R2, R3and Xaare as defined in (a) and (b);

(e) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3, R4X1XaXband Ar1are as defined in (a) and (b); or

(f) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1, R2X1XaXband Ar1are as defined in (a) and (b);

and particularly preferably:

(a) R1, R2, R3and R4are the same or different and each represents a hydrogen atom is whether C1-alkiline group;

X1represents a C1-alkylenes group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 hydroxyl groups;

Xarepresents a methoxy group or a fluorine atom;

Xbrepresents an oxygen atom or methylene group, provided that Xbrepresents only the oxygen atom when Xarepresents a methoxy group; and

Ar1represents an aryl group, pyridinyl group, alloctype or pyridyloxy, which may be substituted by 1-3 substituents selected from group A1 deputies;

(b) Ar1-X1represents a C3-cycloalkyl group condensed with a benzene ring, where one methylene group in the C3-cycloalkyl group may be substituted by oxygen atom, C3-cycloalkyl group may be substituted by 1-3 hydroxy groups and/or C1-alkylidyne groups and the benzene ring may be substituted by 1-3 substituents selected from group A1 substituents, and R1, R2, R3, R4Xaand Xbare as defined in (a); or

(d) Ar1-X1and R4together with the nitrogen atom to which the group Ar1-X1is attached and the carbon atom to cat the rum R 4attached, form a 4-8-membered nitrogen-containing heterocyclic group which may be substituted by an aryl group or pyridinoline group, where one methylene group in the 4-to 8-membered nitrogen-containing heterocyclic group may be substituted methylene group is substituted by 1 or 2 substituents selected from group A1 deputies, vanilinovoi group which may be substituted by 1-3 substituents selected from group A1 substituents, an oxygen atom or aminogroups, which can be substituted by the Deputy selected from the group A1 of the substituents, and the aryl or pyridinoline group may be substituted by 1-3 substituents selected from group A1 substituents, Xbrepresents an oxygen atom, and R1, R2, R3and Xaare as defined in (a) and (b).

In the compound of formula (I) or its pharmacologically acceptable salt

Ar1preferably represents an aryl group or pyridinyl group, or aryl group, or pyridinyl group substituted by 1-3 halogen atoms.

In the compound of formula (I) or its pharmacologically acceptable salt

Ar1more preferably represents a phenyl group or pyridinyl group, or phenyl group or pyridinyl group substituted by 1-3 halogen atoms.

In connection fo the formula (I) or its pharmacologically acceptable salt

Xapreferably represents a methoxy group or a fluorine atom.

In the compound of formula (I) or its pharmacologically acceptable salt

Xbpreferably represents an oxygen atom or methylene group, provided that Xbrepresents only the oxygen atom when Xarepresents a methoxy group.

In the compound of formula (I) or its pharmacologically acceptable salt

preferably 1) R1, R2, R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, 2) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, and the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, 3) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, or 4) R3and R4together with the carbon atom to cat the rum they are attached, form a C3-cycloalkyl group, and R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group.

In the compound of formula (I) or its pharmacologically acceptable salt

X1preferably represents C1-alkylenes group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 hydroxyl groups, X1more preferably represents-CR5R6-where R5and R6are the same or different and each represents a hydrogen atom or C1-alkiline group, C1-alcalina group may be substituted by 1-3 hydroxyl groups, and X1most preferably represents-CH-C(OH)R7-where R7represents a C1-alkiline group.

In the compound of formula (I) or its pharmacologically acceptable salt

Ar1preferably represents an aryl group, pyridinyl group, alloctype or pyridyloxy, which may be substituted by 1-3 substituents selected from group A1 substituents, and Ar1more preferably represents an aryl group or pyridinyl group which may be substituted by 1-3 substituents selected from group the s A1 deputies.

In the compound of formula (II) or its pharmacologically acceptable salt:

Ar1-apreferably represents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 deputies; and

Ar1-amore preferably represents a phenyl group or pyridinyl group which may be unsubstituted or may be substituted by 1-3 halogen atoms.

In the compound of formula (II) or its pharmacologically acceptable salt

preferably R5and R6are the same or different and each represents a hydrogen atom or C1-alkiline group, C1-alcalina group may be substituted by 1-3 hydroxyl groups.

In the compound of formula (II) or its pharmacologically acceptable salt

Xapreferably represents a methoxy group or a fluorine atom.

In the compound of formula (II) or its pharmacologically acceptable salt

Xbpreferably represents an oxygen atom or methylene group, provided that Xbrepresents only the oxygen atom when Xarepresents a methoxy group.

In the compound of formula (II) or its pharmacologically acceptable salt

preferably 1) R1, R2, R3and R4are the same or different and is each represents a hydrogen atom or C1-alkiline group, 2) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, and the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, 3) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, or 4) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group.

In the compound of the formula (I-a) or its pharmacologically acceptable salt

X1preferably represents C1-alkylenes group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, where C1-alkylene groups can be substituted by 1-3 hydroxyl groups, X1more preferably represents-CR5R6-where R5and R6 are the same or different and each represents a hydrogen atom or C1-alkiline group, C1-alcalina group may be substituted by 1-3 hydroxyl groups, and X1most preferably represents-CH-C(OH)R7-where R7represents a C1-alkiline group.

In the compound of the formula (I-a) or its pharmacologically acceptable salt

Ar1preferably represents an aryl group, pyridinyl group, alloctype or pyridyloxy, which may be substituted by 1-3 substituents selected from group A1 substituents, and Ar1more preferably represents an aryl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 deputies.

In the compound of the formula (I-a) or its pharmacologically acceptable salt

preferably 1) R1, R2, R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, 2) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, and the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cyclol the ilen group, where C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, 3) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, or 4) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group.

In the compound of the formula (I-b) or its pharmacologically acceptable salt

preferably R13and R14are the same or different and represent a hydrogen atom or a Deputy selected from the group A1 substituents, and more preferably R13and R14are the same or different and each represents a hydrogen atom, halogen atom or C1-alkoxygroup.

In the compound of the formula (I-b) or its pharmacologically acceptable salt

Y preferably represents a methylene group or an oxygen atom.

In the compound of the formula (I-b) or its pharmacologically acceptable salt

preferably 1) R1, R2, R3and R4are the same or different and each before the hat is hydrogen atom or C1-alkiline group, 2) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, and the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, 3) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, or 4) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group.

In the compound of the formula (I-c) or its pharmacologically acceptable salt:

Ar1-cpreferably represents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 deputies; and

Ar1-cmore preferably represents a phenyl group or pyridinyl group which may be unsubstituted or may be zames is by 1-3 halogen atoms.

In the compound of the formula (I-c) or its pharmacologically acceptable salt:

Z1preferably represents a methylene group or vanilinovoi group which may be substituted by 1 or 2 substituents selected from group A1 substituents, an oxygen atom or aminogroups, which can be substituted by the Deputy selected from the group A1 deputies;

Z1more preferably represents a methylene group which may be substituted by 1 or 2 substituents selected from group A1 substituents, or an oxygen atom; and

Z1most preferably represents a methylene group, a methylene group may be substituted by 1 or 2 substituents which are the same or different and selected from the group consisting of C1-alkiline group and hydroxyl group, or an oxygen atom.

In the compound of the formula (I-c) or its pharmacologically acceptable salt, preferably n and m are the same or different and each is an integer from 0 to 2, and more preferably n and m are each equal to 1.

In the compound of the formula (I-c) or its pharmacologically acceptable salt is preferably 1) R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group or 2) R1and R2together with the atom is m carbon to which they are attached, form a C3-cycloalkyl group.

In the compound of the formula (II-a), (II-b) or (II-d) or its pharmacologically acceptable salt is preferably 1) R1, R2, R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, 2) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, and the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, 3) R1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, or 4) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group.

In the compound of the formula (II-a), (II-b) or (II-d) or its pharmacologically acceptable salt predpochtitel what about the R 5and R6are the same or different and each represents a hydrogen atom or C1-alkiline group, C1-alcalina group may be substituted by 1-3 hydroxyl groups.

In the compound of the formula (II-a), (II-b) or (II-d) or its pharmacologically acceptable salt:

Ar1-apreferably represents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 deputies; and

Ar1-amore preferably represents a phenyl group or pyridinyl group which may be unsubstituted or may be substituted by 1-3 halogen atoms.

In the compound of the formula (II-c) or (II-e) or its pharmacologically acceptable salt

preferably 1) R1, R2, R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, 2) one of R1and R2and one of R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, and the other of R1and R2and the other of R3and R4together with the carbon atoms to which they are respectively attached, form a C3-cycloalkyl group, C3-cycloalkyl group may be substituted by 1-3 substituents selected from group A1 substituents, 3) R 1and R2together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R3and R4are the same or different and each represents a hydrogen atom or C1-alkiline group, or 4) R3and R4together with the carbon atom to which they are attached, form a C3-cycloalkyl group, and R1and R2are the same or different and each represents a hydrogen atom or C1-alkiline group.

In the compound of the formula (II-c) or (II-e) or its pharmacologically acceptable salt

R7preferably represents a hydrogen atom or C1-alkiline group.

In the compound of the formula (II-c) or (II-e) or its pharmacologically acceptable salt:

Ar1-apreferably represents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 deputies; and

Ar1-amore preferably represents a phenyl group or pyridinyl group which may be unsubstituted or may be substituted by 1-3 halogen atoms.

In particular, for example, a compound selected from the following group, or its pharmacologically acceptable salt is particularly suitable and useful as a therapeutic or prophylactic agent for diseases vyzyvae the CSOs amyloid-β, such as Alzheimer's disease, senile dementia, down's syndrome or amyloidosis, including:

1) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(3,4,5-triptorelin)morpholine-3-one,

2) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(2,3,4-triptorelin)morpholine-3-one,

3) (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one,

4) (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one,

5) (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one,

6) (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one,

7) (Z)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

8) (Z)-(R)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

9) (Z)-(S)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

10) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,

11) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(R)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,

12) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethyl Holin-3-one,

13) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

14) (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

15) (Z)-(6S,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

16) (Z)-(6R,9aS)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

17) (Z)-(S)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

18) (Z)-(S)-4-[(R)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

19) (Z)-(S)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

20) (Z)-(S)-4-[(R)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

21) (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

22) (Z)-(S)-4-[(R)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

23) (Z)-(S)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

24) (Z)-(S)-4-[(R)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylide the]-6-methylmorpholin-3-one,

25) (Z)-(S)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

26) (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

27) (Z)-4-[(R)-1-(4-forfinal)-2-hydroxyethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

28) (Z)-(6R)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

29) (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one,

30) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one,

31) (Z)-(S)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

32) (Z)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

33) (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

34) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(Mei-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

35) (Z)-(S)-4-[(S)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-the l)phenyl]methylidene]-6-methylmorpholin-3-one,

36) (Z)-(6S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,

37) (Z)-(6S)-4-[1-(4-forfinal)-1-methylethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

38) (Z)-(6S)-4-[1-(4-forfinal)cyclopropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

39) (Z)-(6S,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

40) (Z)-(6S,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

41) (Z)-(6S,9aR)-6-(2,6-differencein-3-yl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

42) (Z)-(S)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

43) (Z)-(S)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

44) (Z)-(S)-4-[(S)-1-(2-chloro-3-herperidin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

45) (Z)-(S)-4-[(S)-1-(2,6-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

46) (Z)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

47) (Z)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-labels and-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

48) (Z)-4-[(S)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

49) (Z)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

50) (Z)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

51) (Z)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

52) (Z)-(R)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

53) (Z)-(S)-4-(4-terbisil)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

54) (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(4-tryptophanyl)ethyl]-6,6-dimethylmorpholine-3-one,

55) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

56) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

57) (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-3-one,

58) (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,

59) (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl] - methylmorpholin-3-one,

60) (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6,6-dimethylmorpholine-3-one,

61) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,

62) 1-[1-(2,4-differenl)ethyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}piperidine-2-it,

63) (E)-(S)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it,

64) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]piperidine-2-it,

65) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(2R,3R)-3-hydroxy-1,1-dietlinde-2-yl]piperidine-2-it,

66) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(S)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]piperidine-2-it,

67) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[1-(4-forfinal)-1-methylethyl]piperidine-2-it,

68) (E)-(R)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it,

69) (E)-(S)-1-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-5-methylpiperidin-2-it,

70) (Z)-(6S,8aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-one,

71) (6S,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}hexahydropyrazino[2,1-c][1,4]oxazin-4-one,

72) (6R,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}-6-(3,4,5-tryptophanyl)tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one,

73) (6R,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one,

74) (6R,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-one

75) (6R,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c]oxazin-4-one.

Preferred variants of the implementation of the compounds of General formula (I) are as described above. Pharmaceutically active ingredient according to the present invention is not limited to the compounds specifically described in this description, and may be arbitrarily selected any option exercise within the definition of compounds of General formula (I).

The following describes methods of obtaining compounds of General formula (I) according to the present invention.

The connection represented by the General formula (I):

[Formula 16]

where R1, R2, R3, R4X1XaXband Ar1are as defined above, synthesize way, as, for example, the following General method of obtaining 1 or common way to get 2. Obviously, to obtain a suitable connection is possible under the present invention the method includes the appropriate step of the reaction the introduction of protection and the stage of the reaction remove the protection using protective group, well-known specialist in this field, which is chosen appropriately for each stage (see, for example, T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981). It is also obvious that suitable for obtaining compounds of the present invention all isomers and isomeric mixture, such as geometric isomers, which may be formed from the structure of this compound, optical isomers, the formation of which is based on asymmetric carbons, stereoisomers and tautomers can be obtained in the form of a separate connection suitable for each stage of the methods known to the person skilled in the art, such as fractional crystallization or column chromatography.

A common way of obtaining 1

The following describes the General method of obtaining 1, specifically used to obtain compounds of General formula (I) according to the present invention.

[Formula 17]

In this diagram, R1, R2, R3, R4X1(which may have a protective group, when X1contains a hydroxyl group), XaXband Ar1are as defined above.

The above General method of obtaining 1 is an example of a method of obtaining compounds of General formula (I), including the conversion of the aldehyde (1) and 0.3 to 3.0 equivalentcanada (2a) is based on the aldehyde (1) in alderny adduct (3) Alderney condensation on stage 1-1 and subsequent dehydration of the adduct.

Conversion Algologie adduct (3) in compound (I)

The compound of General formula (I) can be obtained by converting Algologie adduct (3) dehydration reaction in stage 1-2. Accordingly, the dehydration reaction at a stage 1-2 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a known method described in many publications (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.194-226). Preferred examples of the method include i) a method including processing Algologie adduct (3) acid (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.194-196) and (ii) a process comprising converting the alcohol group Algologie adduct (3) in a leaving group such as a sulphonate group or a halogen atom, and subsequent processing of the adduct base (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.198-205).

In method (i) conditions for the use of acid, solvent, and temperature vary in accordance with the reference compound and is not particularly limited. Use of 0.1-10 equivalents of an acid such as chloride, the hydrogen acid, sulfuric acid, phosphoric acid, potassium hydrosulfide, oxalic acid, p-toluensulfonate acid complex of boron TRIFLUORIDE-ether, thionyl chloride or aluminum oxide, based on alderny adduct (3). The method can be carried out without solvent or with a solvent or mixture of solvents, which the traveler does not inhibit the reaction and allows the original connection to dissolve in it(her) to a certain extent. Preferred examples of the solvent include water, acetone, dimethylsulfoxide and hexamethylphosphoramide. In addition, the combination of 0.1-10 equivalents of acid based on alderny adduct (3) with an organic base, such as pyridine, can increase the reaction rate and the yield of the reaction. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from room temperature to 200°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Preferred is the reamers of the leaving group in the method (ii) include acetyl group, methanesulfonate group, p-toluensulfonate group, chlorine atom, bromine atom and iodine atom. The method includes transformation in such a leaving group, vary in accordance with the reference compound and is not particularly limited. As such a conversion may be used a method known to the person skilled in the art. Preferably 1.0 to 10 equivalents acetylides agent, such as acetylchloride and acetic anhydride, or sulphurouses agent, such as methanesulfonate and p-toluensulfonate, or 1.0 to 10 equivalents of a halogenation agent such as thionyl chloride, based on alderny adduct (3), for example, can be used preferably, for example, in a halogenated solvent such as methylene chloride and chloroform, nonpolar solvent such as toluene and benzene, ether solvent such as tetrahydrofuran or dimethyl ether of ethylene glycol; or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78 to 100°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled known m today chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization. In the reaction of formation of the leaving group as the second stage as the base is preferably used, for example, 0.1 to 10 equivalents of an organic base, such as databaseconnect, pyridine, 4-dimethylaminopyridine and triethylamine, Quaternary ammonium salt, such as tetrabutylammonium, salts of alkaline metal with alcohol, such as sodium methoxide or tert-piperonyl potassium, hydroxide of alkali metal such as sodium hydroxide, carbonate of alkaline metal such as lithium carbonate or potassium carbonate, or an ORGANOMETALLIC reagent, such as diisopropylamide lithium, based on alderny adduct (3) is preferably, for example in the halogenated solvent such as methylene chloride, nonpolar solvent such as toluene, polar solvent such as acetonitrile, dimethylformamide or dimethylsulfoxide, ether solvent such as tetrahydrofuran or dimethyl ether of ethylene glycol, or a mixed solvent of these solvents.

The solvent can also be used an organic base such as pyridine. The reaction temperature should bititci, which can ensure the completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78 to 100°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Getting Algologie adduct (3)

Alderny adduct (3) can be obtained, for example, of the aldehyde (1) and amide (2a) in accordance with the stage 1-1. In particular, the reaction of aldol condensation stage 1-1 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.20, Yuki Gosei (Organic Synthesis) [11], edited by The Chemical Society of Japan, Maruzen Co., Ltd., July 1992, p.94-100). Preferred examples of the method include i) a method including converting amide (2a) in the enolate of an alkali metal is preferably, for example, of 1.0 to 5.0 equivalents of a base such as preferably diisopropylamide lithium hydride or sodium methoxide in the rija, with the subsequent interaction of enolate with aldehyde (1) (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.20, Yuki Gosei (Organic Synthesis) [11], edited by The Chemical Society of Japan, Maruzen Co., Ltd., July 1992, p.97-98) and (ii) a process comprising converting the amide (2a) in the enolate of an alkali metal is preferably, for example, of 1.0 to 5.0 equivalents of a base such as preferably diisopropylamide lithium, sodium hydride or sodium methoxide, interaction enolate with a halide of silicon, preferably such as trimethylchlorosilane or tert-butyldimethylchlorosilane, obtaining directly a simple similaralcohol ether and subsequent interaction between ether aldehyde (1) in the presence of a Lewis acid, preferably such as titanium tetrachloride or boron TRIFLUORIDE (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.20, Yuki Gosei (Organic Synthesis) [11], edited by The Chemical Society of Japan, Maruzen Co., Ltd., July 1992, p.96-97).

Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, preferably can be used, for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichlorid is h or chloroform, non-polar solvent, such as toluene or xylene, or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to room temperature. In the preferred conditions, the reaction is preferably terminated, for example, for 0.5-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining aldehyde (1)

[Formula 18]

In this diagram, Xais as defined above; L1represents a fluorine atom, chlorine atom, bromine atom, iodine atom, sulfate group, such as triflate group, group triamcinolone, group Bronevoy acid or bornata group, and L2represents a C1-Celecoxibonline group, such as metilscopolamine group, aldehyde group, or cyano.

Obtaining aldehyde (1)

The aldehyde (1) can be obtained from compound (1a) as the source in accordance with what adieu 2-5. In particular, the stage 2-5 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. For example, when L2represents alkoxycarbonyl group may be used in response and recovery described in many well known publications (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], edited by The Chemical Society of Japan, Maruzen Co., Ltd., April 1992, p.159-266). Preferably, the desired aldehyde can be obtained, for example, by reduction using a metal hydride, such as diisobutylaluminium. More preferably, the desired aldehyde can be effectively obtained, for example, by the method of recovery using sociallyengaged or alumohydrides complex in the presence of an amine (see, for example, T. Abe et al., "Tetrahedron", 2001, vol.57, p.2701-2710).

For example, when L2represents a cyano, can be used in response and recovery described in many well known publications (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], edited by The Chemical Society of Japan, Maruzen Co., Ltd., April 1992, p.159-266). Preferably, the desired aldehyde can be obtained, for example, by the method of recovery used the eat metal hydride, such as bis(2-methoxyethoxy)aluminiumhydride sodium or diisobutylaluminium (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], edited by The Chemical Society of Japan, Maruzen Co., Ltd., April 1992, p.231).

Alternatively, the desired aldehyde can be synthesized by the implementation of the recovery stage of the compounds (1a) to alcohol according to the methods known to the person skilled in the art (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], edited by The Chemical Society of Japan, Maruzen Co., Ltd., April 1992, p.159-266), and subsequent oxidation of alcohol to aldehyde (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.23, Yuki Gosei (Organic Synthesis) [V], edited by The Chemical Society of Japan, Maruzen Co., Ltd., October 1991, p.1-550).

The base used in the reaction of recovery vary in accordance with the reference compound and is not particularly limited. As can be used a secondary amine. Preferably, the desired aldehyde can be efficiently obtained by using 0.1 to 1.0 equivalent unbranched or cyclic secondary alkylamine, such as diethylamine or pyrrolidine, based on the compound (1a). Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original connection will dissolve the camping in it to a certain extent, preferably can be used, for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, nonpolar solvent such as toluene or xylene, or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to room temperature. In the preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

The amount of oxidant used at the stage of oxidation, vary in accordance with the reference compound and is not particularly limited. The amount is preferably 0.1 to 10 equivalents based on compound (1a). The solvent and the reaction temperature varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain degree, preferably m is can be used for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane or chloroform, nonpolar solvent such as toluene or xylene, or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to 100°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining the compounds (1a)

The compound (1a) can be obtained, for example, from compound (4a) as the source in accordance with stage 2-1 or from compound (4d) as the source in accordance with stage 2-4.

Stage 2-1

Stage 2-1 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the expert in Yes the Noi area. For example, the way in stage 2-1 can be represented as a substitution reaction of the compound (4a) as the source using 0.3 to 10 equivalents methylimidazole based on the compound (4a). Solvent used and the reaction temperature at this stage varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, preferably can be used, for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane or chloroform, a polar solvent, such as dichlorobenzene, dimethylformamide or N-organic, nonpolar solvent such as toluene, xylene or mesitylene, the solvent in the form of organic bases, such as databaseconnect, pyridine or triethylamine, or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from 0°C to 200°C. At this stage can be used, for example, 0.1 to 10 equivalents of an organic based what I such as diazabicyclo, pyridine or triethylamine, alkali metal salt with alcohol, such as sodium methoxide or tert-piperonyl potassium, hydroxide of alkali metal such as sodium hydroxide, or carbonate of an alkali metal such as cesium carbonate or potassium carbonate, based on the compound (4a). In the preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining the compound (4a)

The compound (4a) is commercially available or can be obtained by a method known to the person skilled in the art. If the compound (4a) is not commercially available, it can be obtained, for example, by methylation of the corresponding phenolic compounds by a method known to the person skilled in the art, when Xarepresents a methoxy group.

Stage 2-4

Stage 2-4 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. T is Abueva compound (1a) can be obtained, for example, by heating the compound (4d) and 1.0 to 20 equivalents of ammonia or ammonium salt based on the compound (4d). Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, can preferably be used, for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane or chloroform, an alcohol solvent such as ethanol or isopropanol, a polar solvent, such as dimethylformamide or N-organic, nonpolar solvent such as toluene or xylene, an organic acid such as acetic acid, propionic acid or triperoxonane acid, or a mixed solvent of these solvents. Preferably, the compound (1a) can be efficiently obtained using, for example, 1.0 to 10 equivalents of ammonium acetate based on the compound (4d) in a solvent in the form of acetic acid. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and is preferably in the range is not, for example, from room temperature to 200°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining compound (4d)

The compound (4d) can be obtained, for example, from compound (4c) as the source in accordance with stage 2-3. In particular, stage 2-3 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. The compound (4d) can be obtained, for example, by mixing the compound (4c) and 2-halogenated acetone (for example, 0.5 to 5.0 equivalents of 2-chloroacetone, 2-bromoacetone or 2-iodization based on the compound (4c)in the presence of a base. It is preferable to use 0.5 to 5.0 equivalents of base based on the compound (4c). Examples of the base include hydrides of alkali metals, such as sodium hydride and lithium hydride, alkali metal salts, such as potassium carbonate, sodium carbonate and cesium carbonate, and alkoxides of metals, nevertheless the as sodium methoxide and tert-butylcalix. Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, preferably can be used, for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane or chloroform, a polar solvent, such as dimethylformamide or N-organic, nonpolar solvent such as toluene or xylene, or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from room temperature to 200°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining compound (4c)

The desired compound (4c) can b is to be obtained, for example, a process comprising heating a compound (4b) at boiling under reflux in formic acid, or a method involving the use of formic acid and the condensing agent dehydration, preferably, such as an acid anhydride or dicyclohexylcarbodiimide. The compound (4c) can be efficiently obtained, preferably using, for example, 1-20 equivalents of formic acid and preferably, for example, 1-3 equivalent condensing agent dehydration. Solvent used varies in accordance with the reference compound and is not particularly limited. As the solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, preferably can be used, for example, a simple ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane or chloroform, a polar solvent, such as dimethylformamide or N-organic, nonpolar solvent such as toluene or xylene, or a mixed solvent of these solvents. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is away in the range for example, from room temperature to 100°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining the compound (4b)

The compound (4b) is commercially available or can be obtained by a method known to the person skilled in the art. If the compound (4b) is not commercially available, it can be obtained, for example by methylation of the corresponding nitrophenols connection method known to the person skilled in the art, and subsequent recovery of the nitrogroup, when Xarepresents a methoxy group.

Getting amide (2a)

[Formula 19]

This diagram L1, R1, R2, R3, R4, R5(which may have a protective group, when R5contains a hydroxyl group), X1(which may have a protective group, when X1contains a hydroxyl group), Ar1, Ar1 - C, Z1, m, and n are as defined above; Xbrepresents an oxygen atom; V1represents for itnow group to the oxygen atom, such as methyl group, ethyl group, benzyl group, allyl group, triphenylmethyl group, tert-bucilina group or tert-butyldimethylsilyl group, and V2represents a protective group for a nitrogen atom such as tert-butyloxycarbonyl group or benzyloxycarbonyl group.

The above diagram shows an example of a method of obtaining amide (2a). In particular, the reaction scheme is shown (i) a process comprising converting an amine (5a) as a starting compound, which is commercially available or obtained by way known to the person skilled in the art, the compound (5c) in accordance with the stage 3-1 and further education ecomorphological rings on stage 3-2; (ii) a process comprising converting a compound (5b) as the source, which is commercially available or obtained by way known to the person skilled in the art, the compound (5c) in accordance with the stage 3-3 and then education ecomorphological rings stage 3-2, when Deputy X1contains at least one hydrogen atom, or (iii) a process comprising converting a compound (5m) as the source, which is commercially available or obtained by way known to the person skilled in the art, the compound (5p) interaction with metalloorganic the m reagent (5n) in accordance with stage 3-4, the conversion of compound (5p) in the compound (5q) removing the protection from a nitrogen atom and the implementation of the intramolecular reaction of reductive amination stage 3-5, the conversion of compound (5q) in the compound (5c) removing the protection from the oxygen atom at the stage 3-6 and further education ecomorphological rings on stage 3-2.

The conversion of compound (5c) amide (2a)

Stage 3-2 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. The reaction can be performed by a method known to the person skilled in the art. Preferably, the reaction is expediently carried out with vigorous stirring, for example, compounds (5c) and 1.0 to 10 equivalents of compound (5f) based on the compound (5c) in the two-phase solvent for the reaction, is composed of an organic solvent and ó solution. Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent. Preferred examples of the solvent which can be used include solvents as ethers, such as diethyl ether, ha is generowanie solvents, such as methylene chloride, 1,2-dichloroethane, and chloroform, and nonpolar solvents such as toluene and xylene. Preferred examples ó solution, which can be used include salts of alkali metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to room temperature. In the preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Preferably, the reaction is also advisable to carry out by mixing the compound (5c), for example, from 1.0 to 10 equivalents of compound (5f) based on the compound (5c) in ó conditions. Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and gives the opportunity to the initial connection to be dissolved therein to a certain extent. Preferred examples of the solvent which can be used include solvents as ethers, such as diethyl ether and tetrahydrofuran, halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform, and nonpolar solvents such as toluene and xylene. Used base varies in accordance with the reference compound and is not particularly limited. The amount of base is preferably 1.0 to 10 equivalents based on compound (5c). Examples of bases which may be used include the alkali metal salts, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate, and organic bases, such as databaseconnect, pyridine, 4-dimethylaminopyridine and triethylamine. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to room temperature. In the preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as is traditionally the first method chromatography extraction and/or crystallization.

Obtaining the compound (5f)

The compound (5f) is commercially available or can be obtained by a method known to the person skilled in the art. The compound (5f) is preferably, for example, chloroacetylation or bromoacetamide.

Obtaining the compound (5c)

The compound (5c) is commercially available or can be obtained by a method known to the person skilled in the art. Preferably, the compound (5c) can be obtained, for example, (i) the conversion of the amine (5a) as a starting compound, which is commercially available or obtained by way known to the person skilled in the art, the compound (5c) in accordance with the stage 3-1; (ii) conversion of the compound (5b) as the source, which is commercially available or obtained by way known to the person skilled in the art, the compound (5c) in accordance with the stage 3-3 or (iii) conversion of the compound (5m) as the source, which is commercially available or obtained by way known to the person skilled in the art, the compound (5p) interaction with the ORGANOMETALLIC reagent (5n) in accordance with stage 3-4, conversion of the compound (5p) in the compound (5q) removing the protection from a nitrogen atom and implementation of an intramolecular reaction to restore the positive amination stage 3-5 and the conversion of the compound (5q) in the compound (5c) removing the protection from the oxygen atom at the stage 3-6.

The conversion of compound (5a) in the compound (5c)

Stage 3-1 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. Preferred examples of the method include the reaction disclosure rings using the compounds (5a) and 1.0 to 10 equivalents oxiranes compounds (5d) based on the compound (5a). Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, or containing mixed solvent. Examples of the solvent which can be used include solvents as ethers, such as diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform, and nonpolar solvents such as toluene and xylene. A preferred result can be obtained without solvent. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably, the loc is in range, for example, from room temperature to 300°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization. The reaction may preferably be continued by adding a Lewis acid such as boron TRIFLUORIDE, tetraisopropoxide titanium or lithium perchlorate (see, for example, Synthesis, 2004, vol.10, p.1563-1565).

Obtaining the compound (5a)

The compound (5a) is commercially available or can be obtained by a method known to the person skilled in the art. If the compound (5a) is not commercially available, it can be obtained by a method described in the literature and known to the person skilled in the art (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], edited by The Chemical Society of Japan, Maruzen Co., Ltd., February 1978, p.1332-1399). Preferred examples of the method include i) a process comprising converting a corresponding carbonyl derivative of the compound (5a) by the reaction of reductive amination; (ii) a process comprising recovering the corresponding carbonyl derivative to alcohol is the first derivative, getting amine equivalent (preferably, for example, azide group or kidney group) of the alcohol derivative substitution reaction known to the person skilled in the art, and subsequent conversion of the amine equivalent of the compound (5a) by the reaction of conversion, well-known specialist in the field; iii) a process comprising converting a corresponding carbonyl derivative in axispointe and subsequent recovery oxenreider to the compound (5a) by the reaction of recovery, well-known specialist in this field; (iv) a process comprising converting a corresponding olefinic compound in an alcohol derived by the oxidation reaction, obtaining amine equivalent (preferably, for example, azide group, or kidney group) of the alcohol derivative substitution reaction known to the person skilled in the art, and subsequent conversion of the amine equivalent of the compound (5a) by the reaction of conversion, well-known specialist in this field, and v) a process comprising converting a corresponding olefinic compounds in aminopyrrolo derived by the reaction of accession and conversion aminopyrrolo derived in the compound (5a) by the reaction of conversion, well-known specialist in this field. The compound (5a) can be commercially available in VI is e optically active compounds or received by way well-known specialist in this field, in the form of optically active compounds (see, for example, Chem. Rev., 1994, vol.94, p.2483-2547; Tetrahedron Letters, 1996, vol.37, p.3219-3222; and Organic Letters, 2000, vol.2, p.2821-2824). Compounds of the present invention can be obtained in the form of optically active compounds, their specified connection as the source.

Getting oxiranes compounds (5d)

Oxirane compound (5d) is commercially available or can be obtained by a method known to the person skilled in the art. If oxirane compound (5d) is not commercially available, it can be obtained by a method described in the literature and known to the person skilled in the art (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., November 1977, p.567-611). The compound (5d) may be commercially available in the form of optically active compounds or obtained by a method known to the person skilled in the art, in the form of optically active compounds (see, for example, K.B. Sharpless et al., "Comprehensive Organic Synthesis", B.M. Trost, Pergamon, 1991, vol.7, ch.3-2). The compound of the present invention can be obtained in the form of optically active compounds, their specified connection as the source.

The conversion of compound (5b) in the compound (5c)

Stage 3-3 vary in accordance with the similar connection and is not particularly limited, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. Preferably, the method may be a reaction of reductive amination between the compound (5b) and carbonyl compound (5e) (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], edited by The Chemical Society of Japan, Maruzen Co., Ltd., February 1978, p.1380-1384). For example, the method is preferably a method including heating at boiling under reflux carbonyl compounds (5e) and 0.5-5.0 equivalents of compound (5b) in the presence of an acid catalyst, such as a conventional inorganic acid, such as chloride-hydrogen acid or sulfuric acid, preferably, an organic acid, such as methanesulfonate acid, p-toluensulfonate acid or camphorsulfonic acid or salt of organic acid such as p-toluensulfonate pyridinium (preferably, for example, from 0.01 to 0.5 equivalent)to cause a dehydration reaction, and recovering the obtained imine derivative to the desired amine derivative is preferably, for example, 1.0 to 10 equivalents of a metal hydride, such as sociallyengaged or borohydride sodium, based on the imine derivative. Can the process of carbonyl compound (5e) and 0.5-5.0 equivalents of compound (5b) in an inert solvent, such as tetrahydrofuran, in the presence of a catalyst in the form of a Lewis acid, preferably such as tetraisopropoxide titanium (preferably 0.01 to 0.5 equivalent), and then restore the compound obtained from 1.0 to 10 equivalents of a metal hydride, such as borohydride sodium. It is also preferable to use the method, including the reduction of carbonyl derivative (5e) and preferably, for example, 0.5 to 5.0 equivalents of a compound (5b) is preferably, for example, 1.0 to 10 equivalents of a metal hydride, such as triacetoxyborohydride sodium or lambrogini sodium, in an inert solvent, such, preferably, as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, methanol or ethanol, to obtain the desired amine derivative. Preferably, for an appropriate continuation of the reaction to add, for example, 1.0 to 10 equivalents of an acidic substance such as acetic acid or chloride-hydrogen acid. The reaction temperature varies in accordance with the reference compound and is not particularly limited. However, the reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from room temperature to 100°C. preferred conditions, the reaction is preferably terminated,for example, for 0.5-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining the compound (5b)

The compound (5b) is commercially available or can be obtained by a method known to the person skilled in the art. If the compound (5b) is not commercially available, it can be obtained by a method described in the literature and known to the person skilled in the art (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], edited by The Chemical Society of Japan, Maruzen Co., Ltd., February 1978, p.1332-1399). The compound (5b) may be commercially available in the form of optically active compounds or obtained by a method known to the person skilled in the art, in the form of optically active compounds (see, for example, Tetrahedron Letters, 1996, vol.37, p.3219-3222). The compound of the present invention can be obtained in the form of optically active compounds, their specified connection as the source.

Getting carbonyl compounds (5e)

Carbonyl compound (5e) is commercially available or can be obtained by a method known to the person skilled in the art. If carbonyl compounds is of (5e) is not commercially available, it can be obtained by a method described in the literature and known to the person skilled in the art (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [11], edited by The Chemical Society of Japan, Maruzen Co., Ltd., December 1977, p.633-875).

The conversion of compound (5q) in the compound (5c)

Stage 3-6 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. Can be used a method of removing the protection, well-known specialist in this field (see, for example, T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981). Alternatively, stage 3-6 preferably may be performed, for example, obtaining the compound (5q) in the form of an ester derivative, where R1and R2form a carbonyl group, and then restoring ester derivative by the reaction of recovery, known to the person skilled in the art, when each of R1and R2represents a hydrogen atom.

