Sphingosine-1-phosphate binding inhibitor

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

 

The technical FIELD

The present invention relates to new compounds which have an inhibitory effect on the binding between synagogen-1-phosphate, with numerous physiological functions, and its receptor Edg-1 Receptor gene in endothelial differentiation of type-1, S1P1). The present invention relates also to pharmaceutical compositions comprising these compounds as active ingredients, and a synthetic intermediate derived for data connections.

The LEVEL of TECHNOLOGY

Sphingosine-1-phosphate (“S1P”) is a physiologically active lipid, which is formed in the metabolism of sphingolipids (e.g., sphingomyelin) in the cells. It is known that S1P has a wide variety of functions, such as induction of cell differentiation, stimulation of cell growth, inhibition of cell motility and inhibition of apoptosis, and it is also known that he has such physiological functions, such as angiogenesis, induction of bradycardia, activation of inflammatory cells and platelet activation (non-Patent document 1).

As S1P receptors known 5 subtypes: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4and Edg-8(S1P5) (Non-patent document 2).

Among these subtypes Edg-1(S1P1) expressive is to a high degree in immune cells (for example, T cells, dendritic cells) and vascular endothelial cells, which may mean that Edg-1(S1P1very encouraging migration S1P-stimulated T cells (non-Patent document 3), the migration of mast cells (non-Patent document 4) and the output of T and b cells from lymphoid organs (non-Patent document 5) and angiogenesis (non-Patent document 6) and are involved in autoimmune diseases such as Crohn's disease, spastic colitis, rheumatoid Segren, multiple sclerosis and systemic lupus erythematosus, as well as in other diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis associated with age-related macular degeneration and other

Thus, the ligand for the Edg-1(S1P1) would be effective for the treatment or prevention of these diseases.

Formerly known Edg-1(S1P1) ligands include some types of thiophene derivatives (non-Patent document 7), derivatives of phosphoric acid (Patent documents 1 and 2, non-Patent documents 8 and 9) and thiazolidinone derivatives (Patent document 3), derivatives of carboxylic acids (Patent documents 4, 5, 6, and 8, non-Patent documents 10 and 11), derivatives containing amino group (Patent document 7), and derivatives of pyrrole (Patent document 9).

Patent document 1: WO2002-8395

Patent document 2: JP 2003-137894 A

Patent document 3: JP 2002-332278 A

Patent document 4: WO2002-092068

Patent document 5: WO 2003-105771

Patent document 6: WO 2004-058149

Patent document 7: WO 2004-103279

Patent document 8: WO 2005-058848

Patent document 9: WO 2005-123677

Non-patent document 1: J Biol Chem. 2004, 279: 20555, FASEB J 2002, 16: 625, Proceedings of the Japanese Society for Immunology 2003, 33: 2-J-W30-20-P

Non-patent document 2: Pharmacol Res 2003, 47: 401

Non-patent document 3: FASEB J 2002, 16:1874

Non-patent document 4: J Exp Med 2004, 199: 959

Non-patent document 5: Nature 2004, 427: 355

Non-patent document 6: J Clin Invest 2000, 106: 951, Biocchim Biophys Acta 2002, 1582: 222

Non-patent document 7: J Biol Chem 2004, 279: 13839

Non-patent document 8: Bioorg Med Chem Lett 2003, 13: 3401

Non-patent document 9: J Biol Chem. 2005; 280: 9833

Non-patent document 10: J Med Chem. 2004, 47: 6662

Non-patent document 11: J Med Chem. 2005, 48: 6169

DISCLOSURE of INVENTIONS

The PROBLEM addressed by the INVENTION

The aim of the present invention is to provide compounds having a new skeleton, which have an inhibitory effect on the binding between S1P and its receptor Edg-1(S1P1) and which are useful for pharmaceutical purposes.

TOOLS FOR PROBLEM SOLVING

As a result of extensive and intensive efforts made in the search for ligand compounds for Edg-1(S1P1), the authors present invention you smile, this goal is achieved by connecting the following formula (I) or its pharmaceutically acceptable salt. This discovery led to the creation of the present invention.

Embodiments of the invention will be given below for the compounds of formula (I) and its intermediate compounds of formula (II) (hereinafter referred to each as a “compound of the present invention”).

1. The compound represented by formula (I)or its pharmaceutically acceptable salt:

[Formula 1]

{where Ar represents a monocyclic heterocyclic ring containing one or two nitrogen atom,

where the specified Ar may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom,

Y1, Y2and Y3each represents a carbon atom or a nitrogen atom,

A represents an oxygen atom, a sulfur atom, a group represented by the formula-SO2-or a group represented by the formula-NR6- (where R6represents a hydrogen atom or a C1-C6alkyl group),

R1represents a hydrogen atom, a C1-C6alkyl group which may be substituted by substituent(s)selected from the following group [where the group consisting of hydroxyl group, halogen atom, With1-C6alkoxy groups is (where specified alkoxy group may be substituted by phenyl group) and phenyl group (where this phenyl group may be substituted by substituent(s), selected from the group consisting of a halogen atom and C1-C6alkyl group)], C3-C8cycloalkyl group2-C8alkenylphenol group2-C8alkylamino group or phenyl group,

R2represents a hydrogen atom, a C1-C6alkyl group or a C3-C8cycloalkyl group,

R3represents (i) hydrogen atom, (ii)1-C18alkyl group, (iii)2-C8alkenylphenol group which may be substituted by phenyl or benzyloxy group, (iv)2-C8alkylamino group which may be substituted by phenyl group, (v)3-C8cycloalkyl group which may be condensed with a benzene ring, (vi)1-C6alkyl group substituted by substituent(s)selected from the following group [where the group consists of a halogen atom, phenyl group (where this phenyl group may be substituted by 1-5 substituents selected from the group consisting of phenyl group, cyano group, halogen atom, With1-C6alkyl group, a C1-C6alkoxy group, triptorelin group, methoxycarbonyl group1-C6alkylthio group, dimethylamino group, a nitro group, acetamido group), With3-C8cycloalkyl group GI is rossilini group, With1-C6alkylthio group1-C6alkoxy group, benzyloxy group, phenoxy group, triptorelin group, deformational group, benzolsulfonate group, naftilos group7-C10criticalcare group, carbomethoxy(phenyl)methyl group, diphenylmethylene group, 1-phenylethylene group, imidazolidine group, indolines group, peredelnoj group, oxetanyl group, oxalanilide group, methylpiperidino group, piperazine derivatives group which may be substituted With1-C6alkyl group(s), benzylpiperidine group, morpholino group, 2-oxopyrrolidin-1-ilen group, 2-Oxymetazoline-1-ilen group, a group represented by the formula

-CO2R11

(where R11represents a hydrogen atom or a C1-C6alkyl group), a group represented by the formula

[Formula 2]

(where R12and R13each represents a hydrogen atom or a C1-C6alkyl group), a group represented by the formula

[Formula 3]

(where R14and R15each represents a hydrogen atom, a C1-C6alkyl group, phenyl group or 4-pyridylcarbonyl group), and the formula

-COR16

(where R16is1/sub> -C6alkyl group or phenyl group)], (vii) oxalanilide group, methylpiperidino group or a group represented by the formula

[Formula 4]

or (viii) optionally substituted aryl group,

R4represents a hydrogen atom or a C1-C6alkyl group which may be substituted by a carboxyl group, and

R5represents (i)1-C10alkyl group, (ii)1-C10alkyl group which is substituted by one or two substituents selected from the following group (where the group consists of a3-C8cycloalkyl group, peredelnoj group and phenyl, phenoxy or naftilos group which may be substituted by one or two substituents selected from the group consisting of a halogen atom and C1-C6alkoxy group), (iii)3-C8cycloalkyl group, (iv)2-C8alkenylphenol group, (v)2-C8alkenylphenol group, substituted phenyl group, (vi)2-C8alkylamino group, (vii)2-C8alkylamino group, substituted phenyl group, or (viii) optionally substituted aryl group, provided that when Ar represents a group represented by the following formula:

[Formula 5]

which the traveler may be substituted With 1-C6alkyl group, R5isn't C1-C10alkyl group.

2. The compound or its pharmaceutically acceptable salt according to embodiment 1, where in formula (I)

Ar represents a monocyclic heterocyclic ring containing one or two nitrogen atom,

A represents an oxygen atom, a sulfur atom or a group represented by the formula-NR6- (where R6represents a hydrogen atom or a C1-C6alkyl group),

R1represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkyl group, substituted phenyl group,

R2is1-C6alkyl group or a C3-C8cycloalkyl group,

R3is1-C6alkyl group or optionally substituted aryl group,

R4represents a hydrogen atom or a C1-C6alkyl group, and

R5represents (i)1-C10alkyl group, (ii)1-C10alkyl group which is substituted by one or two substituents selected from the following group (where the group consists of a3-C8cycloalkyl group, phenyl group, naftilos group, peredelnoj groups and phenyl groups, substituted with one or two substituents selected from GRU the dust, consisting of a halogen atom and C1-C6alkoxy group), (iii)3-C8cycloalkyl group, (iv)2-C8alkenylphenol group, (v)2-C8alkenylphenol group, substituted phenyl group, (vi)2-C8alkylamino group, (vii)2-C8alkylamino group, substituted phenyl group, or (viii) optionally substituted aryl group.

3. The compound or its pharmaceutically acceptable salt according to embodiment 1, where Ar represents a Deputy, represented by the following formula:

[Formula 6]

which may be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom.

4. The compound or its pharmaceutically acceptable salt according to embodiment 1, where Ar represents a Deputy, represented by the following formula:

[Formula 7]

which may be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom.

5. The compound or its pharmaceutically acceptable salt according to embodiment 1, where Ar represents a Deputy, represented by the following formula:

[Formula 8]

which can be zames is on Deputy selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom.

6. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-5, where A represents an oxygen atom.

7. The compound or its pharmaceutically acceptable salt according to any of embodiments 1 and 3-6, where R1is1-C6alkyl group which may be substituted atom(s) halogen, or benzyl group which may be substituted by substituent(s)selected from the group consisting of a halogen atom and C1-C6alkyl groups.

8. The compound or its pharmaceutically acceptable salt according to any of embodiments 1 and 3-6, where R1represents methyl group, ethyl group or a benzyl group which may be substituted atom(s) halogen.

9. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-6, where R1represents methyl group or ethyl group.

10. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-9, where R4represents a hydrogen atom.

11. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-10, where R2is1-C6alkyl group or a C3-C6cycloalkyl group is at.

12. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-10, where R2represents ethyl group or cyclopropyl group.

13. The compound or its pharmaceutically acceptable salt according to any of embodiments 1 and 3-12, where R5represents (i)1-C10alkyl group, (ii)1-C10alkyl group which is substituted by one or two substituents selected from the following group (where the group consists of a3-C8cycloalkyl group, peredelnoj group and phenyl, phenoxy or naftilos group which may be substituted by one or two substituents selected from the group consisting of a halogen atom and C1-C6alkoxy group), (iii)2-C8alkenylphenol group which may be substituted by phenyl group, or (iv) phenyl group, naftalina group, thienyl group, pyrrolidino group, pyrazolidine group, pyridyloxy group, fornillo group, benzothiazoline group, athinodorou group, isoxazolyl group, thiazolidine group, benzothiazolyl group, benzoxazolyl group, phenyl group condensed with a 5 - to 7-membered saturated hydrocarbon ring, which may contain as ring members, one or two oxygen atom, oralloy group, Kuma is strong, dihydroindole or tetrahydroisoquinoline group, where each of these groups may be substituted by 1-5 substituents selected from the following group

[where the group consists of a1-C6alkyl group which may be substituted atom(s) fluorine,2-C8alkenylphenol group, halogen atom, With1-C6alkoxy group which may be substituted atom(s) fluorine, pyrazolidine, oxazolidine, isoxazolidine, thiadiazolidine or pyrimidinyl group which may be substituted by substituent(s)selected from the group Y, where Y consists of a methyl group, triptorelin group, halogen atom and methylsulfonyl group)1-C6alkylthio group1-C6alkylsulfonyl group, benzolsulfonate group, morpholinomethyl group, morpholinosydnonimine group, aminosulfonyl group2-C10alkoxycarbonyl group, morpholino group which may be substituted With1-C6alkyl group(s), phenyl group which may be substituted With1-C6alkoxy group(s), phenoxy group, pyridylcarbonyl group, pyridyloxy group, cyano group2-C7alkanoyloxy group which may be substituted atom(s) fluorine, and2-C7alkanoyl the Ino group].

14. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-12, where R5is1-C10alkyl group, substituted C3-C8cycloalkyl group1-C10alkyl group, a substituted naftilos group2-C8alkenylphenol group, substituted phenyl group, the phenyl or naftalina group which may be substituted by 1-5 substituents selected from the following group (where the group consists of a1-C6alkyl group, halogen atom, With1-C6alkoxy group, triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group1-C6alkylsulfonyl group2-C7alkanoyloxy group2-C7alkoxycarbonyl group and a cyano group), pyrrolidinyl group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl groups and methoxycarbonyl group, fornillo group which may be substituted by substituent(s)selected from the following group (where the group consists of a1-C6alkyl group, triptorelin group and halogen atom), a thienyl group which may be substituted by substituent(s)selected from the following group is s (where the group consists of a 1-C6alkyl group, triptorelin group, thiadiazolyl group, oxazoline group and halogen atom), or benzothiazoline, dihydrobenzofuranyl, benzodioxolyl, dihydroergotoxine, dihydrobenzofuranyl, tetrahydronaphthalene, indenolol, thiadiazolidine, benzoxadiazole or benzothiazolyl group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group and halogen atom.

15. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-12, where R5is1-C6alkyl group, a substituted naftilos group2-C6alkenylphenol group, substituted phenyl group, unsubstituted phenyl group, phenyl group, substituted by 1-5 substituents selected from the following group (where the group consisting of methyl group, methoxy group and halogen atom), a phenyl group substituted by 1-3 substituents selected from the following group, and at least one of its 3 - and 4-positions is substituted (where the group consists of a1-C6alkyl group, halogen atom, methoxy group, triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group, matilal Niley group, acetyl group, methoxycarbonyl group and a cyano group), naftalina group which may be substituted by substituent(s)selected from the following group (where the group consists of a halogen atom, a C1-C6alkyl group, cyano group and1-C6alkylsulfonyl group), fornillo group which may be substituted by substituent(s)selected from the group consisting of triptorelin group and halogen atom, or benzothiazoline, benzoxadiazole, benzodioxolyl, dihydroergotoxine, dihydrobenzofuranyl, indenolol or benzothiazolyl group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group and halogen atom.

16. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-12, where R5represents a phenyl group, 3 - and 4-position which is substituted by halogen atom, or naftalina group which may be substituted by substituent(s)selected from the group consisting of a halogen atom, a C1-C6alkyl group and a cyano group.

17. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-16, where R3represents a phenyl group, naftalina group, pyrazolidine group, pyridyloxy group, the Indus is lilou group, benzothiazolyl group, benzothiazolyl group, pyrazolopyrimidinone group, hyalinella group, athinodorou group, benzothiazoline group or dihydrohelenalin group, where each of these groups may be substituted by 1-3 substituents selected from the following group [where the group consisting of substituents listed below:1-C6alkyl group which may be substituted atom(s) fluorine,3-C8cycloalkyl group, halogen atom, With1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of a fluorine atom, phenyl group, amino group, substituted With two1-C4alkyl groups, and morpholino group), phenoxy group, phenyl group, carboxyl group, With2-C10alkoxycarbonyl group, hydroxyl group, With2-C7monocyclic saturated hydrocarbon group containing the atom(s) of nitrogen as ring members (where specified saturated hydrocarbon group may be substituted With1-C6alkyl group(s)), nitrogen-containing monocyclic unsaturated hydrocarbon group, morpholinyl group which may be substituted With1-C6alkyl group(s), the piperazine derivatives of the group, which the traveler may be substituted by substituent(s), selected from the following group (where the group consists of a1-C6alkyl groups (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl groups, morpholino group, a hydroxyl group or a C1-C6alkoxy group), a formyl group, a C2-C7alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, and C1-C6alkylsulfonyl group), and the formula

-NR7R8

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl group, a hydroxyl group or a C1-C6alkoxy group), With1-C6alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, morpholinosydnonimine group, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, or With1-C alkylsulfonyl group, or, alternatively, R7and R8optional form together with the nitrogen atom that is attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group].

18. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-16, where R3is 2-naftalina group (where specified naftalina group may be substituted by substituent(s)selected from the group consisting of a halogen atom and C1-C6alkyl group), 3-pyrazolidine group (where specified pyrazolidine group may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group, triptorelin group and halogen atom), or 5-benzothiazolyl, 5-benzothiazolyl, 7-dihydrohelenalin, 7-athinodorou, 7-hyalinella, 3-pyridyloxy or indolenine group which may be substituted With1-C6alkyl group(s), an unsubstituted phenyl group or substituted phenyl group, shown below in (A)-(C):

(A) phenyl group, 4-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl g is uppy, With3-C8cycloalkyl group1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, morpholino group and phenyl group), halogen atom, triptoreline group, phenoxy group, phenyl group, 1-pyrrolidino group, and-NRARB(where RAand RBeach pose With1-C6alkyl group, or RAand RBoptional form together with the nitrogen atom that is attached to RAand RBA 3 - to 5-membered saturated hydrocarbon ring), and then 3-position of which may be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, halogen atom and C1-C6alkoxy group,

(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of hydroxyl group, With1-C6alkyl groups and C1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, morpholino group and phenyl group), and further which may be substituted by one or two1-C6Alki the implementing groups, or 4-position of which may be substituted by a halogen atom,

and

(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and, optionally, 4-position may be substituted by a halogen atom:

(i)2-C7monocyclic saturated hydrocarbon groups containing a member(s) of the ring atom(s) nitrogen (where specified saturated hydrocarbon group may be substituted With1-C6alkyl group(s)),

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group,

(iii) morpholinyl group which may be substituted With1-C6alkyl group(s)

(iv) piperazine derivatives group [where specified, piperazine derivatives the group may be substituted With1-C6alkyl group which may be substituted by substituent(s)selected from the following group (where the group consisting of the amino group substituted With two1-C4alkyl groups, and morpholino group), or With2-C7alkanoyloxy group], and

(v) the formula-NR7R8

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one liduma 1-C6alkyl group, a hydroxyl group or a C1-C6alkoxy group), With1-C6alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, morpholinosydnonimine group, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, or With1-C6alkylsulfonyl group, or, alternatively, R7and R8optional form together with the nitrogen atom that is attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

19. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-16, where R3represents a phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and, optionally, 4-position may be substituted by a halogen atom:

(i)2-C7monocyclic saturated hydrocarbon groups containing a member(s) of the ring atom(s) nitrogen (where specified saturated hydrocarbon group may be substituted With1-the 6alkyl group(s)),

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group,

(iii) morpholinyl group which may be substituted With1-C6alkyl group(s)

(iv) piperazine derivatives group [where specified, piperazine derivatives the group may be substituted With1-C6alkyl group which may be substituted by substituent(s)selected from the following group (where the group consisting of the amino group substituted With two1-C4alkyl groups, and morpholino group), or With2-C7alkanoyloxy group], and

(v) the formula-NR7R8

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl group, a hydroxyl group or a C1-C6alkoxy group), With1-C6alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, morpholinosydnonimine group, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, or With1-C6alkylsulfonyl group, or, alternatively, R7and R8optional is about form together with the nitrogen atom, attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

20. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-16, where R3represents phenyl group, 4-position which is substituted by fluorine atom or chlorine.

21. The compound or its pharmaceutically acceptable salt according to any of embodiments 1-16, where R3is 6-indolering group.

22. The compound or its pharmaceutically acceptable salt according to any of embodiments 1 and 3-16, where R3is1-C18alkyl group which may be substituted by substituent(s)selected from the following group (where the group consisting of halogen atom, amino group which may be substituted by one or two1-C6alkyl groups With1-C6alkoxy group, piperazine derivatives group which may be substituted With1-C6alkyl group(s), phenyl group, morpholino group)2-C8alkenylphenol group2-C8alkylamino group or3-C8cycloalkyl group.

23. The compound or its pharmaceutically acceptable salt soglasnoplanu of the embodiments 1 and 3-16, where R3is1-C6alkyl group substituted by substituent(s)selected from the following group (where the group consisting of the amino group which may be substituted by one or two1-C6alkyl groups, and C1-C6alkoxy group), or With3-C5cycloalkyl group.

24. Pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt according to any of embodiments 1-23.

25. The pharmaceutical composition according to embodiment 24, which is a therapeutic agent from autoimmune diseases, such as Crohn's disease, spastic colitis, rheumatoid Segren, multiple sclerosis or systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis and age-related macular degradation.

26. The compound represented by formula (II)or its salt:

[Formula 9]

(where R1, R2and R3have the meanings given above in embodiment 1, and Y4and Y5each represents a nitrogen atom or the formula CR17(where R17represents a hydrogen atom, a C1-C6alkyl group, phenyl group or halogen atom), provided that Odie is from the Y 4and Y5represents a nitrogen atom).

27. The compound or its salt according to embodiment 26, where in the formula (II) Y4represents CH and Y5represents a nitrogen atom.

28. The compound or its salt according to embodiment 26 or 27, where R1is1-C6alkyl group which may be substituted atom(s) halogen, or benzyl group which may be substituted by substituent(s)selected from the group consisting of a halogen atom and C1-C6alkyl groups.

29. The compound or its salt according to embodiment 26 or 27, where R1represents methyl group, ethyl group or a benzyl group which may be substituted atom(s) halogen.

30. The compound or its salt according to embodiment 26 or 27, where R1represents methyl group or ethyl group.

31. The compound or its salt according to any of embodiments 26 to 30, where R2is1-C6alkyl group or a C3-C8cycloalkyl group.