Obtaining compound (5q)

The compound (5q) is commercially available or can be obtained by a method known to the person skilled in the art. If the compound (5q) is not commercially available, it may preferably be obtained, for example, from compound (5p) as the source in accordance with stage 3-5 .THE particular the compound (5q) preferably can be obtained by carrying out two-stage removal of the protective group for the nitrogen atom of the compound (5p) a method including removing the protection, well-known specialist in this field (see, for example, T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981), and subsequent exposure of the connection of the intramolecular reaction of reductive amination (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], edited by The Chemical Society of Japan, Maruzen Co., Ltd., February 1978, p.1380-1384). Alternatively, these stages may preferably be made, for example, using as a starting compound (5p), where R1and R2form a carbonyl group.

Obtaining compound (5p)

The compound (5p) is commercially available or can be obtained by a method known to the person skilled in the art. If the connection (5p) is not commercially available, it may preferably be obtained, for example, from compound (5m) as the source in accordance with stage 3-4. For example, the compound (5p) can be appropriately obtained by the interaction of the compound (5m) from 0.5 to 5.0 equivalents of ORGANOMETALLIC reagent (5n), commercially available or obtained by way known to the person skilled in the art, nucleophilic re is the Ktsia, well-known specialist in this field. Solvent used varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, or a mixed solvent of these solvents. Examples of the solvent which can be used include solvents as ethers, such as diethyl ether and tetrahydrofuran, halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform, and nonpolar solvents such as toluene and xylene. The reaction temperature varies in accordance with the reference compound and is not particularly limited. However, the reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to 50°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization. Alternatives is on, it is preferable to use as the source, for example, the compound (5m), where R1and R2form a carbonyl group.

Obtaining connection (5m)

Connection (5m) is commercially available or can be obtained by a method known to the person skilled in the art. If the connection (5m) is not commercially available, it may preferably be obtained, for example, by subjecting the corresponding original connection reaction injection protection known to the person skilled in the art (see, for example, T. Greene et al., "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 1981; or T. Sakamoto et al., "J. Org. Chem.", 1996, vol.61, p.8496). Alternatively, it is preferable to use as the source, for example, the compound where R1and R2form a carbonyl group.

A common way to obtain 2

The following describes the General way to obtain the 2, usually used to obtain compounds of General formula (I) according to the present invention.

[Formula 20]

This diagram Ar1, R1, R2, R3, R4, L1X1Xaand Xbare as defined above, L3represents triphenylphosphonio group, fotinou group or silyl group, and V represents a protective group for carboxyl group, such as methyl group, Atila the group, benzyl group, allyl group, triphenylmethyl group, tert-bucilina group or tert-butyldimethylsilyl group.

The above General method of obtaining 2 is an example of a method of obtaining compounds of General formula (I)comprising the condensation of aldehyde (1) with amidon (2b) at the stage 4-1, or an example of a method of obtaining compounds of General formula (I)comprising the condensation of aldehyde (1) with a complex ester (6a) at the stage 4-1 and the subsequent interaction of the obtained compound (6b) with the amine (5a) at the stage 4-2.

Stage 4-1

The reaction of condensation stage 4-1 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a known method described in many publications. Preferred examples of the method include the Wittig reaction, Horner reaction of Ammonia and reaction Peterson (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.57-85).

The Wittig reaction is performed with the use of the compound (2b) or (6a), where L3is a salt, halide triphenylphosphine, preferably, for example, 0.8 to 1.5 equivalents of aldehyde (1) and preferably, for example, 1.0 to 5.0 equivalents of a base. This reaction can be represented as i) the persons, including the initial processing of the compound (2b) or (6a) and substrate with the formation of the phosphorus ylides and subsequent addition of the aldehyde (1) to the derived ylides, or (ii) a process comprising adding a base in the presence of compound (2b) or (6a) and aldehyde (1). This reaction is preferably carried out in the presence of a solvent, from the viewpoint of simplifying the process and efficiency of mixing. Solvent used varies according to the source connection and the ground and is not particularly limited, as long as the solvent does not slowed down the reaction and gave the opportunity to the initial connection to be dissolved therein to a certain extent. Preferred examples of the solvent include polar solvents such as nitromethane, acetonitrile, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide, a solvent in the form of ethers, such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethan, nonpolar solvents such as benzene, toluene and xylene, alcohol solvents such as ethanol and methanol, halogenated solvents such as chloroform and dichloromethane, water and mixed solvents of these solvents. Used base varies in accordance with the starting compound and solvent. Preferred examples of the base include hydroxides of locnagetro, such as sodium hydroxide, potassium hydroxide and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, potassium carbonate and sodium bicarbonate, alkali metal salts of alcohols such as sodium methoxide and tert-piperonyl potassium, organic bases such as triethylamine, pyridine, diazabicyclo, ORGANOMETALLIC compounds such as utility and Diisobutylene lithium, and hydrides of alkali metals, such as sodium hydride. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78 to 150°C. preferred conditions, the reaction is completed in 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

The reaction Horner-Emmons carried out using, for example, compound (2b) or (6a), where L3is postit, preferably 0.8 to 1.5 equivalents of aldehyde (1) and preferably, for example, 1.0 to 5.0 equivalents of a base. This reaction may represent (i) a method including the initial processing of the compound (2b) and the and (6a) and the base to form a carbanion and then add the aldehyde (1) to the resulting carbanion, or (ii) a process comprising adding a base in the presence of compound (2b) or (6a) and aldehyde (1). This reaction is preferably carried out in the presence of a solvent, from the viewpoint of simplifying the process and efficiency of mixing. Solvent used varies according to the source connection and the ground and is not particularly limited, as long as the solvent does not slowed down the reaction and gave the opportunity to the initial connection to be dissolved therein to a certain extent. Preferred examples of the solvent include polar solvents such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide, a solvent in the form of ethers, such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethan, nonpolar solvents such as benzene, toluene and xylene, alcohol solvents such as ethanol and methanol, water and mixed solvents of these solvents. Used base varies in accordance with the starting compound and solvent. Preferred examples of the base include hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, potassium carbonate and sodium bicarbonate, alkali metal salts of alcohols such as sodium methoxide and tert-piperonyl potassium, the content of inorganic fillers of the base, such as triethylamine, pyridine, diazabicyclo, ORGANOMETALLIC compounds such as utility and Diisobutylene lithium hydrides of alkali metals, such as sodium hydride, and alkali metal ammonium salts, such as sodium amide. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78 to 150°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

The reaction Peterson carried out using the compound (2b) or (6a), where L3represents a silyl group, preferably, for example, 0.8 to 1.5 equivalents of aldehyde (1) and preferably, for example, 1.0 to 5.0 equivalents of a base. This reaction may represent (i) a method including the initial processing of the compound (2b) or (6a) and the base to form a carbanion and then add the aldehyde (1) to the resulting carbanion, or (ii) a process comprising adding a base in the presence of soybean is inane (2b) or (6a) and aldehyde (1). This reaction is preferably carried out in the presence of a solvent, from the viewpoint of simplifying the process and efficiency of mixing. Solvent used varies according to the source connection and the ground and is not particularly limited, as long as the solvent does not slowed down the reaction and gave the opportunity to the initial connection to be dissolved therein to a certain extent. Preferred examples of the solvent include polar solvents such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide, a solvent in the form of ethers, such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethan, nonpolar solvents such as benzene, toluene and xylene, alcohol solvents such as ethanol and methanol, water and mixed solvents of these solvents. Used base varies in accordance with the starting compound and solvent. Preferred examples of the base include hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, potassium carbonate and sodium bicarbonate, alkali metal salts of alcohols such as sodium methoxide and tert-piperonyl potassium, organic bases such as triethylamine, pyridine, diazabicyclo, metalloorganicheskaya, such as utility and Diisobutylene lithium hydrides of alkali metals, such as sodium hydride, and alkali metal ammonium salts, such as sodium amide. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78 to 150°C. preferred conditions, the reaction is preferably terminated, for example, for 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Stage 4-2

Stage 4-2 is an example of a process involving the interaction of the compound (6b) with the amine (5a), and then converting the reaction product into a compound of General formula (I). Examples of this phase include (i) removing the protective group of the compound (6b) in a manner known to the person skilled in the art (see, for example, T. Greene et al., "Protective Groups in Organic Synthesis" (John Wiley &Sons.Inc., New York, 1981), the implementation of a dehydration condensation compounds with amine (5a) in a manner known to the person skilled in the art (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [III, edited by The Chemical Society of Japan, Maruzen Co., Ltd., February 1978, p.1136-1162; and "Yukikagaku Jikken No Tebiki (Introduction to Organic Chemistry Experiments) [4]", Called-Dojin Publishing Company, Inc., September 1990, p.27-52), and the transformation of the condensate in the compound of General formula (I) processing in ó conditions, and (ii) the binding of the compound (6b) with the amine (5a) in a manner known to the person skilled in the art, the removal of the protective group, and converting the compounds obtained into a compound of General formula (I) directly intramolecular amidation reaction. At this stage, the compound (6b) and amine (5a) can be converted into a compound of General formula (I) in a single phase of the selection of suitable reaction conditions.

Getting amide (2b)

[Formula 21]

This diagram Ar1, L1, L3, R1, R2, R3, R4X1and Xbare as defined above, and R7represents a lower alkyl group.

The above diagram shows an example of a method of obtaining amide (2b). In particular, amide (2b) can be obtained by a method known to the person skilled in the art, although the method varies in accordance with the reference compound. Preferred examples of the method include a method comprising receiving amide (2b) of the amide (2a) as a starting compound in accordance with the stage 5-1, the way in is with the conversion of the compound (5c) as the source in the compound (2c) in stage 5-2 and the subsequent conversion of compound (2c) amide (2b) at the stage 5-3, and method including converting the compound (5j) as in the original connection (5k) at the stage 5-2 and the subsequent conversion of the compound (5k) amide (2b) at the stage 5-4.

Conversion of the amide (2a) amide (2b)

Stage 5-1 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. Preferably, for example, stage 5-1 represents (i) Wittig reaction, where L3represents triphenylphosphonio group, and this reaction is in the way, including halogenoalkane amide (2a) in a manner known to the person skilled in the art (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.430-438), and the subsequent interaction of the compounds with triphenylphosphine (see, for example, Organic Reaction, 1965, vol.14, p.270). Alternatively, stage 5-1 represents ii) reaction Horner-Emmons, where L3is postit, and this reaction is in the way, including halogenoalkane amide (2a) in a manner known to the person skilled in the art (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.430-438), and the subsequent wsimages is of the compounds obtained with alkylphosphonium in accordance with the Arbuzov reaction (see, for example, Chemical Review, 1981, vol.81, p.415) or phosphonites metal in accordance with the reaction Becker (see, for example, Journal of the American Chemical Society, 1945, vol.67, p.1180), to obtain the amide (2b). Alternatively, at the stage 5-1 can be used a way to obtain the amide (2b) of the amide (2a) and chlorophosphate in the presence of a base (see, for example, The Journal of Organic Chemistry, 1989, vol.54, p.4750). Alternatively, stage 5-1 represents iii) reaction Peterson, where L3represents a silyl group, and this reaction is the method of obtaining amide (2b) of the amide (2a) and trialkylsilanes in the presence of a base (see, for example, Journal of Organometallic Chemistry, 1983, vol.248, p.51).

Conversion of the amide (2c) amide (2b)

Stage 5-3 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known to the person skilled in the art. Preferably, for example, stage 5-3 may be a method including the reduction of carbonyl fragment of ester to alcohol (see, for example, Jikken Called Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], edited by The Chemical Society of Japan, Maruzen Co., Ltd., April 1992, p.159-266), conversion of the alcohol in the halogenated compound (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [1],edited by The Chemical Society of Japan, Maruzen Co., Ltd., November 1977, p.331-450), and the transformation of halogenated compounds in the Wittig reagent (2b) (see, for example, Organic Reaction, 1965, vol.14, p.270) or reagent Horner-Emmons (2b) in accordance with the Arbuzov reaction (see, for example, Chemical Review, 1981, vol.81, p.415). Alternatively, the alcohol can be converted to a Wittig reagent (2b) interaction with the hydrobromide of triarylphosphine (see, for example, Synth. Commun., 1996, vol.26, p.3091-3095; and Tetrahedron Lett., 2001, vol.42, p.1309-1331).

Getting amide (2c)

Amide (2c) can be obtained by a method known to the person skilled in the art, although the method varies in accordance with the reference compound. Preferably, the amide (2c) can be obtained from compound (5c) as the source, for example, through a stage 5-2. Preferably, at this stage of the reaction is expediently carried out with vigorous stirring compound (5c) and, for example, 1.0 to 10 equivalents of compound (5g) based on the compound (5c) in the two-phase solvent for the reaction, consisting of organic solvent and ó solution. Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, or a mixed solvent of that is their solvents. Preferred examples of organic solvents that may be used include solvents as ethers, such as diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform, and nonpolar solvents such as toluene and xylene. Preferably, use 1.0 or more equivalents ó solution. Preferred examples ó solution, which can be used include salts of alkali metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to room temperature. In the preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Can also be used on stage 5-2 method including the interaction of the compound (5c) is preferably, for example, 1.0 to 5.0 equival nami compound (5g) in the presence of a base, such as, preferably, an organic amine, such as triethylamine, isopropylethylene or pyridine, preferably, for example, 1.0 to 5.0 equivalents). Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent. Preferred examples of organic solvents that may be used include solvents as ethers, such as diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform, and nonpolar solvents such as toluene and xylene. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to 100°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Stage 5-2, the reaction is, s can also the right way to spend it heating the compound (5c) and 1.0 to 20 equivalents of compound (5h), where R7represents lower alkyl, based on the compound (5c). Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, or a mixed solvent of these solvents. Preferred examples of organic solvents that may be used include solvents as ethers, such as diethyl ether, halogenated solvents such as methylene chloride, 1,2-dichloroethane and 1,2-dichlorobenzene, nonpolar solvents such as toluene and xylene, polar solvents such as dimethylformamide and N-organic, and alcohol solvents such as methanol, ethanol, 2-propanol and tert-butanol. The reaction may also suitably be carried out without solvent. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from 50°C to 200°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction m which should be monitored by known chromatography methods. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Stage 5-2 the reaction may also be appropriate to carry out using the compound (5c) and 1.0 to 5.0 equivalents of a compound (5i) in the above reaction conditions or their combination. The reaction may also be appropriate to carry out the addition of phase transfer catalyst which is a salt of Quaternary ammonium, such as tetrabutylammonium or benzyltriethylammonium, or acidic compound, such as p-toluensulfonate acid or camphorsulfonic acid.

Obtaining compounds (5g), (5h), (5i)

The compound (5g), (5h), (5i) are commercially available or can be obtained by a method known to the person skilled in the art. If compounds are not commercially available, they can be obtained by etherification or halogenoalkanes corresponding derivative of oxalic acid method, well-known specialist in this field.

The conversion of compound (5k) in exomorphic (2b)

Stage 5-4 vary in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. For this reaction can be used a method known Spa is ialist in this area. Preferably, for example, stage 5-4 may be a method including the conversion of olefinic fragment of compound (5k) in polyacetylene derived by the reaction of oxidative cleavage and intramolecular cyclization reaction (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [1], edited by The Chemical Society of Japan, Maruzen Co., Ltd., November 1977, p.331-450), and the transformation polyacetale derived in the Wittig reagent (2b) (see, for example, Organic Reaction, 1965, vol.14, p.270) or reagent Horner-Emmons (2b) in accordance with the Arbuzov reaction (see, for example, Chemical Review, 1981, vol.81, p.415). Polyacetylene derivative can also be converted to a Wittig reagent (2b) interaction with the hydrobromide of triarylphosphine (see, for example, Synth. Commun., 1996, vol.26, p.3091-3095; and Tetrahedron Lett., 2001, vol.42, p.1309-1331). The reaction of the oxidative cleavage of olefinic fragment varies in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. Preferred, for example, ozone oxidation (see, for example, Shin Jikken Called Koza (New Courses in Experimental Chemistry), vol.15, Sanka To Kangen (Oxidation and Reduction) [I-2], edited by The Chemical Society of Japan, Maruzen Co., Ltd., September 1976, p.563-603). The reaction of the oxidative cleavage and intramolecular cyclization reaction in suitable conditions, performed continuously, and therefore they are the Xia suitable for obtaining a compound (2b).

Obtaining compound (5k)

The compound (5k) can be obtained from compound (5j), and preferably, for example, 1.0 to 5.0 equivalents of a compound (5i) based on the compound (5j) in accordance with the stage 5-2.

Obtaining the compound (5j)

The compound (5j) is commercially available or can be obtained by a method known to the person skilled in the art. If the compound (5j) is not commercially available, it preferably receives, for example, intramolecular reaction gidroaminirovaniya amine or sulfanilamide containing athenelol group, using a metallic catalyst, when R4and X1connected to each other, with the formation of the nitrogen-containing heterocycle (see, for example, Journal of The American Chemical Society, 2003, vol.125, p.11956; and Tetrahedron Lett., 1998, vol.39, p.5421-5424). This reaction varies in accordance with the reference compound and is not particularly restricted, only that the conditions were similar to the conditions of this reaction. The metal catalyst is preferably, for example, from 0.001 to 0.1 equivalent of a palladium complex such as palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) or dimer allylpalladium. The reaction may also be appropriate to carry out the addition, preferably, for example, 0.001 to 0.1 equivalent of phosphate ligand, predpochtitel what about such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 1,1'-bis(diphenylphosphino)ferrocene. The reaction can also be appropriate to carry out the addition, preferably, for example, 0.001 to 10 equivalents of acetic acid or chloride-hydrogen acid. Solvent used and the reaction temperature varies in accordance with the reference compound and is not particularly limited. The solvent is preferably a solvent that does not inhibit the reaction and allows the original compound to be dissolved therein to a certain extent, or a mixed solvent of these solvents. Preferred examples of organic solvents that may be used include solvents as ethers, such as diethyl ether and tetrahydrofuran, halogenated solvents such as methylene chloride and 1,2-dichloroethane, nonpolar solvents such as toluene and xylene, polar solvents such as dimethylformamide and N-organic, and alcohol solvents such as methanol, ethanol, 2-propanol and tert-butanol. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from 50°C to 200°C. preferred conditions, the reaction is preferably terminated, for example, for 0.5 to 24 hours, and the course of the reaction can be controlled well-known methods is chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as the traditional method of chromatography, extraction and/or crystallization.

Obtaining the compounds (6a)

[Formula 22]

In this diagram, R1, R2, R3, R4, V, L1, L3and Xbare as defined above, and L4is as defined for L1.

The above diagram shows an example of obtaining the compound (6a). In particular, the compound (6a) is commercially available or can be obtained according to methods described in the diagram above reactions and are known to the person skilled in the art (see, for example, C. Patois et al., "Synth. Commun.", 1991, vol.22, p.2391; and J.A. Jackson et al., "J. Org. Chem.", 1989, vol.20, p.5556). Stage 6-1 is the stage of obtaining the desired compound (6a) processing phosphonate (6c), for example, 1.0 to 2.0 equivalents of the compound (6d) based on phosphonate (6c) in ó conditions. Alternatively, stage 6-2 is the stage of obtaining the desired compound (6a) by treating compound (6e), for example, 1.0 to 2.0 equivalents of ester (6f) in ó conditions. The desired compound (6a) can also be obtained, for example, from compound (6g) in accordance with the above-described stage 5-1.

Used the base at this stage vary with the compliance with the reference compound and not limiting. Preferably use, for example, 1.0 to 1.5 equivalents of base, such as sodium hydride, n-utility, diisopropylamide lithium bis(trimethylsilyl)amide lithium or bis(trimethylsilyl)amide and sodium. The solvent used at this stage will vary in accordance with the reference compound, and particularly not limited only to the solvent is not slowed down the reaction and gave the opportunity to the initial connection to be dissolved therein to a certain extent. Preferred examples of the solvent include hexane, toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, hexamethylphosphoric triamide and a mixed solvent, such as described above. The reaction temperature should be such that can ensure completion of the reaction, not contributing to the formation of undesirable by-product, and preferably is in the range of, for example, from -78°C to 150°C. preferred conditions, the reaction is completed in 1-24 hours, and the course of the reaction can be controlled by the known methods of chromatography. Unwanted by-product can be removed by a method known to the person skilled in the art, such as a method of traditional chromatography and/or crystallization.

Phosphonate (6c), the compound (6d), the compound (6e), ester (6f) and the compound (6g)used on this stage, are commercially available or can b the th received by way well-known specialist in this field.

The compound of General formula (I) or its pharmacologically acceptable salt according to the present invention has the effect of inhibiting the production of Aβ40 or Aβ42 and, thus, effectively(and) as a preventive or therapeutic agent for a disease caused by amyloid-β, and is especially effective(a) as a preventive or therapeutic agent for a neurodegenerative disease caused by Aβ such as Alzheimer's disease or down's syndrome.

Compounds covered by this invention are useful excellent pharmaceutical properties, such as activity in vitro, the activity in vivo, solubility, stability, pharmacokinetics and low toxicity.

Preventive or therapeutic agent for diseases caused by Aβ, in accordance with the present invention can be obtained in the traditional way. Preferred examples of dosage forms include tablets, powders, granules, granules, coated tablets, capsules, syrups, tablets, dosage forms for inhalation, suppositories, injectable solutions, ointments, ophthalmic solutions, ophthalmic ointments, nasal drops, ear drops, poultices and lotions. Therapeutic or prophylactic agent can be obtained using commonly used in ishemic ingredients such as excipient, binder, lubricant, dye and corrigent, and ingredients used according to need, such as a stabilizer, emulsifier, a substance that facilitates absorption, surfactant, pH Adjuster, preservative and antioxidant, and may be obtained by mixing the ingredients commonly used as materials for the manufacture of pharmaceutical preparations. Examples of such ingredients include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; difficult essential oils, such as octyldodecanol and isopropylmyristate; higher alcohols, such as cetosteatil alcohol and beganovic alcohol; silicone resins; silicone oils; surfactants such as esters of polyoxyethylene and fatty acids, ester sorbitan and fatty acid ester of glycerol and fatty acids, esters of polyoxyethylenesorbitan and fatty acids, polyoxyethylene-hydrogenated castor oil and the block copolymer of polyoxyethylene and polyoxypropylene; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methyl cellulose; lower Speer is s, such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, aluminum silicate and magnesium aluminum silicate, and purified water. Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide. Examples of binders include polyvinyl alcohol, simple, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, block-copolymer polypropylenglycol and polyoxyethylene and meglumin. The examples used disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and calcixerollic. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil. Examples of the coloring matter used include dyes that are acceptable for pharmaceutical preparations. Examples of corrigent include cocoa powder, menthol, mpasm (empasm), peppermint oil, borneol and powdered cor is s.

For example, a drug for oral administration obtained by mixing the employee as an active ingredient the compound or its salt or hydrate of the compound or salt, excipient and, when required, for example, binders, disintegrant, lubricant, coloring matter and corrigent and the subsequent transformation of the mixture, for example, in powder, fine granules, granules, tablets, coated tablets or capsules in the traditional way. Obviously, tablets or granules may optionally be fitted with a suitable coating, for example, the sugar coating. Syrup or preparation for injection is produced by mixing, for example, pH regulator, a solubilizer and isotonic means and, when required, facilitate dissolution AIDS, stabilizers and the like in the traditional way. Outdoor product can be manufactured in a traditional way without any limitations. As the material for the base can be used any of various materials commonly used for pharmaceutical preparation, quasilikelihood funds (quasi drug, cosmetic, or the like. Examples of the material for the base include materials such as animal and vegetable oils, mineral oils, essential oils, waxes, higher alcohols, fatty acids, silicone oil is, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and distilled water. If necessary, can be added a pH regulator, antioxidant, helatoobrazovatel, preservative and fungicide, coloring matter, flavoring substance, or the like. In addition, if necessary, may be tainted ingredient, having the effect of inducing differentiation, such as power flow, bactericide, anti-inflammatory agent, an activator of cells, vitamin, amino acid, humidifier or keratolytic agent. The dose for therapeutic or prophylactic agent of the present invention vary, for example, in accordance with the degree of symptoms, age, sex, body weight, method of administration, type of salt and the particular form of the disease. The compound of formula (I) or its pharmacologically acceptable salt according to the present invention is administered orally to an adult usually from about 30 μg to 10 g, preferably from 100 μg to 5 g, and more preferably from 100 μg to 100 mg per day or impose an adult by injection of from about 30 μg to 1 g, preferably 100 μg to 500 mg and more preferably from 100 μg to 30 mg per day in one dose or divided doses, respectively.

The best option of carrying out the invention

Gave the e present invention is described in more detail with reference to examples and sample tests. But the examples and sample tests are given only for illustration purposes. Prophylactic or therapeutic agent of the present invention for diseases caused by Aβ, in any case is not limited to the following specific examples. The person skilled in the art will be able to fully realize the present invention, by making various modifications not only in the following examples and examples of trials, but in this description, as well as modifications within the scope of the claims appended to this description.

In the following examples used the following abbreviations:

DMF: dimethylformamide

THF: tetrahydrofuran

LAH: sociallyengaged

WSC: hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOBT: 1-hydroxybenzotriazole

DIEA: diisopropylethylamine

TEA: triethylamine

TBAF: tetrabutylammonium

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

t: tertiary

LDA: Diisopropylamine lithium

Example 1

Synthesis of (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(3,4,5-triptorelin)morpholine-3-one

[Formula 23]

Synthesis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde

Synthesis of methyl 3-methoxy-4-nitrobenzoate

Methyliodide (463 g) was added dropwise to a mixture of 3-hydroxy-4-nitrobenzoic acid (199 g) Carbo is an atom of potassium (450 g) in DMF (1 l) at room temperature. The reaction solution was stirred at room temperature overnight and then the reaction solution was added methyliodide (230 g). The reaction solution was further stirred at room temperature for 6 hours. The reaction solution was poured into ice water and the precipitated precipitated solid substance was separated by filtration. The obtained solid substance was dried at 50°C during the night, getting 178 g specified in the connection header. Characteristic values corresponded to known values (CAS #5081-37-8).

Synthesis of methyl 4-amino-3-methoxybenzoate

10% Palladium on carbon (containing 50% water, 15 g) was added to a solution of methyl 3-methoxy-4-nitrobenzoate (150 g) in methanol (600 ml) and THF (300 ml) and the reaction solution was stirred at a hydrogen pressure of 0.9 MPa at 50°C-64°C for 6.5 hours. The reaction solution was left to cool to room temperature and then filtered through celite. The obtained filtrate was concentrated under reduced pressure, to obtain 134 g specified in the connection header. Characteristic values corresponded to known values (CAS #41608-64-4).

Synthesis of methyl 4-formylamino-3-methoxybenzoate

Acetic anhydride (268 ml) was added dropwise to formic acid (401 ml) at room temperature and the reaction solution was stirred at room tempera what ur in for 40 minutes. A solution of methyl 4-amino-3-methoxybenzoate (134 g) in THF (600 ml) was added dropwise to the reaction solution at room temperature and the reaction solution was stirred for one hour. Was added to the reaction solution of 3.8 l of ice water and the precipitated precipitated solid was filtered and again washed with water (2 l). The obtained solid substance was dried at 50°C overnight, to obtain 111 g specified in the connection header. Characteristic values corresponded to known values (CAS #700834-18-0).

Synthesis of methyl 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoate

Chloroacetone (84,5 ml) was added dropwise to a mixture of methyl 4-formylamino-3-methoxybenzoate (111 g), cesium carbonate (346 g) and potassium iodide (8,78 g) in DMF (497 ml) at room temperature and the reaction solution was stirred for three hours. The cesium carbonate (173 g) and chloroacetone (42,0 ml) was added to the reaction solution which was then stirred at room temperature for two hours. Ice water and ethyl acetate were added to the reaction solution and the organic layer was separated. Ethyl acetate was added to the aqueous layer and the organic layer was separated. The organic layers were combined and washed with water and saturated saline solution in this order. The obtained organic layers were dried over anhydrous magnesium sulfate and then concentrated p and reduced pressure. The residue was diluted with toluene and the solution was concentrated under reduced pressure. tert-butyl methyl ether and heptane were added to the obtained residue, the precipitated precipitated solid substance was separated by filtration and washed with a solution of 50% tert-butyl methyl ether in heptane. The obtained solid substance was dried in air overnight, to obtain 118 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,19 (s, 3H), 3,91 (s, 3H), of 3.94 (s, 3H), of 4.49 (s, 2H), 7,31 (d, J=8.0 Hz, 1H), 7,63 (d, J=2.0 Hz, 1H), 7,69 (DD, J=8,0, 2.0 Hz, 1H), with 8.33 (s, 1H).

Synthesis of methyl 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoate

A solution of methyl 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoate (118 g) and ammonium acetate (172 g) in acetic acid (255 ml) was heated and stirred at 140°C for one hour. Upon completion of the reaction, the reaction solution was neutralized aqueous ammonia under ice cooling. Ethyl acetate was added to the reaction solution and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate, then filtered on a loose layer of silica gel and the filtrate was concentrated under reduced pressure. tert-butyl methyl ether and heptane were added to the residue, the precipitated precipitated solid substance was separated by filtration and washed with a solution of 50% tert-butyl methyl ether in heptane. The obtained solid substance was dried in the air is during the night, obtaining 68,4 g specified in the connection header. Further, the crystallization mother liquor was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), obtaining of 22.3 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,30 (s, 3H), of 3.94 (s, 3H), of 3.96 (s, 3H), 6,98 (users, 1H), 7,32 (d, J=8,4 Hz, 1H), 7,71-7,73 (m, 2H), 7,79 (users, 1H).

Synthesis of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde

The solution pyrrolidine (18 ml) in THF (45 ml) was added dropwise to a solution of bis(2-methoxyethoxy)aluminum hydride, sodium (65% solution in toluene, 56 ml) in THF (60 ml) at -5°C or below within 15 minutes. The reaction solution was stirred at room temperature for one hour. Then the suspension of tert-butoxide (2.10 g) in THF (15 ml) was added dropwise to the reaction solution at room temperature and the reaction solution was stirred for 15 minutes. The resulting reaction solution was added dropwise to a solution of methyl 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoate (20 g) in THF (50 ml) under cooling with ice for 30 minutes. The reaction solution was stirred at room temperature for two hours and then added to it dropwise 5h. the sodium hydroxide solution (150 ml). Ethyl acetate was added to the reaction solution and the organic layer CTD is ranged. The organic layer was washed with a saturated solution of ameriglide and a saturated solution of salt, in that order. The organic layer was dried over anhydrous magnesium sulfate, filtered on a loose layer of silica gel and then the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and precipitated precipitated solid substance was separated by filtration. The obtained solid substance was dried in air overnight, obtaining 7,10 g specified in the connection header. Further, the crystallization mother liquor was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate-2-propanol), with 2.65 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,31 (s, 3H), of 3.97 (s, 3H), 7,02 (users, 1H), 7,44 (d, J=8.0 Hz, 1H), 7,55 (DD, J=1,6, 8.0 Hz, 1H), 7,58 (d, J=1.6 Hz, 1H), 7,84 (users, 1H), 10,00 (s, 1H).

Synthesis of 2-[(3,4,5-triptorelin)amino]ethanol

Triacetoxyborohydride sodium (14.1 g) was added to a solution of 3,4,5-triptoreline (5.0 ml), ethanolamine (3,52 g) and acetic acid (10.1 ml) in THF (100 ml) under ice cooling and the reaction solution was stirred at room temperature for four hours and 30 minutes. Ice water was added to the reaction solution. The reaction solution was brought to pH 7-8 5h. hydroxide solution, the hydroxide is I and saturated sodium bicarbonate solution and then was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then filtered and the mother liquor was concentrated under reduced pressure. The residue was purified column chromatography using silica gel (chloroform:methanol=1:100-1:5), with 6,91 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,80 (t, J=4,8 Hz, 2H), 3,69 (t, J=4,8 Hz, 2H), of 3.78 (s, 2H), of 6.96-7,00 (m, 2H).

Synthesis of 4-(3,4,5-triptorelin)morpholine-2,3-dione

A mixture of 2-[(3,4,5-triptorelin)amino]ethanol (6,91 g) and diethyloxalate (20 ml) was stirred at 170°C for one hour. The reaction solution was concentrated under reduced pressure and then added to the residue diethyl ether. Precipitated precipitated crystals were separated by filtration and then dried in the air, getting 7,38 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 3,61 (t, J=4,8 Hz, 2H), 4,49 (t, J=4,8 Hz, 2H), 4,63 (s, 2H), 6,95-of 6.99 (m, 2H).

Synthesis of 2-hydroxy-4-(3,4,5-triptorelin)morpholine-3-one

1M solution of three-second-butylbromide lithium in THF (of 31.4 ml) was added dropwise to a solution of 4-(3,4,5-triptorelin)morpholine-2,3-dione (7,38 g) in THF at -15°C and the reaction solution was stirred for two hours. 5h. A solution of sodium hydroxide (2,85 ml) and 30% aqueous hydrogen peroxide (968 ml) was added dropwise to the reaction solution at 20°C or below, which is then stirred at 10°C for about the nogo hours. Sodium bisulfite (888 mg) was added to the reaction solution which was then stirred for 30 minutes. A saturated salt solution and chloroform were added to the reaction solution and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography using silica gel (heptane:ethyl acetate=1:1-0:100), to obtain 3.94 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 3,11-and 3.16 (m, 1H), 3,47-of 3.54 (m, 1H), 3,80-3,86 (m, 1H), 4,28 is 4.35 (m, 1H), and 4.40 (d, J=14,8 Hz, 1H), 4,67 (d, J=14,8 Hz, 1H), lower than the 5.37 (s, 1H), 6.90 to-6,94 (m, 2H).

Synthesis of (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(3,4,5-triptorelin)morpholine-3-one

Thionyl chloride (16.1 ml) was added to a solution of 2-hydroxy-4-(3,4,5-triptorelin)morpholine-3-one (3.94 g) in methylene chloride and the reaction solution was stirred at 50°C for one hour. The reaction solution was concentrated under reduced pressure and the residue was diluted with methylene chloride. Then triphenylphosphine (5.2 g) was added under ice cooling and the reaction solution was stirred at room temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure. Ethanol (64,6 ml), TEA (4,2 ml) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (2,72 g) was added to the residue and the reaction solution was heated the ri boiling under reflux for two hours. The reaction solution was concentrated under reduced pressure and the residue was diluted with 2n. water chloride-hydrogen acid and ethyl acetate. Then the separated aqueous layer. The organic layer was washed 2n. water chloride-hydrogen acid. Then all aqueous layers were combined and podslushivaet concentrated sodium hydroxide solution. The organic layer was separated by extraction of the alkaline solution with chloroform, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography using NH silica gel (heptane:ethyl acetate=1:1-0:100), to obtain 1.92 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): was 2.34 (s, 3H), of 3.56 (t, J=4,8 Hz, 2H), a 3.87 (s, 3H), 4,28 (t, J=4,8 Hz, 2H), of 4.66 (s, 2H), 6,93 (s, 1H), 6,95-of 6.99 (m, 3H), of 7.23 (d, J=8.0 Hz, 1H), 7,40 (DD, J=8,0, 1.2 Hz, 1H), 7,42 (d, J=1,2 Hz, 1H), a 7.85 (s, 1H).

ESI-MS; m/z 444[M++H].

Example 2

Synthesis of (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(2,3,4-triptorelin)morpholine-3-one

[Formula 24]

Synthesis of 2-[(2,3,4-triptorelin)amino]ethanol

891 mg specified in the title compound was obtained from 2,3,4-triptoreline (1.0 g), ethanolamine (573 mg), acetic acid (1,79 ml) and triacetoxyborohydride sodium (2.65 g) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 2,80 (t, J=5,2 Hz, 2H, of 3.69 (t, J=5,2 Hz, 2H), 3,88 (s, 2H), 6,94-of 6.96 (m, 1H), 7,07-to 7.09 (m, 1H).

Synthesis of 4-(2,3,4-triptorelin)morpholine-2,3-dione

903 mg specified in the title compound was obtained from 2-[(2,3,4-triptorelin)amino]ethanol (891 mg) and diethyloxalate (8.0 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 3,70 (t, J=5,2 Hz, 2H), 4,50 (t, J=5,2 Hz, 2H), to 4.73 (s, 2H), 6,97? 7.04 baby mortality (m, 1H), 7.18 in-7,25 (m, 1H).

Synthesis of 2-hydroxy-4-(2,3,4-triptorelin)morpholine-3-one

126 mg specified in the title compound was obtained from 4-(2,3,4-triptorelin)morpholine-2,3-dione (350 mg) and 1M solution of three-second-butylbromide lithium in THF (1,49 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 3,20-of 3.25 (m, 1H), 3,53-3,59 (m, 1H), 3,81-3,86 (m, 1H), 4.26 deaths-to 4.33 (m, 1H), 4,60 (d, J=15.2 Hz, 1H), 4,67 (d, J=15.2 Hz, 1H), 5,31 (s, 1H), of 6.96-7,01 (m, 1H), 7,13-to 7.15 (m, 1H).

Synthesis of (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(2,3,4-triptorelin)morpholine-3-one

95,8 mg specified in the title compound was obtained from 2-hydroxy-4-(2,3,4-triptorelin)morpholine-3-one (126 mg), thionyl chloride (516 μl), triphenylphosphine (166 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (93,9 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 2,35 (s, 3H), of 3.64 (t, J=4,8 Hz, 2H), 3,86 (s, 3H), 4,28 (t, J=4,8 Hz, 2H), and 4.75 (s, 2H), 6.89 in (s, 1H), 6,95 (s, 1H), 6,97-7,02 (m, 1H), 7,17-7,24 (m, 2H), 7,38 (DD, J=8,4, 1.2 Hz, 1H), 7,41 (d, J=1.2 Hz, 1H), 7,88 (s, 1H).

ESI-MS; m/z 444[M++H].

Example 3

Synthesis of (Z)(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one

[Formula 25]

Synthesis of (S)-1-(3,4,5-triptoreline)propan-2-ol

410 mg specified in the title compound was obtained from 3,4,5-triptoreline (370 mg), (S)-1-amino-2-propanol (260 mg), acetic acid (to 0.662 ml) and triacetoxyborohydride sodium (981 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,17 (d, J=6.4 Hz, 3H), of 2.45 (DD, J=12,0, and 9.2 Hz, 1H), 2,72 (DD, J=12,0, 2.8 Hz, 1H, in), 3.75 (d, J=13,2 Hz, 1H), 3,80 (d, J=13,2 Hz, 1H), 3,82-of 3.85 (m, 1H), of 6.96-7,00 (m, 2H).

Synthesis of (S)-6-methyl-4-(3,4,5-triptorelin)morpholine-2,3-dione

439 mg specified in the title compound was obtained from (S)-1-(3,4,5-triptoreline)propan-2-ol (410 mg) and diethyloxalate (2.0 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,44 (d, J=6.4 Hz, 3H), at 3.35 (DD, J=13,6, and 3.2 Hz, 1H), 3,55 (DD, J=13,6, 9.6 Hz, 1H), 4,55 (d, J=15.2 Hz, 1H), 4,67 (d, J=15.2 Hz, 1H), 4,73-4,78 (m, 1H), 6,94-6,98 (m, 2H).

Synthesis of (S)-2-hydroxy-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one

308 mg specified in the title compound was obtained from (S)-6-methyl-4-(3,4,5-triptorelin)morpholine-2,3-dione (400 mg) and 1M solution of three-second-butylbromide lithium in THF (1.70 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1.26 in (d, J=6.0 Hz, 3H), 3,06 (DD, J=12,0, 3.2 Hz, 1H), up 3.22 (DD, J=12,0, 12.0 Hz, 1H), 4,36 (d, J=14,8 Hz, 1H), 4,46-to 4.52 (m, 1H), 4,66 (d, J=14,8 Hz, 1H), lower than the 5.37 (s, 1H), 6.90 to-6,94 (m, 2H).

Synthesis of (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]metaled is h]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one

339 mg specified in the title compound was obtained from (S)-2-hydroxy-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one (308 mg), thionyl chloride (817 μl), triphenylphosphine (353 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (218 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.4 Hz, 3H), of 2.34 (s, 3H), of 3.28 (DD, J=12,8, 2.8 Hz, 1H), 3,50 (DD, J=12,8, 9.6 Hz, 1H), a 3.87 (s, 3H), 4,36-and 4.40 (m, 1H), 4,58 (d, J=14,8 Hz, 1H), 4,69 (d, J=14,8 Hz, 1H), 6.90 to (s, 1H), 6,94-6,98 (m, 3H), of 7.23 (d, J=8,4 Hz, 1H), 7,37 (DD, J=8,4, 2.0 Hz, 1H), 7,54 (d, J=2.0 Hz, 1H), a 7.85 (s, 1H).

ESI-MS; m/z 458[M++H].

Example 4

Synthesis of (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one

[Formula 26]

Synthesis of (R)-1-(3,4,5-triptoreline)propan-2-ol

1.1 g specified in the title compound was obtained from 3,4,5-triptoreline (1.0 g), (R)-1-amino-2-propanol (704 mg), acetic acid (1,79 ml) and triacetoxyborohydride sodium (2.65 g) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Synthesis of (R)-6-methyl-4-(3,4,5-triptorelin)morpholine-2,3-dione

1,15 g specified in the title compound was obtained from (R)-1-(3,4,5-triptoreline)propan-2-ol (1.1 g) and diethyloxalate (4,0 ml) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Sin is ez (R)-2-hydroxy-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one

323 mg specified in the title compound was obtained from (R)-6-methyl-4-(3,4,5-triptorelin)morpholine-2,3-dione (400 mg) and 1M solution of three-second-butylbromide lithium in THF (1.70 ml) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Synthesis of (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one

346 mg specified in the title compound was obtained from (R)-2-hydroxy-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one (323 mg), thionyl chloride (853 μl), triphenylphosphine (368 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (228 mg) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Example 5

Synthesis of (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one

[Formula 27]

Synthesis of (S)-1-(2,3,4-triptoreline)propan-2-ol

968 mg specified in the title compound was obtained from 2,3,4-triptoreline (1.0 g), (S)-1-amino-2-propanol (704 mg), acetic acid (1,79 ml) and triacetoxyborohydride sodium (2.65 g) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): to 1.16 (d, J=6.0 Hz, 3H), 2,47 (DD, J=11,6, and 9.2 Hz, 1H), 2,72 (DD, J=11,6, 2.8 Hz, 1H), 3,83-3,88 (m, 1H), with 3.89 (s, 2H), 6,92-6,99 (m, 1H), 7,06-7,10 (m, 1H).

Synthesis of (S)-6-methyl-4-(2,3,4-three is tormentil)morpholine-2,3-dione

917 mg specified in the title compound was obtained from (S)-1-(2,3,4-triptoreline)propan-2-ol (968 mg) and diethyloxalate (8.0 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,45 (d, J=6.4 Hz, 3H), of 3.48 (DD, J=13,6, and 3.2 Hz, 1H), 3,62 (DD, J=13,6, 10,0 Hz, 1H), 4,66 (d, J=15.2 Hz, 1H), 4,74-4,80 (m, 1H), and 4.75 (d, J=15.2 Hz, 1H), 7,00-7,03 (m, 1H), 7,21-7,27 (m, 1H).

Synthesis of (S)-2-hydroxy-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one

196 mg specified in the title compound was obtained from (S)-6-methyl-4-(2,3,4-triptorelin)morpholine-2,3-dione (350 mg) and 1M solution of three-second-butylbromide lithium in THF (1,49 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): a 1.25 (d, J=7.2 Hz, 3H), of 3.13 (DD, J=12,0, 3.2 Hz, 1H), 3,26 (DD, J=12,0, 12.0 Hz, 1H), 4,47-4,51 (m, 1H), 4,58 (d, J=15.6 Hz, 1H), with 4.64 (d, J=15.6 Hz, 1H), 5,33 (s, 1H), 6,95-7,00 (m, 1H), 7,12-7,15 (m, 1H).

Synthesis of (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one

197 mg specified in the title compound was obtained from (S)-2-hydroxy-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one (196 mg), thionyl chloride (500 μl), triphenylphosphine (243 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (139 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.4 Hz, 3H), 2,31 (s, 3H), 3,39 (DD, J=12,8, 2.8 Hz, 1H), 3,55 (DD, J=12,8, 9.6 Hz, 1H), 3,85 (s, 3H), 4,37-and 4.40 (m, 1H), and 4.68 (d, J=15.2 Hz, 1H), 4,77 (d, J=15.2 Hz, 1H), 6,86 (s, 1H), 6,93 (s, 1H), 6,94-7,03 (m, 1H), 7,16-7,24 (m, 1H), 7,21 (d, J=8,4 Hz, 1H), and 7.3 (DD, J=8,4, 2.0 Hz, 1H), 7,52 (d, J=2.0 Hz, 1H), of 7.75 (s, 1H).

ESI-MS; m/z 458[M++H].

Example 6

Synthesis of (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one

[Formula 28]

Synthesis of (R)-1-(2,3,4-triptoreline)propan-2-ol

1,09 g specified in the title compound was obtained from 2,3,4-triptoreline (1.0 g), (R)-1-amino-2-propanol (704 mg), acetic acid (1,79 ml) and triacetoxyborohydride sodium (2.65 g) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Synthesis of (R)-6-methyl-4-(2,3,4-triptorelin)morpholine-2,3-dione

874 mg specified in the title compound was obtained from (R)-1-(2,3,4-triptoreline)propan-2-ol (1,09 g) and diethyloxalate (8.0 ml) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Synthesis of (R)-2-hydroxy-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one

213 mg specified in the title compound was obtained from (R)-6-methyl-4-(2,3,4-triptorelin)morpholine-2,3-dione (350 mg) and 1M solution of three-second-butylbromide lithium in THF (1,49 ml) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Synthesis of (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholin-it

187 mg specified in the title compound was obtained from (R)-2-hydroxy-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one (213 mg), thionyl chloride (500 μl), triphenylphosphine (264 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (151 mg) according to the similar method of example 1. Values NMR of this compound was consistent with the values of the S-isomer.

Example 7

Synthesis of (Z)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 29]

Synthesis of 1-[(S)-1-(4-forfinal)ethylamino]-2-methylpropan-2-ol

Isobutylene (1.0 g) and (S)-1-(4-forfinal)ethylamine (2.25 ml) was added to a solution of lithium perchlorate (14.8 g) in ether (27.8 ml) at room temperature and the reaction solution was stirred at room temperature for 1.5 hours. Isobutylene (0.5 ml) was added to the reaction solution which was then stirred overnight. Ice water and chloroform were added to the reaction solution and the organic layer was separated. Then the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography using silica gel (chloroform:2-propanol=100:1-1:1), with a 2.13 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): of 1.13 (s, 3H), of 1.16 (s, 3H), of 1.35 (d, J=6,8 Hz, 3), 2,32 (d, J=11,6 Hz, 1H), 2,44 (d, J=11,6 Hz, 1H), 3,75 (kV, J=6,8 Hz, 1H), 6,99-7,10 (m, 2H), 7.23 percent-7,30 (m, 2H).

Synthesis of 4-[(S)-1-(4-forfinal)ethyl]-6,6-dimethylmorpholine-2,3-dione

1.44 g specified in the title compound was obtained from 1-[(S)-1-(4-forfinal)ethylamino]-2-methylpropan-2-ol (2,13 g) and diethyloxalate (7,0 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,19 (s, 3H), of 1.44 (s, 3H), and 1.56 (d, J=6.8 Hz, 3H), of 3.00 (d, J=13,6 Hz, 1H), and 3.31 (d, J=13,6 Hz, 1H), 6,02 (kV, J=6,8 Hz, 1H), 7,06-7,10 (m, 2H), 7,30 and 7.36 (m, 2H).

Synthesis of 4-[(S)-1-(4-forfinal)ethyl]-2-hydroxy-6,6-dimethylmorpholine-3-one

1.22 g specified in the title compound was obtained from 4-[(S)-1-(4-forfinal)ethyl]-6,6-dimethylmorpholine-2,3-dione (1.20 g) and 1M solution of three-second-butylbromide lithium in THF (equal to 4.97 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 0,97 (s, 1,5H), of 1.08 (s, 1,5H), 1,24 (s, 1,5H), 1,31 (s, 1,5H), of 1.52 (d, J=6,8 Hz, 1,5H), 1,53 (d, J=6,8 Hz, 1,5H), was 2.05 (s, 3H), and 2.79 (d, J=12,8 Hz, 0,5H), 2,87 (d, J=12,8 Hz, 0,5H), is 3.08 (d, J=12,8 Hz, 0,5H), 3,13 (d, J=12,8 Hz, 0,5H), of 3.77 (users, 1H), 5,26 (d, J=4.0 Hz, 0,5H), from 5.29 (d, J=4.0 Hz, 0,5H), to 5.93 (q, J=6,8 Hz, 0,5H), of 5.99 (q, J=6,8 Hz, 0,5H), 7.03 is-7,07 (m, 2H), 7,26-7,35 (m, 2H).

Synthesis of (Z)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

500 mg specified in the title compound was obtained from 4-[(S)-1-(4-forfinal)ethyl]-2-hydroxy-6,6-dimethylmorpholine-3-one (1,21 g), thionyl chloride (3.3 ml), triphenylphosphine (1.42 g) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzo is elegida (880 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,35 (d, J=6.8 Hz, 3H), of 1.57 (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), 2,89 (DD, J=12,8, and 9.2 Hz, 1H), 3,18 (DD, J=12,8, 2.8 Hz, 1H), 3,85 (s, 3H), or 4.31 is 4.36 (m, 1H), 6,11 (kV, J=7.2 Hz, 1H), to 6.88 (s, 1H), 6,93 (s, 1H), 7.03 is-was 7.08 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,29-7,35 (m, 3H), 7,52 (d, J=2.0 Hz, 1H), of 7.75 (s, 1H).

ESI-MS; m/z 450[M++H].

Examples 8 and 9

Synthesis of (Z)-(R)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 30]

Synthesis of 1-[(S)-1-(4-forfinal)ethylamino]propane-2-it

A mixture of (S)-1-(4-forfinal)ethylamine (5.0 g), chloroacetone (4,78 ml), cesium carbonate (13,9 g) and DMF (50 ml) was stirred at room temperature overnight. The reaction solution was diluted with water and ethyl acetate and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography using silica gel (hexane:ethyl acetate=5:1-0:100), with a 5.1 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): to 1.37 (d, J=6.8 Hz, 3H), 2,07 (s, 3H), 3,37 (s, 2H), 3,74 (kV, J=6,8 Hz, 1H), 6,97-7,03 (m, 2H), 7.24 to 7,29 (m, 2H).

ESI-MS; m/z 196[M++H].

Synthesis of 1-[(S)-1-(4-forfinal)ethylamino]propan-2-ol

Borohydride sodium (2,39 g) was added to RA is Toro 1-[(S)-1-(4-forfinal)ethylamino]propane-2-she (2.5 g) in ethanol (25 ml) under ice cooling and then the reaction solution was stirred at room temperature for one hour. The reaction solution was diluted with ice water and ethyl acetate and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography using silica gel (chloroform:2-propanol=100:1-0:100), to obtain 1.18 g specified in the title compounds as a mixture of diastereoisomers.

1H-NMR (CDCl3) δ (ppm): 1,09 (d, J=6,4 Hz, 0,9H), 1,10 (d, J=6.0 Hz, 2,1H), 1,35 (d, J=7,2 Hz, 0,9H), of 1.36 (d, J=6,4 Hz, 2,1H), 2,22 (DD, J=12,0, 9.6 Hz, 0,3H), 2,33 (DD, J=12,0, 9,2 Hz, 0,7H), 2,52 (DD, J=of 12.4, 3.6 Hz, 0,7H), at 2.59 (DD, J=11,6, 2,8 Hz, 0,3H), 3,61-3,66 (m, 0,3H), 3,74-of 3.80 (m, 0,7H), of 6.99-7.03 is (m, 2H), 7.24 to 7,29 (m, 2H).

Synthesis of 4-[(S)-1-(4-forfinal)ethyl]-6-methylmorpholin-2,3-dione

1.20 g specified in the title compound was obtained as a mixture of diastereoisomers of 1-[(S)-1-(4-forfinal)ethylamino]propan-2-ol (1.18 g) and diethyloxalate (4,06 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,31 (d, J=6,8 Hz, 1,8H), to 1.37 (d, J=6,8 Hz, 1,2H), 1.55V (d, J=6,8 Hz, 1,2H), and 1.56 (d, J=6,8 Hz, 1,8H), 2,96 (DD, J=12,0, 9.6 Hz, 0,6H), 3.04 from (DD, J=12,0, 3,6 Hz, 0,4H), 3,26 (DD, J=to 12.0, 3.6 Hz, 0,6H), to 3.38 (DD, J=12,0, 9.6 Hz, 0,4H), 4,42-to 4.52 (m, 0,4H), with 4.64-4,74 (m, 0,6H), 5,93-of 6.02 (m, 1H), 7,09 for 7.12 (m, 2H), 7,29-7,39 (m, 2H).

Synthesis of 4-[(S)-1-(4-forfinal)ethyl]-2-hydroxy-6-methylmorpholin-3-one

382 mg specified in the title compound was obtained as a mixture of diastereomers of 4-[(S)-1-(4-forfinal)ethyl]-6-methylmorpholin-2,3-dione (500 mg) and 1M is astora three-second-butylbromide lithium in THF (2,19 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,19 (d, J=6,8 Hz, 1,5H), 1,20 (d, J=6,8 Hz, 1,5H), 1,53 (d, J=6.8 Hz, 3H), 2,61 (DD, J=12,4, to 10.8 Hz, 0,5H), is 2.74 (DD, J=12,0, 2,8 Hz, 0,5H), to 2.94 (DD, J=12,4, 2,8 Hz, 0,5H), of 3.12 (DD, J=to 12.0, 11.2 Hz, 0,5H), 4,11-4.26 deaths (m, 0,5H), 4,37 was 4.42 (m, 0,5H), to 5.35 (s, 0,5H), lower than the 5.37 (s, 0,5H), 5,95 (kV, J=6,8 Hz, 0,5H), of 5.99 (q, J=6,8 Hz, 0,5H), 7,02-7,07 (m, 2H), 7,25-to 7.32 (m, 2H).

Synthesis of (Z)-(R)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

628 mg specified in the title compound was obtained as a mixture of diastereomers of 4-[(S)-1-(4-forfinal)ethyl]-2-hydroxy-6-methylmorpholin-3-one (382 mg), thionyl chloride (330 μl), triphenylphosphine (504 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (294 mg) according to the similar method of example 1. Part of the mixture of diastereomers was separated using a CHIRALCELTMOJ-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=80:20), obtaining specified in the title optically active compound with a retention time of 25 minutes (>95% de) and indicated in the title optically active compound with a retention time of 29 minutes (>95% de).

The characteristic values specified in the title optically active compound with a retention time of 25 minutes (example 8) are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.38 (d, J=6.4 Hz, 3H), 1.5 a (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), of 2.97 (DD, J=of 12.8, 2.4 Hz, 1H), 3,33 (DD, J=12,8, 9.6 Hz, 1H), 3,85 (s, 3H), 4.09 to of 4.12 (m, 1H), 6,13 (kV, J=7.2 Hz, 1H), 6.89 in (s, 1H), 6,94 (s, 1H), 7.03 is-to 7.09 (m, 2H), 7,21 (d, J=and 8.4 Hz, 1H), 7,32 and 7.36 (m, 3H), 7,53 (d, J=2,8 Hz, 1H), 7,74 (s, 1H).

ESI-MS; m/z 436[M++H].

The characteristic values specified in the title optically active compound with a retention time of 29 minutes (example 9) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,35 (d, J=6.8 Hz, 3H), of 1.57 (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), 2,89 (DD, J=12,8, and 9.2 Hz, 1H), 3,18 (DD, J=12,8, 2.8 Hz, 1H), 3,85 (s, 3H), or 4.31 is 4.36 (m, 1H), 6,11 (kV, J=7.2 Hz, 1H), to 6.88 (s, 1H), 6,93 (s, 1H), 7.03 is-was 7.08 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,29-7,35 (m, 3H), 7,52 (d, J=2.0 Hz, 1H), of 7.75 (s, 1H).

ESI-MS; m/z 436[M++H].

Examples 10 and 11

Synthesis of (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one and (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(R)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one

[Formula 31]

Synthesis of 2-[1-(3,4,5-tryptophanyl)ethylamino]ethanol

A mixture of 3,4,5-trifurcation (2.0 g), ethanolamine (2.0 g) and toluene (20 ml) was heated at boiling under reflux in an apparatus of the Dean-stark for 2.5 hours. The reaction solution was concentrated under reduced pressure, then the residue was diluted with ethanol (30 ml) was added under cooling with ice borohydride sodium (1.0 g). The mixture was stirred at room temperature for three hours is in and then diluted with 2n. the sodium hydroxide solution and chloroform. Then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography using silica gel (chloroform:methanol=50:1-5:1), to obtain 860 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,36 (d, J=6.8 Hz, 3H), 2,56 of 2.68 (m, 1H), 2,68-by 2.73 (m, 1H), 3,62-of 3.80 (m, 3H), 6,92-7,00 (m, 2H).

Synthesis of 4-[1-(3,4,5-tryptophanyl)ethyl]morpholine-2,3-dione

340 mg specified in the title compound was obtained from 2-[1-(3,4,5-tryptophanyl)ethylamino]ethanol (860 mg) and diethyloxalate (5.0 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1.55V (d, J=6.4 Hz, 3H), 3.15 and 3.21-in (m, 1H), 3,52-3,59 (m, 1H), or 4.31-4,37 (m, 1H), to 4.41-to 4.46 (m, 1H), 5,90 (kV, J=6,4 Hz, 1H), 6,97-7,01 (m, 2H).

Synthesis of 2-hydroxy-4-[1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one

273 mg specified in the title compound was obtained as a mixture of diastereomers of 4-[1-(3,4,5-tryptophanyl)ethyl]morpholine-2,3-dione (340 mg) and 1M solution of three-second-butylbromide lithium in THF (1,45 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): of 1.52 (d, J=7.2 Hz, 3H), 2,78-and 2.83 (m, 0,5H), 2.95 and-3,03 (m, 0,5H), 3,10-3,15 (m, 0,5H), 3,43-3,50 (m, 0,5H), 3,78-a-3.84 (m, 0,5H), 4,12-4,18 (m, 0,5H), 4,22-to 4.28 (m, 0,5H), 4,24 (users, 1H), of 5.34 (s, 0,5H), are 5.36 (s, 0,5H), 5,88 is 5.98 (m, 1H), 6,92-6,99 (m, 1H).

Synthesis of (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]METI the Eden]-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one and (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(R)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one

145 mg specified in the title compound was obtained in the form of a racemate of 2-hydroxy-4-[1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one (273 mg), thionyl chloride (1,12 ml), triphenylphosphine (360 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (204 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1.55V (d, J=6.8 Hz, 3H), to 2.29 (s, 3H), is 3.08-3,13 (m, 1H), 3,48-3,55 (m, 1H), 3,85 (s, 3H), 4,08-to 4.14 (m, 1H), 4,23-4,27 (m, 1H), 6,06 (kV, J=6,8 Hz, 1H), 6.90 to (s, 1H), 6,92 (s, 1H), of 6.96-7,02 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,37 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,38 (d, J=1.6 Hz, 1H), 7,71 (s, 1H).

ESI-MS; m/z 458[M++H].

Part of the racemate was separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=80:20), obtaining specified in the title optically active compound with a retention time of 21 minutes (>99% ee: example 11) and indicated in the title optically active compound with a retention time of 24 minutes (95% ee: example 10). The values of the NMR data of optically active compounds corresponded to the values NMR of the racemate.

Example 12

Synthesis of (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 32]

Synthesis of 1-[[(S)-chroman-4-yl]amino]-2-methylpropan-2-ol

5,62 g specified in the title compound was obtained from lithium perchlorate (29,6 g), ether (55,6 ml), (S)-4-aminopropane (4,13 g)obtained by the method described in the literature (see, for example, T. Mukaiyama et al., "A European Journal of Chemistry, 2003, vol.9, p.4485-4509), and isobutyramide (3.46 in ml) by the similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1,20 (s, 6H), 1.93 and-to 1.98 (m, 1H), 2,04-of 2.09 (m, 1H), 2,69 (s, 2H), 3,80-of 3.85 (m, 1H), 4,19-4,32 (m, 2H), 6,83 (d, J=8,4 Hz, 1H), 6,91 (t, J=8,4 Hz, 1H), 7,17 (t, J=8,4 Hz, 1H), 7,33 (d, J=8,4 Hz, 1H).

Synthesis of 4-[(S)-chroman-4-yl]-6,6-dimethylmorpholine-2,3-dione

1,53 g specified in the title compound was obtained from 1-[[(S)-chroman-4-yl]amino]-2-methylpropan-2-ol (5,62 g) and diethyloxalate (20 ml) according to the similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1,45 (s, 3H), of 1.48 (s, 3H), 2,10-2,17 (m, 1H), 2,23-of 2.27 (m, 1H), 3,23 (s, 2H), 4,18-4,30 (m, 2H), 5,96 (DD, J=8,4, 7.2 Hz, 1H), make 6.90 (d, J=8,4 Hz, 1H), 6,95 (t, J=8,4 Hz, 1H), 7,05 (d, J=8,4 Hz, 1H), 7.23 percent (t, J=8,4 Hz, 1H).

Synthesis of 4-[(S)-chroman-4-yl]-2-hydroxy-6,6-dimethylmorpholine-3-one

1,11 g specified in the title compound was obtained from 4-[(S)-chroman-4-yl]-6,6-dimethylmorpholine-2,3-dione (1.50 g) and 1M solution of three-second-butylbromide lithium in THF (6.0 ml) according to the similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1.26 in (s, 3H), 1,31 (s, 1,5H), 1,32 (s, 1,5H), 2,10-of 2.25 (m, 2H), 2,99 (d, J=13,2 Hz, 0,5H), 3,05 (d, J=13,2 Hz, 1H), 3,12 (d, J=13,2 Hz, 0,5H), 4,17-of 4.25 (m, 1H), 4.26 deaths is 4.35 (m, 1H), are 5.36 (C, 0,5H), lower than the 5.37 (s, 0,5H), of 5.89 of 5.99 (m, 1H), at 6.84-6.87 in (m, 1H), 6.90 to-6,94 (m, 1H), 7,01? 7.04 baby mortality (m, 0,5H), 7,08-7,11 (m, 0,5H), 7,16-7,21 (m, 1H).

Synthesis of (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Triphenylphosphorane (292 mg) was added to races is thief 4-[(S)-chroman-4-yl]-2-hydroxy-6,6-dimethylmorpholine-3-one (196 mg) in acetonitrile (10 ml) and the reaction solution was heated at the boil under reflux for two hours. The reaction solution was concentrated under reduced pressure. To the residue was added ethanol (15 ml), TEA (221 μl) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (138 mg) and the reaction solution was heated at the boil under reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure and diluted with saturated sodium bicarbonate solution and ethyl acetate, then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography using NH silica gel (heptane:ethyl acetate=1:1-0:100) and then was purified column chromatography using silica gel (heptane:ethyl acetate=1:1-0:100), to obtain 167 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): to 1.42 (s, 3H), of 1.44 (s, 3H), 2,14-2,22 (m, 2H), 2,33 (s, 3H), 3,12 (d, J=12,8 Hz, 1H), 3,19 (d, J=12,8 Hz, 1H), a 3.87 (s, 3H), 4,22-4,34 (m, 2H), 6,13 (DD, J=8,8, 6,8 Hz, 1H), 6,86-to 6.95 (m, 4H), 7,10 (d, J=7.2 Hz, 1H), 7,19 (d, J=7.2 Hz, 1H), 7,22 (d, J=8,4 Hz, 1H), 7,37 (DD, J=8,4, and 1.6 Hz, 1H), EUR 7.57 (d, J=1.6 Hz, 1H), 7,80 (s, 1H).

ESI-MS; m/z 460[M++H].

Examples 13 and 14

Synthesis of (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 33]

70,3 mg of the criminal code is mentioned in the title compound was obtained as a mixture of diastereoisomers of lithium perchlorate (of 3.56 g), ether (6,7 ml), (S)-4-aminochrome (1.0 g) and propylene oxide (609 μl) as starting compounds are analogous to the methods of example 7. The mixture was separated using a CHIRALPAKTMAD-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol 100%), obtaining specified in the title optically active compound with a retention time of 18 minutes (>99% de) and indicated in the title optically active compound with a retention time of 20 minutes (95% de).

The characteristic values specified in the title optically active compound with a retention time of 18 minutes (example 13) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,41 (d, J=6.0 Hz, 3H), 2,28 is 2.10 (m, 2H), 2,33 (s, 3H), to 3.09 (DD, J=13,2, and 3.2 Hz, 1H), 3,17 (DD, J=13,2, 8,8 Hz, 1H), a 3.87 (s, 3H), 4,20-and 4.40 (m, 3H), 6,07 (DD, J=9,2, 6,8 Hz, 1H), 6,86-to 6.95 (m, 4H), 7,06 (d, J=7,6 Hz, 1H), 7,18 (d, J=8,4 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 7,38 (d, J=8,4 Hz, 1H), 7,55 (s, 1H), 7,81 (s, 1H).

ESI-MS; m/z 446[M++H].

The characteristic values specified in the title optically active compound with a retention time of 20 minutes (example 14) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,41 (d, J=6.4 Hz, 3H), 2,10-of 2.21 (m, 2H), a 2.36 (s, 3H), to 3.09 (DD, J=12,8, 2.8 Hz, 1H), 3,33 (DD, J=12,8, 10,0 Hz, 1H), a 3.87 (s, 3H), 4,21-to 4.38 (m, 3H), 6,14 (DD, J=9,2, 7.2 Hz, 1H), 6,86-of 6.96 (m, 4H), 7,06 (d, J=7,6 Hz, 1H), 7.18 in-7,26 (m, 2H), 7,38 (d, J=8,4 Hz, 1H), EUR 7.57 (s, 1H), 7,89 (s, 1H).

ESI-MS; m/z 446[M++H].

Example 15

Synthesis of (Z)-(S)-4-(6-chloropyridin-2-ylmethyl)-2-[1-[3-methoxy-4(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 34]

Synthesis of (S)-1-[(6-chloropyridin-2-ylmethyl)amino]propan-2-ol

394 mg specified in the title compound was obtained from 2-chloro-6-formylpyridine (500 mg), (S)-1-amino-2-propanol (318 mg), acetic acid (0,808 ml) and triacetoxyborohydride sodium (1.12 g) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): to 1.16 (d, J=6.0 Hz, 3H), 2.49 USD (DD, J=12,0, and 9.2 Hz, 1H), 2,78 (DD, J=12,0, 2.8 Hz, 1H), 3,83-a 3.87 (m, 1H), 3,93 (s, 2H), 7.23 percent (d, J=8.0 Hz, 1H), 7,24 (d, J=8.0 Hz, 1H), to 7.64 (t, J=8.0 Hz, 1H).

Synthesis of (S)-4-(6-chloropyridin-2-ylmethyl)-6-methylmorpholin-2,3-dione

411 mg specified in the title compound was obtained from (S)-1-[(6-chloropyridin-2-ylmethyl)amino]propan-2-ol (394 mg) and diethyloxalate (3.0 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.8 Hz, 3H), 3,71 (DD, J=13,6, and 3.2 Hz, 1H), 3,79 (DD, J=13,6, 9.6 Hz, 1H), 4,69 (d, J=15.2 Hz, 1H), 4,77 (d, J=15.2 Hz, 1H), 4,84-of 4.90 (m, 1H), 7,30 (d, J=8.0 Hz, 1H), 7,32 (d, J=8.0 Hz, 1H), 7,68 (t, J=8.0 Hz, 1H).

Synthesis of (S)-4-(6-chloropyridin-2-ylmethyl)-2-hydroxy-6-methylmorpholin-3-one

273 mg specified in the title compound was obtained from (S)-4-(6-chloropyridin-2-ylmethyl)-6-methylmorpholin-2,3-dione (411 mg) and 1M solution of three-second-butylbromide lithium in THF (1,64 ml) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,27 (d, J=6.0 Hz, 3H), 3,30 (DD, J=12,0, 3.2 Hz, 1H), 3,39 (DD, J=12,0, to 10.8 Hz, 1H), 4,48-to 4.52 (m, 1H), 4,49 (d, J=15.2 Hz, 1H), 4,81 (d, J=15.2 Hz, 1H), 5,35 (s, 1H), 7,27 (d, J=7,6 Hz,1H), 7,28 (d, J=7,6 Hz, 1H), 7,66 (t, J=7,6 Hz, 1H).

Synthesis of (Z)-(S)-4-(6-chloropyridin-2-ylmethyl)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

27.9 mg specified in the title compound was obtained from (S)-4-(6-chloropyridin-2-ylmethyl)-2-hydroxy-6-methylmorpholin-3-one (237 mg), thionyl chloride (1,01 ml), triphenylphosphine (315 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (to 21.6 mg) according to the similar method of example 1.

1H-NMR (CDCl3) δ (ppm): 1,47 (d, J=6.4 Hz, 3H), of 2.34 (s, 3H), of 3.57 (DD, J=12,8, 2.8 Hz, 1H), 3,68 (DD, J=12,0, 10,0 Hz, 1H), 3,86 (s, 3H), 4,43-to 4.46 (m, 1H), amounts to 4.76 (s, 2H), 6,85 (s, 1H), 6,95 (s, 1H), 7,22 (d, J=8.0 Hz, 1H), 7,31 (d, J=7,6 Hz, 1H), 7,33 (d, J=8.0 Hz, 1H), 7,35 (DD, J=7,6, and 1.6 Hz, 1H), 7,55 (d, J=1.6 Hz, 1H), 7,66 (t, J=8.0 Hz, 1H), to 7.84 (s, 1H).

Examples 16 and 17

Synthesis of (Z)-(6S,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it (Z)-(6R,9aS)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it

[Formula 35]

Synthesis of 1-(4-forfinal)hepta-5,6-dienyl-1-amine

2.65 g specified in the title compound was obtained from (4-terbisil)-(4-formanilide)amine (3 g) and 6-idexa-1,2-diene (2,97 g) according to the method described in Journal of the American Chemical Society, 2003, vol.125, p.11956. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): a 1.25 to 1.37 (m, 1H), 1,39 of 1.50 (m, 1H), 1,63 is 1.75 (m, 2), 1,95-2,04 (m, 2H), 3,88 (d, J=6,8 Hz, 1H), 4,63 (dt, J=6.8 cm, 2,8 Hz, 2H), 5,04 (quintet, J=6,8 Hz, 1H), 6,99 (t, J=8,8 Hz, 2H), 7,26 (DD, J=8,8, 5.6 Hz, 2H).

Synthesis of (2R*,6S*)-2-(4-forfinal)-6-vinylpyridine

Acetic acid (0,74 ml) was added to a solution of the dimer of allylpalladium (472 mg) and 1,1'-bis(diphenylphosphino)ferrocene (1,43 g) in THF (200 ml) and the reaction solution was stirred at room temperature for 10 minutes. A solution of 1-(4-forfinal)hepta-5,6-dienyl-1-amine (2.65 g) in THF (50 ml) was added to the reaction solution which was then stirred at 70°C for 1.5 hours. The reaction solution was left to cool to room temperature. Then added to the reaction solution of diethyl ether and 1N. water chloride-hydrogen acid and the separated aqueous layer. The resulting aqueous layer washed with diethyl ether and then 5N. the sodium hydroxide solution was added to the aqueous layer until the pH is not reached until 11 or below. Chloroform was added to the aqueous layer and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 2.4 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,24-to 1.60 (m, 3H), 1,67-to 1.77 (m, 2H), 1,88-of 1.95 (m, 1H), 3,24-3,30 (m, 1H), to 3.67 (DD, J=11,2, 2.8 Hz, 1H), 5,01 (userd, J=10.4 Hz, 1H), 5,17 (userd, J=16,8 Hz, 1H), 5,88 (DDD, J=16,8, 10,4, 6.4 Hz, 1H), 6,98 (t, J=8,8 is C, 2H), 7,35 (DD, J=8,8, 5.6 Hz, 2H).

ESI-MS; m/z 206[M++H].

Synthesis of ethyl[(2R*,6S*)-2-(4-forfinal)-6-vinylpyridin-1-yl]oxoacetate

Ethylxanthate (0.5 ml) was added to a solution of (2R*,6S*)-2-(4-forfinal)-6-vinylpyridine (520 mg) and DIEA (0,66 ml) in methylene chloride (10 ml) and the reaction solution was stirred at room temperature for one hour. Chloroform and 1N. water chloride-hydrogen acid was added to the reaction solution and the organic layer was separated. The obtained organic layer was washed saturated aqueous sodium bicarbonate, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane→heptane:ethyl acetate=1:1), with 426 mg specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 306[M++H].

Synthesis of (6R*,9aS*)-6-(4-forfinal)-3-hydroxyhexanoate[2,1-c][1,4]oxazin-4-it

A solution of ethyl[(2R*,6S*)-2-(4-forfinal)-6-vinylpyridin-1-yl]oxoacetate (220 mg) in methanol (5 ml) was cooled to -78°C and gaseous ozone was barbotirovany through the reaction solution for 20 minutes. Borohydride sodium (164 mg) was added to the reaction solution under stirring at -78°C and the reaction solution was stirred at this temperature for 30 minutes the. Ethyl acetate and a saturated solution of ameriglide was added to the reaction solution and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate), to obtain 26 mg specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,35-1,50 (m, 2H), 1,57-to 1.67 (m, 2H), 2.05 is-of 2.26 (m, 2H), 3,57 (users, 1H), 3,80 (DD, J=11,6, 3.6 Hz, 1H), 3,88-3,98 (m, 1H), 4,11 (t, J=11,6 Hz, 1H), 5,22 (t, J=4.0 Hz, 1H), 5,28 (s, 1H), 7,01 (t, J=8,8 Hz, 2H), 7,19 (DD, J=8,8, 5.6 Hz, 2H).