32. The compound or its salt according to any of embodiments 26 to 30, where R2represents ethyl group or cyclopropyl group.

33. The compound or its salt according to any of embodiments 26-32, where R3represents a phenyl group, naftalina group, pyrazolidine group, pyridyloxy group, indolenine gr the PPU, benzothiazolyl group, benzothiazolyl group, pyrazolopyrimidinone group, hyalinella group, athinodorou group, benzothiazoline group or dihydrohelenalin group, where each of these groups may be substituted by 1-3 substituents selected from the following group [where the group consisting of substituents listed below:1-C6alkyl group which may be substituted atom(s) fluorine,3-C8cycloalkyl group, halogen atom, With1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of a fluorine atom, phenyl group, amino group, substituted With two1-C4alkyl groups, and morpholino group), phenoxy group, phenyl group, carboxyl group, With2-C10alkoxycarbonyl group, hydroxyl group, With2-C7monocyclic saturated hydrocarbon group containing the atom(s) of nitrogen as member(s) ring(EC) (where specified saturated hydrocarbon group may be substituted With1-C6alkyl group(s)), nitrogen-containing monocyclic unsaturated hydrocarbon group, morpholinyl group which may be substituted With1-C6alkyl group(s), the piperazine derivatives group which may be substituted by substituent(s), selected from the following group [where the group consists of a1-C6alkyl groups (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl groups, morpholino group, a hydroxyl group or a C1-C6alkoxy group), a formyl group, a C2-C7alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, and C1-C6alkylsulfonyl group], and the formula

-NR7R8

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl group, a hydroxyl group or a C1-C6alkoxy group), With1-C6alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, morpholinosydnonimine group, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, or With1-C alkylsulfonyl group, or, alternatively, R7and R8optional form together with the nitrogen atom that is attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group].

34. The compound or its salt according to any of embodiments 26-32, where R3is 2-naftalina group (where specified naftalina group may be substituted by substituent(s)selected from the group consisting of a halogen atom and C1-C6alkyl group), 3-pyrazolidine group (where specified pyrazolidine group may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group, triptorelin group and halogen atom), or 5-benzothiazolyl, 5-benzothiazolyl, 7-dihydrohelenalin, 7-athinodorou, 7-hyalinella, 3-pyridyloxy or indolenine group which may be substituted With1-C6alkyl group(s), an unsubstituted phenyl group or substituted phenyl group, shown below in (A)-(C):

(A) phenyl group, 4-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl group, a C3-C8the CEC is alkylene group, With1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, morpholino group and phenyl group), halogen atom, triptoreline group, phenoxy group, phenyl group, 1-pyrrolidino group, and-NRARB(where RAand RBeach is1-C6alkyl group, or RAand RBoptional form together with the nitrogen atom to which RAand RBattached, a 3 - to 5-membered saturated hydrocarbon ring), and then 3-position of which can be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, halogen atom and C1-C6alkoxy group,

(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of hydroxyl group, With1-C6alkyl groups and C1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, morpholino group and phenyl group), and optionally may be substituted by one or two1-C6alkyl groups, or 4-progenitores may be substituted by a halogen atom,

and

(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and, optionally, 4-position may be substituted by a halogen atom:

(i)2-C7monocyclic saturated hydrocarbon groups containing a member(s) of the ring atom(s) nitrogen (where specified saturated hydrocarbon group may be substituted With1-C6alkyl group(s)),

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group,

(iii) morpholinyl group which may be substituted With1-C6alkyl group(s)

(iv) piperazine derivatives group [where specified, piperazine derivatives the group may be substituted With1-C6alkyl group which may be substituted by substituent(s)selected from the following group (where the group consisting of the amino group substituted With two1-C4alkyl groups, and morpholino group), or With2-C7alkanoyloxy group], and

(v) the formula-NR7R8

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl groups, morpholino groups is th, a hydroxyl group or a C1-C6alkoxy group), With1-C6alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, morpholinosydnonimine group, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, or With1-C6alkylsulfonyl group, or alternatively R7and R8optional form together with the nitrogen atom that is attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

35. The compound or its salt according to any of embodiments 26-32, where R3is1-C18alkyl group which may be substituted by substituent(s)selected from the following group (where the group consisting of halogen atom, amino group which may be substituted by one or two1-C6alkyl groups With1-C6alkoxy group, piperazine derivatives group which may be substituted With1-C6alkyl group(s), phenyl group, morpholino group)2-C8alkenylphenol group2-C8alkyne is inuu group or 3-C8cycloalkyl group.

The present invention will be illustrated in detail below.

Have in mind that monocyclic heterocyclic ring containing one or two nitrogen atom represented by the symbol Ar, includes pyrrole, imidazole and pyrazole, shown below.

[Formula 10]

The term “halogen atom” refers to fluorine atom, chlorine, bromine or iodine.

The term “C1-C6alkyl group” refers to linear or branched alkyl group containing 1-6 carbon atoms. The examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, sec-boutelou group, n-pentelow group, isopentyl group, neopentyl group, tert-pentelow group and n-hexoloy group.

The term “C3-C8cycloalkyl group” refers to cycloalkyl group containing 3-8 carbon atoms. Examples of it include cyclopropyl group, cyclobutyl group, cyclopentyl group and tsiklogeksilnogo group.

The term “C2-C8Alchemilla group” refers to linear or branched alkenylphenol group containing 2-8 carbon atoms. The examples include vinyl group, allyl group, 1-propenyloxy group,Isopropenyl group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1,3-butadienyl group, 2-methylallyl group, 2-methyl-propenyloxy group, 2-pentanediol group and 3-methyl-but-2-enelow group.

The term “C2-C8Alchemilla group” refers to linear or branched alkenylphenol group containing 2-8 carbon atoms. Examples of it include etinilnoy group, 2-propenyloxy group, 2-butenyloxy group, 1-methyl-prop-2-inlow group, 2-pantanillo group and 4-pantanillo group.

The term “C1-C6alkoxy group” refers to linear or branched alkoxy group containing 1-6 carbon atoms. The examples include a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group.

The term “C1-C10alkyl group” refers to linear or branched alkyl group containing 1-10 carbon atoms. The examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, sec-boutelou group, n-pentelow group, isopentyl group, neopentyl group, tert-pentelow group, n-hexoloy group, n-heptylene group, n-aktiline groups and n-hexadecyl group.

The term “C1-C6alkylthio group” refers to linear or branched, alkylthio group containing 1-6 carbon atoms. The examples include a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutyric group, pentylthio group and hexylthio group.

The term “C1-C6alkylsulfonyl group” refers to linear or branched alkylsulfonyl group containing 1-6 carbon atoms. Examples of it include methanesulfonyl group, ethanolgasoline group, propane-2-sulfonyloxy group and hexanesulfonic group.

The term “C2-C10alkoxycarbonyl group” refers to linear or branched alkoxycarbonyl group containing 2-10 carbon atoms. Examples of its include2-C7alkoxycarbonyl groups, such as methoxycarbonyl group, ethoxycarbonyl group and tert-butoxycarbonyl group, as well as octyloxyphenyl group.

The term “C2-C7alcoolica group” refers to linear or branched alkanoyloxy group containing 2 to 7 carbon atoms. The examples include acetyl, propanolol group, butanoyloxy group and hexanoyl group.

The term “C1-C6alcoolica group” refers to linear or branched and is karolneu group, containing 1-6 carbon atoms. The examples include formyl group, acetyl group, propanolol group and butanoyloxy group.

Have in mind that the phrase “amino group which may be substituted by one or two1-C6alkyl group”includes, for example, amino group, methylamino group, ethylamino group, isopropylamino group, hexylamino group, dimethylamino group, diethylamino group, diisopropylamino group, digoxigenin group.

Have in mind that the phrase “aminosulfonyl group which may be substituted by one or two1-C6alkyl group”includes, for example, sulfamoyl group, dimethylaminomethyl group and diethylaminomethyl group.

Have in mind that the phrase “carnemolla group which may be substituted With1-C4alkyl group(s)”includes karbamoilnuyu group, methylcarbamoyl group, ethylcarbitol group and profilirovannuju group.

The phrase “piperazine derivatives group which may be substituted” or “optionally substituted, piperazine derivatives group”relates to piperazine derivatives group which may be substituted (preferably on its nitrogen atom) substituent(s)selected from the group consisting of C1-C6alkyl groups (where this alkyl group may be the substituted amino group, which may be substituted by one or two1-C6alkyl groups, morpholino group, a hydroxyl group or a C1-C6alkoxy group), a formyl group, a C2-C7alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, and C1-C6alkylsulfonyl group. Specific examples include the piperazine derivatives group, methylpiperazine group, isopropylpiperazine group, dimethylaminopyridine group, acetylpiperidine group.

The phrase “C2-C7monocyclic saturated hydrocarbon group containing the atom(s) of nitrogen as member(s) of the ring”refers to a 3 - to 9-membered monocyclic saturated hydrocarbon group, which contains one or two nitrogen atom as ring members and substituted through its ring carbon atom. Examples include azetidinol group, pyrrolidinyl group and piperidinyloxy group (for example, 4-piperidinyloxy group).

The term “nitrogen-containing monocyclic unsaturated hydrocarbon group” refers to 5 - or 6-membered unsaturated ring containing 1-3 nitrogen atom as ring members. The examples on the receive pyrrolidino group (for example, pyrrol-1-ilen group, imidazol-1-ilen group (for example, imidazolidinyl group), pyrazolidine group, triazole-4-ilen group (e.g., [1,2,4]triazole-4-ilen group) and pyridyloxy group.

Assume that 3 - to 5-membered saturated hydrocarbon ring formed by RAand RBtogether with the nitrogen atom that is attached to RAand RBincludes aziridinyl group, azetidinol group and pyrrolidinyloxy group.

Assume that 3 - to 8-membered saturated hydrocarbon ring formed by R7and R8(or RWithand RDtogether with the nitrogen atom that is attached to R7and R8(or RWithand RD), includes aziridinyl group, azetidinol group, pyrrolidinyl group and piperidinyloxy group.

It is understood that the phrase “phenyl group condensed with a 5 - to 7-membered saturated hydrocarbon ring, which may contain as ring members, one or two oxygen atom”includes benzodioxepine group, benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group and indenolol group.

The term “aryl group”used herein refers to an aromatic hydrocarbon group, a partially saturated aromatic hydrocarbon g is the SCP, aromatic heterocyclic group, or a partially saturated aromatic heterocyclic ring. The aromatic hydrocarbon group includes, for example, With6-C14the aromatic hydrocarbon group include phenyl group, naftalina and untilnow group.

Partially saturated aromatic hydrocarbon group refers to a group obtained by partial saturation With6-C14polycyclic aromatic hydrocarbon group. Examples include tetrahydronaphthalene group and indenolol group.

The aromatic heterocyclic group is a C2-C13monocyclic or polycyclic aromatic heterocyclic group containing 1-6 heteroatoms (such as oxygen atoms, sulfur and/or nitrogen). Examples of it include a thienyl group, fornillo group, pyrrolidino group, isothiazolinone group, isoxazolyl group, pyrazolidine group, thiazolidine group, oxazolidinyl group, imidazolidinyl group, pyridyloxy group, pyridazinyl group, pyrimidinyl group, personilnya group, benzothiazoline group, benzofuranyl group, indolenine group, benzothiazolyl group, benzoxazolyl group, benzimidazolyl group, hyalinella group, athinodorou group, benzoxadiazole, benzothiadiazole group and pyrazolopyrimidinone group (for example, 5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-ilen group).

Partially saturated aromatic heterocyclic ring refers to a heterocyclic ring derived partial saturation of polycyclic aromatic heterocyclic group. Such a heterocyclic ring may be substituted by an oxo group. Examples include dihydrohelenalin group:

[Formula 11]

,

dihydrobenzofuranyl group, dihydroergotoxine group, dihydrobenzofuranyl group, benzodioxolyl group, dihydroisoxazole group and dihydroisoquinoline group.

When such aryl group is substituted, the substituents for the aryl group include the substituents listed below and aryl group may be substituted by 1-5 of these substituents:

halogen atom, cyano group, nitro group, sulfamoyl group, hydroxyl group, carboxyl group, With1-C6alkyl group, triptorelin group, methoxycarbonylamino group1-C6alkoxy group (where specified alkoxy group may be substituted by phenyl group, With1-C6alkylamino group2-C12dialkylamino group or morpholino group is Oh), triptoreline group, deformedarse group, cyanoethoxy group,

With2-C8alkenylphenol group2-C8alkylamino group,

With3-C8cycloalkyl group2-C7alkanoyloxy group, trifluoracetyl group2-C10alkoxycarbonyl group,

phenyl group (where this phenyl group may be substituted With2-C7alkanoyloxy group or1-C6alkoxy group),

phenoxy group which may be substituted With1-C6alkoxy group,

pyrazolidine group, 1-methyl-5-trifluoromethyl-1H-pyrazole-3-ilen group, methylpyrrolidinyl group, 2-methylsulfanyl-pyrimidine-4-ilen group, oxazolidinyl group (for example, oxazol-5-ilen group)

isoxazol-5-ilen group, 5-trifluoromethyl-isoxazol-3-ilen group, pyridyloxy group (for example, 4-pyridyloxy group)

pyridylcarbonyl group, benzoyloxy group, pyrrolidino group (for example, pyrrol-1-ilen group), imidazolidinyl group (for example, imidazol-1-ilen group), thiazolidine group,

[1,2,3]thiadiazole-4-ilen group, triazolyl group (e.g., [1,2,4]triazole-4-ilen group)1-C6alkylthio group (for example, methylthio group), With1-C6alkylsulfonyl group (for example, methanesulfonyl group), Ben is azulfidilne group, pyrrolidinecarbonyl group, morpholinylcarbonyl group, 4-piperidinyloxy group which may be substituted With1-C6alkyl group(s), morpholino group which may be substituted With1-C6alkyl group(s), the piperazine derivatives group, which is substituted With1-C6alkyl group(s) or (C1-C6alkyl group(s)substituted(s) dimethylamino group, or

the group represented by the formula-NR7R8[where R7and R8each represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted With1-C6alkoxy group or a dimethylamino group), With1-C6alkanoyloxy group, karbamoilnuyu group, karbamoilnuyu group, substituted C1-C4alkyl group(s), morpholinosydnonimine group, dimethylaminomethyl group or1-C6alkylsulfonyl group, or, alternatively, R7and R8optional form together with the nitrogen atom that is attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted, dimethylindole group, oxo group or a hydroxyl group] (for example, acetamido, dimethylamino, macilwraith, butylurea, trimethylurea, morpholinyl is ebonyline group), methoxyethylamine group, pyridinedicarboxylate group.

The term “pharmaceutically acceptable salt” refers to salts of alkali, alkaline earth metal, ammonium or alkylamine, or salt of a mineral or organic acid. Examples of it include sodium salt, potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, acetate salt, propionate salt, butyrate salt, formiate salt, trifenatate salt, maleato salt, tartrate salt, citrate, stearate, succinate, ethylsuccinate, lactobionate salt, gluconate salt, glucoheptonate salt, benzoate salt, methansulfonate salt, econsultancy salt, 2-hydroxyethanesulfonic salt, bansilalpet salt, paratoluenesulfonyl salt, laurilsulfate salt, malatoy salt, aspartate salt, glutamate salt, adipate salt, salt with cysteine, salt with N-acetylcysteine, cleaners containing hydrochloride salt, hydrobromide salt, phosphate salt, sulfate salt, hydroiodide salt, nicotinate salt, oxalate salt, picrate salt, thiocyanate salt, undecanoate salt, salt with acrylate polymer and salt with carboxyvinyl polymer.

Compounds of the present invention may have stereoisomers including optical isomers, diastereoisomers and geometric isomers. All of these Stere the isomers and mixtures thereof are covered by the scope of the present invention. Some of the compounds and intermediates of the present invention may also exist, for example, in the form of ketoenols of tautomers.

As shown in test example described below, the compounds of the present invention have a strong inhibitory effect on the binding between S1P and its receptor Edg-1(S1P1), and, therefore, it is expected that they have a preventive or therapeutic effect on autoimmune diseases, such as Crohn's disease, spastic colitis, rheumatoid Segren, multiple sclerosis and systemic lupus erythematosus, as well as other diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age related macular degeneration and other

The preferred embodiment of the compounds of the present invention will be given below.

A preferred example of Ar is a 5-membered unsaturated ring containing one or two nitrogen atom. More preferred is an imidazole group, represented by the following formula:

[Formula 12]

and even more preferred is

These rings can be substituted by the Deputy selected from the group, with the standing of 1-C6alkyl group, phenyl group and halogen atom. More preferably Ar is unsubstituted.

A preferred example, a is an oxygen atom.

A preferred example of R1is1-C6alkyl group which may be substituted atom(s) halogen or benzyl group which may be substituted by substituent(s)selected from the group consisting of a halogen atom and C1-C6alkyl groups. More preferred is methyl, ethyl or benzyl group which may be substituted atom(s) halogen (more preferably by atom(s) fluorine), and even more preferred is a methyl group.

A preferred example of R2is an ethyl group or cyclopropyl group.

A preferred example of R4is a hydrogen atom.

A preferred example of R3is1-C6alkyl group substituted by substituent(s)selected from the following group (where the group consisting of the amino group which may be substituted by one or two1-C6alkyl groups, and C1-C6alkoxy group), With3-C5cycloalkyl group or optionally substituted phenyl group, 2-naftalina group which may be substituted to cover elem(s), selected from the group consisting of a halogen atom and C1-C6alkyl group, 3-pyrazolidine group which may be substituted by substituent(s)selected from the following group [where the group consists of a1-C6alkyl group (preferably methyl group), triptorelin group and halogen atom], or 5-benzothiazolyl, 5-benzothiazolyl, 7-dihydrohelenalin, 7-athinodorou, 7-hyalinella, 3-pyridyloxy or indolenine (preferably 6-indolenine) group which may be substituted With1-C6alkyl group(s) (preferably methyl group).

Have in mind that “optional substituted phenyl group” among the preferred embodiments of the groups R3includes unsubstituted phenyl group and substituted phenyl group, shown below in (A)-(C):

(A) phenyl group, 4-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl group, a C3-C8cycloalkyl group1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, morpholino group and phenyl group), halogen atom, triptoreline group, pheno the si group, phenyl group, 1-pyrrolidino group, and-NRARB(where RAand RBeach is1-C6alkyl group, or RAand RBoptional form together with the nitrogen atom that is attached to RAand RBA 3 - to 5-membered saturated hydrocarbon ring), and then 3-position of which may be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, halogen atom and C1-C6alkoxy group,

(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of hydroxyl group, With1-C6alkyl groups and C1-C6alkoxy group (where specified alkoxy group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, morpholino group and phenyl group), and further which may be substituted by one or two1-C6alkyl group or 4-position of which may be substituted by a halogen atom, and

(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and optionally 4-position of which may be optionally substituted by a halogen atom, where the nitrogen in the specified asused Rasa group is preferably a tertiary and preferably used for attachment to the phenyl group:

(i)2-C7monocyclic saturated hydrocarbon groups containing a member(s) of the ring atom(s) nitrogen which is substituted in the phenyl group via a carbon atom (where specified saturated hydrocarbon group may be substituted With1-C6alkyl group(s)) (for example, piperidinyl group which may be substituted With1-C6alkyl group(s), an example of which is a 4-piperidinyl group),

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group (for example, pyrrolidino group, imidazolidine group)

(iii) morpholinyl group which may be substituted With1-C6alkyl group(s) (for example, morpholino group)

(iv) optionally substituted, piperazine derivatives group [for example, the piperazine derivatives group which may be substituted (preferably by its ring nitrogen atom) substituent(s)selected from the following group [where the group consists of a1-C6alkyl groups (where this alkyl group may be substituted by substituent(s)selected from the group consisting of amino group substituted With two1-C4alkyl groups, and morpholino group), and C2-C7alkanoyloxy group]], and

(v) the formula-NR7R8

where R7and R8each represents the t of a hydrogen atom, With1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one or two1-C6alkyl groups, morpholino group, a hydroxyl group or a C1-C6alkoxy group), With1-C6alkanoyloxy group, carbamoyl group which may be substituted by one or two1-C4alkyl groups, morpholinosydnonimine group, aminosulfonyl group which may be substituted by one or two1-C6alkyl groups, or With1-C6alkylsulfonyl group, or, alternatively, R7and R8optional form together with the nitrogen atom that is attached to R7and R8A 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group].

The formula-NR7R8in (v) is more preferably is a formula-NRWithRDdefined below:

RWithand RDeach represents a hydrogen atom, a C1-C6alkyl group (where this alkyl group may be substituted amino group which may be substituted by one or two1-C4alkyl groups, hydroxy who enoy group or 1-C4alkoxy group), formyl group, acetyl group, aminocarbonyl group, dimethylaminomethylene or methylsulfonyl group, or, alternatively, RWithand RDoptional form together with the nitrogen atom that is attached to RWithand RDA 3 - to 8-membered saturated hydrocarbon ring, where the specified ring may be substituted by substituent(s)selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

Especially preferred embodiment, R3is a phenyl group, a 4-position which is substituted by fluorine atom or chlorine, 6-indlela group or phenyl group which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups shown in (i), (iv) and (v) the embodiments of paragraph (C) above, and, optionally, 4-position may be substituted by a halogen atom.