ESI-MS; m/z 220[M++H].

Synthesis of [(6R*,9aS*)-6-(4-forfinal)-4-oxooctanoate[2,1-c][1,4]oxazin-3-yl]triphenylphosphonium

A solution of (6R*,9aS*)-6-(4-forfinal)-3-hydroxyhexanoate[2,1-c][1,4]oxazin-4-it (26 mg) and triphenylphosphine (40 mg) in acetonitrile (3 ml) was heated at boiling under reflux for one hour and 30 minutes. The reaction solution was left to cool to room temperature and then the solvent is evaporated under reduced pressure, to obtain 57 mg specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 510[M+].

Synthesis of (Z)-(6S*,9aR*)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-meth is l-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it

The triethylamine (0,03 ml) was added to a solution of [(6R*,9aS*)-6-(4-forfinal)-4-oxooctanoate[2,1-c][1,4]oxazin-3-yl]triphenylphosphonium (57 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (21 mg) in ethanol (5 ml) and the reaction solution was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure. Then the residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate), to obtain 27 mg specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,40 is 1.58 (m, 2H), of 1.65 to 1.76 (m, 2H), 2,18 was 2.25 (m, 2H), 2,31 (s, 3H), 3,85 (s, 3H), 4,07 (kV, J=10,8 Hz, 1H), 4,07-to 4.15 (m, 1H), 4,34 (DD, J=10,8, 2.4 Hz, 1H), 5,38 (t, J=4.0 Hz, 1H), PC 6.82 (s, 1H), 6,92 (users, 1H), 7,02 (t, J=8,4 Hz, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,22 (DD, J=8,0, 3.6 Hz, 2H), 7,37 (DD, J=8,0, 1.2 Hz, 1H), 7,39 (d, J=1.2 Hz, 1H), 7,74 (d, J=1.2 Hz, 1H).

ESI-MS; m/z 448[M++H].

Synthesis of (Z)-(6S,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it (Z)-(6R,9aS)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it

The racemate (Z)-(6S*,9aR*)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-she obtained above (27 mg)was separated using a CHIRALCELTMOJ-H Pro is svojstva F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1), obtaining specified in the title optically active compound with a retention time of 24 minutes (6,7 mg,>99% ee) and indicated in the title optically active compound with a retention time of 31 minutes (4,9 mg,>99% ee).

The characteristic values specified in the title optically active compound with a retention time of 24 minutes (example 16) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,40 is 1.58 (m, 2H), of 1.65 to 1.76 (m, 2H), 2,18 was 2.25 (m, 2H), 2,31 (s, 3H), 3,85 (s, 3H), 4,07 (kV, J=10,8 Hz, 1H), 4,07-to 4.15 (m, 1H), 4,34 (DD, J=10,8, 2.4 Hz, 1H), 5,38 (t, J=4.0 Hz, 1H), PC 6.82 (s, 1H), 6,92 (users, 1H), 7,02 (t, J=8,4 Hz, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,22 (DD, J=8,0, 3.6 Hz, 2H), 7,37 (DD, J=8,0, 1.2 Hz, 1H), 7,39 (d, J=1.2 Hz, 1H), 7,74 (d, J=1.2 Hz, 1H).

ESI-MS; m/z 448[M++H].

The characteristic values specified in the title optically active compound with a retention time of 31 minutes (example 17) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,40 is 1.58 (m, 2H), of 1.65 to 1.76 (m, 2H), 2,18 was 2.25 (m, 2H), 2,31 (s, 3H), 3,85 (s, 3H), 4,07 (kV, J=10,8 Hz, 1H), 4,07-to 4.15 (m, 1H), 4,34 (DD, J=10,8, 2.4 Hz, 1H), 5,38 (t, J=4.0 Hz, 1H), PC 6.82 (s, 1H), 6,92 (users, 1H), 7,02 (t, J=8,4 Hz, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,22 (DD, J=8,0, 3.6 Hz, 2H), 7,37 (DD, J=8,0, 1.2 Hz, 1H), 7,39 (d, J=1.2 Hz, 1H), 7,74 (d, J=1.2 Hz, 1H).

ESI-MS; m/z 448[M++H].

Examples 18 and 19

Synthesis of (Z)-(S)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(6-x is herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 36]

Synthesis of (S)-1-[1-(6-chloropyridin-3-yl)ethylamino]propan-2-ol

to 44.9 mg specified in the title compound was obtained from lithium perchlorate (340 mg), ether (0,64 ml), 1-(6-chloropyridin-3-yl)ethylamine (100 mg CAS #132219-51-3) and (S)-propylene oxide (61 μl) according to the similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1,11 (d, J=6,4 Hz, 1,5H), of 1.12 (d, J=6,4 Hz, 1,5H), of 1.39 (d, J=6,8 Hz, 1,5H), of 1.40 (d, J=6,8 Hz, 1,5H), of 2.21 (DD, J=12,0, 9,2 Hz, 0,5H), of 2.38 (DD, J=12,0, 8,8 Hz, 0,5H), 2.49 USD (DD, J=to 12.0, 2.4 Hz, 0,5H), 2.63 in (DD, J=12,0, 2,8 Hz, 0,5H), 3,68-a 3.87 (m, 2H), 7,31 (d, J=8.0 Hz, 0,5H), 7,32 (d, J=8.0 Hz, 0,5H), to 7.67 (DD, J=8,0, 2.0 Hz, 0,5H), to 7.68 (DD, J=8,0, 2.0 Hz, 0,5H), 8,30 (d, J=2,0 Hz, 0,5H), 8,31 (d, J=2.0 Hz, 0,5H).

Synthesis of (S)-4-[1-(6-chloropyridin-3-yl)ethyl]-6-methylmorpholin-2,3-dione

or 37.4 mg of the crude indicated in the title compound was obtained from (S)-1-[1-(6-chloropyridin-3-yl)ethylamino]propan-2-ol (44,8 mg) and diethyloxalate (1.0 ml) according to the similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1,36 (d, J=6.0 Hz, 1,5H), of 1.41 (d, J=6.0 Hz, 1,5H), of 1.62 (d, J=7,2 Hz, 1,5H), of 1.65 (d, J=7,2 Hz, 1,5H), 3,03-3,11 (m, 1H), 3,34 (DD, J=14,0, and 3.2 Hz, 0,5H), 3,47 (DD, J=13,6, 10.4 Hz, 0,5H), to 4.52-4,55 (m, 0,5H), 4,71 was 4.76 (m, 0,5H), 5,94 of 5.99 (m, 1H), 7,37 (d, J=8,4 Hz, 1H), to 7.64 (DD, J=8,4, 2,4 Hz, 0,5H), to 7.68 (DD, J=8,4, 2,4 Hz, 0,5H), of 8.37 (d, J=2.4 Hz, 0,5H), 8,39 (d, J=2,4 Hz, 0,5H).

Synthesis of (S)-4-[1-(6-chloropyridin-3-yl)ethyl]-2-hydroxy-6-methylmorpholin-3-one

3.9 mg specified in the title compound was obtained from (S)-4-[1-(6-chloropyridin-3-yl)ethyl]-6-methylmorpholin-2,3-dione (37 mg) and 1M solution of three-second-butylbromide lithium in THF (153 μl) according to the similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1,22 (d, J=7,2 Hz, 1,5H), of 1.23 (d, J=7,2 Hz, 1,5H), of 1.57 (d, J=8,4 Hz, 3H), 2,68 (DD, J=12,0, to 10.8 Hz, 0,5H), to 2.75 (DD, J=12,0, 2,8 Hz, 0,5H), to 3.02 (DD, J=12,0, 2,8 Hz, 0,5H), 3,18 (DD, J=12,0, to 10.8 Hz, 0,5H), 4.26 deaths-4,30 (m, 0,5H), 4,43-4,47 (m, 0,5H), of 5.34 (s, 0,5H), are 5.36 (s, 0,5H), 5,96 (kV, J=7,2 Hz, 0,5H), of 5.99 (q, J=7.2 Hz, 0,5H), 7,33 (d, J=8,4 Hz, 0,5H), 7,34 (d, J=8,4 Hz, 0,5H), to 7.59 (DD, J=8,4, 2,4 Hz, 0,5H), 7,63 (DD, J=8,4, 2,4 Hz, 0,5H), to 8.34 (d, J=2.4 Hz, 0,5H), 8,35 (d, J=2.4 Hz, 0,5H).

Synthesis of (Z)-(S)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Specified in the title compound was obtained as a mixture of diastereomers of (S)-4-[1-(6-chloropyridin-3-yl)ethyl]-2-hydroxy-6-methylmorpholin-3-one (3.9 mg), triphenylphosphine (5,81 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3,43 mg) according to the similar procedure of examples 16 and 17. The mixture of diastereomers was separated using a CHIRALPAKTMAD-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol 100%), obtaining specified in the title optically active compound with a retention time of 19 minutes (1.25 mg;>80% de) and indicated in the title optically active compound with a retention time of 25 minutes of 0.85 mg;>84% de).

The characteristic values specified in the title optically active compound with a retention time of 19 minutes(example 19) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,39 (d, J=6.8 Hz, 3H), of 1.62 (d, J=6.8 Hz, 3H), of 2.36 (s, 3H), 2,96 (DD, J=13,2, 4.8 Hz, 1H), 3,26 (DD, J=13,2, 2.4 Hz, 1H), 3,86 (s, 3H), or 4.31-and 4.40 (m, 1H), 6,13 (kV, J=6,8 Hz, 1H), to 6.88 (s, 1H), of 6.96 (s, 1H), 7,22 (d, J=8,4 Hz, 1H), 7,34 (d, J=8.0 Hz, 1H), was 7.36 (d, J=8.0 Hz, 1H), 7,52 (s, 1H), to 7.64 (DD, J=8,4, 2.8 Hz, 1H), to 7.93 (s, 1H), scored 8.38 (d, J=2,8 Hz, 1H).

ESI-MS; m/z 453[M++H].

The characteristic values specified in the title optically active compound with a retention time of 25 minutes (example 18) are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.0 Hz, 3H), of 1.61 (d, J=7.2 Hz, 3H), 2,39 (s, 3H), 2,99 (DD, J=of 12.8, 2.4 Hz, 1H), 3,41 (DD, J=12,8, 10.4 Hz, 1H), a 3.87 (s, 3H), 4,10-4,20 (m, 1H), 6,15 (kV, J=7.2 Hz, 1H), 6.89 in (s, 1H), 6,97 (s, 1H), 7.23 percent (d, J=8,4 Hz, 1H), 7,35 (d, J=7,6 Hz, 1H), 7,37 (d, J=7,6 Hz, 1H), 7,55 (s, 1H), to 7.67 (DD, J=8,4, 2.4 Hz, 1H), to 7.99 (s, 1H), 8,39 (d, J=2.4 Hz, 1H).

ESI-MS; m/z 453[M++H].

Examples 20 and 21

Synthesis of (Z)-(S)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 37]

Synthesis of 1-(5-chloropyridin-2-yl)ethanol

The copper iodide (148 mg), 1-ethoxyphenyl-n-botillo (2,97 ml) and bis(triphenylphosphine)palladium(II)chloride (183 mg) was added to a solution of 2-bromo-5-chloropyridine (1 g) in acetonitrile (30 ml) and the reaction solution was stirred in nitrogen atmosphere at 100°C for three hours. P is a promotional solution is again brought up to room temperature. Added 10 ml of 5N. chloride-hydrogen acid and the reaction solution was heated at the boil under reflux for 30 minutes. The reaction solution was again brought to room temperature and neutralized 5h. the sodium hydroxide solution. Diethyl ether was added to the reaction solution and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml) and methanol (10 ml). Borohydride sodium (492 mg) was added and the reaction solution was stirred at room temperature for one hour. Water and diethyl ether was added to the reaction solution and the organic layer was separated. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent: hexane-diethyl ether)to obtain 503 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,50 (d, J=6.8 Hz, 3H), 4,90 (kV, J=6,8 Hz, 1H), 7,28 (DD, J=0,8, 0.8 Hz, 1H), to 7.67 (DD, J=8,4, 2.8 Hz, 1H), and 8.50 (DD, J=2,8, 0.8 Hz, 1H).

Synthesis of 2-(1-azidoethyl)-5-chloropyridine

Diphenylphosphinite (1.0 ml) was added to a solution of 1-(5-chloropyridin-2-yl)ethanol (503 mg) in toluene (8 ml) under nitrogen atmosphere. Re clanny the solution was cooled with ice was added to the solution dropwise 1,8-diazabicyclo[5,4,0]undec-7-ene (0,69 ml). The reaction solution was stirred for three hours. Then the solution is again brought to room temperature and was stirred overnight. Water and diethyl ether was added to the reaction solution and the organic layer was separated. The organic layer was dried over magnesium sulfate and the solvent is then evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane-diethyl ether)to obtain 337 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,60 (d, J=6.8 Hz, 3H), of 4.66 (q, J=6,8 Hz, 1H), 7,32 (d, J=8,4 Hz, 1H), 7,69 (DD, J=8,4, 2.8 Hz, 1H), 8,54 (d, J=2,8 Hz, 1H).

Synthesis of 1-(5-chloropyridin-2-yl)ethylamine

Water (3 ml) and triphenylphosphine (702 mg) was added to a solution of 2-(1-azidoethyl)-5-chloropyridine (333 mg) in tetrahydrofuran (10 ml) and the reaction solution was stirred at 60°C for two hours. The reaction solution was again brought to room temperature. Dichloromethane and 5h. chloride-hydrogen acid was added to the reaction solution and the separated aqueous layer. The aqueous layer was podlachian (pH 14) 5h. the sodium hydroxide solution. Then dichloromethane was added to the reaction solution and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, to obtain 260 mg specified in the header connect the Oia.

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.4 Hz, 3H), 4,18 (kV, J=6,4 Hz, 1H), 7,28 (d, J=8,4 Hz, 1H), 7,63 (DD, J=8,4, 2.4 Hz, 1H), and 8.50 (d, J=2.4 Hz, 1H).

Synthesis of (Z)-(S)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

115 mg specified in the title compound was obtained as a mixture of diastereomers of 1-(5-chloropyridin-2-yl)ethylamine (200 mg) as a starting compound according to a similar procedure of examples 18 and 19. Part of a mixture of diastereomers were separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol 100%), obtaining specified in the title optically active compound with a retention time of 17 minutes (12,3 mg,>99% de) and indicated in the title optically active compound with a retention time of 20 minutes (21,4 mg; 94% de).

The characteristic values specified in the title optically active compound with a retention time of 17 minutes (example 20) are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.38 (d, J=6.4 Hz, 3H), of 1.61 (d, J=7.2 Hz, 3H), 2,31 (s, 3H), 3,19 (DD, J=13,2, 9.6 Hz, 1H), 3,52 (DD, J=13,2, 2.4 Hz, 1H), 3,85 (s, 3H), 4,33 was 4.42 (m, 1H), 6,04 (kV, J=7.2 Hz, 1H), 6,83 (s, 1H), 6,93 (s, 1H), 7,20 (d, J=8.0 Hz, 1H), 7,32 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,33 (d, J=8,4 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,65 (DD, J=8,4, 2.4 Hz, 1H), to 7.77 (s, 1H), charged 8.52 (d, J=2.4 Hz, 1H).

ESI-WHO WITH; m/z 453[M++H].

The characteristic values specified in the title optically active compound with a retention time of 20 minutes (example 21) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,45 (d, J=6.4 Hz, 3H), 1,60 (d, J=7.2 Hz, 3H), by 2.55 (s, 3H), of 3.48 (DD, J=12,8, 10,0 Hz, 1H), 3,60 (DD, J=of 12.8, 2.4 Hz, 1H), with 3.89 (s, 3H), 4,20-4,27 (m, 1H), 5,97 (kV, J=7.2 Hz, 1H), for 6.81 (s, 1H), 7,02 (s, 1H), 7,22 (d, J=7,6 Hz, 1H), 7,37 (d, J=8,4 Hz, 1H), 7,38 (DD, J=7,6, 1.2 Hz, 1H), 7,60 (d, J=1.2 Hz, 1H), 7,66 (DD, J=8,4, 2.4 Hz, 1H), 8,48 (s, 1H), 8,51 (d, J=2.4 Hz, 1H).

ESI-MS; m/z 453[M++H].

Examples 22 and 23

Synthesis of (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 38]

A solution of n-utility in THF (2,62M current, 29,1 ml) was added dropwise to a solution of Diisopropylamine (11.7 ml) in tetrahydrofuran (310 ml) under ice cooling in a nitrogen atmosphere. The reaction solution was stirred under ice cooling for one hour and then cooled to -78°C. a Solution of 2,6-diphereline (8 g) in tetrahydrofuran (10 ml) was added dropwise to the reaction solution. The reaction solution was stirred at -78°C for three hours. Then added in a stream of nitrogen, the excess amount of crushed dry ice, and the reaction solution was stirred n and 78°C for 20 minutes and at room temperature for three hours. Water and diethyl ether was added to the reaction solution and the separated aqueous layer. The aqueous layer was brought to pH 1 with concentrated chloride-hydrogen acid. Ethyl acetate was added to the aqueous layer and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, to obtain 10.4 g specified in the connection header.

1H-NMR (CD3OD) δ (ppm): was 7.08 (DD, J=8,4, 2.8 Hz, 1H), 8,58 (DD, J=17,2, and 8.4 Hz, 1H).

Synthesis of 2,6-debtor-N-methoxy-N-nicotine amide

The hydrochloride of N,O-dimethylhydroxylamine (14,7 g), WSC (28,9 g) and HOBt (20.4 g) was added to a solution of 2,6-diversication acid (6 g) and diisopropylethylamine (10 ml) in DMF (100 ml) and the reaction solution was stirred at room temperature for two days. Water and ethyl acetate were added to the reaction solution and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent: ethyl acetate), obtaining 7,01 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 3,37 (s, 3H), to 3.58 (users, 3H), 6.90 to (DD, J=8.0 a, 2,8 Hz, 1H), 8,02 (DD, J=16,0, 8.0 Hz, 1H).

1-(2,6-differencein-3-yl)alanon

The solution methylacrylamide in THF (0,96M, 88, ml) was added to a solution of 2,6-debtor-N-methoxy-N-nicotine amide (7.01 g) in tetrahydrofuran (180 ml) under ice cooling and the reaction solution was stirred under ice cooling for two hours. A saturated solution of ameriglide and ethyl acetate was added to the reaction solution while cooling with ice and the organic layer was separated. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent: hexane-ethyl acetate), obtaining 4,74 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,05 (s, 3H), 6,93-6,97 (m, 1H), 8,46-charged 8.52 (m, 1H).

1-(2,6-differencein-3-yl)economicsin

Hydroxylaminsulphate (13,1 g) and sodium acetate (10,9 g) was added to a solution of 1-(2,6-differencein-3-yl)ethanone (4,18 g) in aqueous THF (50%, 200 ml) and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent: ethyl acetate), obtaining 2,44 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 2,05 (s, 3H), 6,93-6,97 (m, 1H), 8,46-charged 8.52 (m, 1H).

1-(2,6-differencein-3-yl)ethylamine

Zinc (9,29 g) was added in three portions to a solution of 1-(2,6-differencein-3-yl)who tanorexia (2,44 g) in triperoxonane acid (100 ml) and the reaction solution was stirred at room temperature for two hours. The reaction solution was podlachian (pH 14) 5h. sodium hydroxide, filtered through celite and the celite was washed with chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining 1,61 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6,8 Hz, 1H), 4,39 (kV, J=6,8 Hz, 1H), PC 6.82 (DD, J=8.0 a, 2,8 Hz, 1H), 8,02 (DD, J=17,2, 8.0 Hz, 1H).

Synthesis of (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Specified in the title compound (170 mg) was obtained as a mixture of diastereomers of 1-(2,6-differencein-3-yl)ethylamine (330 mg) as a starting compound according to a similar procedure of examples 18 and 19. The resulting mixture of diastereomers (10 mg) were separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3), obtaining specified in the title optically active compound with a retention time of 33 minutes (4,7 mg) and indicated in the title optically active compound with a retention time of 39 minutes (3.8 mg).

The characteristic is indicated in the title compounds mixture of diastereoisomers is as follows.

ESI-MS: m/z 455[M +H].

The characteristic values specified in the title optically active compound with a retention time of 33 minutes (example 22) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,44 (d, J=6.4 Hz, 3H), 1,67 (d, J=7.2 Hz, 3H), 2,31 (s, 3H), 3,23 (DD, J=12,8, 10,0 Hz, 1H), 3,42 (DD, J=12,8, 2.8 Hz, 1H), 3,84 (s, 3H), 4,37 (m, 1H), 5,74 (kV, J=7.2 Hz, 1H), for 6.81 (s, 1H), 6.87 in (DD, J=8.0 a, 2,8 Hz, 1H), 6,93 (DD, J=1,2, 1.2 Hz, 1H), 7,20 (d, J=8.0 Hz, 1H), 7,31 (DD, J=8,4, and 1.6 Hz, 1H), 7,50 (d, J=1.6 Hz, 1H), to 7.77 (s, 1H), 8,00 (m, 1H).

The characteristic values specified in the title optically active compound with a retention time of 39 minutes (example 23) are as follows:

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.4 Hz, 3H), of 1.65 (d, J=7.2 Hz, 3H), 2,32 (s, 3H), of 3.32 (DD, J=12,8, 2.8 Hz, 1H), 3,50 (DD, J=12,8, 9.6 Hz, 1H), 3,85 (s, 3H), 4,29 (m, 1H), 5,80 (kV, J=7.2 Hz, 1H), PC 6.82 (s, 1H), 6.87 in (DD, J=8.0 a, 2,8 Hz, 1H), 6,93 (DD, J=1,2, 1.2 Hz, 1H), 7,20 (d, J=8.0 Hz, 1H), 7,31 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,79 (s, 1H), 7,99 (m, 1H).

Another synthesis example 22:

Synthesis of (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 39]

Synthesis of 1-(2,6-differencein-3-yl)ethanol

Diisopropylamine (134 ml) was added dropwise to a mixed solution consisting of a solution of n-utility in hexane (2,62 M, 368 ml) and tetrahydrofuran (800 ml)under nitrogen atmosphere at -60°C or below. The reaction solution was stirred for 30 minutes, and C is the solution of 2,6-diphereline (100 g) in tetrahydrofuran (100 ml) was added dropwise to the reaction solution at -60°C or below. The reaction solution was stirred for one hour and then acetaldehyde (97,6 ml) was added dropwise to the reaction solution. Then to the reaction solution was added dropwise 2n. water chloride-hydrogen acid (1,000 ml). Then to the reaction solution were added ethyl acetate (1,000 ml) and toluene (1,000 ml) and the organic layer was separated. The organic layer was concentrated under reduced pressure, to obtain 129 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,51 (d, J=5.6 Hz, 3H), 2,00 (s, 1H), 5,13-5,16 (m, 1H), at 6.84 (DD, J=8.0 a, and 2.1 Hz, 1H), with 8.05 (DD, J=16,0, 8.0 Hz, 1H).

Synthesis of (+)-di-p-toluoyl-D-tartrate (S)-1-[(S)-1-(2,6-differencein-3-yl)ethylamino]propan-2-ol

A solution of 1-(2,6-differencein-3-yl)ethanol (216 g) in toluene (300 ml) was added to a solution of thienylboronic (337 g) in toluene (1,500 ml) under ice cooling and the reaction solution was stirred at room temperature for three hours. Ice water and toluene were added to the reaction solution and the organic layer was separated. The organic layer was washed with water (1,000 ml) three times. The organic layer was dried over anhydrous magnesium sulfate and then filtered through a porous layer of silica gel. (S)-1-amino-2-propanol (157 g), cesium carbonate (1.28 kg) and DMF (2,500 ml) was added to the filtrate and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered and then the mother liquor was concentrated under reduced pressure. The residue was diluted with ethanol (1,000 ml). Then was added a solution of (+)-di-p-toluoyl-D-tartaric acid (152 g) in ethanol (500 ml) and the reaction solution was stirred at room temperature for one hour. Precipitated precipitated crystals were separated by filtration and washed with ethanol. The crystals were dried at 80°C for two hours and suspended in a mixed solvent of ethanol (2,000 ml), heptane (1,000 ml). Then the reaction solution was heated and stirred at 80°C. After one hour, the reaction solution was again brought to room temperature and the crystals were separated by filtration. The crystals were washed with ethanol and dried at 80°C overnight, to obtain 155 g specified in the connection header.

1H-NMR (DMSO-d6) δ (ppm): 1,02 (d, J=6.0 Hz, 6H), to 1.37 (d, J=6.8 Hz, 6H), a 2.36 (s, 6H), 2,37 is 2.51 (m, 4H), 3,67-3,71 (m, 2H), 4,14-4,16 (m, 2H), 5,65 (s, 2H), 7,21 (DD, J=8,0, 2.0 Hz, 2H), 7,31 (d, J=8,4 Hz, 4H), 7,82 (d, J=8,4 Hz, 4H), of 8.27 (DD, J=17,6, 8.0 Hz, 2H).

Synthesis of (S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-6-methylmorpholin-2,3-dione

(+)-Di-p-toluoyl-D-tartrate (S)-1-[(S)-1-(2,6-differencein-3-yl)ethylamino]propan-2-ol (199 g) was dissolved in 5N. aqueous sodium hydroxide solution (450 ml), water (1,000 ml) and a mixture of 50% toluene-THF (2,000 ml) and the organic layer was separated. The aqueous layer was washed with a mixture of 50% toluene-THF (800 ml) three times. The organic layers were combined and concentrated under reduced pressure. Then diethyloxalate (200 ml) was added the to the residue and the reaction solution was heated and stirred at 140-150°C. After three hours, the reaction solution was diluted with toluene (500 ml) and then cooled with ice under stirring. Precipitated precipitated crystals were separated by filtration, washed with toluene and diethyl ether and then dried in air, to obtain 103 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (d, J=6.8 Hz, 3H), 1,70 (d, J=6.8 Hz, 3H), 3,36 (DD, J=13,2, 8,8 Hz, 1H), 3,52 (DD, J=13,2, and 2.1 Hz, 1H), 4.72 in-4,78 (m, 1H), 5,59 (kV, J=6,8 Hz, 1H), to 6.88 (DD, J=8.0 a, 2,8 Hz, 1H), 8,01 (DD, J=16,8, 8.0 Hz, 1H).

Synthesis of (S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-hydroxy-6-methylmorpholin-3-one

1M solution of three-second-butylbromide lithium in THF (20 ml) was added dropwise to a solution of (S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-6-methylmorpholin-2,3-dione (4.5 g) in THF at -50°C or below, and the reaction solution was stirred for two hours. To the reaction solution at -10°C or lower was added dropwise 5h. the sodium hydroxide solution (of 1.66 ml) and 30% aqueous hydrogen peroxide (6,78 ml) and the reaction solution was stirred for one hour. Sodium bisulfite (520 mg) was added to the reaction solution which was then stirred for 30 minutes. A saturated solution of salt and a mixture of 50% toluene-THF was added to the reaction solution and the organic layer was separated. The aqueous layer was washed with a mixture of 50% toluene-THF. The organic layers were combined and concentrated under reduced pressure. The residue was purified column x is omatography using silica gel (heptane:ethyl acetate=1:1-0:100), to obtain 4.52 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): a 1.25 (d, J=6,8 Hz, 2,58H), of 1.30 (d, J=6,8 Hz, 0,42H), 1,60 (d, J=6,8 Hz, 2,58H), of 1.62 (d, J=6,8 Hz, 0,42H), 2,90 (DD, J=12,8, 8,8 Hz, 0,86H), to 3.09 (DD, J=12,8, 8,8 Hz, 0,14H), 3,11 (DD, J=12,8, 2,1 Hz, 0,86H), and 3.31 (DD, J=12,8, 2,1 Hz, 0,14H), 4,39-of 4.49 (m, 1H), 5,14 (s, 0,14H), and 5.30 (s, 0,86H), 5,50 (kV, J=6,8 Hz, 0,14H), 5,71 (kV, J=6,8 Hz, 0,86H), 6.87 in (DD, J=8.0 a, 2,8 Hz, 1H), of 7.96 (DD, J=16,8, 8.0 Hz, 1H).

Synthesis of (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Triphenylphosphorane (of 6.52 g) was added to a solution of (S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-hydroxy-6-methylmorpholin-3-one (4.3 g) in acetonitrile and the reaction solution was heated at boiling under reflux for one hour. The triethylamine (5,28 ml) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.42 g) was added to the reaction solution which was then heated at the boil under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure and the residue was diluted with 2n. water chloride-hydrogen acid and ethyl acetate. Then the separated aqueous layer. The organic layer was washed 2n. water chloride-hydrogen acid. Then all aqueous layers were combined and podslushivaet concentrated sodium hydroxide solution. The organic layer was separated by extraction of the alkaline solution with ethyl acetate and then PR is mawali a saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography using NH silica gel (heptane:ethyl acetate=1:1-0:100), with 4,06 g specified in the connection header. Characteristic values corresponded to those in example 22.

Examples 24 and 25

Synthesis of (Z)-(S)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 40]

1-(2,6-differencein-3-yl)ethylamine

1.13 g specified in the title compound was obtained from 2,3-depersonification acid (2,49 g), which is a known compound (see, for example, Journal of Organic Chemistry, 2005, vol.70, p.3039-3045), analogous to the methods of examples 22 and 23.

1H-NMR (CDCl3) δ (ppm): 1,44 (d, J=6.8 Hz, 3H), 4,50 (kV, J=6,8 Hz, 1H), 7,33 (DD, J=4,8, and 4.8 Hz, 1H), 7,94 (d, J=4,8 Hz, 1H).

Synthesis of (Z)-(S)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Specified in the title compound (500 mg) was obtained as a mixture of diastereomers of 1-(2,6-is afterellen-3-yl)ethylamine (500 mg) as a starting compound according to a similar procedure of examples 18 and 19. The resulting mixture of diastereomers (10 mg) were separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3), obtaining specified in the title optically active compound with a retention time of 39 minutes (2.6 mg) and indicated in the title optically active compound with a retention time of 43 minutes (3.0 mg).

The characteristic is indicated in the title compounds mixture of diastereoisomers is as follows:

ESI-MS: m/z 455[M++H].

The characteristic values specified in the title optically active compound with a retention time of 39 minutes (example 24) are as follows:

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.8 Hz, 3H), 1,67 (d, J=7.2 Hz, 3H), 2,31 (s, 3H), 3,24 (DD, J=13,2, 9.6 Hz, 1H), 3,43 (DD, J=13,2, 2.8 Hz, 1H), 3,85 (s, 3H), 4,39 (m, 1H), 5,93 (kV, J=7.2 Hz, 1H), 6,83 (s, 1H), 6,94 (DD, J=0,8, 0.8 Hz, 1H), 7,19-7,27 (m, 2H), 7,32 (DD, J=8,4, and 1.6 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,79 (d, J=1.2 Hz, 1H), to 7.99 (DD, J=5,2, 0.8 Hz, 1H).

The characteristic values specified in the title optically active compound with a retention time of 43 minutes (example 25) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,49 (d, J=6.4 Hz, 3H), of 1.66 (d, J=7.2 Hz, 3H), 2,32 (s, 3H), 3,29 (DD, J=12,8, 2.8 Hz, 1H), 3,54 (DD, J=12,8, 9.6 Hz, 1H), 3,85 (s, 3H), 4,34 (m, 1H), 5,97 (kV, J=7.2 Hz, 1H), 6,84 (s, 1H), 6,94 (s, 1H), 7.18 in-of 7.23 (m, 2H), 7,33 (DD, J=8,4, and 1.6 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,80 (d, J=1.2 Hz, 1H), to 7.99 (DD, J=5,2, 0.8 Hz, 1H).

Example 26

Synthesis of (Z)-(S-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 41]

Synthesis of 1,2,3-Cryptor-5-[(E)-propenyl]benzene

Tetranitropentaerithrite(0) (of 4.66 g) and cesium fluoride (21,4 g) was added to a solution of 1-bromo-3,4,5-triterpenols (8.5 g) and TRANS-1-propen-1-Voronovo acid (4.1 g) in dioxane (95 ml) and water (5 ml) under nitrogen atmosphere and the reaction solution was stirred at 80°C for five hours. The reaction solution was again brought to room temperature. Then hexane and water were added to the reaction solution and the insoluble substance was removed by filtration. The organic layer was separated, then washed with water and the insoluble material was again removed by filtration. The organic layer was separated, then washed with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The crude product was purified by chromatography on a column of silica gel (hexane), with the receipt of 5.83 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,88 (d, J=6.0 Hz, 3H), 6,18 (CVD, J=6,0, 16.0 Hz, 1H), 6,24 (d, J=16.0 Hz, 1H), 6,85-of 6.96 (m, 2H).

Synthesis of (1S,2S)-1-(3,4,5-tryptophanyl)propane-1,2-diol

1,2,3-Cryptor-5-[(E)-propenyl]benzene (of 5.83 g) was added to a cooled ice mixed solution of AD-Mix-((47,5 g) and methanesulfonamide (3,22 g) in tert-butanol (170 ml) and water (170 ml) reaktsionny the solution was stirred at 5°C during the night. Then sodium sulfite (51 g) was added to the reaction solution which was then stirred for one hour. The reaction solution was extracted with methylene chloride three times. The combined organic layers were washed 2n. the sodium hydroxide solution and then containing the sodium hydroxide layer was again extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The crude product was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1-1:1), obtaining 5,54 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,12 (d, J=6.4 Hz, 3H), 2,20 (users, 1H), 2,79 (users, 1H), 3,78 (CVD, J=6,4, 6.4 Hz, 1H), 4,34 (d, J=6,4 Hz, 1H), of 6.96-7,05 (m, 2H).

Synthesis of (1R,2S)-1-azido-1-(3,4,5-tryptophanyl)propan-2-ol

Tablet of sodium hydroxide (110 mg) was added to a solution of (1S,2S)-1-(3,4,5-tryptophanyl)propane-1,2-diol (5,54 g) dimethylcarbonate (15 ml) under nitrogen atmosphere and the reaction solution was stirred at 70°C for 45 minutes. Then the outdoor temperature was raised to 100°C and dimethylcarbonate removed, blowing with nitrogen. Then to the residue was added dimethylcarbonate (5 ml) and removed by pulling nitrogen. Was added to the residue THF and insoluble substances were removed by filtration through celite. The solvent is then evaporated under reduced pressure, with what rucenim 6,13 g of carbonate compounds.

Water (0.5 ml) and sodium azide (1.92 g) was added to a solution of carbonate compounds in DMF (20 ml) under nitrogen atmosphere and the reaction solution was stirred at 110°C over night. Diethyl ether was added to the reaction solution is brought to room temperature, and the reaction solution was sequentially washed with water (three times) and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=19:1-9:1), obtaining 5,16 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1.14 in (d, J=6.4 Hz, 3H), 1,79 (users, 1H), 3,97 (CVD, J=6,4, and 4.8 Hz, 1H), 4,42 (d, J=4,8 Hz, 1H), of 6.96-7,05 (m, 2H).

Synthesis of tert-butyl[(1R,2S)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]carbamate

Triphenylphosphine (5,85 g) was added to a solution of (1R,2S)-1-azido-1-(3,4,5-tryptophanyl)propan-2-ol (5,16 g) in THF (75 ml) under nitrogen atmosphere and the reaction solution was stirred at room temperature for 10 minutes. Then water (5 ml) was added to the reaction solution which was then stirred at 60°C for 3.5 hours. The reaction solution was again brought to room temperature and di-tert-BUTYLCARBAMATE (5.35 g) was added to the reaction solution which was then stirred at room temperature for 45 min is so The solvent is evaporated under reduced pressure and then the resulting residue was purified by chromatography on a column of silica gel (toluene:ethyl acetate=9:1), obtaining 5,88 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm)with 1.07 (d, J=6.4 Hz, 3H), of 1.41 (s, 9H), 4,10 (users, 1H), 4,47 (users, 1H), 5,44 (users, 1H), 6,92-7,01 (m, 2H).

Synthesis of (1R,2R)-2-tert-butoxycarbonylamino-1-methyl-2-(3,4,5-tryptophanyl)ethyl 4-nitrobenzoate

Diisopropylethylamine (6 ml) was added dropwise to a solution of tert-butyl[(1R,2S)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]carbamate (5,88 g), 4-nitrobenzoic acid (4,84 g) and triphenylphosphine (to 7.59 g) in THF (100 ml) under ice cooling in a nitrogen atmosphere and the reaction solution was stirred at room temperature for two hours. The solvent is evaporated under reduced pressure and the obtained residue was purified by chromatography on a column of silica gel (toluene:ethyl acetate=97:3). Then the resulting powder was triturated in a mixture of toluene-hexane, obtaining 6,69 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): to 1.37 (s, 9H), to 1.38 (d, J=6.4 Hz, 3H), 4,85 (users, 1H), 5,16 (d, J=9,2 Hz, 1H), 5,41 (CVD, J=6,4, 6.0 Hz, 1H), 6,92-7,01 (m, 2H), 8,16 (d, J=8,8 Hz, 2H), 8,29 (d, J=8,8 Hz, 2H).

Synthesis of tert-butyl[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]carbamate

Powder potassium carbonate (to 6.43 g) was added to a mixed solution of (1R,2R)-2-tert-butoxycarbonylamino is about-1-methyl-2-(3,4,5-tryptophanyl)ethyl 4-nitrobenzoate (7,03 g) in methanol (90 ml)-THF (10 ml) and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with water and saturated salt solution (twice). The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. Diethyl ether was added to the obtained residue, and the insoluble substance was removed by filtration. The filtrate was concentrated and the obtained residue was purified by chromatography on a column of silica gel (toluene:ethyl acetate=6:1), obtaining of 4.49 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,28 (d, J=6.4 Hz, 3H), of 1.44 (s, 9H), 4,01 (users, 1H), 4,48 (users, 1H), 5,35 (users, 1H), 6.90 to-7,00 (m, 2H).

Synthesis of tert-butyl[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]carbamate

tert-Butylchloroformate (2.0 ml) was added in four portions to a solution of tert-butyl[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]carbamate (610 mg) and imidazole (817 mg) in DMF (3 ml) under nitrogen atmosphere and the reaction solution was stirred at room temperature for three hours. Ethyl acetate was added to the reaction solution, which is then sequentially washed with water, 1N. chloride-hydrogen acid, water, saturated sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced on the no. The obtained residue was purified by chromatography on a column of silica gel (hexane:diethyl ether (49:1 to 19:1), with 684 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): of 0.95 (s, 9H), of 1.13 (d, J=6.4 Hz, 3H), of 1.47 (s, 9H), was 4.02 (users, 1H), 4,46 (users, 1H), 5,34 (users, 1H), 6,69-to 6.80 (m, 2H), 7,28-7,46 (m, 8H), 7,55 (d, J=8,4 Hz, 2H).

Synthesis of (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)Propylamine

Triperoxonane acid (0.5 ml) was added to a solution of tert-butyl[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]carbamate (370 mg) in methylene chloride (2 ml) and the reaction solution was stirred at room temperature for 11 hours. A saturated solution of sodium bicarbonate was added to the reaction solution and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution and then the solvent is evaporated under reduced pressure, to obtain 275 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 0,93 (d, J=6.4 Hz, 3H), of 1.02 (s, 9H), 3,81 (d, J=4,8 Hz, 1H), 3,91 (DCV, J=4,8, 6.0 Hz, 1H), 6,88-6,97 (m, 2H), 7,32-7,46 (m, 6H), EUR 7.57 (d, J=8.0 Hz, 2H), 7,55 (d, J=8.0 Hz, 2H).

Synthesis of (S)-1-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propylamino]propan-2-ol

A solution of (S)-(-)-propylene oxide (0.1 ml) and (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)Propylamine (212 what g) in diethyl ether (1 ml) was added to a suspension of lithium perchlorate (750 mg) in diethyl ether (1 ml) and the reaction solution was stirred in nitrogen atmosphere at room temperature overnight. Methylene chloride and ice water was added to the reaction solution. After stirring the reaction solution, the organic layer was separated. The aqueous layer was again extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate and then the solvent was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (ethyl acetate:heptane=9:1-4:1), to obtain 172 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): or 0.83 (d, J=6.0 Hz, 3H), of 1.06 (s, 9H), of 1.08 (m, 3H), 2,20-of 2.50 (m, 3H), 3,47 (users, 1H), 3,59 (users, 1H), 3,86 (users, 1H), 6,78-to 6.95 (m, 2H), was 7.36-of 7.48 (m, 6H), to 7.67 (d, J=6,8 Hz, 4H).

Synthesis of (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-2,3-dione

Oxalicacid (45 ml) was added dropwise to a solution of (S)-1-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propylamino]propan-2-ol (171 mg), TEA (0.17 ml) and 4-(N,N-dimethylamino)pyridine (8 mg) in methylene chloride (2 ml) under ice cooling in a nitrogen atmosphere and the reaction solution was stirred at the same temperature for two hours. Ice water was added to the reaction solution and then the mixture was extracted with ethyl acetate. Then the organic layer was sequentially washed with water, 1N. chloride-hydrogen acid, water, saturated sodium bicarbonate solution and saturated solution is m salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (heptane:ethyl acetate=9:1-3:1), to obtain 96 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): of 1.02 (s, 9H), 1,19 (d, J=6.0 Hz, 3H), of 1.28 (d, J=6.4 Hz, 3H), 3,20 (DD, J=5,6, 13,2 Hz, 1H), 3,68 (DD, J=2,4, 13,2 Hz, 1H), 4,42 (DCV, J=5,6, 6.0 Hz, 1H), 4,62 (ddcv, J=2,4, 5,6, 6.4 Hz, 1H), 5,51 (d, J=5.6 Hz, 1H), 6,82-6,94 (m, 2H), 7,40-rate of 7.54 (m, 6H), a 7.62 (d, J=8.0 Hz, 2H), to 7.67 (d, J=8.0 Hz, 2H).

Synthesis of (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]-2-hydroxy-6-methylmorpholin-3-one

The solution of the three-second-butylbromide lithium (1.06 mol) in THF (0.25 ml) was added dropwise to a solution of (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-2,3-dione (95 mg) in THF (3 ml) under nitrogen atmosphere at -20°C and the reaction solution was stirred at the same temperature for 30 minutes. 5h. A solution of sodium hydroxide (0,03 ml) and 30% aqueous hydrogen peroxide (0,07 ml) was added to the reaction solution which was then stirred under ice cooling for one hour. Then the powder of sodium bisulfite (20 mg) was added and the reaction solution was stirred at room temperature for 30 minutes. A saturated salt solution was added to the reaction solution and then was extracted with ethyl acetate. Organic is the cue layer was washed with saturated salt solution, was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (heptane:ethyl acetate=1:1), to obtain 93 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): a 1.01 (s, 9H), 1,11 (d, J=6.0 Hz, 3H), 1,19 (d, J=6.4 Hz, 3H), 2,88, and to 2.99 (DD, J=12,0, 12.0 Hz, 1H), 3,12 and of 3.48 (DD, J=2,4, 12.0 Hz, 1H), 3,16 and 3,91 (d, J=2,8 Hz, 1H), 4,35-4,55 (m, 2H), 5,11 and and 5.30 (d, J=3.6 Hz, 1H), 5.40 to and 5.49 (d, J=6,8 Hz, 1H), 6,79-6,94 (m, 2H), 7,38-rate of 7.54 (m, 6H), the 7.65 (d, J=8.0 Hz, 2H), 7,69 (d, J=8.0 Hz, 2H).

Synthesis of (Z)-(S)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

A solution of (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]-2-hydroxy-6-methylmorpholin-3-one (92 mg) and triphenylphosphorane (68 mg) in acetonitrile (4 ml) was heated at boiling under reflux in nitrogen atmosphere for one hour. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in ethanol (4 ml). To the resulting reaction solution was added 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde obtained in example 1 (40 mg), and TEA (0,12 ml) and the reaction solution was stirred in nitrogen atmosphere at room temperature overnight. The solvent is evaporated under reduced pressure. The obtained residue was dissolved in triperoxonane sour is e (1 ml) and the reaction solution was stirred at room temperature for two hours. The reaction solution was poured into a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution and then the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography using NH silica gel (heptane:ethyl acetate=1:1-0:1), obtaining 61,9 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,33 (d, J=6.0 Hz, 3H), of 1.42 (d, J=6.0 Hz, 3H), of 2.34 (s, 3H), 3,20 (DD, J=9,6, to 12.8 Hz, 1H), 3,61 (DD, J=2,4, of 12.8 Hz, 1H), 3,85 (s, 3H), 4,42-to 4.52 (m, 2H), 5,35 (d, J=6,8 Hz, 1H), 6,85 (s, 1H), to 6.95 (s, 1H), 7,06-to 7.15 (m, 2H), 7,22 (d, J=8.0 Hz, 1H), 7,33 (DD, J=1,6, 8.0 Hz, 1H), 7,53 (d, J=1.6 Hz, 1H), 7,86 (s, 1H).

ESI-MS; m/z 502[M++H].

Example 27

Synthesis of (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 42]

3,15 mg specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)Propylamine obtained in example 26 (280 mg), and isobutyramide (63 μl) as starting compounds according to the similar method of example 26.

1H-NMR (CDCl3) δ (ppm): 1.28 (in s, 3H), of 1.34 (d, J=6.0 Hz, 3H), of 1.47 (s, 3H), 2,31 (s, 3H)3,19 (d, J=12,8 Hz, 1H), 3,61 (d, J=12,8 Hz, 1H), 3,85 (s, 3H), 4, 46 (DCV, J=6,8, 6.0 Hz, 1H), of 5.40 (d, J=6,8 Hz, 1H), 6,91 (, 1H), 6,93 (s, 1H), 7,09-7,17 (m, 2H), 7,21 (d, J8,4 Hz, 1H), 7,32 (DD, J=1,6, and 8.4 Hz, 1H), 7,53 (d, J=1.6 Hz, 1H), to 7.77 (s, 1H).

ESI-MS; m/z 516[M++H].

Example 28

Synthesis of (Z)-4-[(R)-1-(4-forfinal)-2-hydroxyethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 43]

3,48 mg specified in the title compound was obtained from (R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)ethylamine (300 mg) and isobutyramide (101 μl) as starting compounds according to the similar method of example 26.

1H-NMR (CDCl3) δ (ppm): 1,25 (s, 3H), USD 1.43 (s, 3H), of 2.34 (s, 3H), 3,06 (d, J=12,8 Hz, 1H), 3,39 (d, J=12,8 Hz, 1H), 3,84 (s, 3H), 4,12-to 4.23 (m, 2H), by 5.87 (DD, J=6,0, 2.4 Hz, 1H), to 6.88 (s, 1H), 6,94 (s, 1H),? 7.04 baby mortality-to 7.09 (m, 2H), 7,19 (DD, J=8,4, 4.8 Hz, 1H), 7,29-7,34 (m, 3H), 7,52 (d, J=4,8 Hz, 1H), 7,92 (s, 1H).

ESI-MS; m/z 466[M++H].

Example 29

Synthesis of (Z)-(6R)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 44]

144 mg specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)Propylamine obtained in example 26 (500 mg)and (R)-(+)-propylene oxide (0,12 ml) as starting compounds according to the similar method of example 26.

1H-NMR (CDCl3) δ (ppm): 1,33 (d, J=6.4 Hz, 3H), of 1.42 (d, J=6.4 Hz, 3H), of 2.30 (s, 3H), of 3.25 (DD, J=of 12.8, 2.4 Hz, 1H), 3,62 (DD, J=12,8, 10,0 Hz, 1H), 3,84 (s, 3H), 4,19 (DDD, J=10,0, to 6.4, 2.4 Hz, 1H), 4,50 (TD, J=6,4, 6.0 Hz, 1H), 5,41 (d, J=6.0 Hz, 1H), 6,86 (s, 1H), 6,93 (s, 1H), 7,05-7,16 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,32 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,74 (s, 1H).

Example 30

Synthesis of (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one

[Formula 45]

Synthesis of ethyl[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propylamino]acetate

The cesium carbonate (242 mg) and ethylbromoacetate (103 μl) was added to a solution of (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)Propylamine obtained in example 26 (274 mg)in DMF (5 ml) and the reaction solution was stirred at room temperature for 11 hours. Ice water and ethyl acetate were added to the reaction solution and the organic layer was separated. The organic layer was sequentially washed polysystem salt solution and a saturated salt solution, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:diethyl ether=19:1), to obtain 190 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 0.75 in (d, J=6.4 Hz, 3H), of 1.09 (s, 9H), of 1.26 (t, J=7.2 Hz, 3H), 3,03 (d, J=16,8 Hz, 1H), 3,24 (d, J=16,8 Hz, 1H), 3,57 (d, J=6,8 Hz, 1H), 3,80-to 3.92 (m, 1H), 4,19 (kV, J=7.2 Hz, 2H), 6,88-6,98 (m, 2H), was 7.36-of 7.48 (m, 6H), to 7.67-to 7.77 (m, 4H).

Synthesis of 2-[(1R,2R)-2-tert-butyldiphenylsilyl is yloxy-1-(3,4,5-tryptophanyl)propylamino]ethanol

Borohydride lithium (20 mg) was added to a solution of ethyl[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propylamino]acetate (158 mg) in THF (3 ml) under nitrogen atmosphere and the reaction solution was stirred at room temperature for one day. A saturated solution of sodium sulfate was added to the reaction solution and then precipitated precipitated insoluble substance was removed by filtration through celite. Methanol was added to the filtrate and the solvent is then evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (heptane:ethyl acetate=4:1), to obtain 103 mg specified in the connection header.

ESI-MS: m/z 488[MH+].

Synthesis of 4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]morpholine-2,3-dione

A solution of 2-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propylamino]ethanol (102 mg) in diethyloxalate (2 ml) was stirred at 170°C for one hour and 30 minutes. Diethyloxalate evaporated under reduced pressure and the obtained residue was purified by chromatography on a column of silica gel (heptane:ethyl acetate=9:1 to 6:1), to obtain 48 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 0,99 (s, 9H), of 1.18 (d, J=6.0 Hz, 3H), 3,47 (DDD, J=14,0, 5,6, and 3.2 Hz, 1H), 3,83 (DDD, J=14,0, 8,0, 3.6 Hz, 1H), 4,27-4,43 (m, 3H), 5,54 (d, J=5,2 Hz, 1H), 6,80-of 6.90 (m, 2H), was 7.36-rate of 7.54 (m, 6H), a 7.62 (d, J=8.0 Hz, 2H), to 7.67 (d, J=8.0 Hz, 2H)./p>

Synthesis of (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one

18 mg specified in the title compound was obtained from 4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]morpholine-2,3-dione (47 mg) according to the similar method of example 26.

1H-NMR (CDCl3) δ (ppm): 1,33 (d, J=6.0 Hz, 3H), 2.40 a (s, 3H), 3,41 (DDD, J=13,2, of 6.4, 3.2 Hz, 1H), 3,81 (DDD, J=13,2, 7,2, 3.2 Hz, 1H), a 3.87 (s, 3H), 4,17 (DDD, J=11,2, 7,2, 3.2 Hz, 1H), 4,30 (DDD, J=11,2, of 6.4, 3.2 Hz, 1H), 4,51 (dt, J=6,4, 6.0 Hz, 1H), 5,42 (d, J=6,4 Hz, 1H), to 6.88 (s, 1H), 6,98 (s, 1H), 7,08-7,17 (m, 2H), 7.23 percent (d, J=8.0 Hz, 1H), 7,40 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,43 (d, J=1.6 Hz, 1H), 8,04 (s, 1H).

Example 31

Synthesis of (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one

[Formula 46]

Synthesis of (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4-differenl)Propylamine

lower than the 5.37 g specified in the title compound was obtained from 1-bromo-3,4-diferente (19 g) is similar to the method of example 26. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 0,86 (d, J=6.4 Hz, 3H), of 1.03 (s, 9H), 3,82 (d, J=6.0 Hz, 1H), 3,89 (DQC, J=6,4, 6.0 Hz, 1H), 6,95-7,13 (m, 3H), 7,32-7,44 (m, 6H), to 7.59 (DD, J=7,2, 2,8 Hz, 2H), 7,65 (DD, J=7,2, 2,8 Hz, 2H).

Synthesis of (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one

7.3 m is specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4-differenl)Propylamine (825 mg) according to the similar method of example 26. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,33 (d, J=6.4 Hz, 3H), to 2.29 (s, 3H), 3,38 (m, 1H), 3,76 (m, 1H), 3,84 (s, 3H), of 4.13 (m, 1H), 4,27 (m, 1H), 4,51 (DCV, J=7,6, 6.4 Hz, 1H), 5,44 (d, J=7,6 Hz, 1H), 6.87 in (s, 1H), 6,92 (s, 1H), 7,14-7,20 (m, 3H), 7,27-7,39 (m, 3H), of 7.70 (s, 1H).

Example 32

Synthesis of (Z)-(S)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 47]

Synthesis of (1R,2R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)Propylamine

113 mg specified in the title compound was obtained from 1-bromo-4-fervently similar to the method of example 26. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): or 0.83 (d, J=6.4 Hz, 3H), of 1.03 (s, 9H), 3,85 (d, J=6.0 Hz, 1H), 3,92 (DQC, J=6,4, 6.0 Hz, 1H), 6,92-6,97 (m, 2H), 7,21-7,25 (m, 2H), 7,31-the 7.43 (m, 6H), to 7.59 (DD, J=7,2, 2,8 Hz, 2H), 7,66 (DD, J=7,2, 2,8 Hz, 2H).

Synthesis of (Z)-(S)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)Propylamine according to the similar method of example 26. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,30 (d, J=6.0 Hz, 3H), 1,38 (d, J=6.4 Hz, 3H), to 2.29 (s, 3H), of 3.12 (DD, J=12,8, 10,0 Hz, 1H), 3,51 (DD, J=12,8, 2.8 Hz, 1H), 3,83 (s, 3H), 439-4,50 (m, 2H), 5,41 (d, J=7,6 Hz, 1H), 6,84 (s, 1H), 6,92 (s, 1H),? 7.04 baby mortality-was 7.08 (m, 2H), 7,19 (d, J=8.0 Hz, 1H), 7,30-7,38 (m, 3H), 7,50 (s, 1H), of 7.70 (s, 1H).

Example 33

Synthesis of (Z)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 48]

259 mg specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)Propylamine according to the similar method of example 27. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,20 (s, 3H), of 1.31 (d, J=6.0 Hz, 3H), USD 1.43 (s, 3H), to 2.29 (s, 3H)and 3.15 (d, J=12,8 Hz, 1H), 3,52 (d, J=12,8 Hz, 1H), 3,83 (s, 3H), 4,45 (DCV, J=8,8, 6.0 Hz, 1H), vs. 5.47 (d, J=8,8 Hz, 1H), 6.89 in (C, 1H), 6,91 (s, 1H), 7.03 is-was 7.08 (m, 2H), 7,18 (d, J=8.0 Hz, 1H), 7,30 (DD, J=8.0 a, and 1.6 Hz, 1H), was 7.36-7,40 (m, 2H), 7,52 (d, J=1.6 Hz, 1H), of 7.70 (s, 1H).

Example 34

Synthesis of (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 49]

198 mg specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4-differenl)Propylamine according to the similar method of example 26. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,32 (d, J=6.4 Hz, 3H), of 1.40 (d, J=6.0 Hz, 3H), to 2.29 (s, 3H), and 3.16 (DD, J=12,8, 10,0 Hz, 1H), of 3.56 (DD, J=12,8, 2.8 Hz, 1H), 3,83 (s, 3H), to 4.41-4,48 (m, 2H), 5,38 (d, J=7,6 Hz, 1H), 6,84 (s, 1H), 6,92 (1H), 7,11-7,20 (m, 3H), 7,26-to 7.32 (m, 2H), 7,50 (s, 1H), of 7.70 (s, 1H).

Example 35

Synthesis of (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(Mei-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 50]

172 mg specified in the title compound was obtained from (1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4-differenl)Propylamine according to the similar method of example 27. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,24 (s, 3H), of 1.33 (d, J=6.4 Hz, 3H), 1,45 (s, 3H), to 2.29 (s, 3H), 3,17 (d, J=12,8 Hz, 1H), of 3.56 (d, J=12,8 Hz, 1H), 3,84 (s, 3H), 4,45 (DCV, J=7,6, 6.4 Hz, 1H), 5,42 (d, J=7,6 Hz, 1H), 6.89 in (C, 1H), 6,91 (s, 1H), 7,14-7,20 (m, 3H), 7,27-to 7.32 (m, 2H), 7,52 (s, 1H), of 7.70 (s, 1H).

Example 36

Synthesis of (Z)-(S)-4-[(S)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 51]

2.2 mg specified in the title compound was obtained from (S)-4-[(S)-2-tert-butyldiphenylsilyl-1-methyl-1-(3,4,5-tryptophanyl)ethyl]morpholine-2,3-dione according to the similar method of example 26 using (R)-2-tert-butyldiphenylsilyl-1-methyl-1-(3,4,5-tryptophanyl)ethylamine obtained in accordance with a publication (for example, J. Org. Chem. 2001, 66, p.8778), as the source connection. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): ,43 (d, J=6.4 Hz, 3H), of 1.70 (s, 3H), 2,32 (s, 3H), 3,14 (m, 1H), 3,20 (m, 1H), and 3.72 (d, J=12,8 Hz, 1H), 3,86 (s, 3H), 4,14 (d, J=12,8 Hz, 1H), 4,33 (m, 1H), 6,79 (s, 1H), 6,95 (s, 1H), 6,95-7,01 (m, 2H), 7,22 (d, J=8.0 Hz, 1H), 7,34 (d, J=8.0 Hz, 1H), 7,50 (s, 1H), a 7.85 (s, 1H).

Example 37

Synthesis of (Z)-(6S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one

[Formula 52]

Synthesis of (R)-1-(3,4,5-tryptophanyl)ethanol

To a solution of (+)-DIP-chloride (11.8 g) in THF (200 ml), cooled to -30°C, was added dropwise 3,4,5-trifurcation (5.0 g) [CAS 220141-73-1] in nitrogen atmosphere. The reaction solution was stirred at the same temperature for five hours and at room temperature for one hour, and then the THF evaporated under reduced pressure. To a solution of the obtained residue in diethyl ether (150 ml) was added dropwise to 6.5 ml of diethanolamine and the reaction solution was stirred at room temperature overnight. Insoluble substances were removed by filtration and then the solvent evaporated. To the obtained residue was added hexane and the insoluble matter was again removed by filtration. The filtrate was purified by chromatography on a column of silica gel (heptane:ethyl acetate=19:1 to 4:1), obtaining of 3.69 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.8 Hz, 3H), 4,85 (kV, J=6,8, 1H), 6,98-7,05 (m, 2H).

Synthesis of 5-((S)-1-azidoethyl)-1,2,3-tripto the benzene

To a solution of (R)-1-(3,4,5-tryptophanyl)ethanol (3.6 g) and diphenylphosphoryl azide (6.0 ml) in toluene (70 ml) was added dropwise under ice cooling 1,8-diazabicyclo[5,4,0]undec-7-ene (4,1 ml). The reaction solution was stirred at the same temperature for one hour and at room temperature over night. Water was added to the reaction solution and the organic layer was separated. Then the aqueous layer was again extracted with toluene. The organic layers were combined and sequentially washed with 1N. chloride-hydrogen acid, water, saturated sodium bicarbonate solution and saturated salt solution. The organic layers were dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (heptane:ethyl acetate=49:1), obtaining 858 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,50 (d, J=6.8 Hz, 3H), 4,56 (kV, J=6,8, 1H), 6,92-7,01 (m, 2H).

Synthesis of (S)-1-(3,4,5-tryptophanyl)ethylamine

Triphenylphosphine (1.23 g) was added to a solution of 5-((S)-1-azidoethyl)-1,2,3-triterpenols (858 mg) in THF (20 ml) under nitrogen atmosphere and the reaction solution was stirred at room temperature for five minutes. Then water (2.5 ml) was added to the reaction solution which was then stirred at 60°C for 2.5 hours. The reaction solution was again brought the to room temperature and then was extracted with 2n. chloride-hydrogen acid (twice). Containing chloride-hydrogen acid extraction layer was washed with ethyl acetate and then podslushivaet 5h. the sodium hydroxide solution and then extracted with methylene chloride (two times). Methylenchloride layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, to obtain 348 mg specified in the connection header. Then perform the following operation to select specified in the title compound, remaining diluted with ethyl acetate, the reaction solution. Diethyl ether was added to the diluted solution and then the mixture was extracted with water. Water extraction layer was washed with diethyl ether and then podslushivaet 5h. the sodium hydroxide solution and then extracted with methylene chloride (two times). Methylenchloride layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining 413 mg specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,33 (d, J=6.4 Hz, 3H), 4,08 (kV, J=6,4, 1H), 6,95? 7.04 baby mortality (m, 2H).

Synthesis of (Z)-(6S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one

882 mg specified in the title compound was obtained from (S)-1-(3,4,5-tryptophanyl)ethylamine (1,15 g) and (S)-(-)-propylene oxide (0,46 ml) as starting compounds is s similar to the method of examples 18 and 19.

1H-NMR (CDCl3) δ (ppm): 1,40 (d, J=6.4 Hz, 3H), and 1.54 (d, J=7.2 Hz, 3H), to 2.29 (s, 3H), 2,96 (DD, J=12,8, and 5.6 Hz, 1H), 3,20 (DD, J=12,8, and 3.2 Hz, 1H), 3,85 (s, 3H), 4,30-and 4.40 (m, 1H), 6,04 (kV, J=7.2 Hz, 1H), to 6.88 (s, 1H), 6,92 (d, J=1.2 Hz, 1H), 6,92-7,00 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,33 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,50 (d, J=1.6 Hz, 1H), 7,86 (d, J=1.2 Hz, 1H).

Example 38

Synthesis of (Z)-(6S)-4-[1-(4-forfinal)-1-methylethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 53]

of 97.8 mg specified in the title compound was obtained from 1-(4-forfinal)-1-methylethylamine (500 mg) [CAS #17797-10-3] and (S)-(-)-propylene oxide (0,23 ml) as starting compounds according to the similar method of example 26.

1H-NMR (CDCl3) δ (ppm): 1,50 (d, J=6.0 Hz, 3H), of 1.76 (s, 3H), 1.77 in (s, 3H), of 2.28 (s, 3H), 3,49 (DD, J=13,2, 9.6 Hz, 1H), of 3.56 (DD, J=13,2, 2.8 Hz, 1H), 3,82 (s, 3H), of 4.38 (DTD, J=9,6, 6,0, 2.8 Hz, 1H), 6,66 (s, 1H), 6,91 (, 1H), 7,00 (DD, J=8,8, 8,8 Hz, 2H), 7,16 (d, J=8.0 Hz, 1H), 7.24 to 7,33 (m, 3H), 7,45 (d, J=1.2 Hz, 1H), 7,68 (d, J=1.6 Hz, 1H).

Example 39

Synthesis of (Z)-(6S)-4-[1-(4-forfinal)cyclopropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 54]

213 mg specified in the title compound was obtained from 1-(4-forfinal)cyclopropylamine (726 mg) [CAS #474709-83-6] and (S)-(-)-propylene oxide (0.4 ml) as starting compounds according to the similar method of example 26.

1H-NMR (CDCl3) δ (ppm): 1.30 and of 1.42 (m, 4H), of 1.44 (d, J=6.0 Hz, 3H), to 2.29 (s, 3H), 3,47 (the d, J=12,8, and 3.2 Hz, 1H), 3,53 (DD, J=12,8, 9.6 Hz, 1H), 3,84 (s, 3H), 4,33 (DTD, J=9,6, the 6.0, 3.2 Hz, 1H), PC 6.82 (s, 1H), 6,92 (d, J=1.2 Hz, 1H), 6,99 (DD, J=8,8, 8,8 Hz, 2H), 7,18 (d, J=8.0 Hz, 1H), 7,30 (DD, J=8,0, 2.0 Hz, 1H), 7,35 (DD, J=8,8, 5,2 Hz, 2H), 7,49 (d, J=2.0 Hz, 1H), 7,68 (d, J=1.2 Hz, 1H).

Example 40

Synthesis of (Z)-(6S,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-it

[Formula 55]

Synthesis of methyl (R)-2-tert-butoxycarbonylamino-6-oxo-6-(3,4,5-tryptophanyl)hexanoate

To a solution of 2-methyl ester 1-tert-butyl ether (R)-6-oxopiperidine-1,2-dicarboxylic acid (CAS No. 183890-36-0, 7.5 g) in THF (200 ml) was added dropwise at -40°C 3,4,5-tryptophansynthroid (0,35M solution in diethyl ether, 100 ml) and the reaction solution was stirred at room temperature for 6 hours. A saturated solution of ameriglide and ethyl acetate was added to the reaction solution and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane→heptane:ethyl acetate=1:1), to obtain 4.0 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 412[M++Na].

Synthesis of methyl (2R,6S)-6-(3,4,5-tryptophanyl)piperidine-2-carbox the lat

A solution of 4n. chloride-hydrogen acid in ethyl acetate (20 ml) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-oxo-6-(3,4,5-tryptophanyl)hexanoate (4.0 g) in ethyl acetate (20 ml) and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. Then added to the residue ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. To a solution of the obtained residue in ethyl acetate (50 ml) was added 10% palladium on carbon (100 mg) and the reaction solution was stirred in a stream of hydrogen at room temperature for 6 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 2.7 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 274[M++H].

Synthesis of [(2R,6S)-6-(3,4,5-tryptophanyl)piperidine-2-yl]methanol

LAH (75 mg) was added in three portions to a solution of methyl (2R,6S)-6-(3,4,5-tryptophanyl)piperidine-2-carboxylate (270 mg) in THF (5 ml) at -20°C for 15 minutes. The reaction solution was stirred at -20°C for one hour and was sequentially added water (0.1 ml), 5N. Rast is the PR of sodium hydroxide (0.1 ml) and water (0.3 ml). The mixture was heated to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, obtaining 242 mg specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 246[M++H].

Synthesis of (4R,6S)-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-c][1,4]oxazin-3,4-dione

A mixture of [(2R,6S)-6-(3,4,5-tryptophanyl)piperidine-2-yl]methanol (242 mg) diethyloxalate (1.3 ml) was heated and stirred at 120°C for one hour. The reaction solution was left to cool to room temperature and precipitated precipitated solid substance was separated by filtration. The obtained solid was washed with ether and dried in air, to obtain 228 mg specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,36 is 1.48 (m, 1H), 1,58-to 1.67 (m, 1H), 1.70 to to 1.87 (m, 2H), 2,10-of 2.24 (m, 2H), 4.09 to 4,18 (m, 1H), 4,37 (t, J=11,6 Hz, 1H), 4,43 (DD, J=11,6, 3.6 Hz, 1H), 5,19 (t, J=4.0 Hz, 1H), 6,82-of 6.90 (m, 2H).

Synthesis of (4R,6S)-3-hydroxy-6-(3,4,5-tryptophanyl)hydroxyacetamido[2,1-c][1,4]oxazin-4-it

1M solution of three-second-butylbromide lithium in THF (0,79 ml) was added dropwise to a solution of (4R,6S)-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-c][1,4]oxazin-3,4-dione (228 mg) in THF (10 ml) at -15°C and the reaction solution was stirred at -15°C for three hours. Posledovatelnosti to the reaction solution at -15°C for 5h. the sodium hydroxide solution (0.25 ml) and 20% aqueous hydrogen peroxide (0.05 ml). The reaction solution was left to cool to room temperature and was stirred for one hour. A solution of ethyl acetate and sodium sulfite was added to the reaction solution and the organic layer was separated. The obtained organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate), to obtain 240 mg specified in the connection header. The characteristic values of this compound is as follows:

ESI-MS: m/z 302[M++H].

Synthesis of (Z)-(6S,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]}-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-it

A solution of (4R,6S)-3-hydroxy-6-(3,4,5-tryptophanyl)hydroxyacetamido[2,1-c][1,4]oxazin-4-it (240 mg) and triphenylphosphine (328 mg) in acetonitrile (10 ml) was heated at boiling under reflux for one hour and then left to cool to room temperature. Was added to the reaction solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (172 mg) and triethylamine (0.33 ml) and the reaction solution was stirred at room temperature for 13 hours. The ethyl acetate and saturated the aqueous solution of sodium bicarbonate was added to the reaction solution and the organic layer was separated. The obtained organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1), with 1300 mg specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,38 is 1.58 (m, 2H), 1,66-of 1.84 (m, 2H), 2.06 to and 2.14 (m, 1H), 2,17-of 2.28 (m, 1H), 2,30 (s, 3H), 3,86 (s, 3H), Android 4.04 (t, J=10.0 Hz, 1H), 4,06-to 4.14 (m, 1H), 4,36 (userd, J=8,4 Hz, 1H), 5,26 (t, J=4.0 Hz, 1H), 6,83 (s, 1H), 6,86-6,93 (m, 2H), 6,94 (users, 1H), 7,21 (d, J=8.0 Hz, 1H), 7,38 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,39 (d, J=1.6 Hz, 1H), 7,73 (users, 1H).

Example 41

Synthesis of (Z)-(6S,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it

[Formula 56]

Synthesis of methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-differenl)-6-oxohexanoate

To a solution of 2-methyl ester 1-tert-butyl ether (R)-6-oxopiperidine-1,2-dicarboxylic acid (CAS No. 183890-36-0, 5.8 g) in THF (200 ml) was added dropwise at -40°C 3,4-differentialalgebraic (0.5m solution in THF, 50 ml) and the reaction solution was stirred at -40°C for seven hours. A saturated solution of ameriglide and ethyl acetate was added to the reaction solution and the mixture is load the Wali to room temperature. Then the organic layer was separated, the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane→heptane:ethyl acetate=1:1), obtaining 3.8 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 394[M++Na].

Synthesis of methyl (2R,6S)-6-(3,4-differenl)piperidine-2-carboxylate

A solution of 4n. chloride-hydrogen acid in ethyl acetate (20 ml) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-differenl)-6-oxohexanoate (3.8 g) in ethyl acetate (20 ml) and the reaction solution was stirred at room temperature for 5.5 hours. The reaction solution was concentrated under reduced pressure. Then ethyl acetate and saturated aqueous sodium bicarbonate solution was added to the residue and the organic layer was separated. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. To a solution of the obtained residue in methanol (20 ml) was added 10% palladium on carbon (50 mg) and the reaction solution was stirred in a stream of hydrogen at room temperature for two hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure, with the doctrine 2.1 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 256[M++H].

Synthesis of [(2R,6S)-6-(3,4-differenl)piperidine-2-yl]methanol

LAH (90 mg) was added in three portions to a solution of methyl (2R,6S)-6-(3,4-differenl)piperidine-2-carboxylate (300 mg) in THF (5 ml) at -15°C for 15 minutes. The reaction solution was stirred at -15°C for one hour and was sequentially added water (0.1 ml), 5N. a solution of sodium hydroxide (0.1 ml) and water (0.3 ml). The mixture was heated to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, to obtain 267 mg specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 228[M++H].

Synthesis of (4R,6S)-6-(3,4-differenl)hexahydropyrazino[2,1-c][1,4]oxazine-3,4-dione

A mixture of [(2R,6S)-6-(3,4-differenl)piperidine-2-yl]methanol (267 mg) diethyloxalate (1.6 ml) was heated and stirred at 120°C for one hour. The reaction solution was left to cool to room temperature and precipitated precipitated solid substance was separated by filtration. The obtained solid was washed with ether and dried in air, to obtain 192 mg specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.38 to 1.48 (m, 1H), 1.55V is 1.6 (m, 1H), 1,68 of-1.83 (m, 2H), 2,12 was 2.25 (m, 2H), 3,99-4,18 (m, 1H), 4,35 (t, J=11,6 Hz, 1H), 4,42 (DD, J=11,6, and 3.2 Hz, 1H), 5,27 (t, J=4.0 Hz, 1H), 6,94-6,99 (m, 1H), 7,01-7,07 (m, 1H), 7,10-7,17 (m, 1H).

Synthesis of (4R,6S)-6-(3,4-differenl)-3-hydroxyhexanoate[2,1-c][1,4]oxazin-4-it

1M solution of three-second-butylbromide lithium in THF (0,71 ml) was added dropwise to a solution of (4R,6S)-6-(3,4-differenl)hexahydropyrazino[2,1-c][1,4]oxazin-3,4-dione (192 mg) in THF (10 ml) at -15°C and the reaction solution was stirred at -15°C for three hours. Sequentially added to the reaction solution at -15°C for 5h. the sodium hydroxide solution (0.25 ml) and 20% aqueous hydrogen peroxide (0.05 ml). The reaction solution was left to cool to room temperature and was stirred for one hour. A solution of ethyl acetate and sodium sulfite was added to the reaction solution and the organic layer was separated. The obtained organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate), to obtain 151 mg specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 284[M++H].