The preferred embodiment R5is1-C10(preferably1-C6) alkyl group, substituted C3-C8cycloalkyl group1-C10(preferably1-C6) alkyl group, substituted naftilos group2-C8(preferably2-C6) Alchemilla group, substituted phenyl group, phenyl group or naftalina group (PR is doctitle 2-naftalina group), which may be substituted by 1-5 substituents selected from the following group (where the group consists of a1-C6alkyl group, halogen atom, With1-C6alkoxy group, triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group1-C6alkylsulfonyl group2-C7alkanoyloxy group2-C7alkoxycarbonyl group and a cyano group), pyrrolidinyl group which may be substituted by substituent(s)selected from the following group [where the group consists of a1-C6alkyl group (preferably methyl group) and methoxycarbonyl group], fornillo group which may be substituted by substituent(s)selected from the following group [where the group consists of a1-C6alkyl group (preferably methyl group), triptorelin group and halogen atom], a thienyl group which may be substituted by substituent(s)selected from the following group [where the group consists of a1-C6alkyl group (preferably methyl group), triptorelin group, thiadiazolyl group, oxazoline group and halogen atom], or, alternatively, benzothiazoline group (preferably 2-benzothiazoline GRU is PU), phenyl group condensed with a 5 - to 7-membered saturated hydrocarbon ring, which may contain one or two oxygen atom as ring members (e.g., benzodioxepine group, benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group group indenolol group), thiadiazolidine, benzoxadiazole group or benzothiazolyl group (preferably 5-benzothiazolyl group), each of which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group (preferably methyl group) and halogen atom.

Have in mind that the “phenyl group which may be substituted”, among the preferred embodiments of the groups R5includes unsubstituted phenyl group, phenyl group which is substituted by 1-5 substituents selected from the group consisting of C1-C6alkyl group (preferably methyl group), With1-C6alkoxy group (preferably methoxy group) and halogen atom, and a phenyl group which is substituted by 1-3 substituents selected from the following group, and at least one of 3 - and 4-positions is substituted, where the group consists of a1-C6alkyl groups, at the mA halogen, With1-C6alkoxy group (preferably methoxy group), triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group1-C6alkylsulfonyl group (preferably methylsulfonyl group), methoxycarbonyl group, acetyl group, cyano group, more preferably the halogen atom, methyl group and methoxy group, and even more preferably the halogen atom.

Have in mind that “naftalina group which may be substituted”, among the preferred embodiments of the groups R5includes naftalina group which may be substituted by substituent(s) (preferably 1-3 substituents), selected from the group consisting of a halogen atom, a C1-C6alkyl group (preferably methyl group), cyano group and1-C6alkylsulfonyl group (preferably methylsulfonyl group). More preferred is naftalina group, which is substituted by substituent(s)selected from the group consisting of a halogen atom, a C1-C6alkyl group (preferably methyl group), cyano group. In the case of 2-naftilos group, examples include unsubstituted 2-naftalina group and 2-naftalina group, which is substituted by substituent(s)selected from the group sotoyama is from C 1-C6alkyl group (substituted in any position, more preferably a 5-, 7 - and/or 8 - position(s)and other substituents (substituted 5-, 7 - and/or 8-position(s)). Similarly, in the case of 1-naftilos group examples include unsubstituted naftalina group and 1-naftalina group, which is substituted by substituent(s)selected from the group consisting of C1-C6alkyl group (substituted in any position), and other substituents, preferably halogen atom (preferably substituted at the 4-position).

Especially preferred embodiment, R5is a phenyl group, 3 - and 4-position of which are each substituted by a halogen atom, unsubstituted 2-naftalina group or 2-naftalina group, 5-, 7 - and/or 8-position(I) which is substituted(s) of substituent(s)selected from the group consisting of a halogen atom, a C1-C6alkyl (preferably methyl) group and cyano group.

Especially preferred embodiments, R3and R5are the following.

In the case when R3is a phenyl group, a 4-position which is substituted by fluorine atom or chlorine, R5is1-C10(preferably1-C6) alkyl group, substituted naftilos group2-C8(preferably2-C6) alkenylphenol g is the SCP, substituted phenyl group, substituted phenyl group [for example, phenyl group which is substituted by 1-5 of methyl groups, phenyl group which is substituted by 1-3 substituents selected from the following group, and at least one of 3 - and 4-positions is substituted, where the group consists of a1-C6alkyl group (preferably methyl group, ethyl group, through the group), halogen atom, methoxy group, triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group (preferably vinyl groups), methoxycarbonyl group, acetyl group and a cyano group], benzothiazoline group, naftalina group which may be substituted by substituent(s)selected from the following group [where the group consists of a halogen atom, a C1-C6alkyl group (preferably methyl group), cyano group and1-C6alkylsulfonyl group (preferably methylsulfonyl group)], pyrrolidino group which may be substituted by substituent(s)selected from the group consisting of a methyl group and ethoxycarbonyl group, thienyl group, substituted C1-C6alkyl group(s) (preferably methyl group), or benzodioxolyl group, Digi Robinsonville group, dihydrobenzofuranyl group, tetrahydronaphthyl group, indenolol group or benzothiazolyl group (preferably 5-benzothiazolyl group).

In the case when R3is 6-indolering group:

R5is1-C10(preferably1-C6) alkyl group, substituted naftilos group2-C8(preferably2-C6) alkenylphenol group, substituted phenyl group optionally substituted phenyl group [e.g., unsubstituted phenyl group, phenyl group which is substituted by 1-5 of methyl groups, phenyl group which is substituted by 1-3 substituents selected from the following group, and at least one of 3 - and 4-positions is substituted, where the group consists of a1-C6alkyl group (preferably methyl group, ethyl group, through the group), halogen atom, methoxy group, triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group (preferably vinyl groups), methoxycarbonyl group, acetyl group and a cyano group], benzothiazoline group, naftalina group which may be substituted by substituent(s)selected from the following group [where the group consists of atom ha is ogena, With1-C6alkyl group (preferably methyl group), cyano group and1-C6alkylsulfonyl group (preferably methylsulfonyl group)], pyrrolidino group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group (preferably methyl group) and methoxycarbonyl group, or benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group, indenolol group or benzothiadiazole (preferably 5-benzothiadiazole) group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl (preferably methyl) group and halogen atom.

In the case when R3is the embodiment of that shown in (C) above:

R5is1-C6alkyl group, substituted C3-C8cycloalkyl group1-C10(preferably1-C6) alkyl group, substituted naftilos group2-C8(preferably2-C6) alkenylphenol group, substituted phenyl group optionally substituted phenyl group [e.g., unsubstituted phenyl group, phenyl group which is substituted by 1-5 substituents selected from C 1-C6alkyl group (preferably methyl group) and halogen atom, phenyl group which is substituted by 1-3 substituents selected from the following group, and at least one of 3 - and 4-positions is substituted, where the group consists of a1-C6alkyl group, halogen atom, methoxy group, triptoreline group, deformedarse group, triptorelin group1-C6alkenylphenol group1-C6alkylsulfonyl group (preferably methylsulfonyl group)], methoxycarbonyl group, acetyl group and a cyano group], naftalina group which may be substituted by substituent(s)selected from the following group [where the group consists of a halogen atom, a C1-C6alkyl group (preferably methyl group), cyano group and1-C6alkylsulfonyl group (preferably methylsulfonyl group)], pyrrolidino group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group (preferably methyl group) and methoxycarbonyl group, thienyl group which may be substituted by substituent(s)selected from the following group [where the group consists of a1-C6alkyl groups (prepost the tion of a methyl group), triptorelin group, thiadiazolyl group, oxazoline group and halogen atom], fornillo group which may be substituted by substituent(s)selected from the following group [where the group consists of a1-C6alkyl group (preferably methyl group), triptorelin group and halogen atom], or benzothiazoline, benzodioxolyl, dihydroergotoxine, dihydrobenzofuranyl, tetrahydronaphthalene, indenolol, thiadiazolidine (preferably 5-thiadiazolyl), benzoxadiazole or benzothiadiazole (preferably 5-benzothiadiazole) group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl (preferably methyl) group and halogen atom.

Preferred optically active forms of the compounds of the present invention are compounds having the following structure.

[Formula 13]

Compounds of the present invention can be synthesized, for example, by using the procedures shown below by example.

[Formula 14]

(Scheme 1)

[Formula 15]

(Scheme 1)

(Scheme 1)

In the above stages with Moly R 1, R2, R3, R5and a have the meanings given above, R41has the same meaning as R4with the exception of the hydrogen atom, REis1-C6alkyl or phenyl group, Met represents a typical metal such as Li, Na, MgCl or MgBr, Met' is a typical metal (such as Li, Na, B, Mg, Al, Zn, Sn), or a group represented by a complex between this typical metal and its ligand (the ligand may be a hydroxyl group, halogen atom, methoxy group or bidentate ligand represented by the formula- (CH2)3O-), L represents a leaving group (where the leaving group may be, for example, halogen atom such as chlorine atom, bromine or iodine, atomic charges of the group, methanesulfonate group or p-toluensulfonate group), and X represents a halogen atom such as chlorine atom, bromine or iodine.

[Formula 16]

(Scheme 2)

In the above stages of the symbols R1, R2, R3, R5and a have the meanings given above, R41has the same meaning as R4with the exception of the hydrogen atom, REis1-C6alkyl or phenyl group, Met represents a typical metal such as Li, Na, MgCl or MgBr, Met' is a typical metal (such as Li, Na, B, Mg, Al, Zn, Sn), or group, presented the military complex between this typical metal and its ligand (the ligand may be a hydroxyl group, halogen atom, methoxy group or bidentate ligand represented by the formula- (CH2)3O-), L represents a leaving group (where the leaving group may be, for example, halogen atom such as chlorine atom, bromine or iodine, atomic charges of the group, methanesulfonate group or p-toluensulfonate group), and X represents a halogen atom such as chlorine atom, bromine or iodine.

[Formula 17]

(Scheme 3)

In the above stages of the symbols R1, R3, R5and a have the meanings given above, R41has the same meaning as R4with the exception of the hydrogen atom, R2Arepresents-CH2-R21(where R21is1-C5alkyl group), RBBis1-C6alkyl or phenyl group, Met represents a typical metal such as Li, Na, MgCl or MgBr, L represents a leaving group (where the leaving group may be, for example, halogen atom such as chlorine atom, bromine or iodine, atomic charges of the group, methanesulfonate group or p-toluensulfonate group), and X represents a halogen atom such as chlorine atom, bromine or iodine.

Below is given a detailed description of each scheme.

Scheme 1, Procedure And

Stage 1A-1: Compound represented by the formula (1A), may be injected into reaction with the imidazole is the presence of a base with or without using a solvent, to obtain compounds represented by a formula (1b). The amount used of the compound represented by formula (1A)is generally 1-10 equivalents, preferably 1.0 to 3.0 equivalents of imidazole. Examples are available for use bases include hydroxides of alkali metals (for example, NaOH, KOH), alkali metal salts (for example, NaHCO3, K2CO3), amides of alkali metals (for example, LiNH2, NaNH2), and sodium hydride. The amount used of the base is usually 1 to 10 equivalents, preferably 1.0 to 3.0 equivalents of imidazole. The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux. When required, the solvent may be any solvent as long as it is inert to the reaction include water, ethers (e.g. dioxane, tetrahydrofuran (THF)), polar aprotic solvents such as dimethylformamide (DMF), N,N'-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), N,N'-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), dimethyl sulfoxide (DMSO), ammonia or mixtures thereof. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 1A-2: Compound represented by the formula (1b)may be re who work with a halogenation agent to obtain compounds represented by the formula (1C). Examples of the halogenation agent include Cl2, Br2, I2N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), 2,4,4,6-tetrabromocyclooctane, hexachlorethane, PCl5and SOCl2. The amount of halogenation agent is generally 1-10 equivalents, preferably 1.0 to 1.5 equivalent, from compounds represented by formula (1b). When required, the solvent may be any solvent as long as it is inert to the reaction include water, ethers (e.g. dioxane, THF, Et2O), polar aprotic solvents such as DMF, DMA, NMP, DMPU, HMPA), alcohols (e.g., MeOH, EtOH), halogenated solvents (e.g., CCl4, CHCl3CH2Cl2), CH3CN, acetic acid or mixtures thereof. If necessary, is added to the base. Examples of the base include hydroxides of alkali metals (for example, NaOH, KOH), alkali metal salts (for example, NaHCO3, K2CO3, AcONa), amines (e.g., Et3N iPr2Been certified with qi net, iPr2NH), n-BuLi, diisopropylamide lithium (LDA) and NaH. The amount of base is usually 1 to 10 equivalents, preferably 1.0 to 1.2 equivalents, of the compound represented by formula (1b). The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, p is edocfile from -78°C to room temperature. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 1A-3: Compound represented by the formula (1C)may be the reaction of the compound represented by formula (1d)in the presence of a base with or without using a solvent, to obtain the compound represented by the formula (1E). The amount used of the compound (1d) is generally 1-5 equivalents, preferably 1-3 equivalents, from compounds represented by the formula (1C). Examples of the base include alkali metal salts (for example, Na2CO3, K2CO3Cs2CO3, NaHCO3, KHCO3, NaOH, dimesylate, NaH, NaNH2, tert-BuOK, t-BuONa), amines (e.g., Et3N iPr2Been certified with qi net, iPr2NH, pyrrolidine, piperidine), AcONa and Asok. The amount of base is generally 1-10 equivalents, preferably 1-3 equivalents, from compounds represented by the formula (1C). The reaction temperature ranges from 0°C to 300°C, and the reaction can be performed, for example, at normal pressure, increased pressure or under microwave irradiation. Examples of the reaction is available for use of the solvent include ethers (e.g. dioxane, THF, Et2O), DMF, DMA, NMP, DMPU, HMPA, DMSO, or a mixture thereof. what if you, the additive will be applied. Examples of additives include metal salts (e.g., CuI, CuCl) or copper powder. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 1 to 12 hours.

Stage 1A-4: Compound represented by the formula (1E)can be subjected to reaction with a base in a solvent, and then subjected to reaction with the compound represented by the formula (1f), with compounds represented by formula (1g). The amount used of the compound (1f) is generally 1-5 equivalents, preferably 1-2 equivalents, of the compound represented by the formula (1E). Examples of the base include n-BuLi and LDA. The amount used of the base is generally 1-5 equivalents, preferably 1-1,2 equivalent, from compounds represented by the formula (1E). The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, preferably from -78°C to room temperature. Examples of the reaction is available for use of the solvent include ethers (e.g. dioxane, THF, Et2O), DMF, DMA, DMPU, HMPA, DMSO, or a mixture thereof. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 12 hours.

Stage 1A-5: Connection, assuming the i.i.d. formula (1g), can podvergatsya reaction with regenerating agent in a solvent to obtain the compound represented by formula (1h). Examples of the reducing agent include NaBH4, KBH4, LiB(sec-Bu)3H, (ISO-Bu)2AlH and LiAlH4. The amount of reducing agent is 0.5 to 5 equivalents, preferably 0.5 to 1.2 equivalent, from compounds represented by formula (1g). Examples of the solvent include ethers (e.g. dioxane, THF, Et2O) and alcohols (e.g., MeOH, EtOH). The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, preferably from 0°C. to room temperature. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 2 hours.

Stage 1A-6: Compound represented by formula (1h), can undergo reactions with methanesulfonamido, p-toluensulfonate, anhydrous triflate or equivalent in a solvent and, if necessary, in the presence of a base such as pyridine or triethylamine, followed by reaction with aidarous agent (for example, NaN3, LiN3, Zn(N3)2), or, alternatively, can be directly processed by diethylazodicarboxylate (DEAD)/PPh3/HN3, diphenylphosphorylacetate (DPPA)/1,8-Diaz is bicyclo[5.4.0]undec-7-Yong (DBU), Zn(N3)2/2-pyridine or the like, to obtain compounds represented by the formula (1i). Examples of the solvent include ethers (e.g. dioxane, THF), halogenated solvents (e.g., CH3CN, CCl4, CHCl3CH2Cl2), benzene and toluene.

Stage 1A-7: Compound represented by the formula (1i), can undergo reactions with regenerating agent in a solvent and, if necessary, in the presence of a catalyst (such as Pd/C, Pd(OH)2A /C, PtO2) to obtain the compound represented by the formula (1j). Examples of the reducing agent include hydrogen, ammonium formate, hydrazine, PPh3and Mg. Examples are available for use of the solvent include ethers (e.g. dioxane, THF, Et2O), alcohols (e.g., MeOH, EtOH), water, AcOEt, or a mixture thereof.

Stage 1A-8: Compound represented by the formula (1j), can undergo reaction with the compound represented by the formula (1k), in the presence of a base using a solvent or without him, followed by the formation of salt as is necessary to obtain compounds represented by the formula (1l)or its pharmaceutically acceptable salt. The amount used of the compound represented by the formula (1k), is generally 1-5 equivalents, preferably 1-1,2 equivalent, from compounds represented by the formula (1j). Por the measures available for use bases include hydroxides of alkali metals (for example, NaOH, KOH), alkali metal salts (for example, NaHCO3, K2CO3) and amines (e.g., Et3N iPr2Been certified with qi net, iPr2NH). The amount of base is generally 1-10 equivalents, preferably 1-3 equivalents, from compounds represented by the formula (1j). The reaction temperature ranges from 0°C to the boiling point of the solvent under reflux, preferably from 0°C. to room temperature. When required, the solvent may be any solvent as long as it is inert to the reaction, including halogenated hydrocarbons (for example, CHCl3CH2Cl2), ethers (e.g. dioxane, THF, Et2O) or mixtures thereof. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 1A-9: Compound represented by the formula (1l), can undergo reaction with the compound represented by formula (1m), in the presence of a base with or without using a solvent, followed by the formation of salt needed to obtain compounds represented by the formula (1n), or its pharmaceutically acceptable salt. The amount used of the compound represented by formula (1m)is 1 to 10 equivalents, preferably 1.1 to 1.5 equivalents, with the organisations, represented by the formula (1l). Examples are available for use bases include hydroxides of alkali metals (for example, NaOH, KOH), alkali metal salts (for example, Panso3, K2CO3) and amines (e.g., Et3N iPr2Been certified with qi net, iPr2NH). The amount of base is usually 1 to 10 equivalents, preferably 1.0 to 3.0 equivalents, of the compound represented by the formula (1l). The reaction temperature ranges from 0°C to the boiling point of the solvent under reflux, preferably from 0°C. to room temperature. When required, the solvent may be any solvent as long as it is inert to the reaction include water, ethers (e.g. dioxane, THF, Et2O), DMF, DMA, NMP, DMPU, HMPA, DMSO, or a mixture thereof. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Next, based on the compound represented by formula (1ga), which is obtained by the halogenation of the compounds represented by formula (1g), the procedure shown in stages 1A-5 1A-9 of Scheme 1 may be repeated to obtain halogen-substituted compounds represented by the formula (1nb).

Further, the compound represented by formula (1ga), can undergo reactions with the connection made is by the formula (1gb) obtaining the compounds represented by formula (1gc). On the basis of the resulting compound represented by the formula (DS), the procedure shown in stages 1A-5 1A-9 of Scheme 1 may be repeated to obtain the compound represented by formula (1 PA)having the substituent RE.

Stage 1A-5A: Compound represented by formula (1g)can be subjected to reaction with a halogenation agent to obtain the compound represented by formula (1ga). Examples of the halogenation agent include Cl2, Br2, I2, NCS, NBS, NIS, 2,4,4,6-tetrabromocyclooctane, PCl5and SOCl2. The amount of halogenation agent is usually from 2 to 10 equivalents, preferably 1.0 to 2.5 equivalents, of the compound represented by formula (1g). When required, the solvent may be any solvent as long as it is inert to the reaction include water, ethers (e.g. dioxane, THF), polar aprotic solvents such as DMF, DMA, NMP, DMPU, HMPA, DMSO), alcohols (e.g., MeOH, EtOH), halogenated solvents (e.g., CCl4, CHCl3CH2Cl2), CH3CN, acetic acid or mixtures thereof. If necessary, is added to the base. Examples of the base include hydroxides of alkali metals (for example, NaOH, KOH), alkali metal salts (for example, NaHCO3, K2 3, AcONa) and amines (e.g., Et3N iPr2Been certified with qi net). The amount used of the base is usually 1 to 10 equivalents, preferably 1.0 to 1.2 equivalents, of the compound represented by formula (1g). The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, preferably from -78°C to room temperature. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 1A-5B: Compound represented by the formula (1ga), can undergo reaction with the compound represented by formula (1gb), in the presence of a transition metal and, if necessary, in the presence of a base to obtain the compound represented by formula (1gc). In the compound represented by formula (1gb), Met' is a typical metal (such as Li, Na, B, Mg, Al, Zn, Sn) or a group represented by a complex between this typical metal and its ligand (the ligand may be a hydroxyl group, halogen atom, methoxy group or bidentate ligand represented by the formula- (CH2)3O-). The amount used of the compound represented by formula (1gb)is 1-10 equivalents, preferably 1.0 to 1.5 equivalent of the compound represented by formula (1ga). Examples of the transition metal in luchot tetrakis(triphenylphosphine)palladium(0), the palladium(II)acetate, palladium(II)chloride, Tris(dibenzylideneacetone)dipalladium(0)chloroform adduct and bis(acetylacetonato)Nickel(0). The amount used of such transition metal is usually from 0.01 to 0.5 equivalent of the compound represented by formula (1ga).