Synthesis of (Z)-(6S,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]ox is Zin-4-it

A solution of (4R,6S)-6-(3,4-differenl)-3-hydroxyhexanoate[2,1-c][1,4]oxazin-4-it (151 mg) and triphenylphosphine (220 mg) in acetonitrile (7 ml) was heated at boiling under reflux for one hour and then left to cool to room temperature. To the reaction solution was added 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (115 mg) and triethylamine (0,22 ml) and the reaction solution was stirred at room temperature for 12 hours. The ethyl acetate and saturated aqueous sodium bicarbonate solution was added to the reaction solution and the organic layer was separated. The obtained organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate), to obtain 150 mg specified in the connection header. The characteristic values of the compounds are the following:

ESI-MS; m/z 466[M++H].

1H-NMR (CDCl3) δ (ppm): 1,38 is 1.58 (m, 2H), 1,66 and 1.80 (m, 2H), 2,10-of 2.28 (m, 2H), 2,30 (s, 3H), 3,85 (s, 3H), a 4.03 (t, J=10.4 Hz, 1H), 4,05-4,16 (m, 1H), 4,35 (DD, J=10,4, 2.0 Hz, 1H), 5,33 (t, J=4.0 Hz, 1H), PC 6.82 (s, 1H), 6,92 (users, 1H), 6,98-7,02 (m, 1H),? 7.04 baby mortality-7,16 (m, 2H), 7,20 (d, J=8.0 Hz, 1H), 7,35 (d, J=2.0 Hz, 1H), was 7.36 (DD, J=8,0, 2.0 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H).

Example 42

Synthesis of (Z)-(6S,9aR)-6-(2,6-differencein-3-yl-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it

[Formula 57]

Synthesis of methyl (R)-2-tert-butoxycarbonylamino-6-(2,6-differencein-3-yl)-6-oxohexanoate

LDA (1.5 m solution in THF, 3.2 ml) was added to a solution of 2,6-diphereline (492 mg) in THF (25 ml) at -78°C and the reaction solution was stirred at -78°C for 2.5 hours. A solution of 2-methyl ester 1-tert-butyl ether (R)-6-oxopiperidine-1,2-dicarboxylic acid (CAS No. 183890-36-0, 1.0 g) in THF (5 ml) was added to the reaction solution at -78°C. the Reaction solution was stirred at -78°C for one hour and at 0°C for 2.5 hours. A saturated solution of ameriglide and ethyl acetate was added to the reaction solution and the mixture was heated to room temperature. Then the organic layer was separated, the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane:ethyl acetate=1:1→ethyl acetate), to obtain 148 mg specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 395[M++Na].

Synthesis of (Z)-(6S,9aR)-6-(2,6-differencein-3-yl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]hexahydropyrazino[2,1-c][1,4]oxazin-4-it

18 mg specified in the title compound was obtained from methyl (R)-2-tert-butoxycarbonylamino-6(2,6-differencein-3-yl)-6-oxohexanoate (148 mg) according to the similar method of example 41. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,44-to 1.63 (m, 2H), 1,68-of 1.81 (m, 1H), 1.85 to was 1.94 (m, 1H), 2,09-of 2.27 (m, 2H), to 2.29 (s, 3H), of 3.84 (s, 3H), of 4.05 (t, J=10.0 Hz, 1H), 4,07-to 4.15 (m, 1H), 4,39 (userd, J=8,4 Hz, 1H), 5.25 in (t, J=5,2 Hz, 1H), 6,76 (s, 1H), 6,79 (DD, J=8.0 a, and 3.2 Hz, 1H), 6,92 (users, 1H), 7,19 (d, J=7,6 Hz, 1H), 7,35 (DD, J=7,6, and 1.6 Hz, 1H), was 7.36 (d, J=1.6 Hz, 1H), 7,70 (users, 1H), 7,73 (DD, J=17,2, 8.0 Hz, 1H).

Examples 43 and 44

Synthesis of (Z)-4-[(R)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one and (Z)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one

[Formula 58]

The racemate specified in the title compounds was obtained from 2,6-diphereline, aminoethanol and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde as starting compounds are analogous to the methods of another process for the synthesis of example 22. The resulting racemate was separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=6:4), obtaining specified in the title optically active compound with a retention time of 18 minutes (of 38.7 mg) and indicated in the title optically active compound with a retention time of 22 minutes, or 37.9 mg).

The characteristic values specified in the title optically active compound with a retention time of 18 min is t (example 43) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,68 (d, J=6.8 Hz, 3H), to 2.29 (s, 3H), 3,41-3,47 (m, 1H), 3,63-3,68 (m, 1H), 3,85 (s, 3H), 4,22-to 4.28 (m, 2H), 5,77 (kV, J=6,8 Hz, 1H), 6,83 (s, 1H), 6.87 in (DD, J=8,4, 2.8 Hz, 1H), 6,92 (s, 1H), 7,20 (d, J=8,4 Hz, 1H), 7,35 (d, J=8,4 Hz, 1H), 7,38 (s, 1H), 7,71 (s, 1H), 8,00 (DD, J=16,8, and 8.4 Hz, 1H).

The characteristic values specified in the title optically active compound with a retention time of 22 minutes (example 44) are as follows:

1H-NMR (CDCl3) δ (ppm): 1,68 (d, J=6.8 Hz, 3H), to 2.29 (s, 3H), 3,41-3,47 (m, 1H), 3,63-3,68 (m, 1H), 3,85 (s, 3H), 4,22-to 4.28 (m, 2H), 5,77 (kV, J=6,8 Hz, 1H), 6,83 (s, 1H), 6.87 in (DD, J=8,4, 2.8 Hz, 1H), 6,92 (s, 1H), 7,20 (d, J=8,4 Hz, 1H), 7,35 (d, J=8,4 Hz, 1H), 7,38 (s, 1H), 7,71 (s, 1H), 8,00 (DD, J=16,8, and 8.4 Hz, 1H).

Examples 45 and 46

Synthesis of (Z)-(S)-4-[(S)-1-(2-herperidin-5-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(2-herperidin-5-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 59]

Synthesis of 1-(6-herperidin-3-yl)ethylamine

1-(6-Herperidin-3-yl)alanon (7,8 g) was synthesized from 6-fornicating acid (10 g) according to the similar method of example 22. Specified in the title compound (457 mg) was obtained from 1-(6-herperidin-3-yl)ethanone (1,09 g). The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,40 (d, J=6.4 Hz, 3H), 4,21 (kV, J=6,4 Hz, 1H), 6.90 to (DD, J=3.2, and an 8.4 Hz, 1H), to 7.84 (m, 1H), 8,17 (d, J=0.8 Hz, 1H).

Synthesis of(Z)-(S)-4-[(S)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Diastereomer mixture specified in the title compound (48 mg) was obtained in the form of a crude product of 1-(6-herperidin-3-yl)ethylamine (457 mg) according to the similar method of example 22. The resulting mixture of diastereomers (45 mg) were separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=8:2), obtaining specified in the title optically active compound with a retention time of 57 minutes (20 mg) and indicated in the title optically active compound with a retention time of 63 minutes (6.8 mg).

Characteristic value diastereomeric mixture specified in the header of the compounds is as follows:

ESI-MS: m/z 437[M++H].

The characteristic values specified in the title optically active compound with a retention time of 57 minutes is the following:

1H-NMR (CDCl3) δ (ppm): 1,39 (d, J=6.4 Hz, 3H), of 1.62 (d, J=7,6 Hz, 3H), 2,30 (d, J=0.8 Hz, 3H), 2,95 (DD, J=9,6, to 12.8 Hz, 1H), 3,26 (DD, J=2,8, 13,2 Hz, 1H), 3,85 (s, 3H), 4,37 (m, 1H), 6,15 (kV, J=7.2 Hz, 1H), 6.89 in (C, 1H), 6,93 (s, 1H), of 6.96 (DD, J=2,8, and 8.4 Hz, 1H), 7,21 (d, J=8.0 Hz, 1H), 7,34 (m, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,72 (d, J=1.2 Hz, 1H), to 7.77 (m, 1H), 8,21 (DD, J=1,2, 1.2 Hz, 1H).

The characteristic values specified in the title optically active compound with a retention time of 63 minutes are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.4 Hz, 3H), of 1.61 (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), 2,99 (DD, J=2,8, and 12.4 Hz, 1H) 3,40 (DD, J=10,0, and 12.4 Hz, 1H), 3,86 (s, 3H), of 4.13 (m, 1H), 6,17 (kV, J=6,8 Hz, 1H), 6.89 in (s, 1H), 6,94 (s, 1H), of 6.96 (DD, J=2,8, 8,8 Hz, 1H), 7,21 (d, J=8,4 Hz, 1H), 7,34 (DD, J=1,6, and 8.4 Hz, 1H), 7,53 (d, J=1.6 Hz, 1H), 7,73 (d, J=1.2 Hz, 1H), 7,81 (m, 1H), they were 8.22 (d, J=1.6 Hz, 1H).

Examples 47 and 48

Synthesis of (Z)-(S)-4-[(S)-1-(2-herperidin-4-yl)ethyl]-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(2-herperidin-4-yl)ethyl]-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-6-methylmorpholin-3-one

[Formula 60]

Specified in the title compound was obtained as a mixture of diastereomers according to the similar procedure of example 22 1-(2-herperidin-4-yl)ethylamine obtained by the similar procedure of example 22. The connection is shared using a CHIRALCEL OD-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: system ethanol-hexane), to obtain specified in the title compound with a retention time of 23 minutes (example 47) and indicated in the title compound with a retention time of 26 minutes (example 48). The characteristic values specified in the header of the compound of example 47 are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.0 Hz, 3H), 1,60 (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), 3,03 (DD, J=12,4, and 9.2 Hz, 1H), 3,24 (DD, J=13,2, 2.8 Hz, 1H), 3,86 (s, 3H), 4,34 was 4.42 (m, 1H), 6,11 (t, J=7.2 Hz, 1H), 6.89 in (users, 1H), make 6.90 (s, 1H), 6,94 (users, 1H), 7,14 (userd, J=5,2 Hz, 1H), 7,22 (d, J=8.0 Hz, 1H), 7,35 (DD, J=8.0 a, and 1.6 Hz, 1H), 7,52 (d, J=1.6 Hz, 1H), 7,73 (d, J=1.2 Hz, 1H), 8,23 (d, J=5 Hz, 1H).

Examples 49 and 50

Synthesis of (Z)-(S)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 61]

Synthesis of 1-(5-herperidin-2-yl)ethanone

Iodide copper (811 mg), 1-ethoxyphenyl-n-botillo (19.2 ml) and bis(triphenylphosphine)palladium(II)chloride (1 g) was added to a solution of 2-bromo-5-herperidin (5 g) in acetonitrile (250 ml) and the reaction solution was heated and stirred under nitrogen atmosphere at 100°C for two hours. The reaction solution was again brought to room temperature and the solvent evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated solution of salt. The organic layer was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was diluted with acetone (120 ml) and the reaction solution was added (1S)-(+)-10-camphorsulfonic acid (9,9 g). After confirmation thin-layer chromatography of education of the target product, the solvent is evaporated under reduced pressure. The residue was diluted with ether and neutralized with sodium carbonate. Was added to the reaction solution, water and the separated organic solution. The organic layer was dried over sulfate is Agnes and the residue was purified by chromatography on a column of silica gel (carrier: Chromatorex; eluting solvent: hexane-ethyl acetate), to obtain 3.55 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): a 2.71 (s, 3H), 7,51 (m, 1H), 8,11 (DDD, J=0,4, 4,8, 8,8 Hz, 1H), 8,51 (d, J=2,8 Hz, 1H).

Synthesis of 1-(5-herperidin-2-yl)ethylamine

Specified in the title compound (483 mg) was obtained from 1-(5-herperidin-2-yl)ethanone (525 mg) according to the similar method of example 22. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.4 Hz, 3H), 4,18 (kV, J=6,4 Hz, 1H), 7,30-7,37 (m, 2H), to 8.41 (d, J=2.4 Hz, 1H).

Synthesis of (Z)-(S)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(S)-4-[(R)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Diastereomer mixture specified in the title compound (248 mg) was obtained in the form of a crude product of 1-(5-herperidin-2-yl)ethylamine (483 mg) according to the similar method of example 22. The resulting mixture of diastereomers (30 mg) were separated using a CHIRALPAKTMOD-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=8:2) and CHIRALPAKTMAD-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol)to obtain specified in the title optically active compound over time by keeping the of 23 minutes (1.7 mg) and indicated in the title optically active compound with a retention time of 27 minutes (3.9 mg).

Characteristic value diastereomeric mixture specified in the header of the compounds is as follows:

ESI-MS: m/z 437[M++H].

The characteristic values specified in the title optically active compound with a retention time of 23 minutes are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.37 (d, J=6.4 Hz, 3H), of 1.61 (d, J=7.2 Hz, 3H), to 2.29 (s, 3H), 3,17 (DD, J=1,2, 13,2 Hz, 1H), 3,52 (DD, J=2,8, 13,2 Hz, 1H), 3,84 (s, 3H), 4,37 (m, 1H), 6,06 (kV, J=6,4 Hz, 1H), 6,84 (s, 1H), 6,92 (s, 1H), 7,20 (d, J=8,4 Hz, 1H), 7,32 (m, 1H), 7,37-7,40 (m, 2H), 7,51 (d, J=1.2 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H), 8,42 (DD, J=1,2, 1.2 Hz, 1H).

The characteristic values specified in the title optically active compound with a retention time of 27 minutes are as follows:

1H-NMR (CDCl3) δ (ppm): USD 1.43 (d, J=6.8 Hz, 3H), 1,60 (d, J=7.2 Hz, 3H), to 2.29 (s, 3H), 3.43 points of 3.56 (m, 2H), 3,85 (s, 3H), 4,17 (m, 1H), 6,02 (kV, J=6,8 Hz, 1H), 6,83 (s, 1H), 6,93 (s, 1H), 7,20 (d, J=8.0 Hz, 1H), 7,32 (d, 1H), was 7.36-the 7.43 (m, 2H), 7,53 (d, J=1.6 Hz, 1H), 7,71 (d, J=1.2 Hz, 1H), to 8.41 (d, J=1.6 Hz, 1H).

Example 51

Synthesis of (Z)-(S)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 62]

Synthesis of 1-(2-chloropyridin-4-yl)ethanone

Specified in the header connection (7,18 g) was obtained from 2-chlorisondamine acid (8.5 g) is similar to the method of example 22. The characteristic values of the compounds are the following:

1H-NMR (CDCl ) δ (ppm): 2.63 in (s, 3H), 7,66 (m, 1H), to 7.77 (m, 1H), 8,59 (m, 1H).

Synthesis of (R)-1-(2-chloropyridin-4-yl)ethanol

A solution of 1-(2-chloropyridin-4-yl)ethanone (7,18 g) in tetrahydrofuran (10 ml) was added dropwise to a solution of (+)-DIP-chloride (19.2 g) in tetrahydrofuran (340 ml) at -20°C and the reaction solution was stirred at the same temperature throughout the night. The reaction solution was again brought to room temperature and the solvent evaporated under reduced pressure. The residue was diluted with ether, was added diethanolamine (12.1 g) and the reaction solution was stirred at room temperature for four hours. The insoluble matter was separated by filtration through celite and the mother liquor was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex, eluting solvent: heptane-ethyl acetate), obtaining specified in the connection header (of 3.84 g). The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,50 (d, J=6.8 Hz, 3H), of 4.90 (m, 1H), 7,21 (m, 1H), was 7.36 (m, 1H), 8.34 per (DD, J=0,4, and 5.2 Hz, 1H).

Synthesis of 4-((S)-1-azidoethyl)-2-chloropyridine

Diphenylphosphinite (6,57 ml) was added to a solution of (R)-1-(2-chloropyridin-4-yl)ethanol in toluene (50 ml) under nitrogen atmosphere and the reaction solution was cooled to 0°C. DBU (4.52 ml) was added to the reaction solution which was then heated to room so the temperature and was stirred overnight. Water and ether were added to the reaction solution and the organic layer was separated. The organic layer was dried over magnesium sulfate and the residue was purified by chromatography on silica gel (carrier: Chromatorex; eluting solvent: hexane-ethyl acetate), obtaining specified in the title compound (4.44 g). The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1.55V (d, J=6.8 Hz, 3H), to 4.62 (d, J=6,8 Hz, 1H), 7,18 (m, 1H), 7,30 (m, 1H), 8,39 (DD, J=0,4, and 5.2 Hz, 1H).

Synthesis of (S)-1-(2-chloropyridin-4-yl)ethylamine

Triphenylphosphine (of 9.56 g) was added to a solution of 4-((S)-1-azidoethyl)-2-chloropyridine (4.44 g) in a mixture of tetrahydrofuran-water (4:1, 50 ml), the reaction solution was heated and stirred at 60°C for two hours. The reaction solution was again brought to room temperature and the solvent evaporated under reduced pressure. Chloroform and 5h. chloride-hydrogen acid was added to the residue and the separated aqueous layer. The aqueous layer was podslushivaet 5h. the sodium hydroxide. Chloroform was added to the reaction solution and the organic layer was separated. The organic layer was dried over magnesium sulfate and the solvent evaporated under reduced pressure, to obtain specified in the title compound (2.24 g). The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.38 (d, J=6.8 Hz, 3H), of 4.12 (d, J=6,8 Hz, 1H), was 7.36 (m, 1H), and 7.3 (m, 1H), 8,31 (d, J=5,2 Hz, 1H).

Synthesis of (Z)-(S) - 4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Specified in the title compound, containing the geometric isomer (518 mg)was obtained from (S)-1-(2-chloropyridin-4-yl)ethylamine (1.25 g) are analogous to the methods of examples 18 and 19. The resulting mixture (54 mg) were separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3), obtaining specified in the connection header with the retention time of 38 minutes (6.5 mg). The characteristic values of the compounds are as follows.

The characteristic values specified in the title optically active compound with a retention time of 38 minutes is the following:

ESI-MS; m/z 453[M++H].

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.8 Hz, 3H), of 1.59 (d, J=7.2 Hz, 3H), 2,30 (d, J=0.8 Hz, 3H), to 3.02 (DD, J=9,6, to 12.8 Hz, 1H), 3,23 (DD, J=2,4, 13,2 Hz, 1H), 3,85 (s, 3H), 4,36 (m, 1H), 6,07 (kV, J=7.2 Hz, 1H), 6.90 to (C, 1H), 6,94 (DD, J=1,2, 1.2 Hz, 1H), 7,17 (m, 1H), 7,22 (d, J=8.0 Hz, 1H), 7,28 (m, 1H), was 7.36 (m, 1H), 7,52 (d, J=1.2 Hz, 1H), 7,73 (d, J=1.2 Hz, 1H), 8,39 (DD, J=0,8, 5,2 Hz, 1H).

Example 52

Synthesis of (Z)-(S)-4-[(S)-1-(2-chloro-3-herperidin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 63]

Synthesis of 2-chloro-3-personication acid

Specified in the header connection (6,34 g) which was alocale from 2-chloro-3-herperidin (5 g) according to the similar method of example 22. The characteristic values of the compounds are the following:

1H-NMR (DMSO-d6) δ (ppm): 7,78 (DD, J=4,8, and 4.8 Hz, 1H), 8,27 (d, J=4,8 Hz, 1H).

Synthesis of (S)-1-(2-chloro-3-herperidin-4-yl)ethylamine

Specified in the title compound (3.13 g) was obtained from 2-chloro-3-personication acid (6,34 g) according to the similar method of example 51. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.8 Hz, 3H), of 4.45 (q, J=6,8 Hz, 1H), 7,40 (DDD, J=0,4, to 4.8, 4.8 Hz, 1H), 8,18 (d, J=4,8 Hz, 1H).

Synthesis of (Z)-(S)-4-[(S)-1-(2-chloro-3-herperidin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

Specified in the title compound, containing the geometric isomer (623 mg)was obtained from (S)-1-(2-chloro-3-herperidin-4-yl)ethylamine (1.2 g) are analogous to the methods of examples 18 and 19. The resulting mixture (14 mg) were separated using a CHIRALPAKTMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1), obtaining specified in the title compound with a retention time of 24 minutes (9.5 mg). The characteristic values of the compounds are the following:

ESI-MS; m/z 471[M++H].

1H-NMR (CDCl3) δ (ppm): of 1.46 (d, J=6.4 Hz, 3H), 1,67 (d, J=7.2 Hz, 3H), to 2.29 (s, 3H), 3,23 (DD, J=9,6, and 12.4 Hz, 1H), 3,41 (DD, J=2,4, of 12.8 Hz, 1H), 3,85 (s, 3H), of 4.38 (m, 1H), by 5.87 (q, J=7.2 Hz, 1H), 6,83 (s, 1H), 6,93 (s, 1H), 7,20 (d, J=8,4 Hz, 1H), 7,30-7,33 (m, 2H), 7,50 (d, J=1.2 Hz, 1H), 7,72 (s, 1H), 8,23 (d, J=5,2 Hz, 1H).

Example 53

Synthesis of (Z)-(S)-4-[(S)-1-(2,6-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 64]

Specified in the title compound was obtained according to a similar procedure of examples 18 and 19 of (S)-1-(2,6-differencein-4-yl)ethylamine obtained by the similar procedure of example 51.

ESI-MS; m/z 455[M++H].

1H-NMR (CDCl3) δ (ppm): 1,44 (d, J=6.4 Hz, 3H), of 1.61 (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), to 3.09 (DD, J=9,2, to 12.8 Hz, 1H), 3.27 to (DD, J=2,4, of 12.8 Hz, 1H), 3,86 (s, 3H), 4,34-of 4.44 (m, 1H), 6,09 (kV, J=7.2 Hz, 1H), 6,78 (s, 2H), make 6.90 (s, 1H), 6,94 (s, 1H), 7,22 (d, J=8.0 Hz, 1H), 7,35 (d, J=8.0 Hz, 1H), 7,52 (s, 1H), 7,72 (s, 1H).

Example 54

Synthesis of (Z)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 65]

Synthesis of 4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-6,6-dimethylmorpholine-2,3-dione

The lithium perchlorate (10.2 g) was added to a solution of (S)-1-(2-chloropyridin-4-yl)ethylamine obtained in example 51 (1 g)in ether (18.5 ml) and the reaction solution was stirred for five minutes. Isobutylene (1.7 ml) was added to the reaction solution which was then stirred overnight. Was added to the reaction solution at 0°C for 5h. the sodium hydroxide solution and then the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and dissolve Italy evaporated under reduced pressure. Dichloromethane (20 ml) and pyridine (20 ml) was added to the residue and the reaction solution was cooled to 0°C. Oxalicacid (669 μl) was added to the reaction solution which was then stirred at 0°C for one hour and at room temperature for one hour. Oxalicacid (0.4 ml) was added to the reaction solution, which was further stirred for one hour. The solvent is evaporated under reduced pressure. Water and ethyl acetate were added to the residue and the organic layer was separated. The organic layer was dried over magnesium sulfate and the residue was purified by chromatography on a column of silica gel (Chromatorex; eluting solvent: heptane-ethyl acetate), obtaining specified in the title compound (1.07 g). The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,31 (s, 3H), 1,49 (s, 3H), of 1.59 (d, J=7.2 Hz, 3H), 3,05 (d, J=13,6, 1H), 3,35 (d, J=14,0 Hz, 1H), 5,97 (kV, J=7.2 Hz, 1H), 7,21 (DDD, J=0.8, the 1,2, and 5.2 Hz, 1H), 7,30 (DD, J=0,8, 0.8 Hz, 1H), 8,42 (d, J=5,2 Hz, 1H).

Synthesis of (Z)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Specified in the title compound, containing the geometric isomer (1,33 g), was obtained from 4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-6,6-dimethylmorpholine-2,3-dione (1.07 g) are analogous to the methods of examples 18 and 19. The resulting mixture (56 mg) were separated using a CHIRALPAKTMIA is produced in the production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3), obtaining specified in the connection header with a retention time of 36 minutes (13 mg). The characteristic values of the compounds are the following:

ESI-MS; m/z 467[M++H].

1H-NMR (CDCl3) δ (ppm): 1,31 (s, 3H), of 1.46 (s, 3H), of 1.57 (d, J=7.2 Hz, 3H), of 2.30 (s, 3H), 2.95 points (d, J=12,8 Hz, 1H), 3,29 (d, J=12,8 Hz, 1H), 3,86 (s, 3H), 6,13 (kV, J=7.2 Hz, 1H), 6,93 (DD, J=1,2, 1.2 Hz, 1H), 6,94 (s, 1H), 7,20-of 7.23 (m, 2H), 7,31 (DD, J=0,8, 0.8 Hz, 1H), 7,35 (DD, J=1,6, 8.0 Hz, 1H), 7,53 (d, J=1.6 Hz, 1H), 7,72 (d, J=1.2 Hz, 1H), 8,40 (d, J=4,8 Hz, 1H).

Example 55

Synthesis of (Z)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 66]

Synthesis of (S)-1-(2,6-differencein-3-yl)ethylamine

Specified in the header connection (9,36 g) was obtained from 2,6-diphereline (15 g) according to the similar procedure of example 52. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,40 (d, J=6.8 Hz, 3H), 4,37 (kV, J=6,8 Hz, 1H), for 6.81 (DD, J=2,8, 8.0 Hz, 1H), 8,02 (DD, J=8,0, 8.0 Hz, 1H).

Synthesis of (Z)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Specified in the title compound, containing the geometric isomer (422 mg)was obtained from (S)-1-(2,6-differencein-3-yl)ethylamine (500 mg) according to the similar procedure of examples 18 and 19. Poluchenno the mixture (10 mg) were separated using a CHIRALPAK TMIA production F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3), obtaining specified in the connection header with a retention time of 28 minutes (6.8 mg). The characteristic values of the compounds are the following:

ESI-MS; m/z 469[M++H].

1H-NMR (CDCl3) δ (ppm): to 1.35 (s, 3H), of 1.46 (s, 3H), of 1.65 (d, J=7.2 Hz, 3H), 2,30 (d, J=0.8 Hz, 3H), 3,20 (d, J=12,8 Hz, 1H), 3.43 points (d, J=12,4 Hz, 1H), 3,84 (s, 3H), 5,86 (kV, J=7.2 Hz, 1H), 6,86 (s, 1H), to 6.88 (DD, J=2,8, and 8.4 Hz, 1H), 6,92 (m, 1H), 7,19 (d, J=8,4 Hz, 1H), 7,31 (DD, J=2.0 a, and 8.4 Hz, 1H), 7,51 (d, J=1.6 Hz, 1H), 7,71 (d, J=1.6 Hz, 1H), 8,01 (DD, J=8.0 a, and 9.2 Hz, 1H).

Example 56

Synthesis of (Z)-4-[(S)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 67]

Synthesis of (S)-1-(6-herperidin-3-yl)ethylamine

Specified in the header connection (3,95 g) was obtained from 6-fornicating acid (10 g) according to the similar procedure of example 52. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,40 (d, J=6.4 Hz, 3H), 4,21 (kV, J=6,4 Hz, 1H), 6.90 to (DD, J=3.2, and an 8.4 Hz, 1H), to 7.84 (m, 1H), 8,17 (d, J=0.8 Hz, 1H).

Synthesis of (Z)-4-[(S)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Specified in the title compound, containing the geometric isomer (1,02 g), was obtained from (S)-1-(6-herperidin-3-yl)ethylamine (500 mg) by similar methods the examples 18 and 19. The resulting mixture (1.01 g) was recrystallized from a mixture of ethyl acetate/ether, to obtain specified in the title optically active compound (120 mg). The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): of 1.23 (s, 3H), 1,45 (s, 3H), of 1.61 (d, J=7.2 Hz, 1H), 2,30 (s, 3H), of 2.92 (d, J=12,8 Hz, 1H), 3,32 (d, J=12,4 Hz, 1H), 3,85 (s, 3H), 6,21 (kV, J=7.2 Hz, 1H), 6,92-6,97 (m, 3H), 7,21 (d, J=8.0 Hz, 1H), 7,33 (DD, J=0,8, 8.0 Hz, 1H), 7,52 (d, J=1.2 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H), 7,81 (m, 1H), they were 8.22 (s, 1H).

Example 57

Synthesis of (Z)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 68]

Synthesis of (S)-1-(6-chloropyridin-3-yl)ethylamine

Specified in the header of the connection (? 7.04 baby mortality g) was obtained from 6-chloronicotinic acid (13 g) is similar to the method of example 52. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,39 (d, J=6.4 Hz, 3H), 4,19 (kV, J=6,4 Hz, 1H), 7,29 (d, J=8.0 Hz, 1H), of 7.70 (DD, J=2,4, 8.0 Hz, 1H), at 8.36 (d, J=2.4 Hz, 1H).

Synthesis of (Z)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Specified in the title compound containing a geometric isomer, was obtained from (S)-1-(6-chloropyridin-3-yl)ethylamine (600 mg) according to the similar procedure of examples 18 and 19, and was stirred solution of the mixture triperoxonane acid/chlorof the RM/4h. chloride-hydrogen acid (5/5/2) in ethyl acetate for four hours, for the isomerization of E-isomer Z-isomer. The reaction solution was neutralized 5h. NaOH solution and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (Chromatorex NH; heptane/ethyl acetate→ethyl acetate/methanol), to obtain the specified title compound (251 mg).

1H-NMR (CDCl3) δ (ppm): 1,24 (s, 3H), 1,45 (s, 3H), 1,60 (d, J=7.2 Hz, 1H), 2,30 (s, 3H), of 2.92 (d, J=12,4 Hz, 1H), 3,30 (d, J=12,4 Hz, 1H), 3,85 (s, 3H), to 6.19 (q, J=7.2 Hz, 1H), 6,92 s, 1H), 6,93 (d, J=3.2 Hz, 1H), then 7.20 (d, J=8,4 Hz, 1H), 7,32 and 7.36 (m, 2H), 7,52 (s, 1H), 7,68 (DD, J=2,4, and 8.4 Hz, 1H), 7,71 (d, J=0.8 Hz, 1H), 8,40 (d, J=2.4 Hz, 1H).

Example 58

Synthesis of (Z)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 69]

Synthesis of (S)-1-(2,3-differencein-4-yl)ethylamine

Specified in the header connection (7,09 g) was obtained from 2,3-depersonification acid (16.6 g), which is a known compound (see, for example, The Journal of Organic Chemistry, 2005, vol.70, p.3039-3045), similar to the method of example 52. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.4 Hz, 3H), 4,49 (kV, J=6,4 Hz, 1H), 7,32 (DD, J=4,8, and 4.8 Hz, 1H), to 7.93 (d, J=4,8 Hz, 1).

Synthesis of (Z)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Specified in the title compound containing a geometric isomer, was obtained from (S)-1-(2,3-differencein-4-yl)ethylamine (1 g) are analogous to the methods of examples 18 and 19 and isomerically similar to the method of example 57, obtaining specified in the title compound (830 mg). The characteristic values of the compounds are the following:

ESI-MS; m/z 469[M++H].

1H-NMR (CDCl3) δ (ppm): to 1.37 (s, 3H), of 1.47 (s, 3H), of 1.65 (d, J=7.2 Hz, 1H), 2,30 (s, 3H), 3,18 (d, J=12,4 Hz, 1H), 3,42 (d, J=12,4 Hz, 1H), 3,85 (s, 3H), 6,04 (kV, J=7.2 Hz, 1H), to 6.88 (s, 1H), 6,93 (s, 1H), 7,20 (d, J=8,4 Hz, 1H), 7.23 percent-7,33 (m, 2H), 7,51 (s, 1H), 7,71 (s, 1H), 8,00 (d, J=3.2 Hz, 1H).

Example 59

Synthesis of (Z)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 70]

Synthesis of (S)-1-(5-herperidin-2-yl)ethylamine

Specified in the title compound (1.23 g) was obtained from 1-(5-herperidin-2-yl)ethanone described in example 49 (3,05 g), similar to the method of example 52. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.4 Hz, 3H), 4,17 (kV, J=6,4 Hz, 1H), 7,30-7,39 (m, 1H), 8,40 (d, J=2.4 Hz, 1H).

Synthesis of (Z)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methyl is den]-6,6-dimethylmorpholine-3-one

Specified in the title compound containing a geometric isomer, was obtained from (S)-1-(5-herperidin-2-yl)ethylamine (700 mg) according to the similar procedure of examples 18 and 19 and isomerically similar to the method of example 57, obtaining specified in the title compound (640 mg). The characteristic values of the compounds are the following:

ESI-MS; m/z 451[M++H].

1H-NMR (CDCl3) δ (ppm): to 1.16 (s, 3H), of 1.46 (s, 3H), of 1.59 (d, J=6,8 Hz, 1H), to 2.29 (s, 3H), 3,34 (d, J=12,8 Hz, 1H), 3,47 (d, J=12,8 Hz, 1H), 3,84 (s, 3H), 6,10 (kV, J=7.2 Hz, 1H), 6,86 (s, 1H), 6,92 (DD, J=1,2, 1.2 Hz, 1H), 7,19 (d, J=8,4 Hz, 1H), 7,31 (DD, J=2.0 a, and 8.4 Hz, 1H), was 7.36-7,46 (m, 2H), 7,53 (d, J=2,8 Hz, 1H), of 7.70 (m, 1H), to 8.41 (d, J=2,8 Hz, 1H).

Example 60

Synthesis of (Z)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 71]

Synthesis of (S)-1-(5-chloropyridin-2-yl)ethylamine

Specified in the header connection (2,72 g) was obtained from 1-(5-chloropyridin-2-yl)ethanone described in example 20 (4,29 g), similar to the method of example 52. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.4 Hz, 3H), 4,17 (kV, J=6,4 Hz, 1H), 7,30-7,39 (m, 1H), 8,40 (d, J=2.4 Hz, 1H).

Synthesis of (Z)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

Specified in the title compound containing geometrician is ical isomer, received from (S)-1-(5-chloropyridin-2-yl)ethylamine (1 g) are analogous to the methods of examples 18 and 19 and isomerically similar to the method of example 57, obtaining specified in the title compound (310 mg). The characteristic values of the compounds are the following:

ESI-MS; m/z 467[M++H].

1H-NMR (CDCl3) δ (ppm): 1,19 (s, 3H), of 1.46 (s, 3H), of 1.59 (d, J=6,8 Hz, 1H), to 2.29 (s, 3H), 3,35 (d, J=12,8 Hz, 1H), 3,48 (d, J=12,8 Hz, 1H), 3,84 (s, 3H), between 6.08 (kV, J=6,8 Hz, 1H), 6,86 (s, 1H), 6,92 (s, 1H), 7,19 (d, J=8.0 Hz, 1H), 7,31 (d, J=8,4 Hz, 1H), 7,38 (d, J=8.0 Hz, 1H), 7,53 (s, 1H), 7,66 (DD, J=1,6, and 8.4, 1H), of 7.70 (s, 1H), 8,51 (d, J=2.0 Hz, 1H).

The compounds in tables 1-1 and 1-2 was obtained by a similar method.

Table 1-1

Table 1-2

Example 65

Synthesis of (Z)-(S)-4-(4-terbisil)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 72]

9,06 mg specified in the title compound was obtained from (S)-4-(4-terbisil)-2-hydroxy-6-methylmorpholin-3-one, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde for a similar method of example 5.

1H-NMR (CDCl3) δ (ppm): 1,44 (d, J=6.8 Hz, 3H), of 2.38 (s, 3H), 3,26 (DD, J=12,8, and 3.2 Hz, 1H), 3,43 (DD, J=12,8, 9.6 Hz, 1H), 4,32-and 4.40 (m, 1H), to 4.62 (d, J=14.4 Hz, 1H), 4,73 (d, J=14.4 Hz, 1H), 6.87 in (s, 1H), 7,01-to 7.09 (m, 3H), 7,27-7,35 (m, 3H), 7,50 (d, J=8,4 Hz, 1H), to 7.77 (d, J=12,8 Hz, 1H), of 7.96 (s, 1H).

Example 66

Synthesis of (Z)-2-[1-[3-fluoro-4-(4-shall ethyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(4-tryptophanyl)ethyl]-6,6-dimethylmorpholine-3-one

[Formula 73]

31,55 mg specified in the title compound was obtained from 4-[(S)-1-(4-forfinal)ethyl]-2-hydroxy-6,6-dimethylmorpholine-3-one, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde for a similar method of example 7.

1H-NMR (CDCl3) δ (ppm): 1,20 (s, 3H), USD 1.43 (s, 3H), of 1.55 (d, J=6.8 Hz, 3H), of 2.34 (s, 3H), 2,90 (d, J=12,8 Hz, 1H), 3,24 (d, J=12,8 Hz, 1H), 6,16 (kV, J=6,8 Hz, 1H), 6.87 in (s, 1H), 7,00 (s, 1H),? 7.04 baby mortality-was 7.08 (m, 2H), 7,28-of 7.36 (m, 3H), 7,47 (DD, J=8,4, and 1.6 Hz, 1H), 7,74 (DD, J=12,8, and 1.6 Hz, 1H), a 7.85 (s, 1H).