It is also desirable to add a phosphine, except when the phosphine is already coordinated. Examples of the phosphine include triethylphosphine, tributylphosphine, triphenylphosphine, bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane, bis(diphenylphosphino)butane and bis(diphenylphosphino)ferrocene. The amount used of such phosphine is 1-2 equivalent of the transition metal. Examples of the base include hydroxides of alkali metals (for example, NaOH, KOH) and alkali metal salts (for example, NaHCO3, Na2CO3, K2CO3To3RHO4Cs2CO3). The amount used of the base is generally 1-10 equivalents, preferably 1.5 to 3.0 equivalent, from compounds represented by the formula (1ga). The reaction temperature ranges from 0°C to the boiling point of the solvent under reflux, preferably from room temperature up to the boiling point of the solvent under reflux. Examples are available for use of the solvent include water, ethers (e.g. dioxane, THF, Et2O), DMF, DMA, NMP, DMU, HMPA, DMSO, or a mixture thereof. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Alternatively, as shown in Scheme 1, steps b and C, the compound represented by formula (1n)can also be synthesized by changing the order of reactions in the stages of Scheme 1, Procedure A.

Scheme 1, the Procedure In

Stage 1B-1: Compound represented by the formula (1C), which is obtained at the stage 1A-2 of Scheme 1, may be subjected to reaction with a base, and then from DMF to formirovaniya obtaining compounds represented by formula (1o). The used amount of DMF is generally 1-5 equivalents, preferably 1-2 equivalents, of the compound represented by formula (1C). Examples of the base include n-BuLi and LDA. The amount used of the base is generally 1-5 equivalents, preferably 1-1,2 equivalent, from compounds represented by the formula (1C). The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, preferably from -78°C to room temperature. Examples of the reaction solvent available for use include ethers (e.g. dioxane, THF, Et2O), DMF, DMA, DMPU, HMPA, DMSO, or a mixture thereof. Although the reaction time will vary in zavisimost and on the reaction temperature and/or source connection, it usually takes from 30 minutes to 12 hours.

Stage 1B-2: Compound represented by the formula (1B)may be subjected to reaction with the compound represented by formula (1d), in the same way, as shown in stage 1A-3 Scheme 1, to obtain the compound represented by formula (1P).

Stage 1B-3: Compound represented by formula (1P), can undergo reaction with the compound represented by formula (1q), with compounds represented by formula (1h). The amount used of the compound represented by formula (1q)is 1-10 equivalents, preferably 1.1 to 1.5 equivalent, from compounds represented by formula (1h). Examples are available for use of the solvent include ethers (e.g. dioxane, THF, Et2O) or mixtures thereof. The reaction temperature ranges from -78°C to room temperature, preferably from -30°C. to 0°C. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

On the basis of the obtained compound represented by formula (1h), the procedure shown in stages 1A-6 1A-9 of Scheme 1 may be repeated to obtain the compound represented by formula (1n).

Next, based on the compound represented by formula (RA), which is obtained by halogenation with the organisations, represented by formula (1P), the procedure shown in stage 1B-3 and 1A-6 1A-9 of Scheme 1 may be repeated to obtain halogen-substituted compounds represented by the formula (1nb).

Further, the compound represented by formula (R), can undergo reaction with the compound represented by formula (1gb), with compounds represented by the formula (1pb). On the basis of the obtained compound represented by the formula (1pb), the procedure shown in stage 1B-3 and 1A-6 1A-9 of Scheme 1 may be repeated to obtain the compound represented by formula (1na)having the substituent RE.

Stage 1B-3A: Based on the compound represented by formula (1P), the same procedure as shown in stages 1A-5A Scheme 1 may be repeated to obtain the compound represented by formula (R).

Stage 1B-3B: Based on the compound represented by formula (RA), and compounds represented by the formula (1gb), the same procedure as shown in stages 1A-5V Scheme 1 may be repeated to obtain the compound represented by formula (1b).

Scheme 1, treatment With

Stage 1C-1: Starting from the compound represented by formula (1B)obtained in stage 1B-1 of Scheme 1, compounds represented by the formula (1q), the same procedure as shown in stage 1B-3 of Scheme 1 may be repeated to obtain the compound represented by formula (1r).

Stage 1C-2: Starting from the compound represented by formula (1r), the same procedure as shown in stage 1A-6 of Scheme 1 may be repeated to obtain the compound represented by formula (1s).

Stage 1C-3: Based on the compound represented by formula (1s), the same procedure as shown in stage 1A-7 of Scheme 1 may be repeated to obtain the compound represented by formula (1t).

Stage 1C-4: Based on the compound represented by formula (1t), and compounds represented by formula (1d), the same procedure as shown in stage 1A-3 of Scheme 1 may be repeated to obtain the compound represented by the formula (1j).

On the basis of the obtained compound represented by the formula (1j), the procedure shown in stages 1A-8 1A-9 of Scheme 1 may be repeated to obtain the compound represented by formula (1n).

Scheme 2

Stage 2-1: Starting from the compound represented by formula (1b), and compounds represented by the formula (1f), the same procedure as shown in stage 1A-4 of Scheme 1 may be repeated to obtain the compound represented by the formula (2a).

Stage 2-2: Compound represented by the formula (2A), can undergo reaction with a halogenation agent to obtain the compound represented by formula (2b). Examples of the halogenation agent include Cl2, Br2, I2, NCS, NBS, NIS, 2,4,4,6-tetrabromo logication, PCl5and SOCl2. The amount of halogenation agent is usually from 2 to 10 equivalents, preferably 1.0 to 2.5 equivalents, of the compound represented by the formula (2a). When required, the solvent may be any solvent as long as it is inert to the reaction include water, ethers (e.g. dioxane, THF), polar aprotic solvents such as DMF, DMA, NMP, DMPU, HMPA, DMSO), alcohols (e.g., MeOH, EtOH), halogenated solvents (e.g., CCl4, CHCl3CH2Cl2), CH3CN, acetic acid or mixtures thereof. If necessary, is added to the base. Examples of the base include hydroxides of alkali metals (for example, NaOH, KOH), alkali metal salts (for example, NaHCO3, K2CO3, AcONa) and amines (e.g., Et3N iPr2Been certified with qi net). The amount used of the base is usually 1 to 10 equivalents, preferably 1.0 to 1.2 equivalents, of the compound represented by the formula (2a). The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, preferably from -78°C to room temperature. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 2-3: on the Basis of the connection shown is of the formula (2b), and compounds represented by formula (1d), the same procedure as shown in stage 1A-3 of Scheme 1 may be repeated to obtain the compound represented by the formula (2c).

Stage 2-4: Compound represented by the formula (2C)may be subjected to reaction in a solvent in the presence of a catalyst (such as Pd/C, Pd(OH)2A /C, PtO2in the atmosphere of hydrogen in a compound represented by the formula (2d). Examples of the solvent include ethers (e.g. dioxane, THF), alcohols (e.g., MeOH, EtOH) and AcOEt. The amount used of the catalyst is usually 0.01-1 part by weight of the compound represented by the formula (2C).

Stage 2-5: on the Basis of the connection represented by the formula (2d), the same procedure as shown in stage 1A-5 of Scheme 1 may be repeated to obtain the compound represented by formula (2e).

Stage 2-6: Starting from the compound represented by formula (2e), the same procedure as shown in stage 1A-6 of Scheme 1 may be repeated to obtain the compound represented by formula (2f).

Stage 2-7: on the Basis of the connection represented by the formula (2f), the same procedure as shown in stage 1A-7 of Scheme 1 may be repeated to obtain the compound represented by the formula (2g).

Stage 2-8: on the Basis of the connection represented by the formula (2g), and compounds represented by the formula (1k), the same PR is the procedure, as shown in stage 1A-8 of Scheme 1 may be repeated to obtain the compound represented by formula (2h).

Stage 2-9: Starting from the compound represented by formula (2h), and compounds represented by formula (1m), the same procedure as shown in stage 1A-9 of Scheme 1 may be repeated to obtain the compound represented by the formula (2i).

Furthermore, starting from the compound represented by the formula (2c), the procedure shown in stages 2-5 - 2-9 Scheme 2, may be repeated to obtain halogen-substituted compounds represented by the formula (2ib).

In addition, the compound represented by the formula (2C)may be introduced into reaction with the compound represented by formula (1gb), with compounds represented by the formula (s). On the basis of the obtained compound represented by the formula (sa), the procedure shown in stages 2-5 and 2-9 Scheme 2, may be repeated to obtain the compound represented by formula (2ia), having substituent RE.

Stage 2-4A: on the Basis of the connection represented by the formula (2c), the procedure shown in stages 1A-5B Scheme 1 may be repeated to obtain the compound represented by formula (sa).

Scheme 3

Stage 3-1: Diethyloxalate sodium salt and the compound represented by formula (3A), can be introduced into the reaction in the presence of acetic acid with recip is of connection, represented by formula (3b).

Stage 3-2: Compound represented by the formula (3b)may be subjected to reaction with a halogenation agent (for example, POCl3) in DMF to obtain compound represented by formula (3C).

Stage 3-3: Based on the compound represented by formula (3C), and compounds represented by formula (1d), the same procedure as shown in stage 1A-3 of Scheme 1 may be repeated to obtain the compound represented by the formula (3d).

Stage 3-4: Compound represented by the formula (3d), can be subjected to reaction with the compound represented by the formula (3E), with compounds represented by the formula (3f). The amount used of the compound represented by the formula (3E), is 1-10 equivalents, preferably 1.1 to 1.5 equivalent, from compounds represented by the formula (3d). Examples are available for use of the solvent include ethers (e.g. dioxane, THF, Et2O) or mixtures thereof. The reaction temperature ranges from -78°C to room temperature, preferably from -30°C. to 0°C. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 3-5: Compound represented by the formula (3f), can undergo reactions with regenerating agent in the presence of Ki is lots Lewis getting connection represented by formula (3g). Examples of the Lewis acid include triperoxonane acid (TFA), TiCl4, SnCl4and AlCl3. The amount of Lewis acid is 1-20 equivalents, preferably 5 to 10 equivalents, of the compound represented by formula (3f). Examples of the reducing agent include Et3SiH, Bu3SnH and NaBH4. The amount of reducing agent is 1-5 equivalents, preferably 1-3 equivalents, from compounds represented by the formula (3f). When required, the solvent may be any solvent as long as it is inert to the reaction, including halogenated solvents (e.g., CCl4, CHCl3CH2Cl2) or mixtures thereof. The reaction temperature ranges from -78°C to the boiling point of the solvent under reflux, preferably from 0°C. to room temperature.

Stage 3-6: Compound represented by the formula (3g), may be injected into reaction with a regenerating agent to obtain the compound represented by the formula (3h). Examples of the reducing agent include NaBH4, KBH4, LiB(H)Et3, LiB(sec-Bu)3H, (ISO-Bu)2AlH Al H (O-t-Bu)3, LiAlH4, LiHAl(O-t-Bu)3and NaH2Al(OCH2CH2OCH3). The amount of reducing agent is 0.5 to 5 equivalents, prefer the Ino 0.5 to 1.2 equivalent, from the compounds represented by formula (3g). Examples are available for use of the solvent include ethers (e.g. dioxane, THF, diethyl ether, hexane, benzene, toluene or mixtures thereof. The reaction temperature ranges from -78°C to room temperature, preferably from -78°C to 0°C. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 4 hours.

Stage 3-7: Compound represented by the formula (3h), may be injected into reaction with the compound represented by formula (1q), in the same way, as shown in stage 1B-3 Scheme 1, to obtain the compound represented by formula (3i). The amount of compounds represented by formula (1q)is 1-10 equivalents, preferably 1.1 to 1.5 equivalent, from compounds represented by the formula (3h). Examples are available for use of the solvent include ethers (e.g. dioxane, THF, Et2O) or mixtures thereof. The reaction temperature ranges from -78°C to room temperature, preferably from -30°C. to 0°C. Although the reaction time will vary depending on the reaction temperature and/or the original connection, it usually takes from 30 minutes to 24 hours.

Stage 3-8 and 3-9: Starting from the compound represented by formula (3i), the same procedure that shows the stages 1A-6 1A-7 Scheme 1, may be repeated to obtain the compound represented by formula (3j).

Stage 3-10: Starting from the compound represented by formula (3j), and compounds represented by the formula (1k), the same procedure as shown in stage 1A-8 of Scheme 1 may be repeated to obtain the compound represented by formula (3k).

Stage 3-11: Based on the compound represented by formula (3k), and compounds represented by formula (1m), the same procedure as shown in stage 1A-9 of Scheme 1 may be repeated to obtain the compound represented by formula (3l).

Stage 3-12: Compound represented by the formula (3l)may be subjected to reaction with acid to obtain the compound represented by the formula (3m). Examples of the acid include hydrochloric acid/pyridine and BBr3. The amount used of the acid is 1 to 20 equivalents, preferably 10 to 20 equivalents, from compounds represented by the formula (3l). When required, the solvent may be any solvent as long as it is inert to the reaction, including halogenated solvents (e.g., CCl4, CHCl3CH2Cl2) or mixtures thereof. The reaction temperature ranges from room temperature to 200°, preferably from room temperature to 180°C.

For use as pharmaceutical compositions to connect eniam of the present invention can be added commonly used excipients, extenders, pH regulators, soljubilizatory etc. and then accesses the preparation of pharmaceutical forms using standard techniques in the form of tablets, granules, pills, capsules, powders, solutions, suspensions, injectable compositions, etc. thus Obtained pharmaceutical compositions can be administered in the form of oral or parenteral forms.

Compounds of the present invention can be administered to adult patients in the amount of 1-1000 mg / day as a single dose or divided doses. This dosage may be increased or decreased depending on the type of disease, age, body weight and symptoms of the patient, etc.

ADVANTAGES IZOPETRecommended reading

It was found that the compounds of the present invention are strong ligands Edg-1 (S1P1), as can be seen from the following example tests.

The BEST WAY of carrying out the INVENTION

The present invention will be further described in more detail using the following examples and sample tests.

Example 1

3,4-Dichloro-N-[1-(3-ethyl-2(4-methylphenoxy)-3H-imidazol-4-yl)ethyl]benzosulfimide(Compound 74)

[Formula 18]

1-Ethyl-2-iodine-1H-imidazol

[Formula 19]

(1) To a solution of 1-ethyl-1H-imidazole (2,844 g) in THF (60 ml) in an atmosphere of argon is at -78°C was added dropwise n-BuLi (n-utility) (11,6 ml, 2,59 N. in hexane). After stirring at the same temperature for 30 minutes was added dropwise a solution of I2(7,614 g) in THF (25 ml). The reaction mixture was heated to room temperature, diluted with saturated aqueous sodium bicarbonate and was extracted with AcOEt. After washing with a saturated aqueous solution of Na2S2O3the organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated to remove the solvent, thus obtaining specified in the header connection (6,492 g) as a pale yellow solid.

1H NMR (200 MHz, CDCl3) δ ppm: 1,40 (t, J=7.4 Hz, 3H), 3,95 (kV, J=7,4 Hz, 2H), 7,02-7,06 (m, 1H), 7,07-7,11 (m, 1H).

1-Ethyl-2(4-methylphenoxy)-1H-imidazol

[Formula 20]

(2) the Mixture of compounds obtained in Example 1-(1), (30,27 g), 4-cresol (17,69 g), Cs2CO3(53,43 g) and N,N'-dimethylpropyleneurea (DMPU) (136 ml) was stirred at 200°C for 3 hours. The mixture was cooled to room temperature, diluted with water and was extracted with AcOEt. After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting crude product was purified by column chromatography (SiO2neutral HE-type, hexane/AcOE = 10% - 40%), receiving the specified reception in the e connection (8,54 g, yellow oil).

1H NMR (200 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), 2,32 (s, 3H), 3,89 (kV, J=7,3 Hz, 3H), of 6.65 (d, J=1.8 Hz, 1H), 6,70 (d, J=1.8 Hz, 1H), 7.03 is-7,320 (m, 4H).

1-(3-Ethyl-2-(4-methylphenoxy)-3H-imidazol-4-yl)ethanol

[Formula 21]

(3) To a solution of the compound obtained in example 1-(2,) (2,493 g)in THF (123 ml) in an argon atmosphere at -78°C was added dropwise n-BuLi (4.8 ml, 2,59 N. in hexane) and stirred at the same temperature for 3.5 hours. The reaction mixture was cooled to -100°C, was mixed with AU2Of (2.3 ml)was heated to 65°C for 50 minutes, diluted with saturated aqueous sodium bicarbonate and was extracted with AcOEt. After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and then evaporated to remove solvent. The resulting crude product was purified by column chromatography (NH silica gel, AcOEt/hexane = 10% - 30%), receiving a mixture of 1-(3-ethyl-2-(4-methylphenoxy)-3H-imidazol-4-yl)ethanone and 1-ethyl-2(4-methylphenoxy)-1H-imidazole (1,509 g, colorless oil). To a solution of the obtained compounds (1,508 g) in the Meon (13 ml) at 0°C was added NaBH4(243 mg) and was stirred at the same temperature for 15 minutes and then at room temperature for 15 minutes. The reaction mixture was concentrated, diluted with water and was extracted with AcOEt. After washing with saline'or is anceschi layer was dried over magnesium sulfate, was filtered and evaporated to remove solvent. The resulting crude product was purified by column chromatography (NH silica gel, AcOEt/hexane = 20% - 99%), receiving specified in the header connection (1,131 g, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.62 (d, J=6.6 Hz, 3H), of 2.33 (s, 3H), 3,86-4,20 (m, 2H), 4,70-4,88 (m, 1H), 6,60 (d, J=0.9 Hz, 1H),? 7.04 baby mortality-7,21 (m, 4H).

5-(1-Azidoethyl)-1-ethyl-2-(4-methylphenoxy)-1H-imidazol

[Formula 22]

To a solution of the compound obtained in Example 1-(3), (1,130 g)in toluene (46 ml) at 0°C was added diphenylphosphoryl (DPPA) (1,48 ml) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and stirred at room temperature for 11.5 hours. The reaction mixture was diluted with water and was extracted with AcOEt. After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and then evaporated to remove solvent. The resulting crude product was purified by column chromatography (NH silica gel, AcOEt/hexane = 0% to 10%), receiving specified in the header connection (983 mg, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), 1,67 (d, J=6.8 Hz, 3H), of 2.33 (s, 3H), 3,90-4,07 (m, 2H), 4,25-and 4.40 (m, 1H), of 6.68 (d, J=0.9 Hz, 1H), 7,02-7,30 (m, 4H).

1-(3-Ethyl-2(4-methylphenoxy)-3H-imidazol-4-yl)ethylamine

[Formula 23]

(5) a Mixture of compounds, recip is spent in Example 1-(4), (983 mg), and palladium-activated carbon (197 mg, Pd 10 wt.%) in toluene (46 ml) was stirred in hydrogen atmosphere (about 1 atmosphere) at room temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The resulting crude product was purified by column chromatography (NH silica gel, AcOEt/hexane = 10% - 99%), getting mentioned in the title compound (754 mg, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: to 1.37 (t, J=7,1 Hz, 3H), 1,49 (d, J=6.6 Hz, 3H), 2,32 (s, 3H), 3,82-4,12 (m, 3H), 6,53 (d, J=0.9 Hz, 1H),? 7.04 baby mortality-7,20 (m, 4H).

3,4-Dichloro-N-[1-(3-ethyl-2(4-methylphenoxy)-3H-imidazol-4-yl)ethyl]benzosulfimide(Compound 74)

[Formula 24]

(6) To a solution of the compound obtained in Example 1-(5), (24 mg)in THF (2.0 ml) at room temperature was added Et3N level (0.041 ml) and 3,4-dichlorobenzenesulfonate (48 mg) and stirred at room temperature for 12 hours. After addition of AcOEt organic layer was washed successively 1 N. aqueous solution of hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and then evaporated under reduced pressure to remove solvent. The resulting crude product was purified using silicagel NH-type column chromatography (eluent:AcOEt) followed by recrystallization (AcOEt/hexane)to give the criminal code is related to the title compound (Compound 74) (25 mg, colorless powder).

1H NMR (200 MHz, DMSO-d6) δ ppm: of 1.18 (t, J=7,1 Hz, 3H), of 1.26 (d, J=6.8 Hz, 3H), to 2.29 (s, 3H), 3,65-3,91 (m, 2H), to 4.41-to 4.62 (m, 1H), 6.42 per (s, 1H), 6,97-7,07 (m, 2H), 7,13-7,24 (m, 2H), 7,71 (DD, J=8,4, and 2.1 Hz, 1H), 7,87 (d, J=8,4 Hz, 1H), to 7.93 (d, J=2.1 Hz, 1H), 8,28-8,43 (m, 1H).

Melting point: 142,5-143,5°C

Example 2

3,4-Dichloro-N-[1-(1-ethyl-5-(4-methylphenoxy)-1H-imidazol-2-yl)ethyl]benzosulfimide(Compound 179)

[Formula 25]

1-(1-Ethyl-1H-imidazol-2-yl)alanon

[Formula 26]

(1) To a solution of 1-ethyl-1H-imidazole (1,923 g) in THF (40 ml) in an argon atmosphere at -78°C was added dropwise n-BuLi (7.7 ml, 2,59 N. in hexane). After stirring at the same temperature for 30 minutes the reaction mixture was added dropwise at -78°C through the funnel to the solution l (1,56 ml) in THF (40 ml). The reaction mixture was heated to room temperature for 2 hours, diluted with saturated aqueous sodium bicarbonate and was extracted with AcOEt. After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and then evaporated to remove solvent. The resulting crude product was purified by column chromatography on silica gel (NH silica gel, AcOEt/hexane = 0% to 10%), getting mentioned in the title compound (335 mg, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: to 1.42 (t, J=7,3 Hz, 3H), to 2.67 (s, 3H), 443 (kV, J=7,3 Hz, 2H), to 7.09 (s, 1H), 7,15 (d, J=0.7 Hz, 1H).

1-(4,5-Dibromo-1-ethyl-1H-imidazol-2-yl)alanon

[Formula 27]

To a solution of the compound obtained in Example 2-(1), (1.08 g)in CH3CN (78 ml) at 0°C was added N-bromosuccinimide (NBS) (2,782 g), the mixture was heated at the boiling point under reflux for 3 hours and then stirred overnight at room temperature. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel (silica gel neutral HE-type, AcOEt/hexane = 5% - 20%), receiving specified in the header of the connection (at 1,865 g, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: to 1.35 (t, J=7,1 Hz, 3H), 2.63 in (s, 3H), 4,51 (kV, J=7,1 Hz, 2H).

1-(4-Bromo-1-ethyl-5-(4-methylphenoxy)-1H-imidazol-2-yl)alanon

[Formula 28]

(3) the Mixture of compounds obtained in Example 2-(2), (833 mg), 4-cresol (883 mm), Cs2CO3(2,979 g) and DMPU (2.8 ml) was stirred at 100°C for 30 minutes and then at 150°C for 1 hour. The reaction mixture was cooled to room temperature, diluted aqueous solution of NaOH (2,0 BC) and was extracted with a mixture of ethyl acetate/hexane (1/4). After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting crude about the SPS was purified by column chromatography (NH silica gel-type, AcOEt/hexane = 2% - 5%), getting mentioned in the title compound (235 mg, colorless solid).

1H NMR (200 Hz, CDCl3) δ ppm: of 1.27 (t, J=7.2 Hz, 3H), of 2.33 (s, 3H), 2.63 in (s, 3H), or 4.31 (q, J=7.2 Hz, 2H), 6,76-to 6.88 (m, 2H), 7,08-7,20 (m, 2H).

1-(1-Ethyl-5-(4-methylphenoxy)-1H-imidazol-2-yl)alanon

[Formula 29]

(4) the Mixture of compounds obtained in Example 2-(3), (154 mg), palladium-activated charcoal (31 mg, Pd 10 wt.%) and AcONa (47 mg) in Meon (4.0 ml) was stirred in hydrogen atmosphere (1 ATM.) at room temperature for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated, diluted with water and extracted with ethyl acetate.

The organic layer was washed with saline, dried over magnesium sulfate, filtered and then evaporated under reduced pressure to remove the solvent, thus obtaining specified in the title compound (113 mg, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: to 1.35 (t, J=7,1 Hz, 3H), of 2.35 (s, 3H), 2,61 (s, 3H), and 4.40 (q, J=7,1 Hz, 2H), 6,53 (s, 1H), 6,94-7,06 (m, 2H), 7,12-7,22 (m, 2H).

1-(1-Ethyl-5-(4-methylphenoxy)-1H-imidazol-2-yl)ethanol

[Formula 30]

(5) To a solution of the compound obtained in Example 2-(4), (171 mg), Meon (7.0 ml) at 0°C was added NaBH4(26 mg) and was stirred at the same temperature for 15 minutes. The reaction mixture was washed in the Oh and extracted with ethyl acetate. After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and evaporated to remove the solvent, obtaining mentioned in the title compound (158 mg, colorless oil).

1H NMR (200 Hz, CDCl3) δ ppm: of 1.33 (t, J=7,3 Hz, 3H), 1,67 (d, J=5,9 Hz, 3H), 2,32 (s, 3H), 3,92-4,07 (m, 2H), 4,76-to 4.98 (m, 1H), 6,35-6,53 (m, 1H), 6.90 to-7,02 (m, 2H), 7,07-to 7.18 (m, 2H).

2-(1-Azido-ethyl)-1-ethyl-5-(4-methylphenoxy)-1H-imidazol

[Formula 31]

(6) Based on the compound obtained in Example 2-(5), repeated the same procedure that was used in Example 1-(4), getting mentioned in the title compound (colorless oil, yield 40%).

1H NMR (200 Hz, CDCl3) δ ppm: of 1.34 (t, J=7,3 Hz, 3H), 1,79 (d, J=6.8 Hz, 3H), of 2.33 (s, 3H), 3,81-of 4.05 (m, 2H), to 4.38-4.53-in (m, 1H), 6,47 (s, 1H), 6,91-7,01 (m, 2H), 7,08-to 7.18 (m, 2H).

1-(1-Ethyl-5-(4-methylphenoxy)-1H-imidazol-2-yl)ethylamine

[Formula 32]

(7) Based on the compound obtained in Example 2-(6), repeated the same procedure that was used in Example 1-(5), receiving specified in the title compound (colorless oil) with a quantitative yield.

1H NMR (200 Hz, CDCl3) δ ppm: 1.30 on (t, J=7,3 Hz, 3H), 1,53 (d, J=6.8 Hz, 3H), 2,32 (s, 3H), of 3.77-4,16 (m, 3H), 6,44 (s, 1H), 6.90 to-7,00 (m, 2H), 7,06-7,16 (m, 2H).

3,4-Dichloro-N-[1-(1-ethyl-5-(4-methylphenoxy)-1H-imidazol-2-yl)ethyl]benzosulfimide(Compound 179)

[Formula 33]

(8) on the Basis of the compound obtained in Example 2-(7), repeated the same procedure that was used in Example 1-(6), receiving specified in the title compound (Compound 179) (colourless oil, yield 73%).

1H NMR (200 MHz, DMSO-d6) δ ppm: 1,12 (t, J=7,1 Hz, 3H), of 1.30 (d, J=6.8 Hz, 3H), of 2.28 (s, 3H), 3,67-3,88 (m, 2H), 4.53-in-4,70 (m, 1H), and 6.25 (s, 1H), 6,84-to 6.95 (m, 2H), 7,12-7,25 (m, 2H), 7,69 (DD, J=8,5, and 2.1 Hz, 1H), to 7.84 (d, J=8.5 Hz, 1H), of 7.90 (d, J=2.1 Hz, 1H), of 8.47-8,64 (m, 1H).

Melting point: 133,0-134,5°C

Example 3

N-[1-(3-Ethyl-2-p-tolyloxy-3H-imidazol-4-yl)-ethyl]-4-methoxybenzenesulfonamide (Compound 23)

[Formula 34]

To a solution of the compound obtained in Example 1-(5), (12,3 mg)in THF (0.3 ml), was added Et3N (25 μl) and a solution of 4-methoxybenzenesulfonamide (15,5 mg) in THF (0.3 ml) and stirred at room temperature for 2 hours. After adding PSA (amine on the polymer carrier, VARIAN, 1,4 meqv/g) (785 μl), the reaction mixture was stirred at room temperature for 12 hours and filtered to remove insoluble substances. After removal of the solvent the resulting crude product was purified by column chromatography on silica gel (SiO2acid IT-type, ethyl acetate/hexane = 50%-100%, Meon/HCl3= 10%), getting mentioned in the title compound (Compound 23, 14.3 mg) as colorless powder./p>

APCI MS(M-H)-: 414, APCI MS(M-H)+: 416

Example 4

3,4-Dichloro-N-[1-(4-chloro-1-ethyl-5-p-tolyloxy-1H-imidazol-2-yl)ethyl]benzosulfimide (Compound 183)

[Formula 35]

1-(4,5-Dichloro-1-ethyl-1H-imidazol-2-yl)alanon

[Formula 36]

(1) Repeating the same procedure that was used in Example 2-(2), getting mentioned in the title compound (colorless oil, yield 47%), except that instead of N-bromosuccinimide (NBS) used N-chlorosuccinimide (NCS).

1H NMR (600 MHz, CDCl3) δ ppm: 1,36 (t, J=7.2 Hz, 3H), 2,61 (s, 3H), 4,48 (kV, J=7.2 Hz, 2H).

1-(4-Chloro-1-ethyl-5-p-tolyloxy-1H-imidazol-2-yl) alanon

[Formula 37]

(2) Proceeding from the compound obtained in Example 4-(1)was repeated the same procedure that was used in Example 2-(3), getting mentioned in the title compound (colorless solid, yield 47%).

1H NMR (600 MHz, CDCl3) δ ppm: 1.28 (in t, J=7.2 Hz, 3H), of 2.33 (s, 3H), 2,62 (s, 3H), 4,32 (kV, J=7.2 Hz, 2H), for 6.81-6,86 (m, 2H), 7,12-7,16 (m, 2H).

1-(4-Chloro-1-ethyl-5-p-tolyloxy-1H-imidazol-2-yl)ethanol

[Formula 38]

(3) on the Basis of the compound obtained in Example 4-(2)was repeated the same procedure that was used in Example 2-(5), receiving specified in the title compound (light yellow oil, yield 87%).

<> 1H NMR (600 MHz, CDCl3) δ ppm: 1.28 (in t, J=7,3 Hz, 3H), of 1.66 (d, J=6.4 Hz, 3H), 2,32 (s, 3H), 3,83-3,98 (m, 2H), 4,81-4,88 (m, 1H), for 6.81-6.87 in (m, 2H), 7,09-7,14 (m, 2H).

2-(1-Azidoethyl)-4-chloro-1-ethyl-5-p-tolyloxy-1H-imidazol

[Formula 39]

(4) Based on the compound obtained in Example 4-(3)was repeated the same procedure that was used in Example 1-(4), getting mentioned in the title compound (light yellow oil, yield 87%).

1H NMR (600 MHz, CDCl3) δ ppm: 1.28 (in t, J=7,1 Hz, 3H), of 1.78 (d, J=6.4 Hz, 3H), 2,32 (s, 3H), 3,82-of 3.94 (m, 2H), 4,40-of 4.45 (m, 1H), for 6.81-6,86 (m, 2H), 7,10-to 7.15 (m, 2H).

1-(4-Chloro-1-ethyl-5-p-tolyloxy-1H-imidazol-2-yl)ethylamine

[Formula 40]

(5) To a solution of the compound obtained in Example 4-(4), (460 mg), and h3(790 mg) in THF (50 ml) was added N2About (0.6 ml) and was heated at the boiling point under reflux for 15 hours. Next add H2About (0.6 ml), the reaction mixture was heated at the boil under reflux additionally for 4 hours, cooled to room temperature and evaporated to remove solvent. The resulting crude product was purified by column chromatography on silica gel (SiO2neutral HE-type Meon/l3= 0%-10%), getting mentioned in the title compound (372 mg, colorless oil).

1H NMR (600 MHz, CDCl3) δ m is.: of 1.26 (t, J=7,3 Hz, MN), of 1.52 (d, J=6.9 Hz, 3H), 2,31 (s, 3H), 3,79-of 3.96 (m, 2H), 4,03-4,10 (m, 1H), 6,82-to 6.88 (m, 2H), 7,08-to 7.15 (m, 2H).

3,4-Dichloro-N-[1-(4-chloro-1-ethyl-5-p-tolyloxy-1H-imidazol-2-yl)ethyl]benzosulfimide (Compound 183)

[Formula 41]

(6) Based on the compound obtained in Example 4-(5), repeated the same procedure that was used in Example 1-(6), receiving specified in the title compound (Compound 183) (colorless powder, yield 66%).

1H NMR (600 MHz, CDCl3) δ ppm: 1,17 (t, J=7,3 Hz, 3H), 1,49 (d, J=6.9 Hz, 3H), 2,32 (s, 3H), 3,68-to 3.89 (m, 2H), to 4.52 with 4.65 (m, 1H), 5,55-5,72 (m, 1H), 6,72-6,77 (m, 2H), 7,10-7,16 (m, 2H), 7,52-to 7.61 (m, 2H) to 7.84 (d, J=2.3 Hz, 1H).

Melting point: 122,5-to 123.5°C

Example 5

3,4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-5-methyl-3H-imidazol-4-yl]ethyl}benzosulfimide (Compound 188)

[Formula 42]

2-Chloro-1-ethyl-1H-imidazol

[Formula 43]

(1) To a solution of 1-ethyl-1H-imidazole (2.2 g) in THF (12 ml) in an argon atmosphere at -78°C was added dropwise n-BuLi (9.1 ml, 2,64 N. in hexane). After stirring at the same temperature for 30 minutes was added dropwise a solution of hexachloroethane (5.7 g) in THF (12 ml) and stirred at the same temperature for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride, warmed to room temperature and was extracted with ethylacetamide washing with water and saturated aqueous sodium chloride the organic layer was dried over magnesium sulfate, was filtered and then evaporated under reduced pressure to remove solvent. The resulting crude product was purified by column chromatography (SiO2HE is the type, AcOEt/hexane = 0% to 20%), receiving specified in the header connection (2,74 mg, colorless oil).

1H NMR (600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,3 Hz, 3H), 3.96 points (kV, J=7,3 Hz, 2H), 6,88-6,98 (m, 2H).

1-(2-Chloro-3-ethyl-3H-imidazol-4-yl)alanon

[Formula 44]

(2) To a solution of the compound obtained in Example 5-(1), (2,74 g)in THF (40 ml) in an argon atmosphere at -78°C was added dropwise n-BuLi (8,35 ml, 2,64 N. in hexane) and stirred at the same temperature for 30 minutes. The resulting reaction mixture was added at -78°C to a solution of AU2Of (2.1 ml) in THF (40 ml) and was heated to 0°C for 2.5 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. After washing with a saturated aqueous solution of sodium chloride the organic layer was dried over magnesium sulfate, filtered and then evaporated to remove solvent. The resulting crude product was purified by column chromatography (SiO2NH-type, AcOEt/hexane = 10%), getting mentioned in the title compound (2.57 m) mg, light yellow oil).

1H NMR (600 MHz, CDCl3) δ ppm: of 1.33 (t, J=7.2 Hz, 3H), of 2.46 (s, 3H) was 4.42 (q, J=7.2 Hz, 2H) of 7.69 (s, 1H).

1-[3-Ethyl-2-4-pertenece)-3H-imidazol-4-yl)alanon

[Formula 45]

(3) the Mixture of compounds obtained in Example 5-(2), (13,20 g), 4-terfenol (12,86 g), Cs2CO3(to 49.9 g) and DMPU (15 ml) was stirred at 200°C for 2 hours. After cooling to room temperature was added Meon/CHCl3(Meon/CHCl3= 20%) and insoluble substances were filtered off. The filtrate was concentrated and the resulting crude product was purified by column chromatography (neutral SiO2HE is the type, AcOEt/hexane = 0% to 30%), receiving specified in the header connection (22,37 g, pale yellow oil).

1H NMR (600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7.2 Hz, 3H), 2,42 (s, 3H), of 4.38 (q, J=7.2 Hz, 2H),? 7.04 baby mortality for 7.12 (m, 2H), 7,19-of 7.23 (m, 2H), 7,47 (s, 1H).

1-[5-Bromo-3-ethyl-2-(4-pertenece)-3H-imidazol-4-yl)alanon

[Formula 46]

(4) To a solution of the compound obtained in example 5-(3), (5.0 g)in DMF (50 ml) was added N-bromosuccinimide (NBS) (7,15 g) and stirred at room temperature for 6 hours. After further adding NBC (1,83 g) and stirring for an additional 4 hours the reaction mixture was concentrated. The obtained residue was purified by column chromatography on silica gel (neutral SiO2HE is the type, AcOEt/hexane = 0% to 10%), receiving specified in the header connection (4,916 g, yellow oil).

1H NMR (600 MHz, CDCl3) δ ppm: to 1.35 (t, J=7,1 Hz, 3H), of 2.64 (s, 3H), 4,7 (kV, J=7,1 Hz, 2H), 7,06-7,11 (m, 2H), 7,20-7,24 (m, 2H).

1-[3-Ethyl-2-(4-pertenece)-5-methyl-3H-imidazol-4-yl]-alanon

[Formula 47]

(5) the Mixture of compounds obtained in Example 5-(4), (3,66 g), trimethylboroxine (1,57 ml), Pd(PPh3)4(1.29 g) and K2CO3(with 4.64 g) in dioxane (25 ml) was stirred in argon atmosphere at 115°C for 6 hours. To this mixture was then added trimethylboroxine (0,52 ml) and was stirred at the same temperature additionally for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble substances. The filtrate was concentrated and the obtained residue was purified by column chromatography (neutral SiO2HE is the type, AcOEt/hexane = 0% to 50%), getting mentioned in the title compound (627 mg, yellow oil).

1H NMR (600 MHz, CDCl3) δ ppm: of 1.33 (t, J=7.0 Hz, 3H), 2,46 (2s, 6H), 4,32 (kV, J=7,0 Hz, 2H) 7,05-7,10 (m, 2H) 7,19-7,22 (m, 2H).

1-[3-Ethyl-2-(4-pertenece)-5-methyl-3H-imidazol-4-yl]ethanol

[Formula 48]

(6) Based on the compound obtained in Example 5-(5), repeated the same procedure that was used in Example 2-(5), receiving specified in the title compound (light yellow oil, yield 42%).

1H NMR (600 MHz, CDCl3) δ ppm: to 1.35 (t, J=7,1 Hz, 3H), 1,58 (DD, J=6,9, 1.8 Hz, 3H), 2.13 and (s, 3H), 3,93-4.09 to (m, 2H), 4,94-free 5.01 (m, 1H), 6,99-7,06 (m, 2H), 7,15-7,20 (who, 2H).

1-[3-Ethyl-2-(4-pertenece)-5-methyl-3H-imidazol-4-yl]utilised

[Formula 49]

(7) Based on the compound obtained in Example 5-(6), repeated the same procedure that was used in Example 1-(4), getting mentioned in the title compound (yellow oil, yield 44%).

1H NMR (600 MHz, CDCl3) δ ppm: 1,36 (t, J=7,3 Hz, 3H), 1,60 (d, J=7,3 Hz, 3H), 2,19 (s, 3H), 3,88-4,00 (m, 2H), 4,70 was 4.76 (m, 1H), 7,00-was 7.08 (m, 2H), 7,17-7,22 (m, 2H).

5-(1-amino-ethyl)-1-ethyl-2-(4-pertenece)-4-methyl-1H-imidazol

[Formula 50]

(8) a Mixture of the compound obtained in Example 5-(7), (120 mg), and palladium-activated carbon (24 mg, Pd 10 wt.%) in the Meon (3.0 ml) was stirred in hydrogen atmosphere (about 1 atmosphere) at room temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated, obtaining mentioned in the title compound (120 mg, colorless oil).

1H NMR (600 MHz, CDCl3) δ ppm: of 1.33 (t, J=7,1 Hz, 3H), of 1.48 (d, J=6.9 Hz, 3H), of 2.16 (s, 3H), 3,92-to 4.14 (m, 2H), 4,27 (kV, J=6,9 Hz, 1H), 6,99-7,05 (m, 2H), 7,14-7,21 (m, 2H).

3,4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-5-methyl-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 188)

[Formula 51]

(9) Proceeding from the compound obtained in Example 5-(8), repeated the same procedure that was used in Example 1-(6), receiving specified the title compound (Compound 188) (colorless powder, yield 73%).

1H NMR (600 MHz, CDCl3) δ ppm: 1,25 (t, J=7,1 Hz, 3H), of 1.55 (d, J=6.9 Hz, 3H), from 2.00 (s, 3H), 3,60-to 3.73 (m, 1H), of 3.77-to 3.89 (m, 1H), 4.63 to-4,74 (m, 1H), 4.95 points-to 5.03 (m, 1H), 7,00-was 7.08 (m, 2H), 7,11-to 7.18 (m, 2H), 7,43-7,52 (m, 2H), 7,75 (d, J=1.8 Hz, 1H).

Melting point: 119,5-120,0°C

Example 6

3,4-Dichloro-N-[1-(4-ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-yl)ethyl]benzosulfimide (Compound 180)

[Formula 52]

Ethyl ester of 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid

[Formula 53]

(1) To a solution of sodium salt of diethyloxalate (30.0 g) in toluene (200 ml) was added acetic acid (200 ml) and methylhydrazine (15 ml) and stirred at 100°C for 8.5 hours. The reaction mixture was concentrated and the resulting residue was diluted with saturated aqueous sodium chloride and was extracted with AcOEt. The obtained organic layer was dried over magnesium sulfate, filtered and then evaporated under reduced pressure to remove solvent. The obtained solid substance was washed with a mixture of E2O/hexane (Et2O/hexane = 2/1), and dried, obtaining specified in the header connection (18,8 g, brown powder).

1H NMR (600 MHz, DMSO-d6) δ ppm: 1,25 (t, J, and 7.1 Hz, 3H)and 3.59 (s, 3H), 4,16-of 4.25 (m, 2H), 5,77 (s, 1H).

Ethyl ester of 5-chloro-4-formyl-1-methyl-1H-pyrazole-3-carboxylic acid

[Formula 54]

(2) To 1,2-DIH is oratane (75 ml), was added dropwise DMF (13,7 ml) and POCl 3(82,5 ml) at 0°C under nitrogen atmosphere. To this mixture was added dropwise a solution of the compound obtained in Example 6-(1), (10 g) in 1,2-dichloroethane (75 ml) and was heated to room temperature. After stirring at 110°C for 4.5 hours, the reaction mixture was cooled to room temperature and evaporated to remove solvent. The obtained residue was added to saturated aqueous sodium bicarbonate solution and was stirred for 2 hours. After extraction AcOEt organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting crude product was recrystallized (AcOEt/hexane)to give specified in the header connection (14,7 g, yellow solid).

1H NMR (600 MHz, DMSO-d6) δ ppm: to 1.32 (t, J=7.0 Hz, 3H), 3,92 (s, 3H), 4,36 (kV, J=7,0 Hz, 2H), 10,24 (s, 1H).

Ethyl ester of 4-formyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-carboxylic acid

[Formula 55]

(3) To a solution of 4-cresol (3,62 ml) in DMF (80 ml) at room temperature was added Pan (1,38 g, 60% in mineral oil) and stirred at room temperature for 15 minutes followed by the addition of the compound obtained in Example 6-(2), (5,00 g). After stirring at 110°C for 1.5 hours, the reaction mixture was cooled to room temperature and evaporated to remove Rast is orites. The obtained residue was purified by column chromatography (SiO2HE is the type, AcOEt/hexane = 0%-50%), receiving specified in the header connection (3,54 g, colorless solid).