Example 67

Synthesis of (Z)-4-(4-terbisil)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethyl morpholine-3-one

[Formula 74]

to 44.7 mg specified in the title compound was obtained from 4-(4-terbisil)-2-hydroxy-6,6-dimethylmorpholine-3-one, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde for a similar method of example 7.

1H-NMR (CDCl3) δ (ppm): of 1.39 (s, 6H), 2.57 m (s, 3H), at 3.35 (s, 2H), 4,67 (s, 2H), 6.89 in (s, 1H), 7.03 is-was 7.08 (m, 2H), 7,13 (s, 1H), 7,29-7,33 (m, 2H), 7,41 (DD, J=8,0, 8.0 Hz, 1H), EUR 7.57 (d, J=8.0 Hz, 1H), 7,82 (d, J=12,8 Hz, 1H), to 8.70 (s, 1H).

Example 68

Synthesis of (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 75]

to 25.4 mg specified in the title compound was obtained from 4-[(S)-chroman-4-yl]-2-hydroxy-6,6-dimethylmorpholine-3-one, trif is selfoperated and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde for a similar method of example 12.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (s, 3H), 1,45 (s, 3H), 2,14-of 2.21 (m, 2H), 2,34 (s, 3H), 3,12 (d, J=13,2 Hz, 1H), 3,19 (d, J=13,2 Hz, 1H), 4,23-to 4.33 (m, 2H), 6,11 (t, J=7.2 Hz, 1H), 6,86-to 6.95 (m, 3H), 7,01 (s, 1H), 7,09 (d, J=8.0 Hz, 1H), 7,20 (t, J=8.0 Hz, 1H), 7,32 (t, J=8.0 Hz, 1H), 7,49 (d, J=8.0 Hz, 1H), 7,76 (DD, J=12,8, 1.2 Hz, 1H), 7,82 (s, 1H).

Examples 69 and 70

Synthesis of (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one and (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 76]

66,4 mg specified in the title compound was obtained as a mixture of diastereomers of 4-[(S)-chroman-4-yl]-2-hydroxy-6-methylmorpholin-3-one, triphenylphosphorane and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde as starting compounds are analogous to the methods of examples 12, 13 and 14. The mixture was separated using a CHIRALPAKTMAD-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol 100%), obtaining specified in the title optically active compound with a retention time of 20 minutes (>99% de) and indicated in the title optically active compound with a retention time of 24 minutes (>99% de).

The characteristic values specified in the title optically active compound with a retention time of 20 minutes (example 69) are as follows:

1H-NMR (CDCl3) δ (ppm): USD 1.43 (d, J=6.0 Hz, 3H), 2,14-of 2.24 (m, 2H), 2,35 (s, 3H, of 3.12-3.15 in (m, 2H), 4,24-to 4.38 (m, 3H), equal to 6.05 (DD, J=8,8, 6.4 Hz, 1H), 6,86-6,89 (m, 2H), 6,93 (t, J=7.2 Hz, 1H), 7,01-7,07 (m, 2H), 7,20 (t, J=8.0 Hz, 1H), 7,33 (t, J=8.0 Hz, 1H), 7,51 (d, J=8.0 Hz, 1H), 7,78 (d, J=12,8 Hz, 1H), 7,87 (s, 1H).

The characteristic values specified in the title optically active compound with a retention time of 24 minutes (example 70) are as follows:

1H-NMR (CDCl3) δ (ppm): to 1.42 (d, J=6.0 Hz, 3H), 2,14-of 2.20 (m, 2H), a 2.36 (s, 3H), 3,10 (DD, J=of 12.8, 2.4 Hz, 1H), 3,32 (DD, J=12,8, 10,0 Hz, 1H), 4,24-4,37 (m, 3H), 6,13 (t, J=8,4 Hz, 1H), 6,86-6,94 (m, 3H), 7,02-7,07 (m, 2H), 7,20 (t, J=8,4 Hz, 1H), 7,33 (t, J=8,4 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,78 (DD, J=12,8, 1.2 Hz, 1H), 7,89 (s, 1H).

Example 71

Synthesis of (Z)-(S)-4-(6-chloropyridin-2-ylmethyl)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 77]

24,3 mg specified in the title compound was obtained from (S)-4-(6-chloropyridin-2-ylmethyl)-2-hydroxy-6-methylmorpholin-3-one, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde for a similar method of example 15.

1H-NMR (CDCl3) δ (ppm): 1,48 (d, J=6.0 Hz, 3H), of 2.33 (s, 3H)and 3.59 (DD, J=12,8, 2.8 Hz, 1H), 3,68 (DD, J=12,8, 9.6 Hz, 1H), 4,43-4,47 (m, 1H), 4,73 (d, J=14,8 Hz, 1H), 4,78 (d, J=14,8 Hz, 1H), PC 6.82 (s, 1H), 7,00 (s, 1H), 7,26-7,33 (m, 3H), 7,47 (DD, J=8,4, and 1.6 Hz, 1H), 7,66 (DD, J=8,0, 8.0 Hz, 1H), of 7.75 (DD, J=12,8, and 1.6 Hz, 1H), 7,80 (s, 1H).

Example 72

Synthesis of (Z)-(S)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 78]

p>

Specified in the title compound (11.6 mg) was obtained from 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde as a starting compound according to a similar procedure of examples 18 and 19.

1H-NMR (CDCl3) δ (ppm): 1,40 (d, J=6.4 Hz, 3H), of 1.62 (d, J=7.2 Hz, 3H), 2,31 (s, 3H), 2,95 (DD, J=12,8, and 9.2 Hz, 1H), or 3.28 (DD, J=12,8, 2.8 Hz, 1H), 4,35-to 4.41 (m, 1H), 6,12 (kV, J=7.2 Hz, 1H), 6,85 (s, 1H), 6,99 (s, 1H), 7,31 (t, J=8,4 Hz, 1H), 7,34 (d, J=8,4 Hz, 1H), 7,46 (DD, J=8,4, 2.0 Hz, 1H), 7,63 (DD, J=8,4, 2.4 Hz, 1H), 7,72 (DD, J=13,2, 2.0 Hz, 1H), 7,74 (s, 1H), scored 8.38 (d, J=2.4 Hz, 1H).

Example 73

Synthesis of (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 79]

Specified in the title compound (11.2 mg) was obtained from 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde as a starting compound according to a similar method of another process for the synthesis of example 22.

1H-NMR (CDCl3) δ (ppm): 1,45 (d, J=6.4 Hz, 3H), 1,67 (d, J=6.8 Hz, 3H), of 2.30 (s, 3H), up 3.22 (DD, J=12,8, and 5.2 Hz, 1H), 3,44 (DD, J=12,8, and 3.2 Hz, 1H), 4,34 was 4.42 (m, 1H), 5,73 (kV, J=6,8 Hz, 1H), 6,76 (s, 1H), 6.87 in (DD, J=8,0, and 3.2 Hz, 1H), 6,97 (s, 1H), 7,29 (d, J=8.0 Hz, 1H), 7,42 (d, J=8.0 Hz, 1H), of 7.70 (d, J=11.2 Hz, 1H), of 7.75 (s, 1H), to 7.99 (DD, J=16,0, 8.0 Hz, 1H).

Example 74

Synthesis of (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-3-one

[Formula 80]

Synthesis of 3-fluoro-4-(4-methyl-1-imidazol-1-yl)benzaldehyde

To a solution of 3,4-diferentialglea (40,0 g) in DMF (533 ml) was added at room temperature 4-Mei (46.4 g) and potassium carbonate (78.0 g) and the reaction solution was stirred at 90°C for 6 hours. The reaction solution was left to cool to room temperature. Ethyl acetate was added to the reaction solution, which is then sequentially washed with water and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate) and besieged tert-butylmethylamine ether, to obtain 10.1 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 2,33 (d, J=0.8 Hz, 3H), 7,07 (users, 1H), EUR 7.57 (DD, J=7,2, 7.2 Hz, 1H), 7,76-of 7.82 (m, 2H), 7,87 (users, 1H), 10,01 (d, J=1.6 Hz, 1H).

Synthesis of (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-3-one

A solution of (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]-2-hydroxy-6-methylmorpholin-3-one (2.16 g) and triphenylphosphorane (1,61 g) in acetonitrile (70 ml) was heated at boiling under reflux in nitrogen atmosphere for one hour. The solvent is evaporated when eigendom pressure and the obtained residue was dissolved in ethanol (80 ml). To the resulting reaction solution was added 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (869 mg) and TEA (2,68 ml) and the reaction solution was stirred in nitrogen atmosphere at room temperature for 10 hours. The solvent is evaporated under reduced pressure. The obtained residue was dissolved in a mixed solvent of triperoxonane acid (30 ml) and methylene chloride (30 ml) and the reaction solution was stirred at room temperature for 13 hours. The reaction solution was poured into a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution and then the solvent is evaporated under reduced pressure. The obtained residue was purified column chromatography using NH silica gel (heptane:ethyl acetate=1:1-0:1) and precipitated with a mixture of heptane-ethyl acetate to obtain 1,32 g specified in the connection header.

1H-NMR (CDCl3) δ (ppm): 1,33 (d, J=6.4 Hz, 3H), of 1.42 (d, J=6.0 Hz, 3H), of 2.30 (s, 3H), 3,19 (DD, J=12,4, and 9.2 Hz, 1H), 3,63 (DD, J=12,4, 2.0 Hz, 1H), of 4.44 figure-4.49 (m, 2H), are 5.36 (d, J=6,8 Hz, 1H), 6,80 (s, 1H), 6,97 (s, 1H), to 7.09 (DD, J=8,4, 6.4 Hz, 2H), 7,29 (t, J=8,4 Hz, 1H), 7,44 (DD, J=8,4, 2.0 Hz, 1H), 7,71 (DD, J=12,8, 1.2 Hz, 1H), 7,74 (s, 1H).

Example 75

Synthesis of (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one

[Formula 81]

img src="https://img.russianpatents.com/1046/10465196-s.jpg" height="31" width="68" />

1,15 g specified in the title compounds were obtained according to a similar method of example 26 from (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4-differenl)propyl]-2-hydroxy-6-methylmorpholin-3-one was obtained from 1-bromo-4,5-diferently as the parent compound, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde.

1H-NMR (CDCl3) δ (ppm): 1,31 (d, J=6.4 Hz, 3H), of 1.41 (d, J=6.8 Hz, 3H), 2,20 (d, J=6,4 Hz, 1H), 2,30 (s, 3H), 3.15 in (DD, J=12,8, 9.6 Hz, 1H), only 3.57 (DD, J=of 12.8, 2.4 Hz, 1H), 4,42-4,48 (m, 2H), 5,38 (d, J=7,6 Hz, 1H), 6,80 (s, 1H), 6,97 (s, 1H), 7,12-to 7.18 (m, 2H), 7,26-7,31 (m, 2H), 7,44 (DD, J=8,4, 2.0 Hz, 1H), 7,71 (DD, J=12,8, and 1.6 Hz, 1H), 7,73 (s, 1H).

Example 76

Synthesis of (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-6-methylmorpholin-3-one

[Formula 82]

11.0 mg specified in the title compounds were obtained according to a similar method of example 26 from (S)-4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)propyl]-2-hydroxy-6-methylmorpholin-3-one was obtained from 1-bromo-4-fervently as the parent compound, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde.

1H-NMR (CDCl3) δ (ppm): 1,31 (d, J=6.0 Hz, 3H), 1,38 (d, J=6.0 Hz, 3H), of 2.30 (s, 3H), of 3.12 (DD, J=12,8, 9.6 Hz, 1H), only 3.57 (DD, J=of 12.8, 2.4 Hz, 1H), 4,46-4,50 (m, 2H), 5,46 (d, J=8.0 Hz, 1H), 6,79 (s, 1H), 6,97 (s, 1H), 7,05-to 7.09 (m, 2H), 7,27-7,31 (m, 1H), was 7.36-7,39 (m, 2H), 7,43 (DD, J=8,4, and 1.6 Hz, 1H), of 7.70 (DD, J=13,2, and 1.6 Hz, 1H), 7,76 (s, 1H).

Example 77

Synthesis of (Z)-2-[1-[3-fluoro-4-(4-methyl-1H and idazole-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6,6-dimethylmorpholine-3-one

[Formula 83]

11.6 mg specified in the title compounds were obtained by the similar procedure of example 27, 4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4,5-tryptophanyl)propyl]-2-hydroxy-6,6-dimethylmorpholine-3-one and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde.

1H-NMR (CDCl3) δ (ppm): 1.28 (in s, 3H), of 1.34 (d, J=6.0 Hz, 3H), of 1.47 (s, 3H), of 2.30 (s, 3H), 2,35 (d, J=4,8 Hz, 1H), 3,19 (d, J=12,8 Hz, 1H), 3,60 (d, J=12,8 Hz, 1H), to 4.41 ñ 4.50 (m, 1H), of 5.40 (d, J=7.2 Hz, 1H), 6,84 (s, 1H), 6,97 (s, 1H), 7,12 (DD, J=8,4, 6.4 Hz, 2H), 7,28 (t, J=8,4 Hz, 1H), 7,43 (DD, J=8,4, 2.0 Hz, 1H), 7,71 (DD, J=12,8, 1.2 Hz, 1H), 7,73 (s, 1H).

Example 78

Synthesis of (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one

[Formula 84]

13.9 mg specified in the title compounds were obtained by the similar procedure of example 27, 4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(3,4-differenl)propyl]-2-hydroxy-6,6-dimethylmorpholine-3-one and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde.

1H-NMR (CDCl3) δ (ppm): 1,25 (s, 3H), 1,32 (d, J=6.0 Hz, 3H), of 1.46 (s, 3H), of 2.15 (d, J=6,4 Hz, 1H), 2,30 (s, 3H), 3,17 (d, J=12,8 Hz, 1H), 3,55 (d, J=12,8 Hz, 1H), 4,43-4,48 (m, 1H), 5,42 (d, J=7,6 Hz, 1H), 6,85 (s, 1H), 6,97 (s, 1H), 7,14-to 7.18 (m, 2H), 7,27-7,30 (m, 2H), 7,43 (DD, J=8,4, and 1.6 Hz, 1H), 7,71 (DD, J=13,2, and 1.6 Hz, 1H), 7,73 (s, 1H).

Example 79

Synthesis of (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-1-(4-forfinal)-2-Ki is oxypropyl]-6,6-dimethylmorpholine-3-one

[Formula 85]

35.1 mg specified in the title compounds were obtained by the similar procedure of example 27, 4-[(1R,2R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)propyl]-2-hydroxy-6,6-dimethylmorpholine-3-one and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde.

1H-NMR (CDCl3) δ (ppm): of 1.18 (s, 3H), of 1.31 (d, J=6.0 Hz, 3H), of 1.44 (s, 3H), 2,31 (s, 3H), and 3.16 (d, J=12,8 Hz, 1H), of 3.56 (d, J=12,8 Hz, 1H), 4,45 figure-4.49 (m, 1H), 5,51 (d, J=8,4 Hz, 1H), 6,84 (s, 1H), 6,97 (s, 1H), 7.03 is-to 7.09 (m, 2H), 7,25-7,30 (m, 1H), 7,35-7,44 (m, 3H), of 7.70 (d, J=12,8 Hz, 1H), 7,76 (s, 1H).

Example 80

Synthesis of (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(R)-1-(4-forfinal)-2-hydroxyethyl]-6,6-dimethylmorpholine-3-one

[Formula 86]

18.6 mg specified in the title compounds were obtained by the similar procedure of example 28, from the obtained 4-[(R)-2-tert-butyldiphenylsilyl-1-(4-forfinal)ethyl]-2-hydroxy-6,6-dimethylmorpholine-3-one and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde.

1H-NMR (CDCl3) δ (ppm): 1.26 in (s, 3H), of 1.44 (s, 3H), 2,32 (s, 3H), 3,06 (d, J=12,8 Hz, 1H), 3,40 (d, J=12,8 Hz, 1H), 4.09 to 4.26 deaths (m, 2H), by 5.87 (DD, J=8,0, 5.6 Hz, 1H), 6,85 (s, 1H), 6,98 (s, 1H),? 7.04 baby mortality-7,10 (m, 2H), 7,22-7,26 (m, 1H), 7,33-7,39 (m, 3H), of 7.69 (d, J=12,8 Hz, 1H), of 7.75 (s, 1H).

Compounds in table 2 were obtained by a similar method.

Table 2

Examples 82 and 83

Synthesis of 1-[1-(2,4-differenl)ethyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)Fe is Il]-(E)-methylidene}piperidine-2-it

[Formula 87]

Synthesis of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde

3,4-Differentally (30.0 g) was dissolved in DMF (400 ml) and was added to the solution at room temperature 4-methyl-1H-imidazole (34.8 g) and potassium carbonate (58.5 g). The reaction solution was stirred at 90°C for 6 hours. The reaction solution was left to cool to room temperature. Then added to the reaction solution, ethyl acetate and water and the organic layer was separated. The obtained organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), besieged tert-butylmethylamine ether and separated by filtration, obtaining 6,28 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 2,32 (d, J=0.8 Hz, 3H), 7,07 (users, 1H), EUR 7.57 (DD, J=7,2, 7.2 Hz, 1H), 7,76-of 7.82 (m, 2H), 7,87 (users, 1H), 10,01 (d, J=1.6 Hz, 1H).

Synthesis of tert-butyl (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerate

3-Fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (to 2.29 g) and tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (3,68 g) was dissolved in a mixed solvent of THF (30 ml) and ethanol (10 ml). Monohydro the lithium hydroxide (1,41 g) was added to the reaction solution at room temperature and the reaction solution was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and then the mixture was extracted with ethyl acetate. The obtained extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), besieged tert-butylmethylamine ether and heptane and separated by filtration, obtaining a 1.96 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): and 1.56 (s, 9H), 1,98-2,07 (m, 2H), 2,31 (d, J=0.8 Hz, 3H), 2,64-2,70 (m, 2H)and 3.59 (t, J=6.4 Hz, 2H), 7,01 (userd, J=1.2 Hz, 1H), 7,22-7,31 (m, 2H), 7,39 (DD, J=8.0 Hz, 8.0 Hz, 1H), 7,55 (s, 1H), to 7.77-7,80 (m, 1H).

Synthesis of triptoreline (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid

Chloroform (5 ml) and TFA (10 ml) was added to tert-butyl (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerate (1,96 g) and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The residue is precipitated with methylene chloride, ethyl acetate and heptane and separated by filtration, obtaining 2,19 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 323[M++H].

Synthesis of (E)-1-[1-(2,4-differenl)ethyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}piperidine-2-it

DIEA (0,12 ml), WSC (88 mg) and HOBT (62 mg) was added to a solution of triptoreline (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (100 mg) and 1-(2,4-differenl)ethylamine (54 mg) in DMF (5 ml) at room temperature and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with saturated aqueous sodium bicarbonate, water, saturated solution of ameriglide and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate), to obtain 98 mg of [1-(2,4-differenl)ethyl]amide (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid. [1-(2,4-Differenl)ethyl]amide (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (98 mg) was dissolved in DMF (3 ml). Was added to the reaction solution at room temperature, 60% sodium hydride (10 mg) and the reaction solution was stirred at room temperature for 30 minutes. Saturated aqueous masturbirovat sodium was added to the reaction solution and then the mixture was extracted with ethyl acetate. The obtained extraction layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate), to obtain 69 mg specified in the connection header in the form of a racemate. Compound (20 mg) were separated using a CHIRALCEL OJ-H manufactured by F. Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol-hexane system), to obtain specified in the title optically active compound with a retention time of 18 minutes (example 82) (7 mg) and indicated in the title optically active compound with a retention time of 24 minutes (example 83) (4 mg). The characteristic values specified in the header connections are as follows:

1H-NMR (CDCl3) δ (ppm): 1,59 (d, J=6.8 Hz, 3H), 1.77 in-to 1.87 (m, 2H), 2,31 (d, J=0.8 Hz, 3H), 2,69-2,82 (m, 1H), 2,98-of 3.06 (m, 1H), 3,26-to 3.33 (m, 1H), 3,69 is 3.76 (m, 1H), 6,13 (kV, J=6,8 Hz, 1H), for 6.81 (DDD, J=10,4, of 8.8 and 2.8 Hz, 1H), 6,85-6,91 (m, 1H), 6,98 (users, 1H), 7,19-7,28 (m, 2H), 7,31-7,38 (m, 2H), 7,74 (users, 1H), 7,80 (users, 1H).

Example 84

Synthesis of (E)-(S)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it

[Formula 88]

Synthesis of ((R)-3-bromo-2-methylpropoxy)of tert-butyldiphenylsilyl

tert-Butyldiphenylchlorosilane (83 ml) and imidazole (30 g) was added to a solution of (R)-3-b is ω-2-methyl-1-propanol (45 g) in THF (150 ml) under ice cooling and the reaction mixture was stirred at room temperature overnight. Was added to the reaction mixture water and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate), to obtain 117 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1,00 (DD, J=0.8 Hz, 6.8 Hz, 3H), of 1.06 (s, 9H), 2,00-2,09 (m, 2H), 3,50-the 3.65 (m, 4H), of 7.36-7,46 (m, 6H), 7,65-to 7.68 (m, 4H).

Synthesis of tert-butyl (S)-5-(tert-butyldiphenylsilyl)-2-(diethoxyphosphoryl)-4-methylvalerate

A solution of tert-butyl diethylphosphonoacetate (64 g) in THF (100 ml) was added dropwise to a suspension of sodium hydride (containing 40% mineral oil, and 13.2 g) in THF (400 ml) under ice cooling and the reaction mixture was stirred at room temperature for 75 minutes. A solution of ((R)-3-bromo-2-methylpropoxy)of tert-butyldiphenylsilyl (99,4 g) in THF (100 ml) was added dropwise to the reaction mixture, which was then heated at the boil under reflux for 23 hours. Ice water was added to the reaction mixture and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous sulfate mA is occurring and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), obtaining 74,6 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 0,91-of 0.95 (m, 3H), of 1.05 (s, 9H), of 1.29 and 1.35 (m, 6H), 1,45 (s, 9H), 1,68-to 1.79 (m, 1H), 1,83-2,04 (m, 1H), 2,16-of 2.26 (m, 1H), 2.95 and-3,14 (m, 1H), 3.46 in-3,51 (m, 2H), 4.09 to-4,17 (m, 4H), 7,35-7,42 (m, 6H), 7,63-to 7.67 (m, 4H).

tert-Butyl (E)-(S)-5-(tert-butyldiphenylsilyl)-2-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-methylvalerate

A solution of tert-butyl (4S)-5-(tert-butyldiphenylsilyl)-2-(diethoxyphosphoryl)-4-methylvalerate in THF (50 ml) was added to a solution of tert-butoxylate (3.3 grams) in THF (50 ml) under nitrogen atmosphere at -70°C and the reaction mixture was stirred for 40 minutes. A solution of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (6 g) in THF (50 ml) was added to the reaction mixture at -70°C and the reaction mixture was stirred for 100 minutes and at room temperature over night. Water was added to the reaction mixture and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), obtaining 9,34 g ukazannoj is in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1.55V (s, 9H), 1,99-of 2.08 (m, 2H), 2,30 (s, 3H), 2.63 in-a 2.71 (m, 2H)and 3.59 (t, J=6.4 Hz, 2H), a 3.87 (s, 3H), 6,93 (m, 1H), 7,00 (d, J=1.2 Hz, 1H), to 7.09 (DD, J=8,4, 1.2 Hz, 1H), 7,27 (d, J=8,4 Hz, 1H), 7,58 (s, 1H), 7,72 (m, 1H).

Synthesis of tert-butyl (E)-(S)-5-chloro-2-[3-fluoro-4-(4-Mei-1-yl)phenyl]methylidene]-4-methylvalerate

TBAF (1M solution in THF, 22,8 ml) was added to a solution of tert-butyl (E)-(S)-5-(tert-butyldiphenylsilyl)-2-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-methylvalerate (9,34 g) in THF (100 ml) under ice cooling and the reaction mixture was stirred at room temperature for four hours. Ice water was added to the reaction mixture and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), the target fractions were collected and concentrated, to obtain a colorless oil (4.2-d). Triphenylphosphine (3.15 g) was dissolved in a solution of a colorless oil in methylene chloride (50 ml). N-chlorosuccinimide (1.47 g) was added to the reaction solution under ice cooling and the reaction mixture was stirred at 0°C for one hour. Ice water was added to the reaction, see the C and then the mixture was extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate), obtaining 2,84 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 0,96 (d, J=6.8 Hz, 3H), of 1.55 (s, 9H), 2,12-2,22 (m, 1H), 2.49 USD (DD, J=14 Hz, 8 Hz, 1H), 2,74 (DD, J=14 Hz, 6.4 Hz, 1H), 3,37-of 3.46 (m, 2H), 7,00-7,02 (m, 1H), 7,22-7,29 (m, 1H), 7,38 (t, J=8 Hz, 1H), 7,56 (s, 1H), to 7.77 (t, J=1.6 Hz, 1H).

Synthesis of hydrochloride of (E)-(S)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-4-methylvaleramide acid

A solution of tert-butyl (E)-(S)-5-chloro-2-[3-fluoro-4-(4-Mei-1-yl)phenyl]methylidene]-4-methylvalerate (2,84 g) in triperoxonane acid (20 ml) was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, was added to the residue ethyl acetate (10 ml) and a 4n solution. chloride-hydrogen acid in ethyl acetate (10 ml) and the reaction solution was concentrated under reduced pressure. This operation was repeated twice. Was added to the residue, diethyl ether and the reaction mixture is triturated with a spatula. Utverjdenie and the precipitated insoluble substance was separated by filtration, to obtain the 2,05 specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 337[M++H].

Synthesis of (E)-(S)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it

DIEA (0,47 ml), WSC (257 mg) and HOBT (181 mg) was added to a suspension of the hydrochloride of (E)-(S)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-4-methylvaleramide acid (250 mg) hydrochloride and (1R,2R)-1-amino-1-(3,4,5-tryptophanyl)propan-2-ol (243 mg) in DMF (5 ml) at room temperature and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with saturated aqueous sodium bicarbonate, water, saturated solution of ameriglide and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in DMF (8 ml). Was added 60% sodium hydride (32 mg) at 0°C and the reaction solution was stirred at 0°C for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with saturated aqueous sodium bicarbonate, water, saturated solution of ameriglide and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then what was koncentrirebuli under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate→system ethyl acetate-methanol), to obtain 176 mg specified in the connection header. The characteristic values of the compounds are the following:

ESI-MS; m/z 488[M++H].

1H-NMR (CDCl3) δ (ppm): of 1.03 (d, J=6.8 Hz, 3H), 1,32 (d, J=6.4 Hz, 3H), 1,86 is 2.00 (m, 1H), 2,31 (s, 3H), 2,39 (DDD, J=15,6, to 11.6, 2.8 Hz, 1H), 2,65 (users, 1H), 2,93 (userd, J=15,6, 3.6 Hz, 1H), 3,20 to be 3.29 (m, 2H), of 4.44-4.53-in (m, 1H), 5,32 (d, J=7.2 Hz, 1H), 6,99-7,02 (m, 1H), 7,05-7,11 (m, 2H), 7,22-7,30 (m, 2H), 7,39 (DD, J=8,0, 8.0 Hz, 1H), 7,75 for 7.78 (m, 1H), 7,81 (users, 1H).

Example 85

Synthesis of (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]piperidine-2-it

[Formula 89]

A solution of 4n. hydrogen chloride in dioxane (10 ml) was added to a solution of tert-butyl[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]carbamate (2.85 g) in dioxane (10 ml) at room temperature and the reaction solution was stirred at room temperature for five hours. Hexane (80 ml) was added to the reaction solution at room temperature and the reaction solution was stirred at room temperature for 20 minutes. The obtained solid substance was separated by filtration, to obtain the hydrochloride of (1R,2R)-1-amino-1-(3,4,5-tryptophanyl)propan-2-ol (2.16 g). DIEA (1,59 ml), WSC (880 mg)and HOBT (620 mg) was added to a solution of triptoreline (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (1,00 g) hydrochloride and (1R,2R)-1-amino-1-(3,4,5-tryptophanyl)propan-2-ol (664 mg) in DMF (25 ml) at room the temperature and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with saturated aqueous sodium bicarbonate, water, saturated solution of ameriglide and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained solid was washed with heptane, to obtain [(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]amide (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (1.10 g). [(1R,2R)-2-Hydroxy-1-(3,4,5-tryptophanyl)propyl]amide (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (1.10 g) was dissolved in DMF (25 ml). Was added to the reaction solution at room temperature, 60% sodium hydride (104 mg) and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with saturated aqueous sodium bicarbonate, water, saturated solution of ameriglide and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel(carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate→system ethyl acetate-methanol), precipitated with ethyl acetate and heptane and separated by filtration, to obtain 780 mg specified in the connection header. The characteristic values of the compounds are the following:

ESI-MS; m/z 474[M++H].

1H-NMR (CDCl3) δ (ppm): 1,31 (d, J=6.0 Hz, 3H), 1.77 in-to 1.98 (m, 2H), 2,31 (d, J=0.8 Hz, 3H), 2,73 (userd, J=6,4 Hz, 1H), 2.77-to 2,85 (m, 2H), with 3.27 (DDD, J=12,4, 7,2, 4.0 Hz, 1H), 3,54 (DDD, J=12,4, to 8.0, 4.0 Hz, 1H), 4,43-a 4.53 (m, 1H), 5,28 (d, J=7,6 Hz, 1H), 6,99-7,02 (m, 1H),? 7.04 baby mortality for 7.12 (m, 2H), 7.23 percent-7,31 (m, 2H), 7,38 (DD, J=8,0, 8.0 Hz, 1H), 7,75-to 7.77 (m, 1H), 7,80-7,83 (m, 1H).

Example 86

Synthesis of (E)-1-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}piperidine-2-it

[Formula 90]

A solution of 4n. hydrogen chloride in ethyl acetate (10 ml) was added to a solution of tert-butyl[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]carbamate (960 mg) in methanol (10 ml) at room temperature and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, to obtain the hydrochloride of (1R,2R)-1-amino-1-(3,4-differenl)propan-2-ol (747 mg). DIEA (1,59 ml), WSC (880 mg) and HOBT (620 mg) was added to a solution of triptoreline (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (1,00 g) hydrochloride and (1R,2R)-1-amino-1-(3,4-debtor the Nile)propan-2-ol (612 mg) in DMF (20 ml) at room temperature and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which is then sequentially washed with saturated aqueous sodium bicarbonate, water, saturated solution of ameriglide and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained solid was washed with heptane to obtain [(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]amide (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (977 mg). [(1R,2R)-1-(3,4-Differenl)-2-hydroxypropyl]amide (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerianic acid (977 mg) was dissolved in DMF (25 ml). Was added to the reaction solution at room temperature, 60% sodium hydride (95 mg) and the reaction solution was stirred at room temperature for 30 minutes. Water was added to the reaction solution and then the mixture was extracted with ethyl acetate. The obtained extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system ethyl acetate : methanol), precipitated with ethyl acetate and heptane and separated by filtration, to obtain 740 mg specified in the connection header. The characteristic values of the compounds are trail is who:

ESI-MS; m/z 456[M++H].

1H-NMR (CDCl3) δ (ppm): 1,30 (d, J=6.0 Hz, 3H), 1,74 is 1.96 (m, 2H), 2,31 (d, J=0.4 Hz, 3H), 2,68-to 2.85 (m, 3H), 3,19 of 3.28 (m, 1H), 3,47 of 3.56 (m, 1H), 4,43-to 4.52 (m, 1H), are 5.36 (d, J=8.0 Hz, 1H), 6,99 (s, 1H), 7,10-to 7.18 (m, 2H), 7,21-7,29 (m, 3H), of 7.36 (DD, J=8,4, 7,6 Hz, 1H), 7,75 (users, 1H), 7,80 (users, 1H).

The compounds in tables 3-1, 3-2 and 3-3 were obtained by a similar method.

[Table 3-1]

Table 3-2

Table 3-3

Example 106

Synthesis of (Z)-(6S,8aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-it

[Formula 91]

Synthesis of ethyl (2R,5S)-5-(3,4,5-tryptophanyl)pyrrolidin-2-carboxylate

To a solution of 2-ethyl ester 1-tert-butyl ether (R)-5-oxopyrrolidin-1,2-dicarboxylic acid (CAS No. 128811-48-3; 4.1 g) in tetrahydrofuran (100 ml) was added dropwise at -40°C for 20 minutes 3,4,5-tryptophansynthroid (0,35M solution in diethyl ether; 55 ml) and the reaction solution was stirred at -40°C for five hours. Was added to a solution of saturated aqueous solution of ameriglide and ethyl acetate. The reaction solution was heated to room temperature and the organic layer was separated. The obtained organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (heptane→heptane:ethyl acetate=1:1), to obtain 4.8 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-tryptophanyl)pentanoate. A solution of 4n. chloride-hydrogen acid in ethyl acetate (30 ml) was added to a solution of the obtained ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-tryptophanyl)pentanoate in ethyl acetate (30 ml) and the solution was stirred for 15 hours. The reaction solution was concentrated under reduced pressure. The ethyl acetate and saturated aqueous sodium bicarbonate solution was added to the residue and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a solution of the residue in ethyl acetate (50 ml) was added 10% palladium on carbon (100 mg) and the reaction solution was stirred in a stream of hydrogen at 1 ATM for 6 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure, obtaining only 2.91 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 274[M++H].

Synthesis of [(2R,5S)-5-(3,4,5-tryptophanyl)pyrrolidin-2-yl]methanol

LAH (483 mg) was added to a solution of ethyl (2R,5S)-5-(3,4,5-tryptophanyl)pyrrolidin-2-carboxylate (only 2.91 g) in THF (50 ml) at -15°C for one hour. The reaction RA the solution was stirred at -15°C for 19 hours. Water (0.5 ml), 5N. the sodium hydroxide solution (0.5 ml) and water (1.5 ml) was sequentially added to the reaction solution and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 2.4 g specified in the connection header. The characteristic values of the compounds are the following:

ESI-MS; m/z 232[M++H].

1H-NMR (CDCl3) δ (ppm): 1,51-to 1.63 (m, 1H), from 1.66-1.77 in (m, 1H), 1,89 is 2.00 (m, 1H), 2,10-of 2.20 (m, 1H), 3,43 (DD, J=10,0, 5.6 Hz, 1H), 3,47-3,55 (m, 1H), 3,64 (DD, J=10,0, 3.6 Hz, 1H), 4,23 (t, J=8.0 Hz, 1H), 7,02 (t, J=8.0 Hz, 2H).

Synthesis of (Z)-(6S,8aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)tetrahydropyrrolo[2,1-c][1,4]oxazin-4-it

521 mg specified in the title compound was obtained from [(2R,5S)-5-(3,4,5-tryptophanyl)pyrrolidin-2-yl]methanol as a starting compound according to a similar method of example 41. The characteristic values of the compounds are the following:

ESI-MS; m/z 470[M++H].

1H-NMR (CDCl3) δ (ppm): 1,71-to 1.82 (m, 1H), 1,92-to 1.98 (m, 1H), 2,10-of 2.20 (m, 2H), 2,30 (s, 3H), 2,37-2,48 (m, 1H), 3,86 (s, 3H), 4.09 to-4,13 (m, 1H), and 4.68 (d, J=8 Hz, 1H), 5,14 (d, J=9,2 Hz, 1H), 6.75 in (s, 1H), at 6.84 (DD, J=8,4 Hz, 6.4 Hz, 2H), 6,93-6,94 (m, 1H), 7,21 (d, J=8 Hz, 1H), 7,37-7,41 (m, 2H), 7,72 (d, J=1.2 Hz, 1H).

Example 107

Synthesis of (6S,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}hexahydropyrazino[2,1-c][1,4]oxazin-4-is

[Formula 92]

Synthesis of methyl (2R,6S)-6-(4-chlorophenyl)piperidine-2-carboxylate

To a solution of 1-tert-butyl (R)-6-oxopiperidine-1,2-in primary forms (CAS No 183890-36-0, 9.00 g) in THF (120 ml) was added 4-chlorpheniramine (1.0m solution in diethyl ether, 42 ml) in nitrogen atmosphere at -78°C for 20 minutes. The reaction solution was stirred at a temperature of from -78 to -40°C for 1.5 hours and then extinguished with a saturated solution of ameriglide at -40°C. was Added to the reaction solution, water and then the mixture was extracted with ethyl acetate. The obtained extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (at 9.53 g). A solution of 4n. hydrogen chloride in ethyl acetate (90 ml) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (at 9.53 g) in ethyl acetate (90 ml) at room temperature and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and the residue was podslushivaet a saturated solution of sodium bicarbonate. Then chloroform was added to the residue and the mixture was stirred at room the Oh temperature for two hours. The organic layer was separated, dried over magnesium sulfate and then concentrated under reduced pressure. To a solution of the residue in methanol (150 ml) at 0°C was added lambrogini sodium (3,29 g) and then acetic acid (4,27 ml) and the reaction solution was stirred at 0°C for one hour and at room temperature for one hour. A saturated solution of sodium bicarbonate was added to the reaction solution and then the mixture was extracted with chloroform. The obtained extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate) and precipitated with a mixture of heptane-diisopropyl ether, to obtain the 2,47 g specified in the connection header. The characteristic values of the compounds are the following:

ESI-MS; m/z 254[M++H].