1H NMR (600 MHz, DMSO-d6) δ ppm: 1,27-to 1.38 (m, 3H), and 2.27 (s, 3H), 3,74 (s, 3H), 4,32 was 4.42 (m, 2H), 6,84-6,94 (m, 2H), 7,10-7,20 (m, 2H), 10,08 (s, 1H).

Ethyl ester of 4-(1-hydroxyethyl)-1-methyl-5-p-tolyloxy-1H-pyrazole-3-carboxylic acid

[Formula 56]

(4) To a solution of the compound obtained in Example 6-(3), (3.50 g) in THF (20 ml)/Et2O (120 ml) was added MeMgBr (5,26 ml, 3.0 mmol in Et2O) in nitrogen atmosphere at -30°C. After warming to 0°C. the reaction mixture was stirred for 2.5 hours, diluted with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and then was extracted with AcOEt. The organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure to remove solvent. The resulting crude product was purified by column chromatography (SiO2HE is the type, AcOEt/hexane = 0%-50%), getting mentioned in the title compound (2.17 g, pale yellow oil).

1H NMR (600 MHz, DMSO-d6) δ ppm: 1,22 (d, J=6.4 Hz, 3H), 1,28-of 1.32 (m, 3H), and 2.26 (s, 3H), of 3.56 (s, 3H), 4,28 (kV, J=6, 9 Hz, 2H), and 4.75 (d, J=4,6 Hz, 1H), 5,03-5,11 (m, 1H), 6,79-6,84 (m, 2H), 7,13-7,19 (m, 2H).

Ethyl ester 4-ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-carboxylic acid

[Formula 57]

(5) To a solution of the compound obtained in Example 6-(4), (2.14 g), l3(40 ml) at -20°C was added CF3COOH (5,4 ml) and Et3SiH (2.3 ml) and stirred at room temperature for 3.5 hours. The resulting reaction mixture was purified by column chromatography (SiO2HE is the type, AcOEt/hexane = 0%-50%), receiving specified in the header connection (1,36 g, colorless oil).

1H NMR (600 MHz, DMSO-d6) δ ppm: 0,93 (t, J=7.5 Hz, 3H), of 1.29 (t, J=7.0 Hz, 3H), and 2.27 (s, 3H), 2,42 (kV, J=7.5 Hz, 2H), 3,63 (s, 3H), 4,27 (kV, J=7,0 Hz, 2H), 6,78-6,87 (m, 2H), 7,16-7,22 (m, 2H).

4-Ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-carbaldehyde

[Formula 58]

(6) To a solution of the compound obtained in Example 6-(5), (1,36 g)in THF (30 ml) at -20°C was added LiB(C2H5)3H (9,9 ml, 1.0 M in THF) and stirred for 2 hours. Then the reaction mixture was heated to 0°C and was stirred for 2 hours followed by the addition Asón (10% in EtOH). After stirring at room temperature for 0.5 hours, the reaction mixture is evaporated to remove solvent, diluted aqueous solution of Hcl (1.0 M) and was extracted with AcOEt. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting crude product was purified using column chromium is ographie (SiO 2HE is the type, AcOEt/hexane = 0%-99%), getting mentioned in the title compound (72 mg, colorless oil) and 4-ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-yl)-methanol (554 mg, colorless oil).

4-Ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-carbaldehyde

1H NMR (600 MHz, DMSO-d6) δ ppm: to 0.94 (t, J=7.5 Hz, 3H), and 2.27 (s, 3H), 2,42 (kV, J=7.5 Hz, 2H), 3,71 (s, 3H), at 6.84-6.89 in (m, 2H), 7.18 in-7,22 (m, 2H), 9,81 (s, 1H).

4-Ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-yl)-methanol

1H NMR (600 MHz, DMSO-d6) δ ppm: to 0.94 (t, J=7.8 Hz, 3H), 2,23 (kV, J=7.8 Hz, 2H), and 2.26 (s, 3H), of 3.48 (s, 3H), 4,34 (d, J=5.5 Hz, 2H), 4,90 (t, J=5.5 Hz, 1H), 6,76-6,83 (m, 2H), 7,12-7,22 (m, 2H).

1-(4-Ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-yl)ethanol

[Formula 59]

(7) To a solution of 4-ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-carbaldehyde obtained in Example 6-(6), (470 mg) in Et2O (10 ml) was added MeMgBr (of 0.71 ml, 3.0 mmol in Et2O) at -30°C in nitrogen atmosphere. After stirring at 0°C for 4 hours the reaction mixture was diluted with saturated aqueous ammonium chloride and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting crude product was purified by column chromatography (SiO2HE is the type, AcOEt/hexane = 0%-50%), getting mentioned in the title compound (406 mg, colorless oil).

1H NMR (600 MHz, DMSO-d6) δ ppm: 093 (m, 3H), of 1.39 (d, J=6.4 Hz, 3H), 2,22 of-2.32 (m, 5H), 3,47 (s, 3H), with 4.64-4.72 in (m, 1H), 4.92 in (d, J=5.0 Hz, 1H), 6.75 in-for 6.81 (m, 2H), 7,14-7,20 (m, 2H).

3-(1-Azidoethyl)-4-ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole

[Formula 60]

(8) on the Basis of the compound obtained in Example 6-(7), repeated the same procedure that was used in Example 1-(4), getting mentioned in the title compound (colorless oil, yield 70%).

1H NMR (600 MHz, DMSO-d6) δ ppm: to 0.92 (t, J=7.8 Hz, 3H), 1,53 (d, J=6.9 Hz, 3H), 2,23 (kV, J=7.8 Hz, 2H), and 2.27 (s, 3H), of 3.54 (s, 3H), 4,69 (kV, J=6,9 Hz, 1H), 6.75 in-6,83 (m, 2H), 7,14-7,22 (m, 2H).

1-(4-Ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-yl)ethylamine

[Formula 61]

(9) Proceeding from the compound obtained in Example 6-(8), repeated the same procedure that was used in Example 1-(5), receiving specified in the title compound (colorless oil, yield 89%).

1H NMR (600 MHz, DMSO-d6) δ ppm: to 0.92 (m, 3H), of 1.29 (d, J=6.9 Hz, 3H), 2,18-to 2.29 (m, 5H), of 3.46 (s, 3H), 3,94 (kV, J=6,9 Hz, 1H), 6.75 in-PC 6.82 (m, 2H), 7,14-7,20 (m, 2H).

3,4-Dichloro-N-[1-(4-ethyl-1-methyl-5-p-tolyloxy-1H-pyrazole-3-yl)ethyl]benzosulfimide (Compound 180)

[Formula 62]

(10) on the Basis of the compound obtained in Example 6-(9), repeated the same procedure that was used in Example 1-(6), receiving specified in the title compound (Compound 180) (colorless powder, yield 48%).

1H NMR (mg, DMSO-d6) δ ppm: 0,78 (t, J=7,6 Hz, 3H), of 1.33 (d, J=6.9 Hz, 3H), 1,95-2,12 (m, 2H), and 2.26 (s, 3H), 3,37 (s, 3H), 4,37-4,51 (m, 1H), 6,60-6,70 (m, 2H), 7,12-7,22 (m, 2H), to 7.64 (DD, J=8,5, and 2.1 Hz, 1H), to 7.77-7,89 (m 2N), to 8.41 (users, 1H).

Melting point: 114,0-115,0°C

Example 7

3, 4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-3H-imidazol-4-yl]propyl}benzosulfimide (Compound 191)

[Formula 63]

2-Chloro-3-ethyl-3H-imidazole-4-carbaldehyde

[Formula 64]

(1) To a solution of 2-chloro-1-ethyl-1H-imidazole obtained in Example 5-(1), (15.0 g)in THF (570 ml) was added dropwise n-BuLi (2,64 M in hexane, to 45.5 ml) at -78°C for 1 hour and was stirred at the same temperature for 30 minutes. At the same temperature for 15 minutes was added dropwise dimethylformamide (8,9 ml) and the reaction mixture was heated to 0°C for 5 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and the aqueous layer was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography on silica gel (SiO2HE is the type, AcOEt/hexane = 0% to 60%), getting mentioned in the title compound (14.1 g) as colorless crystals.

1H NMR (600 MHz, CDCl3) δ ppm: to 1.37 (t, J=7,1 Hz, 3H), 4,27-4,50 (m, 2H), 7,69 (s, 1H), for 9.64 (who, 1H).

3-Ethyl-2-(4-pertenece)-3H-imidazole-4-carbaldehyde

[Formula 65]

(2) Suspension of the compound obtained in Example 7-(1), (5.0 g), 4-terfenol (2,87 g) and Cs2CO3(10.4 g) in DMPU (10 ml) was stirred at 200°C for 1 hour. After cooling to room temperature the reaction mixture was diluted with a mixture of methanol/chloroform (1/4) and filtered. The filtrate was concentrated and the obtained residue was purified by column chromatography (SiO2HE is the type, AcOEt/hexane = 0% to 30%), receiving specified in the header connection (4,16 g) as a pale yellow liquid.

1H NMR (600 MHz, CDCl3) δ ppm: the 1.44 (t, J=7,3 Hz, 3H), 4,37 (kV, J=7,3 Hz, 2H), 7,10-7,17 (m, 2H), was 7.36-7,40 (m, 2H).

1-[3-Ethyl-2-(4-pertenece)-3H-imidazol-4-yl]-propan-1-ol

[Formula 66]

(1) To a solution of the compound obtained in Example 7-(2), (468 mg), Et2O (4,0 ml) at 0°C was added EtMgBr (1.0 M in THF, 4.0 ml) and stirred from the same temperature to room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and the aqueous layer was extracted with ethyl acetate. After washing with a saturated aqueous solution of sodium chloride the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the resulting residue was purified using a column of chromatogra the AI on silica gel (SiO 2HE is the type, AcOEt/hexane = 0% to 50%), getting mentioned in the title compound (1.1 g) as a colourless solid.

1H NMR (600 MHz, CDCl3) δ ppm: 1,06 (t, J=7,3 Hz, 3H), of 1.39 (t, J=7,1 Hz, 3H), 1,83-2,02 (m, 2H), 3.95 to 4,10 (m, 2H), 4,43-4,51 (m, 1H), 6,53-6,60 (m, 1H), 7,02-7,10 (m, 2H), 7,17-7,25 (m, 2H).

5-(1-Azithromy)-1-ethyl-2-(4-pertenece)-1H-imidazol

[Formula 67]

(4) Based on the compound obtained in Example 7-(3), (550 mg), repeated the same procedure that was used in Example 1-(4), getting mentioned in the title compound (606 mg) as a colourless oil.

1H NMR (600 MHz, CDCl3) δ ppm: 1,02-1,11 (m, 3H), of 1.39 (t, J=7,1 Hz, 3H), 1,96-to 2.06 (m, 2H), 3,89-was 4.02 (m, 2H), was 4.02-4,08 (m, 1H), 6,64-of 6.71 (m, 1H), 7,02-7,41 (m, 4H).

1-[3-Ethyl-2-(4-pertenece)-3H-imidazol-4-yl]Propylamine

[Formula 68]

(5) on the Basis of the compound obtained in Example 7-(4), (606 mg), repeated the same procedure that was used in Example 1-(5), receiving specified in the title compound (214 mg) as colorless powder.

1H NMR (600 MHz, CDCl3) δ ppm: 1.00 and (t, J=7,3 Hz, 3H), of 1.37 (t, J=7,1 Hz, 3H), 1,63-of 1.73 (m, 1H), 1,84-of 1.94 (m, 1H), 3,70 (t, J=6,9 Hz, 1H), 3,93-4,10 (m, 2H), 6,50 (s, 1H), 7,01-7,07 (m, 2H), 7,17-7,24 (m, 2H).

3,4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-3H-imidazol-4-yl]propyl}benzosulfimide(Compound 191)

[Formula 69]

(6) on the Basis of the connection is Oia, obtained in Example 7-(5), (107 mg), repeated the same procedure that was used in Example 1-(6), receiving specified in the title compound (Compound 191) (144 mg) as colorless powder.

1H NMR (600 MHz, CDCl3) δ ppm: to 0.92 (t, J=7,3 Hz, 3H), of 1.30 (t, J=7,1 Hz, 3H), 1,68-to 1.87 (m, 2H), of 3.77-3,93 (m, 2H), 4,30-and 4.40 (m, 1H), 4.80 to to 4.92 (m, 1H), gold 6.43 (s, 1H), 7,02-7,11 (m, 2H), 7,14-7,22 (m, 2H), 7,52-7,56 (m, 1H), 7,56-a 7.62 (m, 1H), 7,86 (d, J=1.8 Hz, 1H).

Melting point: 137,5-138,5°C

Example 8

*3,4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-3H-imidazol-4-yl]propyl}benzosulfimide(Compound 253 and 254)

[Formula 70]

The compound obtained in example 7, (80 mg)was subjected to optical splitting the optical separation column (column: CHIRALPAK AD [Diacel Chemical Industries, Ltd., Japan], 2 cm ⌀ × 25 cm L; eluent: i-D/hexane = 50%, flow rate: 6.0 ml/min), getting mentioned in the title compound (Compound 253) [(R)-(+)-form, 31 mg, colorless powder, whose configuration was determined by x-ray structural analysis] and others mentioned in the title compound (Compound 254) [(S)-(-)-form, 28 mg, colorless powder, whose configuration was determined by x-ray structural analysis].

(R)-(+)-3,4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-3H-imidazol-4-yl]propyl}benzosulfimide(Compound 253)

[Formula 71]

[b]D26+19,7° c0,436, CHCl3)

Retention time: about 7.6 min (column: CHIRALPAK AD [Diacel Chemical Industries, Ltd., Japan], 4.6 mm ⌀ × 250 mm L; eluent: i-D/hexane = 60%, flow rate: 0.5 ml/min)

(S)-(-)-3,4-Dichloro-N-{1-[3-ethyl-2-(4-pertenece)-3H-imidazol-4-yl]propyl}benzosulfimide(Compound 254)

[Formula 72]

[b]D25- 17, 3C° (c0,557, CHCl3)

Retention time: 14,7 min (column: CHIRALPAK AD [Diacel Chemical Industries, Ltd., Japan], 4.6 mm ⌀ × 250 mm L; eluent: i-D/hexane = 60%, flow rate: 0.5 ml/min)

Example 9

3,4-Dichloro-N-{1-[3-ethyl-2-(4-chlorphenoxy)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 189)

[Formula 73]

1-(2-Chloro-3-ethyl-3H-imidazol-4-yl)ethanol

[Formula 74]

(1) To a solution of 2-chloro-3-ethyl-3H-imidazole-4-carbaldehyde obtained in Example 7-(1), (13,60 g), Et2O (429 ml) at -30°C in argon atmosphere was added MeMgBr (37,2 ml, 3.0 M in Et2O). After warming to 0°C the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The resulting crude product (brown solid) was washed with hexane and then dried, obtaining specified in the header connection (13,01 g) in the de light brown solid.

1H NMR (200 MHz, CDCl3) δ ppm: to 1.37 (t, J=7,3 Hz, 3H), of 1.62 (d, J=6.6 Hz, 3H), 3,89-4,30 (m, 2H), 4,80 (kV, J=6,6 Hz, 1H), 6,80 (s, 1H).

5-(1-Azidoethyl)-2-chloro-1-ethyl-1H-imidazol

[Formula 75]

(2) Proceeding from the compound obtained in Example 9-(1), (11,95 g), repeating the same procedure that was used in Example 1-(4), getting mentioned in the title compound (light yellow oil, 13,67 g).

1H NMR (200 MHz, CDCl3) δ ppm: to 1.37 (t, J=7,3 Hz, 3H), 1.69 in (d, J=6.6 Hz, 3H), 3,90-to 4.15 (m, 2H), 4.26 deaths-and 4.40 (m, 1H), 6,95 (d, J=0.9 Hz, 1H).

1-(2-Chloro-3-ethyl-3H-imidazol-4-yl)ethylamine

[Formula 76]

(3) To a solution of the compound obtained in Example 9-(2), (5,99 g), and PPh3(7,869 g) in THF (300 ml) was added N2About (10 ml) and was heated at the boiling point under reflux in the course of 15.5 hours. After cooling to room temperature the solvent is kept off and the resulting crude product was dissolved in CHCl3(200 ml). To separate the organic layer was added hydrochloric acid (1,0 N., 100 ml) and the aqueous layer was added CHCl3(200 ml) for further separation of the organic layer. The aqueous layer was brought to basic pH with NaOH (5.0 g)was vysalivanie with NaCl and was extracted with CHCl3(200 ml × 2). The combined organic layers were dried with sodium sulfate, filtered and concentrated, obtaining specified in the header is VCE compound (colorless oil, 4,588 g).

1H NMR (200 MHz, CDCl3) δ ppm: 1,36 (t, J=7,3 Hz, 3H), 1,49 (d, J=6.6 Hz, 3H), 3,90-the 4.29 (m, 3H), 6,80 (s, 1H).

1-[2-(4-Chlorophenoxy)-3-ethyl-3H-imidazol-4-yl]ethylamine

[Formula 77]

(4) In the pressure-resistant tube with screw cap was placed compound obtained in Example 9-(3), (120 mg), 4-chlorophenol (133 mg), Cs2CO3(563 mg) and DMPU (0,69 ml) and stirred at 200°C for 3 hours and then at 250°C for 1.5 hours. After cooling to room temperature was added a mixture of MeOH/CHCl3(MeOH/CHCl3= 20%, 5 ml) and the reaction mixture was purified (SiO2NH-type, MeOH/CHCl3= 1/4, 5 ml), giving a brown oil which was then purified by column chromatography (SiO2neutral HE-type, AcOEt, MeOH/CHCl3= 0% - 20%), getting mentioned in the title compound (58 mg, brown oil).

1H NMR (200 MHz, CDCl3) δ ppm: 1,36 (t, J=7.0 Hz, 3H), 1,50 (d, J=6.6 Hz, 3H), 3,79-4,12 (m, 3H), 6,55 (d, J=0.9 Hz, 1H), 7,12 and 7.36 (m, 4H).

3,4-Dichloro-N-{1-[3-ethyl-2-(4-chlorphenoxy)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 189)

[Formula 78]

(5) on the Basis of the compound obtained in Example 9-(4), (55 mg), repeated the same procedure that was used in Example 1-(6), receiving specified in the title compound (Compound 189) (53 mg) as colorless powder.

1H NMR (600 MHz, CDCl3) δ is d: 1,35 (t, J=7,1 Hz, 3H), of 1.37 (d, J=6.9 Hz, 3H), a 3.87-of 4.05 (m, 2H), 4,58-4,70 (m, 1H), 4,81 (users, 1H), 6,55 (s, 1H), 7,14-7,22 (m, 2H), 7,34 (d, J=8.7 Hz, 2H), to 7.61 (d, J=8.7 Hz, 1H), to 7.67 to 7.75 (m, 1H), 7,94 shed 8.01 (m, 1H).

Melting point: 153,0-157,0°C

Example 10

3,4-Dichloro-N-{1-[2-(4-chlorophenoxy)-3-ethyl-3H-imidazol-4-yl]ethyl}-N-methyl-benzosulfimide(Compound 248)

[Formula 79]

To a solution of the compound obtained in Example 9-(5), (36 mg)in DMF (2.0 ml) was added To a2CO3(21 mg) and MeI (5 ml) and stirred at room temperature for 7 hours. Insoluble substances were filtered off and the filtrate was concentrated. The resulting crude product was purified by column chromatography (SiO2NH-type, MeOH/CHCl3= 0% - 2%) followed by recrystallization (t-hexane), getting mentioned in the title compound (Compound 248) (30 mg, colorless powder).

1H NMR (200 MHz, CDCl3) δ ppm: 1,15 (d, J=7,0 Hz, 3H), of 1.39 (t, J=7,3 Hz, 3H), 2.63 in (s, 3H), 4.04 the-4,16 (m, 2H), from 5.29 (q, J=7,0 Hz, 1H), 6,59 (s, 1H), 7,16-7,24 (m, 2H), 7,30 and 7.36 (m, 2H), to 7.64 (d, J=8,4 Hz, 1H), 7,69 (DD, J=8.4 and, 1.8 Hz, 1H), of 7.96 (d, J=1.8 Hz, 1H).

Melting point: 142,0-144, 0mm°C

Example 11

N-{1-[2-(3-Aminophenoxy)-3-ethyl-3H-imidazol-4-yl]ethyl}-3,4-dichlorobenzenesulfonate(Compound 233)

[Formula 80]

1.5 triperoxonane salt of 1-(2-chloro-3-ethyl-3H-imidazol-4-yl)ethylamine

[Formula 81]

(1) is unity, obtained in Example 9-(3), (4,20 g), was dissolved in CHCl3(48 ml) followed by the addition triperoxonane acid (2.8 ml) at 0°C. After warming to room temperature the reaction mixture was stirred for 1 hour and then concentrated, receiving specified in the header connection (8,262 g, colorless powder).

1H NMR (200 MHz, DMSO-d6) δ ppm: of 1.23 (t, J=7,3 Hz, 3H), 1,53 (d, J=6.6 Hz, 3H), of 3.77-to 4.23 (m, 2H), 4,45-4,59 (m, 1H), was 7.08 (s, 1H), 8,25 (users, 3H).

Elementary analysis: calculated (C:34,85%, N:3,95%, N:12,19%), found (C:34,58%, N:3,85%, N:12,11%)

3-[5-(1-amino-ethyl)-1-ethyl-1H-imidazol-2-yloxy]phenylamine

[Formula 82]

(2) In a pressure-resistant tube with screw cap was placed compound obtained in Example 11-(1), (1,00 g), 3-aminophenol (633 mg), Cs2CO3(2.83 g) and DMPU (4.0 ml) and stirred at 250°C for 2 hours. After cooling to room temperature was added CHCl3and water and the mixture was concentrated. The resulting crude product was purified by column chromatography (SiO2neutral HE-type, MeOH/CHCl3= 10% - 20%), getting mentioned in the title compound (103 mg, brown oil).

1H NMR (600 MHz, DMSO-d6) δ ppm: 1,19-of 1.24 (m, 3H), of 1.35 (d, J=6.4 Hz, 3H), of 3.80-4.00 points (m, 3H), 5,19-5,24 (m, 2H), to 6.19-6.22 per (m, 1H), 6,29-6,33 (m, 2H), to 6.43 (d, J=0.9 Hz, 1H), 6,93-6,98 (m, 1H).

N-{1-[2-(3-Aminophenoxy)-3-ethyl-3H-imidazol-4-yl]ethyl}-3,4-dichlorobenzenesulfonate(Compound 233)

[Formula 83]

(3) To a solution of the compound obtained in Example 11-(2), (97 mg), and Et3N (of 0.11 ml) in THF (1.0 ml) at -78°C was added a solution of 3,4-dichlorobenzenesulfonate (96,7 mg) in THF (1.0 ml) and stirred at room temperature overnight. The reaction mixture was concentrated and the resulting crude product was purified by column chromatography on silica gel (SiO2NH-type Meon/CHCl3= 2%), getting mentioned in the title compound (Compound 233) (150 mg, light brown amorphous substance).

1H NMR (600 MHz, CDCl3) δ ppm: 1,31 (t, J=7,1 Hz, 3H), of 1.36 (d, J=6.9 Hz, 3H), of 3.73 (users, 2H), 3,84-3,95 (m, 2H), 4,59 with 4.65 (m, 1H), to 5.03 (d, J=8,3 Hz, 1H), 6,45-of 6.49 (m, 1H), of 6.49 (s, 1H), 6,51-6,56 (m, 2H), 7,09-7,14 (m, 1H), EUR 7.57 (d, J=8,3 Hz, 1H), 7,63-7,66 (m, 1H), of 7.96 (d, J=2.3 Hz, 1H).

Example 12

3,4-Dichloro-N-{1-[3-ethyl-2-(3-methanesulfonylaminoethyl)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 234)

[Formula 84]

To a solution of the compound obtained in Example 11-(3), (37 mg)in pyridine (0,37 ml) at room temperature was added methanesulfonamide (0.01 ml) and the mixture was stirred at room temperature for 5 hours. After adding water, the reaction mixture was concentrated and the resulting crude product was purified by column chromatography (SiO2NH-type, MeOH/CHCl3= 5% - 10%), receiving specified in the header is VCE compound (33 mg, colourless amorphous substance).

1H NMR (600 MHz, CDCl3) δ ppm: 1,31-of 1.39 (m, 6H), of 2.97 (s, 3H), 3,90-of 3.97 (m, 2H), 4,59-of 4.67 (m, 1H), is 5.06 (d, J=8,3 Hz, 1H), 6,56 (s, 1H), 6,91-6,97 (m, 2H),? 7.04 baby mortality (s, 1H), 7.24 to 7,29 (m, 1H), 7.62mm (d, J=8,3 Hz, 1H), of 7.70 (d, J=to 8.7 Hz, 1H), 7,87 (s, 1H), of 7.97 (d, J=1.4 Hz, 1H).

Example 13

3,4-Dichloro-N-{1-[3-ethyl-2-(3-pyrrol-1-yl-phenoxy)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 249)

[Formula 85]

To a solution of the compound obtained in Example 11-(3), (40 mg)in the Asón (300 ml) was added 2,5-dimethoxy-tetrahydrofuran (20,3 μl) and stirred at 130°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (SiO2neutral HE-type, MeOH/CHCl3= 0% - 2%), and then was purified by column chromatography (SiO2NH-type, AcOEt), getting mentioned in the title compound (Compound 249) (19 mg, colorless powder connection).

1H NMR (600 MHz, Dl3) δ ppm: 1,36 (t, J=7,3 Hz, 3H), of 1.40 (d, J=6.9 Hz, 3H), 3,91-4,00 (m, 2H), to 4.52-of 4.57 (m, 1H), 4.63 to-4,69 (m, 1H), 6,32-6,34 (m, 1H), to 6.57 (s, 1H),? 7.04 baby mortality-7,73 (m, N), 7,95-to 7.99 (m, 1H).

Example 14

3,4-Dichloro-N-[1-(3-ethyl-2-p-tamilselvan-3H-imidazol-4-yl)ethyl]benzosulfimide (Compound 241)

[Formula 86]

3-Ethyl-2-p-tamilselvan-3H-imidazole-4-carbaldehyde

[Faure, the ula 87]

(1) In the pressure-resistant tube with screw cap was placed compound obtained in Example 7-(1), (500 mg), DMF (2.0 ml) of 4-methylbenzoyl (803 mg), Cs2CO3(is 3.08 g) and stirred at 150°C for 2 hours and then at 170°C for 2 hours. After cooling to room temperature the reaction mixture was diluted with saturated aqueous NH4Cl and was extracted with AcOEt. The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography (acidic SiO2HE is the type, AcOEt/hexane = 0%-20%), getting mentioned in the title compound (571 mg, yellow solid).

1H NMR (600 MHz, Dl3) δ ppm: 1,31 (t, J=7,l Hz, 3H), of 2.35 (s, 3H), 4,39-4,48 (m, 2H), 7,06-7,29 (m, 2H), was 7.36-the 7.43 (m, 2H), of 7.75 (s, 1H), 9,62 (s, 1H).

1-(3-Ethyl-2-p-tamilselvan-3H-imidazol-4-yl)ethanol

[Formula 88]

(2) To a solution of the compound obtained in Example 14-(1), (571 mg)in THF (5.0 ml) in an argon atmosphere at room temperature was added Memduh (of 1.55 ml, 3.0 M in Et2O) and was stirred for 5 hours. The reaction mixture was diluted with saturated aqueous NH4Cl was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The resulting cheese is the first product was purified by column chromatography (neutral SiO 2HE is the type, AcOEt/hexane = 20%-99%), getting mentioned in the title compound (490 mg, colorless oil).

1H NMR (600 MHz, Dl3) δ ppm: 1,25 (t, J=7.8 Hz, 3H), of 1.65 (d, J=6.9 Hz, 3H), to 2.29 (s, 3H), 4,07-to 4.28 (m, 2H), 4,79-4,89 (m, 1H), 7,05 for 7.12 (m, 3H), 7,14-7,21 (m, 2H).

5-(1-Azidoethyl)-1-ethyl-2-p-tamilselvan-1H-imidazol

[Formula 89]

(3) on the Basis of the compound obtained in Example 14-(2), (490 mg), repeated the same procedure that was used in Example 1-(4), getting mentioned in the title compound (colorless oil, 360 mg).

1H NMR (600 MHz, CDCl3) δ ppm: 1,25 (t, J=7, 3 Hz, 3H), 1,70 (d, J=6.9 Hz, 3H), to 2.29 (s, 3H), was 4.02-4,18 (m, 2H), 4,32-and 4.40 (m, 1H), was 7.08 (d, J=8.7 Hz, 2H), 7,13-7,20 (m, 3H).

3,4-Dichloro-N-[1-(3-ethyl-2-p-tamilselvan-3H-imidazol-4-yl)ethyl]benzosulfimide (Compound 241)

[Formula 90]

(4) To a solution of the compound obtained in Example 14-(3), (360 mg), and PPh3(657 mg) in THF (4.0 ml) was added N2O protector (0.44 ml) and was heated at the boiling point under reflux for 4.5 hours. After cooling to room temperature the solvent is kept off and the resulting crude product was purified by column chromatography (neutral SiO2HE is the type, AcOEt/hexane = 0%-60%)to give a colorless oil (284 mg), which was then dissolved in THF (2.0 ml). To this solution at room temperature was added Et3 N (0,30 ml) and 3,4-dichlorobenzenesulfonate (316 mg) and stirred at room temperature for 12 hours. After addition of AcOEt organic layer was washed successively 1 N. hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting crude product was purified by column chromatography on silica gel NH-type (eluent: AcOEt) followed by recrystallization (AcOEt/hexane), getting mentioned in the title compound (Compound 241) (267 mg, colorless powder).

1H NMR (600 MHz, CDCl3) δ ppm: 1,20 (t, J=7,3 Hz, 2H), 1,37 (d, J=6.9 Hz, 3H), of 2.30 (s, 3H), 4,00-4,20 (m, 2H), 4,59-4,71 (m, 1H), 5,27 (d, J=8,3 Hz, 1H), 6.89 in (s, 1H), 7,07 for 7.12 (m, 2H), 7,16-7,21 (m, 2H), 7,53 (d, J=8,3 Hz, 1H), to 7.64 (DD, J=8,3, 2.3 Hz, 1H), 7,95 (d, J=2.3 Hz, 1H).

Melting point: 173, 0mm-174,0°C

Example 15

3,4-Dichloro-N-{1-[3-ethyl-2-(toluene-4-sulfonyl)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 252)

[Formula 91]

To a solution of the compound obtained in Example 14-(4), (100 mg)in chloroform (2.0 ml) was added m-chloroperbenzoic acid (611 mg) and stirred at room temperature overnight. Then was added m-chloroperbenzoic acid (410 mg) and stirred at room temperature for additional 3 hours. After addition of AcOEt organic layer was washed p is therefore 5% aqueous solution of Na 2S2O3and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to remove solvent. The resulting crude product was purified by column chromatography (SiO2neutral HE-type, AcOEt/hexane = 0% to 30%) and was further purified by column chromatography (SiO2NH-type (AcOEt/hexane = 0% to 99%), followed by recrystallization (AcOEt/hexane), getting mentioned in the title compound (Compound 252) (13 mg, colorless powder connection).

1H NMR (600 MHz, CDCl3) δ ppm: 1,38 was 1.43 (m, 6H), of 2.45 (s, 3H), 4,32-a 4.53 (m, 2H), 4,62-4,70 (m, 1H), 6,84 (s, 1H), 7,35-7,39 (m, 2H), 7,52-7,56 (m, 1H), to 7.59-7,63 (m, 1H), 7,89-7,94 (m, 3H).

Melting point: 180,0-USD 183.0°C

Example 16

3,4-Dichloro-N-{1-[3-ethyl-2-(1H-indol-6-yloxy)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 250)

[Formula 92]

1-[3-Ethyl-2-(1H-indol-6-yloxy)-3H-imidazol-4-yl]ethylamine

[Formula 93]

(1) In the pressure-resistant tube with screw cap was placed compound obtained in Example 11-(1), (500 mg), 1H-indol-6-ol (405 mg), Cs2CO3(1.42 g) and DMPU (2.0 ml) and stirred at 250°C for 2.5 hours. After cooling to room temperature was added a mixture of MeOH/CHCl3(MeOH/CHCl3= 1/4) and the insoluble substance was filtered. The filtrate was concentrated, and the scientists crude product was purified by column chromatography (NH silica gel-type, MeOH/CHCl3= 0% - 2%), and further purified by column chromatography (SiO2neutral HE-type, MeOH/CHCl3= 20% - 50%), getting mentioned in the title compound (146 mg, brown oil).

1H NMR (600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,1 Hz, 3H), 1,49 (d, J=6.4 Hz, 3H), 3,97-4,12 (m, 3H), 6,46-of 6.49 (m, 1H), is 6.54 (s, 1H), of 6.96 (DD, J=8,5, and 2.1 Hz, 1H), 7,11-7,14 (m, 1H), 7,30-7,34 (m, 1H), 7,56 (d, J=8.7 Hz, 1H), 8,42 (users, 1H).

3,4-Dichloro-N-{1-[3-ethyl-2-(1H-indol-6-yloxy)-3H-imidazol-4-yl]ethyl}benzosulfimide(Compound 250)

[Formula 94]

(2) To a solution of the compound obtained in Example 16-(1), (36 mg), and Et3N (37,1 μl) in THF (0.5 ml) at -78°C was added a solution of 3,4-dichlorobenzenesulfonate (20,8 μl) in THF (0.5 ml). The reaction mixture was heated to room temperature and was stirred overnight. The reaction mixture was concentrated and the resulting crude product was purified by column chromatography (SiO2NH-type Meon/CHCl3= 2% - 5%) followed by recrystallization (AcOEt-hexane), getting mentioned in the title compound (Compound 250) (19 mg, colorless powder).

1H NMR (600 MHz, CDCl3) δ ppm: 1,33-of 1.40 (m, 6H), 3,90-4,01 (m, 2H), br4.61-4,72 (m, 2H), of 6.49 (s, 1H), 6,51-6,53 (m, 1H), 6,95 (DD, J=8,5, and 2.1 Hz, 1H), 7,16-7,19 (m, 1H), 7,32 (d, J=2.3 Hz, 1H), EUR 7.57-to 7.61 (m, 2H), 7,65-of 7.69 (m, 1H), of 7.97 (d, J=2.3 Hz, 1H), 8,28 (users, 1H).

Melting point: 150,5-153,5°C

Example 17

3,4-Dichloro-N-(1-{3-ethyl-2-[3-(4-mailpipe Azin-1-yl)phenoxy]-3H-imidazol-4-yl}ethyl)benzosulfimide

(Compound 184)

[Formula 95]

1-{3-Ethyl-2-[3-(4-methylpiperazin-1-yl)phenoxy]-3H-imidazol-4-yl}alanon

[Formula 96]

(1) a Mixture of 2-chloro-1-ethyl-1H-imidazole obtained in Example 5-(2), (1.0 g), 3-(4-methylpiperazin-1-yl)phenol (1,67 g), Cs2CO3(of 3.78 g) and DMPU (3.0 ml) was stirred at 200°C for 1 hour. After cooling to room temperature was added AcOEt and the insoluble substance was filtered. The filtrate was concentrated and the resulting crude product was purified by column chromatography (SiO2neutral HE-type, AcOEt/hexane = 0% to 99%), getting mentioned in the title compound (1.88 g, yellow oil).

1H NMR (600 MHz, CDCl3) δ ppm: 1,36 (t, J=7,1 Hz, 3H), of 2.35 (s, 3H), 2,41 (s, 3H), 2,53-of 2.58 (m, 4H), 3,19 of 3.28 (m, 4H), or 4.31-and 4.40 (m, 2H), 6,63-of 6.71 (m, 1H), 6,74-for 6.81 (m, 2H), 7,21-7,31 (m, 1H), 7,49 (s, 1H).

1-{3-Ethyl-2-[3-(4-methylpiperazin-1-yl)phenoxy]-3H-imidazol-4-yl}ethanol

[Formula 97]

(2) To a solution of the compound obtained in Example 17-(1), (1,87 g), Meon (10.0 ml) at 0°C was added NaBH4(325 mg) and was stirred at the same temperature for 2 hours. The reaction mixture was diluted with saturated aqueous NH4Cl and was extracted with AcOEt. After washing with saline solution, the organic layer was dried over magnesium sulfate, filtered and then evaporated to Claudine solvent. The resulting crude product was purified by column chromatography (SiO2neutral HE-type, AcOEt/hexane = 0% to 99%, MeOH/CHCl3= 0% - 3%), getting mentioned in the title compound (1.40 g, yellow oil).

1H NMR (600 MHz, CDCl3) δ ppm: to 1.37 (t, J=7,3 Hz, 3H), of 1.62 (d, J=6.4 Hz, 3H), of 2.34 (s, 3H), 2,52 at 2.59 (m, 4H), 3,18-3,24 (m, 4H), 3,92-4,11 (m, 2H), 4,77-is 4.85 (m, 1H), 6,61 is 6.67 (m, 2H), 6,69-of 6.73 (m, 1H), 6,76-6,79 (m, 1H), 7.18 in-of 7.23 (m, 1H).

1-{3-[5-(1-Azidoethyl)-1-ethyl-1H-imidazol-2-yloxy]phenyl}-4-methylpiperazin

[Formula 98]

(3) To a solution of the compound obtained in Example 17-(2), (408 mg)in toluene (6.0 ml) at 0°C. was added DPPA (1,48 ml) and DBU (368 μl) and stirred at room temperature for 16 hours. After addition of CHCl3the reaction mixture was purified by column chromatography (SiO2neutral HE-type, MeOH/CHCl3= 5% - 10%), getting mentioned in the title compound (332 mg, light brown oil).

1H NMR (600 MHz, CDCl3) δ ppm: to 1.37 (t, J=7 Hz, 3H), 1,68 (d, J=6.9 Hz, 3H), of 2.34 (s, 3 H), 2,52-2,61 (m, 4H), 3,18-of 3.25 (m, 4H), 3,86-Android 4.04 (m, 2H), 4,30-4,37 (m, 1H), 6,64 is 6.67 (m, 1H), 6,70-of 6.73 (m, 2H), 6,74-6,76 (m, 1H), 7,19-7,24 (m, 1H).

1-{3-ethyl-2-[3-(4-methylpiperazin-1-yl)phenoxy]-3H-imidazol-4-yl}ethylamine

[Formula 99]

(4) a Mixture of the compound obtained in Example 17-(3), (322 mg), and palladium-activated carbon (32 mg, Pd 10 wt.%) in the Meon (6.5 ml) was stirred atmospheres is hydrogen (about 1 atmosphere) at room temperature for 14 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The resulting crude product was purified by column chromatography (NH silica gel, MeOH/CHCl3= 0% - 2%), getting mentioned in the title compound (190 mg, colorless oil).

1H NMR (600 MHz, CDCl3) δ ppm: 1,36 (t, J=7,1 Hz, 3H), 1,49 (d, J=6.4 Hz, 3H), of 2.35 (s, 3H), 2,53-2,60 (m, 4H), 3,19-of 3.25 (m, 4H), 3,90-4,11 (m, 3H), 6,55-6,56 (m, 1H), 6,63-of 6.71 (m, 2H), 6,76-6,79 (m, 1H), 7,15-7,25 (m, 1H).

3,4-Dichloro-N-(1-{3-ethyl-2-[3-(4-methylpiperazin-1-yl)phenoxy]-3H-imidazol-4-yl}ethyl)benzosulfimide

(Compound 184)

[Formula 100]

(5) To a solution of the compound obtained in Example 17-(4), (60 mg)in THF (3.0 ml) at room temperature was added Et3N (50 ml) and 3,4-dichlorobenzenesulfonate (30 mg) and stirred at room temperature for 3 hours. The reaction mixture was concentrated, the resulting crude product was purified by column chromatography (SiO2neutral HE-type, AcOEt/hexane = 50% - 99%, Meon/CHCl3= 0% - 5%) and then was purified by column chromatography (SiO2NH-type, AcOEt/hexane = 50% - 99%, Meon/CHCl3= 0% - 2%) followed by recrystallization (AcOEt-hexane), getting mentioned in the title compound (Compound 184) (65 mg, colorless powder).

1H NMR (600 MHz, CDCl3) δ ppm: of 1.33 (t, J=7,1 Hz, 3H), of 1.37 (d, J=6.9 Hz, 3H), of 2.36 (s, 3H), 2,50-to 2.65 (m, 4H), 3,18-3.30 m, 4H), 3,83-4,00 (m, 2H), 4,58-4,69 (m, 1H), 4.75 V-free 5.01 (m, 1H), 6.48 in-6,55 (m, 1H), 6,60 of 6.66 (m, 1H), 6,69-6,77 (m, 2H), 7.18 in-7,25 (m, 1H), 7,56 to 7.62 (m, 1H), 7,63-7,72 (m, 1H), of 7.97 (s, 1H).

Melting point: 164,5-165,5°C

On the basis of relevant background material, repeating the same procedures as described in Examples 1-17, followed by the formation of salt, if necessary, to obtain the compounds shown in Table 1 below.

The compound obtained in the above examples, also shown in Table 1, along with other compounds.

In Table 1 some compounds have values of two data for each of the APCI MS (M-H)- APCI MS (M+H)+. This is because due to the presence of isotopes of chlorine or of bromine was determined by two peaks.

The Test example 1 (test of inhibition of binding S1P1)

The effect of the compounds of the present invention on the inhibition of binding of Edg-1 (S1P1) was determined using the membrane fraction of strain NECK-293 cells with gene transfer of human Edg-1 (S1P1in accordance with a method described in the literature (Science. 2002, 296: 346) (showing the binding Kd = 0,15 nm, Bmax = 2.5 fmol/μg and [33R]-S1P). The membrane fraction was obtained by processing cells solubilization buffer (1 mm Tris/HCl, pH to 7.2) for 10 minutes on ice, centrifugation at 1000 × g for 5 minutes to remove insoluble fractions, and then centrifugation at 40,000 × g for 30 minutes is at 4°C. The obtained membrane fraction was dissolved in binding buffer (20 mm Tris-HCl, pH of 7.4, 100 mm NaCl, 15 mm NaF, 2 mm deoxypyridoxine, 4 mg/ml BSA free fatty acids) and then added a [33R]-S1P (produced by ARC, final concentration 0.1 nm) and a solution of DMSO (final concentration is 10-5M, final concentration of DMSO of 0.1%) of the tested compounds. After that, the mixture was stirred and then treated for 1 hour at 30°C. using a device for collecting cell membrane fraction was collected on GF/C filter unifilter-96 (manufactured by Perkin Elmer), washing was carried out four times with binding buffer and the filter was dried. Added twenty-five μl of Microscint 0 (manufactured by Perkin Elmer) and measured the radioactivity using a Top Count NXT (manufactured by Packard) to calculate the number () [33R]-S1P associated with the membrane fraction, adding connections.

The same procedure was carried out in the absence of the test compound was calculated amount (In) associated with [33R]-S1P. Next, the same procedure was carried out in the absence of the test compound using SOME 293 cells, which were not introduced Edg-1 (S1P1) gene, and was calculated background number (S) associated with [33R]-S1P.