1H-NMR (CDCl3) δ (ppm): 1,38-to 1.60 (m, 3H), 1,72-of 1.78 (m, 1H), 1,96-2,03 (m, 1H), 2.05 is-a 2.12 (m, 1H), 2,17 (users, 1H), 3,49 (DD, J=10,8, 2.8 Hz, 1H), 3,63 (DD, J=11,2, 2.8 Hz, 1H), of 3.73 (s, 3H), 7,25-7,34 (m, 4H).

Synthesis of [(2R,6S)-6-(4-chlorophenyl)piperidine-2-yl]methanol

Sociallyengaged (508 mg) suspended in THF (50 ml) under nitrogen atmosphere. Methyl (2R,6S)-6-(4-chlorophenyl)piperidine-2-carboxylate (2,47 g) was added to the suspension at -20°C and the reaction solution was stirred at -20°C for one hour. Water (0.51 ml), 5N. the solution Hydra is xida sodium (0.51 ml) and water (1,53 ml) was sequentially added to the reaction solution at -20°C and the reaction solution was stirred at room temperature for 15 minutes. Ethyl acetate was added to the reaction solution. Then the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (carrier: Chromatorex NH; eluting solvent system heptane-ethyl acetate), obtaining 1,90 g specified in the connection header. The characteristic value of this connection is the following:

ESI-MS: m/z 226[M++H].

Synthesis of (6S,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}hexahydropyrazino[2,1-c][1,4]oxazin-4-it

199 mg specified in the title compound was obtained from [(2R,6S)-6-(4-chlorophenyl)piperidine-2-yl]methanol (270 mg) according to the similar procedure of example 40. The characteristic values of the compounds are the following:

ESI-MS; m/z 464[M++H].

1H-NMR (CDCl3) δ (ppm): 1,39-and 1.54 (m, 2H), of 1.66-1.77 in (m, 2H), 2,14 was 2.25 (m, 2H), 2,30 (s, 3H), 3,86 (s, 3H), 4,03 is 4.13 (m, 2H), 4,35 (DD, J=10,4, 2.4 Hz, 1H), lower than the 5.37 (t, J=4.0 Hz, 1H), 6,83 (s, 1H), 6,93 (s, 1H), 7,20-of 7.23 (m, 3H), 7,30-7,33 (m, 2H), was 7.36-7,40 (m, 2H), 7,73 (s, 1H).

Example 108

Synthesis of (6R,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}-6-(3,4,5-tryptophanyl)tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-it

[Formula 93]

Synthesis of (S)-5-benzoyloxymethyl-3-one

Bromocatechol (5,06 ml) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-propanol (10 g) in toluene (100 ml) and 2n. of sodium hydroxide solution (100 ml) under cooling with ice. The reaction solution was stirred at 0°C for 30 minutes and then at 60°C for one hour. The reaction solution was again brought to room temperature. Then, a mixed solution of toluene-THF (1:1) was added to the reaction solution and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), obtaining 1,36 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 3.42 points (t, J=9,2 Hz, 1H), 3,54 (DD, J=9,2, 5,2 Hz, 1H), 3,62 (DD, J=12,0, 6.0 Hz, 1H, in), 3.75 (m, 1H), 3,86 (DD, J=12,0, 4.0 Hz, 1H), 4,12 (d, J=16,8 Hz, 1H), 4,18 (d, J=16,8 Hz, 1H), 4.53-in (s, 2H), 6,29 (users, 1H), 7,28-7,40 (m, 5H).

Synthesis of tert-butyl (S)-3-benzoyloxymethyl-5-exmortis-4-carboxylate

TEA (1,72 ml), 4-dimethylaminopyridine (189 mg) and di-tert-BUTYLCARBAMATE (2,02 g) was added to a solution of (S)-5-benzoyloxymethyl-3-one (1,36 g) in acetonitrile (25 ml). The reaction solution was stirred at room temperature for two hours. Then a saturated salt solution and ethyl acetate were added to the reaction solution and the organic layer was separated. The obtained organic layer was dried over betwo the major magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent system heptane-ethyl acetate), obtaining of 1.65 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 1.50 in (s, 9H), of 3.57 (DD, J=8,8, 4.8 Hz, 1H), 3,68 of 3.75 (m, 2H), 4,08-to 4.28 (m, 4H), 4,53 (d, J=12.0 Hz, 1H), 4,58 (d, J=12.0 Hz, 1H), 7,25 was 7.36 (m, 5H).

Synthesis of tert-butyl{(S)-1-benzoyloxymethyl-2-[2-oxo-2-(3,4,5-tryptophanyl)ethoxy]ethyl}carbamate

To a suspension of magnesium (249 mg) in diethyl ether (5 ml) was added dropwise 1-bromo-3,4,5-triftorbyenzola (446 μl) at 40°C for 10 minutes and the reaction solution was stirred at 40°C for one hour. The resulting solution was added dropwise to a solution of tert-butyl (S)-3-benzoyloxymethyl-5-exmortis-4-carboxylate (1.1 g) in tetrahydrofuran (30 ml) at -40°C for 10 minutes and the reaction solution was stirred at -40°C for one hour. A saturated solution of ameriglide was added to the solution in small portions at -40°C and the reaction solution was again brought to room temperature. Ethyl acetate was added to the reaction solution and the organic layer was separated. The obtained organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica compound is elem system (heptane-ethyl acetate), obtaining 952 mg specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): USD 1.43 (s, 9H), of 3.54 (DD, J=9,2, 6.0 Hz, 1H), 3,61-3,71 (m, 3H), of 3.96 (m, 1H), 4,51 (s, 2H), br4.61 (s, 2H), 5,02 (m, 1H), 7,21-to 7.35 (m, 5H), 7,50 to 7.62 (m, 2H).

Synthesis of [(3S,5R)-5-(3,4,5-tryptophanyl)morpholine-3-yl]methanol

A solution of 4n. chloride-hydrogen acid in ethyl acetate (30 ml) was added to a solution of tert-butyl{(S)-1-benzoyloxymethyl-2-[2-oxo-2-(3,4,5-tryptophanyl)ethoxy]ethyl}carbamate (3.55 g) in ethyl acetate (30 ml) at room temperature. The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure. To a solution of the obtained residue in methanol (50 ml) was added 10% palladium on carbon (containing 50% water, 167 mg) and the reaction solution was stirred in hydrogen atmosphere at room temperature for 18 hours. Palladium on carbon was removed from the reaction solution by filtration and then the filtrate was concentrated under reduced pressure. A saturated solution of sodium bicarbonate and ethyl acetate were added to the obtained residue, and the organic layer was separated. The organic layer was washed with a saturated solution of salt. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified of chromatogr is via on a column of silica gel (eluting solvent system heptane-ethyl acetate), to obtain 1.52 g specified in the connection header. The characteristic values of the compounds are the following:

1H-NMR (CDCl3) δ (ppm): 3,13-up 3.22 (m, 2H), 3,34 (DD, J=10,8, 10.4 Hz, 1H), 3,53 (DD, J=10,8, 6.4 Hz, 1H), to 3.67 (DD, J=10,8, 4.0 Hz, 1H), of 3.77 (DD, J=10,8, and 3.2 Hz, 1H), 3,85 (DD, J=10,8, and 3.2 Hz, 1H), 3.96 points (DD, J=10,4, 3.2 Hz, 1H), 7,02-7,25 (m, 2H).

Synthesis of (6R,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}-6-(3,4,5-tryptophanyl)tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-it

Specified in the title compound (110 mg) was obtained from [(3S,5R)-5-(3,4,5-tryptophanyl)morpholine-3-yl]methanol (250 mg) according to the similar procedure of example 40. The characteristic values of the compounds are the following:

ESI-MS; m/z 486[M++H].

1H-NMR (CDCl3) δ (ppm): 2,28 (s, 3H), 3.46 in-3,55 (m, 1H), 3,64 (DD, J=7,6, and 12.4 Hz, 1H), 3,83 (s, 3H), 4,06-4.26 deaths (m, 3H), 4,30 (m, 1H), 4,36 (DD, J=2,4, 10.4 Hz, 1H), 4,74 (DD, J=4,4, 7.2 Hz, 1H), 6,77 (s, 1H), 6,91 (users, 1H), 6,95-of 6.99 (m, 2H), 7,19 (d, J=8,8 Hz, 1H), 7,31-7,34 (m, 2H), of 7.70 (d, J=0.8 Hz, 1H).

Example 109

Synthesis of (6R,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-it

[Formula 94]

185 mg specified in the title compound was obtained from [(3S,5R)-5-(3,4-differenl)morpholine-3-yl]methanol (338 mg) according to the similar method of example 108. The characteristic values of the compounds are the following:

ESI-MS; m/z 468[M++H].

1H is the Mr (CDCl 3) δ (ppm): to 2.29 (s, 3H), 3,53 (DD, J=11,2, 11.2 Hz, 1H), 3,68 (DD, J=12,0, 7.2 Hz, 1H), 3,84 (s, 3H), 4.04 the-is 4.21 (m, 3H), 4,27-4,37 (m, 2H), 4,80 (DD, J=7,2, 4,4 Hz, 1H), 6,78 (s, 1H), 6,91 (s, 1H), 7,06-7,20 (m, 4H), 7,31-7,34 (m, 2H), of 7.70 (s, 1H).

Example 110

Synthesis of (6R,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-c][1,4]oxazin-4-it

[Formula 95]

242 mg specified in the title compound was obtained from [(3S,5R)-5-(4-forfinal)morpholine-3-yl]methanol (311 mg) according to the similar method of example 108. The characteristic values of the compounds are the following:

ESI-MS; m/z 450[M++H].

1H-NMR (CDCl3) δ (ppm): to 2.29 (s, 3H), 3,55 (DD, J=11,6, and 11.6 Hz, 1H), and 3.72 (DD, J=12,0, 7,6 Hz, 1H), 3,83 (s, 3H), was 4.02-is 4.21 (m, 3H), 4,30 is 4.36 (m, 2H), around 4.85 (DD, J=7,6, 4.0 Hz, 1H), 6,79 (s, 1H), 6,91 (s, 1H), 7.03 is-7,07 (m, 2H), 7,19 (d, J=8,8 Hz, 1H), 7,30-7,34 (m, 4H), of 7.70 (s, 1H).

Example 111

Synthesis of (6R,9aR)-6-(4-chlorophenyl)-3-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene]tetrahydro[1,4]oxazino[3,4-c]oxazin-4-it

[Formula 96]

Specified in the title compound (357 mg) was obtained from [(3S,5R)-5-(4-chlorophenyl)morpholine-3-yl]methanol (470 mg) according to the similar method of example 108. The characteristic values of the compounds are the following:

ESI-MS; m/z 466[M++H].

1H-NMR (CDCl3) δ (ppm): to 2.29 (s, 3H), 2,52 (t, J=11.2 Hz, 1H), 3,68 (DD, J=12,4, 8.0 Hz, 1H), 3,83 (s, 3H), Android 4.04 (DD, J=11,2, 4,4 Hz, 1H), 4.09 to-4,20 (m, 2H), 4.26 deaths is 4.36 (m,2H), to 4.81 (DD, J=7,6, and 4.4 Hz, 1H), 6,78 (s, 1H), 6,91 (s, 1H), 7,19 (d, J=8,4 Hz, 1H), 7.23 percent-7,34 (m, 6H), of 7.70 (s, 1H).

The authors of the present invention conducted the following tests to show the usefulness of the compounds of General formula (I) according to the present invention.

Example 1 test

Quantification of Aβ-peptide in the culture of neurons from the brain of a fetus of the rat

(1)Primary culture of neural cells of the rat

Primary cultures of neurons were obtained from the cerebral cortex 18-day-old embryos of Wistar rats (Charles River Japan, Yokohama, Japan). In particular, the embryos were aseptically extracted from pregnant rats under ether anesthesia. The brain was removed from the embryo and immersed in a cooled ice medium L-15 (e.g., Invitrogen Corp.Cat #11415-064, Carlsbad, CA, USA or SIGMA L1518). The cerebral cortex was collected from the extracted brain under stereoscopic microscope. The collected fragments of the cortex of the brain enzyme was treated in an enzyme solution containing 0.25% trypsin (Invitrogen Corp.Cat #15050-065, Carlsbad, CA, USA) and 0.01% DNase has (Sigma D5025, St. Louis, MO, USA), at 37°C for 30 minutes to disperse the cells. Then the enzymatic reaction was stopped by adding to a solution of inactivated horse serum. Enzyme treated solution was centrifuged at 1500 rpm for five minutes to remove the supernatant. To the resulting cell mass is added 5-10 ml of medium. As a researcher who as medium (Neurobasal/B27/2-ME) was used neuropathology medium (Invitrogen Corp.Cat #21103-049, Carlsbad, CA, USA), supplemented with 2% B27 Supplement (Invitrogen Corp.Cat #17504-044, Carlsbad, CA, USA), 25 μm 2-mercaptoethanol (2-ME, WAKO Cat #139-06861, Osaka, Japan), 0.5 mm L-gluamine (Invitrogen Corp.Cat #25030-081, Carlsbad, CA, USA) and antibiotics and antimycotics (Invitrogen Corp.Cat #15240-062, Carlsbad, CA, USA). However, for the analysis used above neuropathology environment, not supplemented with 2-ME (Neurobasal/B27). The cell was again dispersible moderate treatment with a pipette and cell mass, to which was added the specified environment. The cell dispersion was filtered through a 40-μm nylon mesh (Cell Strainer, Cat #35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to remove any remaining cell mass and as a result received a suspension of nerve cells. Suspension of nerve cells bred specified environment and then were placed in a volume of 100 μl/well at an initial density of cells 5×105cells/cm2on 96-well polystyrene culture tablet, pre-coated with poly-L - or D-lysine (Falcon Cat #35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA, coated with poly-L-lysine, using the method described below, or BIOCOATTMcell environments Poly-D-lysine cell ware 96-well plate, Cat #35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). Coating of poly-L-lysine was carried out as follows. 100 µg/ml poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) aseptically prepared using 0.15 M borate buffer (pH 8.5). 100 μl/well of the obtained solution was made in the wells of 96-well polystyrene which CSOs cultural tablet, and incubated at room temperature for one or more hours, or at 4°C over night or more. Equipped with coated 96-well polystyrene culture the tablet was washed with sterile water four times or more, then was dried or rinsed, for example, sterile PBS or medium, and used for seeding cells. Seeded cells were grown on a culture plate at 37°C in an atmosphere of 5% CO2-95% air for one day. Then all the medium was replaced with fresh Neurobasal mediumTM/B27/2-ME and then cells were cultured for another three days.

(2)Making connections

On the fourth day of cultivation in wells made the drug as follows. All medium was removed from the wells and brought them in 180 µl/well neuropathology environment, not containing 2-ME and containing 2% B-27 (Neurobasal/B27). The solution of the test compound in dimethyl sulfoxide (hereinafter referred to as DMSO) was diluted medium Neurobasal/B27 so that the initial concentration was equal to 10 times the final concentration. Located in the holes of medium were added to 20 μl/well of the obtained diluted solution and thoroughly mixed it environment. The final concentration of DMSO was 1% or less. The control group was only added DMSO.

(3)Sample

After adding the connection, the cells were cultured for three days and the whole environment was collected. Received Wednesday ISOE is isovale as a sample for ELISA. The sample was not diluted for measurement of Aβx-42 by ELISA method and diluted to 5-fold dilution with the diluent supplied with the ELISA kit, ELISA measurements of Aβx-40.

(4)Evaluation of the survival rate of cells

Cell survival was assessed by MTT analysis according to the following procedure. After collecting medium in the wells was made 100 μl/well of pre-warmed medium. Then the wells were added to 8 μl/well of a solution of 8 mg/ml MTT (SIGMA M2128, St. Louis, MO, USA) in D-PBS(-) (phosphate buffered saline, Dulbecco, SIGMA D8537, St. Louis, MO, USA). 96-well polystyrene culture tablet incubated in the incubator at 37°C in an atmosphere of 5% CO2-95% air for 20 minutes. Added 100 μl/well buffer for MTT lysis and the MTT crystals formazan thoroughly dissolved in the buffer in an incubator at 37°C in an atmosphere of 5% CO2-95% air. Then measured the optical density at 550 nm in each well. Buffer for MTT lysis was prepared as follows. 100 g of SDS (sodium dodecyl sulphate (sodium lauryl sulphate), WAKO 191-07145, Osaka, Japan) was dissolved in a mixed solution of 250 ml of N,N'-dimethylformamide (WAKO 045-02916, Osaka, Japan) with 250 ml of distilled water. Then to the solution was added 350 μl of concentrated chloride-hydrogen acid and concentrated acetic acid to provide the ultimate pH of about 4.7.

When measuring wells not containing seeded cells and containing only the environment and Astor MTT, considered background (bkg). The measured values are respectively used in the following formula, subtracting from them bkg values. Thus, for comparison and evaluation activity in relation to the survival rate of cells was calculated percentage to the control group (group not treated with the drug, CTRL) (% of CTRL).

% CTRL=(A550_sample-A550_bkg)/(A550_CTRL-bkg)×100

(A550_sample: optical density at 550 nm of the wells with the sample,

A550_bkg: optical density at 550 nm background wells

A550_CTRL: optical density at 550 nm of the wells of the control group)

(5)The definition of A(using ELISA method

To determine A(using ELISA method used a set of Human/Rat (Amyloid (42) ELISA Kit Wako (#290-62601) and a set of Human/Rat (Amyloid (40) ELISA Kit Wako (#294-62501) F. Wako Pure Chemical Industries, Ltd., or a set of Human Amyloid beta (1-42) Assay Kit (#27711) and a set of Human Amyloid beta (1-40) Assay Kit (#27713) F. Measurement-Biological Laboratories, Co., Ltd. (IBL Co., Ltd.). Analysis of Aβ-ELISA was carried out according to the instructions recommended by the manufacturer (the techniques described in the attached publications). However, Aβ-calibration curve was obtained using beta-amyloid peptide 1-42, rat and beta-amyloid peptide 1-40, rat (Calbiochem, #171596 [Aβ42], #171593 [Aβ40]).

(6)Results

The results are shown in tables 4-1, 4-2 and 4-3 in the form of a percentage of the concentration of Aβ in the medium control group (% of CTRL).

Table 4-1
Test connectionActivity in reducing the production of Aβ42 IC50 (nm)
Example 177
Example 2187
Example 341
Example 469
Example 5125
Example 6156
Example 776
Example 8113
Example 960
Example 1084
Example 12101
Example 13129
Example 14146
Example 16201
Example 18183
Example 1954
Example 2082
Example 21195
Example 2230
Example 23130
Example 2436
Example 25141
Example 266
Example 275
Example 2816

Table 4-2
Test connectionActivity in reducing the production of Aβ42 IC50 (nm)
Example 2923
Example 3054
Example 3131
Example 3241
Example 3363
Example 3423
P the emer 35 23
Example 36109
Example 3720
Example 3852
Example 39130
Example 40100
Example 41141
Example 5167
Example 5286
Example 5340
Example 5474
Example 55111
Example 5867
Example 6096
Example 63103
Example 74140
Example 75146
Example 77141
Example 8437
Example 8564
Example 9689
Example 10188
Example 10561

Table 4-3
Test connectionActivity in reducing the production of Aβ42 IC50 (nm)
Example 10778
Example 10860
Example 109100
Example 111129

The results in tables 4-1, 4-2 and 4-3, confirmed that the compounds of the present invention have an effect of inhibiting the production of Aβ42.

Example 2 test

The effect on the production of amyloid (cerebrospinal fluid, brain and plasma of rats

Animals were transported to the laboratory on the day preceding the beginning of the experiment (day 0). Preliminary individual rooms inflicted with an oil pencil on the tail of animals. We measured their body weight and assigned to the treatment site. Then animals with the ova was assigned an individual number. Rats were forcibly introduced orally media or sample (5 ml/kg) once daily for three days after the start of the experiment (day 1). Six hours after the last oral administration to rats were injected intraperitoneal Nembutal (Dainippon Pharmaceutical Co., Ltd., Osaka) (50 mg/kg). Dissected under anesthesia the back of the neck and inserted into approaches cerebral tank 25G needle for taking about 100 μl of cerebrospinal fluid. Taken cerebrospinal fluid was introduced into a test tube containing 1 μl of p-ABSF (100 mmol/l)and kept in ice to prevent decomposition of Aβ. Then opened the abdominal cavity and, using a syringe with heparin, was taken from the abdominal aorta approximately 2.5 ml of blood and kept it in ice. Finally, rats were killed, removed the brain and gently washed his saturated salt solution, and then measured the wet weight of each half of the brain, each half of the brain was placed in a 15 ml tube and frozen in liquid nitrogen. The sampled brain kept frozen until measurement. Cerebrospinal fluid was centrifuged at 4°C at 7000 rpm for five minutes and then collected supernatant to determine the amount of Aβ. The blood was centrifuged at 4°C at 3000 rpm for five minutes and then collected plasma to determine the amount of Aβ.

To determine the amount of Aβ40 and Aβ42 of cerebros the national fluid or plasma diluted with diluent comes with the kit for measuring the amount of Aβ. To brain tissue (right brain) was added 70% formic acid at a rate of 1 ml per 100 mg (wet weight) tissue and subjected to tissue to ultrasound treatment. Immediately after ultrasonic treatment the mixture was subjected to 20-fold dilution of Tris-buffer (0.9 mol/l) (pH 12) and neutralized. The neutralized liquid directly used for measuring the amount of Aβ.

The amount of Aβ was determined according to the instructions attached to the measuring set. In particular, the microplate containing the solid phase antibodies to Aβ40 and Aβ42, put 100 ál of diluted cerebrospinal fluid, diluted plasma sample or source of brain fluid to neutralize. Added to the microplate, 100 μl of each of the different concentrations of standard solutions of Aβ and reaction was performed at 4°C over night. The microplate was washed five times with wash solution supplied with the measuring set. Then she deposited the microplate HRP-labeled secondary antibody and the reaction was performed at 4°C for one hour. Upon completion of the reaction, the microplate was washed five times with the same washing solution, were stained with TMB solution and stop the staining reaction stop solution. Then measured the optical density at 450 nm using a SPECTRA MAX 190 (Molecular Devices, Sunnyvale, California, USA). Con is entrely Aβ40 and Aβ42 were calculated from the standard curve.

The effects of the invention

The compound of General formula (I) or its pharmacologically acceptable salt according to the present invention has the effect of reducing the production of Aβ42 or the like. Therefore, the present invention can, in particular, to provide a therapeutic or prophylactic agent for a neurodegenerative disease caused by Aβ such as Alzheimer's disease or down's syndrome.

Industrial applicability

The compound of General formula (I) according to the present invention has the effect of reducing the production of Aβ40 and Aβ42 and, thus, is particularly useful as a preventive or therapeutic agent for a neurodegenerative disease caused by Aβ such as Alzheimer's disease or down's syndrome.

1. The compound represented by formula (I):

or its pharmacologically acceptable salt, where
(a) R1, R2, R3and R4are the same or different, and each represents a hydrogen atom or C1-alkiline group;
X1represents a C1-alkylenes group, C1-Allenova group may be substituted by 1-3 hydroxyl groups or C1-alkylidyne groups, or C3-cycloalkyl group formed by two C1-alkylidyne groups together are attached to the same carbon atom SLI group;
Xandrepresents a methoxy group or a fluorine atom;
Xbrepresents an oxygen atom or methylene group, provided that Xbrepresents only the oxygen atom when Xandrepresents a methoxy group; and
Ar1represents an aryl group, pyridinyl group which may be substituted by 1-3 substituents selected from the group of Al deputies;
(b) Ar1-X1represents a C5-cycloalkyl group condensed with a benzene ring, where one methylene group in C5-cycloalkyl group may be replaced by oxygen atom, C5-cycloalkyl group may be substituted by 1-3 hydroxy groups and/or C1-alkylidyne groups, and R1, R2, R3, R4, Xandand Xbare as defined in (a);
(d) Ar1-X1and R4together with the nitrogen atom to which the group Ar1-X1is attached and the carbon atom to which R4attached, form a 5-7-membered nitrogen-containing heterocyclic group which is substituted by an aryl group or pyridinoline group, where one methylene group in the 5-7-membered nitrogen-containing heterocyclic group may be replaced by oxygen atom, and aryl or pyridinoline group may be substituted by 1-3 substituents selected from the group of Al, C is mustiala, Xbrepresents an oxygen atom, and R1, R2, R3and Xandare as defined in (a) and (b);
group Al deputies: (1) halogen atom.

2. The compound or its pharmacologically acceptable salt according to claim 1, where the compound represented by formula (I-a):

where R1, R2, R3, R4X1and Ar1are as defined in claim 1.

3. The compound or its pharmacologically acceptable salt according to claim 1, where the compound represented by formula (II):

where R1, R2, R3, R4, Xandand Xbare as defined in claim 1, R5and R6are the same or different, and each represents a hydrogen atom or C1-alkiline group, C1-alcalina group may be substituted by 1-3 hydroxyl groups, and Ar1-arepresents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents selected from group A1 substituents defined in claim 1.

4. The compound or its pharmacologically acceptable salt according to claim 3 where the compound represented by formula (II-a):

where R1, R2, R3and R4are as defined in claim 1, and R5, R6and Ar1-aare as defined in item 3.

p> 5. The compound or its pharmacologically acceptable salt according to claim 3 where the compound represented by formula (II-b):

where R1, R2, R3and R4are as defined in claim 1, and R5, R6and Ar1-aare as defined in item 3.

6. The compound or its pharmacologically acceptable salt according to claim 3 where the compound represented by formula (II-C):

where R1, R2, R3and R4are as defined in claim 1, R7represents a hydrogen atom or C1-alkiline group and Ar1-ais the same as defined in item 3.

7. The compound or its pharmacologically acceptable salt according to claim 3 where the compound represented by formula (II-d):

where R1, R2, R3and R4are as defined in claim 1, and R5, R6and Ar1-aare as defined in item 3.

8. The compound or its pharmacologically acceptable salt according to claim 3 where the compound represented by formula (II-e):

where R1, R2, R3and R4are as defined in claim 1, Ar1-ais such as defined in claim 3, and R7is the same as defined in item 6.

9. The compound or its pharmacologically acceptable salt according to claim 1, where the connection performance is established with representation formula (I-b):

where R1, R2, R3and R4are as defined in claim 1, R13and R14are the same or different and each represents a hydrogen atom or a Deputy selected from the group of Al substituents defined in claim 1, and Y represents a methylene group or an oxygen atom.

10. The compound or its pharmacologically acceptable salt according to claim 1, where the compound represented by formula (I-c):

where R1and R2are as defined in claim 1, Ar1-crepresents a phenyl group or pyridinyl group which may be substituted by 1-3 substituents, which are the same or different and selected from the group of Al substituents, Z1represents a methylene group or an oxygen atom, and n and m are the same or different and each is an integer from 0 to 2, provided that n+m is an integer from 1 to 3.

11. The compound or its pharmacologically acceptable salt of claim 10, where Z1represents a methylene group.

12. The compound or its pharmacologically acceptable salt of claim 10, where Z1represents an oxygen atom, and n and m represent an integer of 1.

13. The compound or its pharmacologically acceptable salt according to claim 1, where Ar1 represents a phenyl group or pyridinyl group, or phenyl group or pyridinyl group substituted by 1-3 halogen atoms.

14. The compound or its pharmacologically acceptable salt according to claim 1, where the compound is selected from the following group including:
1) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(3,4,5-triptorelin)morpholine-3-one,
2) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-(2,3,4-triptorelin)morpholine-3-one,
3) (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one,
4) (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(3,4,5-triptorelin)morpholine-3-one,
5) (Z)-(S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one,
6) (Z)-(R)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-(2,3,4-triptorelin)morpholine-3-one,
7) (Z)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
8) (Z)-(R)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
9) (Z)-(S)-4-[(S)-1-(4-forfinal)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
10) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,
11) (Z)-2-[1-[3-methoxy-4-(4-methyl-1H-shall midazol-1-yl)phenyl]methylidene]-4-[(R)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,
12) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
13) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
14) (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
15) (Z)-(6S,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]}hexahydropyrazino[2,1-C][1,4]oxazin-4-one,
16) (Z)-(6R,9aS)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]}hexahydropyrazino[2,1-C][1,4]oxazin-4-one,
17) (Z)-(S)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
18) (Z)-(S)-4-[(R)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
19) (Z)-(S)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
20) (Z)-(S)-4-[(R)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
21) (Z)-(S)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
22) (Z)-(S)-4-[(R)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
23) (Z)-(S)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
24)(Z)-(S)-4-[(R)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
25) (Z)-(S)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
26) (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
27) (Z)-4-[(R)-1-(4-forfinal)-2-hydroxyethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
28) (Z)-(6R)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
29) (Z)-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one,
30) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]morpholine-3-one,
31) (Z)-(5)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
32) (Z)-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
33) (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
34) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-methoxy-4-(Mei-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
35) (Z)-(5)-4-[(5)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]METI the Eden]-6-methylmorpholin-3-one,
36) (Z)-(6S)-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methyl-4-[(S)-1-(3,4,5-tryptophanyl)ethyl]morpholine-3-one,
37) (Z)-(6S)-4-[1-(4-forfinal)-1-methylethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
38) (Z)-(6S)-4-[1-(4-forfinal)cyclopropyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
39) (Z)-(6S,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]}-6-(3,4,5-tryptophanyl)hexahydropyrazino[2,1-C][1,4]oxazin-4-one,
40) (Z)-(6S,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]}hexahydropyrazino[2,1-C][1,4]oxazin-4-one,
41) (Z)-(6S,9aR)-6-(2,6-differencein-3-yl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]}hexahydropyrazino[2,1-C][1,4]oxazin-4-one,
42) (Z)-(S)-4-[(S)-1-(5-herperidin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
43) (Z)-(S)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
44) (Z)-(S)-4-[(S)-1-(2-chloro-3-herperidin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
45) (Z)-(S)-4-[(S)-1-(2,6-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
46) (Z)-4-[(S)-1-(2-chloropyridin-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
47) (Z)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyln-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
48) (Z)-4-[(S)-1-(6-herperidin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
49) (Z)-4-[(S)-1-(6-chloropyridin-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
50) (Z)-4-[(S)-1-(2,3-differencein-4-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
51) (Z)-4-[(S)-1-(5-chloropyridin-2-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
52) (Z)-(R)-4-[(S)-1-(2,6-differencein-3-yl)ethyl]-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
53) (Z)-(S)-4-(4-terbisil)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
54) (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(S)-1-(4-tryptophanyl)ethyl]-6,6-dimethylmorpholine-3-one,
55) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
56) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
57) (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6-methylmorpholin-3-one,
58) (Z)-(S)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6-methylmorpholin-3-one,
59) (Z)-(S)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-1-(4-forfinal)-2-hydroxypropyl]-6-metalmorph the n-3-one,
60) (Z)-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-4-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-6,6-dimethylmorpholine-3-one,
61) (Z)-4-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]-6,6-dimethylmorpholine-3-one,
62) 1-[1-(2,4-differenl)ethyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}piperidine-2-it,
63) (E)-(S)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it,
64) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]piperidine-2-it,
65) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(2R,3R)-3-hydroxy-1,1-dietlinde-2-yl]piperidine-2-it,
66) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(S)-2-hydroxy-1-methyl-1-(3,4,5-tryptophanyl)ethyl]piperidine-2-it,
67) (E)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[1-(4-forfinal)-1-methylethyl]piperidine-2-it,
68) (E)-(R)-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-1-[(1R,2R)-2-hydroxy-1-(3,4,5-tryptophanyl)propyl]-5-methylpiperidin-2-it,
69) (E)-(S)-1-[(1R,2R)-1-(3,4-differenl)-2-hydroxypropyl]-3-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-5-methylpiperidin-2-it,
70) (Z)-(6S,8aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-(3,4,5-tryptophanyl)tetrahydropyrrolo[2,1-C][1,4]oxazin-4-one,
71) (6S,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-niridazole-1-yl)phenyl]-(Z)-methylidene}hexahydropyrazino[2,1-C][1,4]oxazin-4-one,
72) (6R,9aR)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(2)-methylidene}-6-(3,4,5-tryptophanyl)-tetrahydro[1,4]oxazino[3,4-C][1,4]oxazin-4-one,
73) (6R,9aR)-6-(3,4-differenl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-C][1,4]oxazin-4-one,
74) (6R,9aR)-6-(4-forfinal)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-C][1,4]oxazin-4-one and
75) (6R,9aR)-6-(4-chlorophenyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(Z)-methylidene}tetrahydro[1,4]oxazino[3,4-C]oxazin-4-one.

15. Pharmaceutical composition having inhibitory activity against the production of amyloid-β containing the compound or its pharmacologically acceptable salt according to any one of claims 1 to 14 as an active ingredient.

16. The pharmaceutical composition according to § 15 for the prevention or treatment of disease caused by amyloid-β.

17. The pharmaceutical composition according to 17, where the disease caused by amyloid-β is Alzheimer's disease, senile dementia, down's syndrome or amyloidosis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: novel chemical compounds of formula (I) or their pharmaceutically acceptable salts possess inhibiting activity with respect to kinase p-38 MAP and kinase FGFR, and can be used in treatment of such diseases as arthritis, obstructive lung disease, Alzheimer's disease or oncological and other diseases. In general formula (I) , R1 is hydrogen, R2 is 6-member oxygen-containing heterocyclyl, aryl, selected from unsubstituted phenyl or phenyl substituted with aliphatic acyl group which contains 1-6 carbon atoms, halogen cyano, hydroxyl, C1-6alkylsulfinyl, C1-6alkylsulfonyloxy, C1-6alkylsulfonyl, C1-6alkylsulfanyl, tret-butydimethylsilanyloxy, 6-member heterocyclyl, containing 1-2-heteroatoms, selected from nitrogen and oxygen, R3 is C1-6alkyl, Ar1 is phenyl, substituted with 1-2 substituents, selected from atoms of halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, X1 is oxygen and X2 is chemical bond.

EFFECT: efficient application of invention compounds in pharmaceutical composition.

13 cl, 1 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of the substituted esters of 1,2,3,7-tetrahydro-pyrrolo [3,2-f][1,3]benzoxazine-5-carboxylic acid of general formula 1 or their racemoids, or their pharmaceutically acceptable and/or hydrates as substances of pharmaceutical compositions having anti-influenza virus activity: , where: R1 and R4 independently represent amines substitute selected from hydrogen, optionally substituted by liner or branched alkyl, containing 3-12 carbon atoms, optionally substituted cycloalkyl containing 3-10 carbon atoms, optionally substituted aryl, and probably, annelated heterocyclyl, which can be aromatic or non-aromatic and contains from 3 to 10 atoms in the ring, with one or several heteroatoms selected from nitrogen, oxygen or sulphur or their oxides; R2 represents alkyl substitute selected from hydrogen, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents substitute of the cyclic system selected from hydrogen, optionally substituted linear or branched alkyl, containing 3-12 carbon atoms, optionally substituted cycloalkyl containing 3-10 carbon atoms optionally substituted aryl or optionally substituted and optionally substituted annelated heterocyclyl, which can be aromatic or non-aromatic and contains from 3 to 10 atoms in the ring with one or several heteroatoms selected from nitrogen, hydrogen or sulphur or their oxides; R6 represents substitute of cyclic system selected from hydrogen, halogen atom, cyano group, optionally substituted aryl or optionally substituted annelated heterocycle, which can be aromatic or non-aromatic and contains from 3 to 10 atoms in the ring with one or several heteroatoms selected from nitrogen, hydrogen or sulphur or their oxides.

EFFECT: production of the pharmaceutical compositions having anti-influenza virus activity.

12 cl, 2 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound of the formula (I) , where R1 is a group of the formula and, in which R2, R3, R4, R5, R6, R7 and R8, each one independently represents a hydrogen atom or C1-6alkyl or its salt, to the method of its producing, to the method of antagonist effect on angiotensin II in the mammal, to the application of compounds of formula (I) as well as to methods of diseases prevention or treatment.

EFFECT: there are produced and provided new compounds that can be applied for prevention or treatment of disturbed circulation.

16 cl, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

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