The degree of inhibition of binding of Edg-1 (S1P1the connection calculated using the following equation, is provided in Table 1.

The degree of inhibition (%) = [1-(a-C)/(b-C)]×100.

In addition, as figured (IC50) the concentration of test compound required to provide 50% inhibition of binding caused in the absence of the test compound. The above-mentioned test binding membrane system was carried out in the presence of the test compounds at various concentrations to calculate the degree of inhibition of binding of Edg-1 (S1P1) at each concentration according to the above equation, followed by calculating the value of the IC50for each connection using software for data analysis Origin (Lightstone Corp., Japan).

The results showed that the compounds listed below have the meanings IC5070 nm or below, and show particularly strong activity:

Connection 186, 189, 194, 214, 229 and 236.

Moreover, the compounds listed below have the meanings IC5035 nm or below, and show stronger activity:

Connection 187 and 234.

The compounds listed below have the meanings IC5015 nm or below, and show a much stronger activity:

Connection 208, 246 and 247.

Detailed data IC50shown below for each of the compounds (unit: nm):

Compound 184: 14,3; 185 Connection: 3,7; Connection 190: 10,9; Connection 192: 23, 0mm; Connection 195: 20, 0mm; 198 Connection: 10,3; Connect the s 200: 17, 0mm; Compound 203: 23.5cm; Connection 207: 18,2; Connection 209: 42,0; Connection 213: 49,0; 235 Connection: 58,5; Connection 244: 32,5; Connection 250: 20,5; Connection 253: 27,5.

[Table 1-1]

[Table 1-2]

[Table 1-3]

[Table 1-4]

[Table 1-5]

[The table is and 1-6]

[Table 1-7]

[Table 1-8]

[Table 1-9]

[Table 1-10]

[Table 1-11]

[Table 1-12]

[Table 1-13]

[Table 1-14]

[Table 1-15]

[Table 1-16]

[Table 1-17]

td align="left">
[Table 1-18]

[Table 1-19]

[Table 1-20]

[Table 1-21]

[Table 1-22]

[Table 1-23]

[Table 1-24]is the

[Table 1-25]

[Table 1-26]

[Table 1-27]

[Table 1-28]

[Table 1-29]

[Table 1-30]

[Table 1-31]

[Table 1-32]

[Table 1-33]

[Table 1-34]

[Table 1-35]

[Table 1-36]

[Table 1-37]

Below are Examples of receipt for the intermediate compounds of formula (II) according to the present invention.

Proceeding from the appropriate starting compounds, repeated the same procedure shown in Example 1-(1) to (5), Example 2-(1) to (7), Example 4-(1) to (5), Example 5-(1) - (8), Example 7-(1) - (8), Example 9-(1) - (4), Example 11-(1) and (2), Example 16-(1) and Example 17-(1) - (4), followed by the formation of salts, if necessary, to obtain the intermediate compounds or their salts, which are useful in producing compounds of formula (I) according to the present invention. Thus obtained intermediate compound shown in Table 2, along with the intermediate compounds obtained in the examples shown above.

INDUSTRIAL APPLICABILITY

Due to the fact that the compounds of the present invention are excellent Edg-1 (S1P ) ligands, they are useful as therapeutic and/or prophylactic agents against autoimmune diseases such as Crohn's disease, spastic colitis, rheumatoid Segren, multiple sclerosis and systemic lupus erythematosus, as well as other diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age-related macular degeneration, etc.

1. The compound represented by formula (I)or its pharmaceutically acceptable salt:
[Formula 1]

where AG represents an imidazole or pyrazole,
where specified AG may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom,
Y1, Y2and Y3each represents a carbon atom or a nitrogen atom,
A represents an oxygen atom, a sulfur atom or a group represented by the formula-SO2-,
R1represents a hydrogen atom, a C1-C6alkyl group which may be substituted by one phenyl group (where this phenyl group may be substituted by one Deputy, selected from the group consisting of a halogen atom, and C1-C6alkyl group, or phenyl group,
R2represents C1-C6alkyl the second group,
R3represents (i) C1-C18alkyl group, (ii) C2-C8alkenylphenol group, (iii) C2-C8alkylamino group, (iv)3-C8cycloalkyl group, (v) C1-C6alkyl group substituted by 1-3 substituent(s)selected from the following group [where the group consists of a halogen atom, phenyl group, C1-C6alkoxygroup, piperazinone, which may be substituted C1-C6alkyl group(s), morpholinopropan,
group represented by the formula:
[Formula 3]

(where R14and R15each represents C1-C6alkyl group),
or (vi) phenyl group, naftalina group, pyrazolidine group, pyridyloxy group, indolenine group, hyalinella group or athinodorou group, where each of these groups may be substituted by 1-3 substituents selected from the following group [where the group consisting of substituents listed below: C1-C6alkyl group which may be substituted atom(s) fluorine, halogen atom, With1-C6alkoxygroup (where specified alkoxygroup may be substituted by substituent(s)selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), p is peridiniales group or piperidino (where specified piperidinyl or piperidinium may be substituted C 1-C6alkyl group(s)), imidazolidine group, pyrrolidino group, morpholinyl group, piperazinone, which may be substituted C1-C6alkyl group(s), and the formula:

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group],
R4represents a hydrogen atom or a C1-C6alkyl group, and
R5represents (i)1-C10alkyl group, (ii) C1-C10alkyl group which is substituted by one or two substituents selected from the following group (where the group consists of a3-C8cycloalkyl group, peredelnoj group and phenyl, phenoxy or naftilos group which may be substituted by one or two substituents selected from the group consisting of a halogen atom, and C1-C6alkoxygroup), (iii) C2-C8alkenylphenol group which may be substituted by phenyl group, or (iv) phenyl group, naftalina group, thienyl group, pyrrolidino group, pyrazolidine group, pyridyloxy group, fornillo group, benzothiazoline group, athinodorou group, isoxazolyl group, thiazolidine group, benzothiazolyl group, benzoxazolyl g is the SCP, phenyl group condensed with a 5 to 7-membered saturated hydrocarbon ring, which may contain as ring members, one or two oxygen atom, oralloy group or tetrahydroisoquinoline group, where each of these groups may be substituted by 1-5 substituents selected from the following group
[where the group consists of C1-C6alkyl group which may be substituted atom(s) fluorine, C2-C8alkenylphenol group, halogen atom, a C1-C6alkoxygroup, which may be substituted atom(s) fluorine, oxazolidines, isoxazolidine or thiadiazolyl group which may be substituted triptoreline(s) group(s), C1-C6allylthiourea, C1-C6alkylsulfonyl group, benzolsulfonate group, morpholinomethyl group, morpholinosydnonimine,2-C10alkoxycarbonyl group, morpholinopropan, phenyl group which may be substituted C1-C6alkoxygroup(AMI), fenoxaprop, pyridylcarbonyl, pyridyloxy, ceanography, C2-C7alkanoyloxy group which may be substituted atom(s) fluorine, and3-C7alkanolamines],
provided that when AG is a group represented by the following formula:
[Fo the mule 5]

which may be substituted C1-C6alkyl group, R5is not C1-C10alkyl group,
and the compound of formula (I) is not
5-(3,5-dichlorophenylthio)-4-isopropyl-2-methanesulfonylaminoethyl-1-methyl-1H-imidazole or
5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluensulfonate-1 H-imidazole}.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where in formula (I)
AG represents an imidazole or pyrazole,
A represents an oxygen atom or a sulfur atom,
R1represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkyl group, substituted phenyl group,
R2represents C1-C6alkyl group,
R represents (i)1-C6alkyl group, or (ii) phenyl group, naftalina group, pyrazolidine group, pyridyloxy group, indolenine group, hyalinella group or athinodorou group, where each of these groups may be substituted by 1-3 substituents selected from the following group [where the group consisting of substituents listed below: C1-C6alkyl group which may be substituted atom(s) fluorine, halogen atom, a C1-C6alkoxygroup (where specified alkoxygroup can be substituted to cover elem(s), selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), piperidinyl group or piperidino (where specified piperidinyl or piperidinium may be substituted C1-C6alkyl group(s)), imidazolidine group, pyrrolidino group, morpholinyl group, piperazinone, which may be substituted C1-C6alkyl group(s), and the formula:

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group],
R4represents a hydrogen atom or a C1-C6alkyl group, and
R5represents (i) C1-C10alkyl group, (ii) C1-C10alkyl group which is substituted by one or two substituents selected from the following group (where the group consists of a3-C8cycloalkyl group, phenyl group, naftilos group, peredelnoj groups and phenyl groups, substituted with one or two substituents selected from the group consisting of a halogen atom, and C1-C6alkoxygroup), (iii) C2-C8alkenylphenol group, (iv) C2-C8alkenylphenol group, substituted phenyl group, or (v) phenyl group, naftalin the th group, thienyl group, pyrrolidino group, pyrazolidine group, pyridyloxy group, fornillo group, benzothiazoline group, athinodorou group, isoxazolyl group, thiazolidine group, benzothiazolyl group, benzoxazolyl group, phenyl group condensed with a 5 to 7-membered saturated hydrocarbon ring, which may contain as ring members, one or two oxygen atom, oralloy group or tetrahydroisoquinoline group, where each of these groups may be substituted by 1-5 substituents selected from the following group
[where the group consists of C1-C6alkyl group which may be substituted atom(s) fluorine, C2-C8alkenylphenol group, halogen atom, a C1-C6alkoxy group which may be substituted atom(s) fluorine, oxazolidines, isoxazolidine or thiadiazolyl group which may be substituted triptoreline(s) group(s), C1-C6allylthiourea, C1-C6alkylsulfonyl group, benzolsulfonate group, morpholinomethyl group, morpholinosydnonimine group2-C10alkoxycarbonyl group, morpholinopropan, phenyl group which may be substituted C1-C6alkoxygroup(AMI), fenoxaprop, pyridinyl Niley, pyridyloxy, ceanography, C2-C7alkanoyloxy group which may be substituted atom(s) fluorine, and C2-C7alkanolamines].

3. The compound or its pharmaceutically acceptable salt according to claim 1, where AG is the Deputy, represented by the following formula:
[Formula 6]
or
which can be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom.

4. The compound or its pharmaceutically acceptable salt according to claim 1, where AG is the Deputy, represented by the following formula:
[Formula 7]
or
which can be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom.

5. The compound or its pharmaceutically acceptable salt according to claim 1, where AG is the Deputy, represented by the following formula:
[Formula 8]

which can be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, phenyl group and halogen atom.

6. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 5, where a p is ecstasy the oxygen atom.

7. The compound or its pharmaceutically acceptable salt according to any one of claims 1 and 3-5, where R1represents C1-C6alkyl group or a benzyl group which may be substituted by one Deputy, selected from the group consisting of a halogen atom, and C1-C6alkyl groups.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 and 3-5, where R1represents methyl group, ethyl group or a benzyl group which may be substituted by a halogen atom.

9. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R1represents methyl group or ethyl group.

10. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R4represents a hydrogen atom.

11. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R2represents ethyl group.

12. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R5represents C1-C10alkyl group, substituted C3-C8cycloalkyl group, C1-C10alkyl group, a substituted naftilos group, C2-C8alkenylphenol group, substituted phenyl group, the phenyl or naftalina group which may be substituted by 1-5 substituents selected from the following group (where the group SOS is the RTO from C 1-C6alkyl group, halogen atom, a C1-C6alkoxygroup, cryptometer, dipterocarp, triptorelin group2-C6alkenylphenol group, C1-C6alkylsulfonyl group, C2-C7alkanoyloxy group, C2-C7alkoxycarbonyl group and ceanography), pyrrolidinyl group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl groups and methoxycarbonyl group, fornillo group which may be substituted by substituent(s)selected from the following group (where the group consists of C1-C6alkyl group, triptorelin group and halogen atom), a thienyl group which may be substituted by substituent(s)selected from the following group (where the group consists of C1-C6alkyl group, triptorelin group, thiadiazolyl group, oxazoline group and halogen atom), or benzothiazoline, dihydrobenzofuranyl, benzodioxolyl, dihydroergotoxine, dihydrobenzofuranyl, tetrahydronaphthalene, indenolol, benzoxadiazole or benzothiazolyl group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl groups and atom ha is Ohana.

13. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R5represents C1-C6alkyl group, a substituted naftilos group2-C6alkenylphenol group, substituted phenyl group, unsubstituted phenyl group, phenyl group, substituted by 1-5 substituents selected from the following group (where the group consisting of methyl group, metoxygroup and halogen atom), a phenyl group substituted by 1-3 substituents selected from the following group, and at least one of 3 - and 4-positions is substituted (where the group consists of C1-C6alkyl group, halogen atom, metoxygroup, cryptometer, dipterocarp, triptorelin group2-C6alkenylphenol group, methylsulfonyl group, acetyl group, methoxycarbonyl group and ceanography), naftalina group which may be substituted by substituent(s)selected from the following group (where the group consists of a halogen atom, a C1-C6alkyl group, ceanography and C1-C6alkylsulfonyl group), fornillo group which may be substituted by substituent(s)selected from the group consisting of triptorelin group and halogen atom, or benzothiazoline, benzoxadiazole, benzodioxol the ilen, dihydroergotoxine, dihydrobenzofuranyl, indenolol or benzothiazolyl group which may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group and halogen atom.

14. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R5represents a phenyl group, 3 - and 4-position which is substituted by halogen atom, or naftalina group which may be substituted by substituent(s)selected from the group consisting of a halogen atom, a C1-C6alkyl groups and ceanography.

15. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R3represents a phenyl group, naftalina group, pyrazolidine group, pyridyloxy group, indolenine group, hyalinella group or athinodorou group, where each of these groups may be substituted by 1-3 substituents selected from the following group [where the group consisting of substituents listed below: C1-C6alkyl group which may be substituted atom(s) fluorine, halogen atom, a C1-C6alkoxygroup (where specified alkoxygroup may be substituted by substituent(s)selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), piperidinyl the group or piperidino (where specified piperidinyl or piperidinium may be substituted C 1-C6alkyl group(s)), imidazolidine group, pyrrolidino group, morpholinyl group, piperazinone, which may be substituted With1-C6alkyl group(s), and the formula:

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group].

16. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R3is 2-naftalina group (where specified naftalina group may be substituted by substituent(s)selected from the group consisting of a halogen atom, and C1-C6alkyl group), 3-pyrazolidine group (where specified pyrazolidine group may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group, triptorelin group and halogen atom), or 7-athinodorou, 7-hyalinella, 3-pyridyloxy or indolenine group which may be substituted C1-C6alkyl group(s), an unsubstituted phenyl group or substituted phenyl group, shown below in (A)-(C):
(A) phenyl group, 4-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl group, a C1-C6alkoxygroup (where specified alkoxy group may be behind esena substituent(s), selected from the group consisting of amino, substituted two C1-C4alkyl groups and morpholinopropan), halogen atom, 1-pyrrolidino group, and-NRARB(where RAand RBeach represents C1-C6alkyl group), and then 3-position of which may be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, halogen atom and C1-C6alkoxygroup,
(B) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl groups and C1-C6alkoxygroup (where specified alkoxygroup may be substituted by substituent(s)selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), and further which may be substituted by one or two C1-C6alkyl groups, or 4-position of which may be substituted by a halogen atom,
and
(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and, optionally, 4-position may be substituted by a halogen atom:
(i) piperidinyloxy or piperidinium (where specified piperidinyl or piperidino group may be substituted C1-C alkyl group(s)),
(ii) imidazolidine or pyrrolidino group,
(iii) morpholinyl group,
(iv) piperazinone [where specified, piperazine derivatives the group may be substituted C1-C6alkyl group], and
(v) the formula-NR7R8
where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group.

17. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R3represents a phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and, optionally, 4-position may be substituted by a halogen atom:
(i) piperidinyloxy or piperidinium (where specified piperidinyl or piperidinium may be substituted C1-C6alkyl group(s)),
(ii) imidazolidine or pyrrolidino group,
(iii) morpholinyl group,
(iv) piperazinone [where the specified piperazinone may be substituted C1-C8alkyl group], and
(v) the formula-NR7R8
where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group.

18. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R3represents the t of the phenyl group, 4-position which is substituted by fluorine atom or chlorine.

19. The compound or its pharmaceutically acceptable salt according to claims 1-5, where R3is 6-indolering group.

20. The compound or its pharmaceutically acceptable salt according to any one of claims 1 and 3-5, where R3represents C1-C18alkyl group, a C1-C6alkyl group substituted by 1-3 substituent(s)selected from the following group (where the group consists of a halogen atom, an amino group which may be substituted by two C1-C6alkyl groups, C1-C6alkoxygroup, piperazinone, which may be substituted C1-C6alkyl group(s), phenyl group and morpholinopropan), C2-C8alkenylphenol group, C2-C8alkylamino group or3-C8cycloalkyl group.

21. The compound or its pharmaceutically acceptable salt according to any one of claims 1 and 3-5, where R3represents C1-C6alkyl group substituted by 1-3 substituent(s)selected from the following group (where the group consists of the amino group which may be substituted by two C1-C6alkyl groups, and C1-C6alkoxygroup), or C3-C5cycloalkyl group.

22. Pharmaceutical composition, which is an inhibitor of binding S1P s e what about the Edg1 receptor (S1P1), comprising the compound or its pharmaceutically acceptable salt according to claims 1 to 21.

23. The pharmaceutical composition according to item 22, which is a therapeutic agent from autoimmune diseases, such as Crohn's disease, spastic colitis, rheumatoid Segren, multiple sclerosis or systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis and age-related macular degradation.

24. The compound represented by formula (II)or its salt:
[Formula 9]

(where R1, R2and R3have the meanings defined above in claim 1, and Y4and Y5each represents a nitrogen atom or the formula CR17(where R17represents a hydrogen atom, a C1-C6alkyl group, phenyl group or halogen atom), provided that one of Y4and Y5represents a nitrogen atom).

25. The compound or its salt according to paragraph 24, where in the formula (II) Y4is CH, and Y5represents a nitrogen atom.

26. The compound or its salt according to paragraph 24 or 25, where R1represents C1-C6alkyl group or a benzyl group which may be substituted by one Deputy, selected from the group consisting of a halogen atom, and C1-C6alkyl groups.

27. The compound or its salt according to paragraph 24 or 25, where R1represents methyl group, ethyl group or a benzyl group which may be substituted by a halogen atom.

28. The compound or its salt according to paragraph 24 or 25, where R1represents methyl group or ethyl group.

29. The compound or its salt according to paragraph 24 or 25, where R2represents ethyl group.

30. The compound or its salt according to paragraph 24 or 25, where R3represents a phenyl group, naftalina group, pyrazolidine group, pyridyloxy group, indolenine group, hyalinella group, athinodorou group, where each of these groups may be substituted by 1-3 substituents selected from the following group [where the group consisting of substituents listed below: C1-C6alkyl group which may be substituted atom(s) fluorine, halogen atom, a C1-C6alkoxygroup (where specified alkoxygroup may be substituted by substituent(s)selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), piperidinyloxy group, piperidino (where specified piperidinyl or piperidinium may be substituted C1-C6alkyl group(s)), imidazolidine group, pyrrolidino group, morpholinyl group, piperazinone to ora may be substituted C 1-C6alkyl(s) group(s), and the formula:

where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group].

31. The compound or its salt according to paragraph 24 or 25, where R3is 2-naftalina group (where specified naftalina group may be substituted by substituent(s)selected from the group consisting of a halogen atom, and C1-C6alkyl group), 3-pyrazolidine group (where specified pyrazolidine group may be substituted by substituent(s)selected from the group consisting of C1-C6alkyl group, triptorelin group and halogen atom), or 7-athinodorou, 7-hyalinella, 3-pyridyloxy or indolenine group which may be substituted C1-C6alkyl group(s), an unsubstituted phenyl group or substituted phenyl group, shown below in (A)-(C):
(A) phenyl group, 4-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl group, a C1-C6alkoxygroup (where specified alkoxygroup may be substituted by substituent(s)selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), halogen atom, 1-pyrrolidino g is uppy and-NR ARB(where RAand RBeach represents C1-C6alkyl group), and, optionally, the 3-position of which may be substituted by the Deputy selected from the group consisting of C1-C6alkyl group, halogen atom and C1-C6alkoxygroup,
(B) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of C1-C6alkyl groups and C1-C6alkoxygroup (where specified alkoxygroup may be substituted by substituent(s)selected from the group consisting of amino, substituted two C1-C4alkyl groups, and morpholinopropan), and further which may be substituted by one or two C1-C6alkyl groups, or 4-position of which may be substituted by a halogen atom,
and
(C) phenyl group, 3-position which is substituted by the Deputy selected from the group consisting of nitrogen-containing groups, shown below in (i)to(v), and, optionally, 4-position may be substituted by a halogen atom:
(i) piperidinyloxy or piperidinium (where specified piperidinyl or piperidinium may be substituted C1-C6alkyl group(s)),
(ii) imidazolidine or pyrrolidino group,
(iii) morpholinyl group,
(iv) piperazinone [where the specified piperazino the PAP may be substituted C 1-C6alkyl group], and
(v) the formula-NR7R8
where R7and R8each represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group.

32. The compound or its salt according to paragraph 24 or 25, where R3represents C1-C18alkyl group, a C1-C6alkyl group substituted by 1-3 substituent(s)selected from the following group (where the group consists of a halogen atom, an amino group which may be substituted by two C1-C6alkyl groups, C1-C6alkoxygroup, piperazinone, which may be substituted C1-C6alkyl group(s), phenyl group and morpholinopropan), C2-C8alkenylphenol group, C3-C8alkylamino group or3-C8cycloalkyl group.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

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