Heterocyclic compound derivatives and pharmaceutical agents

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.

EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.

15 cl, 3 tbl, 109 ex

 

The technical FIELD

The present invention relates to new heterocyclic compound, which may be used as a drug or its salts and the agonist receptor PGI2containing the specified heterocyclic compound as the active ingredient.

BACKGROUND of INVENTION

Prostaglandin I2(PGI2) is formed in vivo from arachidonic acid via the prostaglandin H2(PGH2) and has various drastic actions, such as inhibition of platelet aggregation, vasodilation, inhibition of the deposition of lipids and inhibition of activation of leukocytes. It is therefore considered that PGI2is effective for the treatment of peripheral vascular disease (for example, obliterating arteriosclerosis, intermittent claudication, peripheral arterial embolism, vibration disease and disease, Raynaud's disease), systemic lupus erythematosus, reocclusion or restenosis after percutaneous intraluminal coronary angioplasty (RTSA), arteriosclerosis, thrombosis, diabetic neuropathy, diabetic nephropathy, hypertension, ischemic diseases (such as cerebral infarction and myocardial infarction), transient disorders of cerebral circulation and glomerulonephritis or accelerate the development of Kroenen the x vessels in the way of reconstruction of peripheral blood vessels or therapy, associated with the development of blood vessels.

However, PGI2not suitable for use as a drug because it is chemically unstable and has a very short biological half-life of existence and, in addition, the use of it creates the problem of side effects, which probably occurs because it is difficult to separate the desired effect from another effect. To achieve the duration of efficacy of a drug, mitigate the side effects and improve compliance, has been researched and developed preparations of prostaglandins for long periods. However, satisfactory results were not achieved.

In these circumstances it is assumed that the agonist receptor PGI2that is not a prostanoid and exhibits excellent affinity to the receptor PGI2and chemical stability, has excellent therapeutic effect as a drug compared to conventional drugs PGI2and so it is intensively researched and developed.

For example, it was known that imidazole derivatives (Br. J. Pharmacol., 102, 251 (1991)), derivative oxazole (J. Med. Chem., 35, 3498 (1922), J. Med. Chem., 36, 3884 (1993), derivatives of pyrazole (Folia Phermacol. Jp., 106, 181 (1995), Bioorg. Med. Chem. Lett., 5, 1071 (1995), Bioorg. Med. Chem. Lett., 5, 1083 (1995)), derivative Piras the Nona (Bioorg. Med. Chem. Lett., 10, 2787 (2000)) and derivative Asimov (Folia Phermacol. Jp., 106, 181(1995), Bioorg. Med. Chem. Lett., 5, 1071 (1995), Bioorg. Med. Chem. Lett., 5, 1083 (1995)) have agonistic activity against receptor PGI2.

It is also known that derivatives of 2,3-diphenylpyrazine (Japanese, which has not passed the examination patent publication No. Hei.-7-33752) have herbicide action, derivatives of 2,3-diphenylpyridine and derivatives of 5,6-diphenylpyridine (WO 92/01675) have antagonism against leukotriene4and derivatives of 2,3-diphenylpyridine (WO 96/18616) have inhibitory action on the synthesis of nitric oxide. However, it is not known that these compounds have agonistic activity against receptor PGI2.

Description of the INVENTION

The purpose of the present invention is to develop a new agonist of the receptor PGI2and new heterocyclic compounds.

To achieve the above purpose, the authors of the present invention have synthesized various compounds in the process of research and found that heterocyclic compounds represented by the following General formula (I) (hereinafter also referred to as heterocyclic compounds (1)) have excellent agonistic towards the receptor PGI2and thus was established the present invention.

where R1and R2are the same or different, and each represents optionally substituted aryl, the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro,

Y represents N, N→O or CR5Z represents N or CR6and R5and R6are the same or different and each represents hydrogen, alkyl or halogen,

And represents NR7, O, S, SO, SO2or ethylene, and R7represents hydrogen, alkyl, alkenyl or cycloalkyl,

D represents alkylene or albaniles, which is optionally substituted by hydroxy, or a and D are connected to each other to form divalent group represented by the following formula (2):

r is an integer from 0 to 2, q is an integer 2 or 3 and t is an integer from 0 to 4,

E is a phenylene or a simple bond, or E and D are connected to each other to form divalent group represented by the following formula (3):

(is a question the th bond or double bond)

u is an integer from 0 to 2, and v is 0 or 1,

G represents O, S, SO, SO2or C(R8)(R9and R8and R9are the same or different and each represents hydrogen or alkyl,

R3and R4are the same or different and each represents hydrogen or alkyl,

Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, monoalkylammonium, dialkylammonium or a group represented by the following formula (22):

-CONH-SO2-R10(22)

R10represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Among the heterocyclic compounds represented by the formula (1), the preferred compounds are the following compounds, where R1and R2are the same or different, and each represents an optional is entrusted substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y and Z correspond to any of the following cases (1) and (2):

(1) Y represents N or CH, and Z represents N or CH and

(2) Y is N→O and Z represents CH,

And represents NR7and R7represents hydrogen, alkyl or cycloalkyl,

D represents alkylene or albaniles,

E represents a simple bond,

G represents O, S, SO, SO2or C(R8)(R9and R8and R9each represent hydrogen,

R3and R4are the same or different and each represents hydrogen or alkyl and

Q represents carboxy, alkoxycarbonyl, tetrazolyl or a group represented by the formula (22), and R10represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dia is calamine, carboxy, cyano and nitro.

Among the heterocyclic compounds represented by the formula (1), more preferred compounds are the following compounds, in which R1and R2are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y and Z correspond to any of the following cases (1) and (2):

(1) Y is N and Z represents CH and

(2) Y represents CH and Z represents N or CH,

And represents NR7and R7represents hydrogen or alkyl,

D represents alkylene,

E is a simple communication

G represents O,

R3and R4are the same or different and each represents hydrogen or alkyl,

Q represents carboxy, tetrazolyl or a group represented by the formula (22), and R10represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different is CNAME, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Among the heterocyclic compounds represented by the formula (1), particularly preferred compounds are the following compounds, in which R1and R2are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y is N and Z represents CH,

And represents NR7and R7represents alkyl,

D represents alkylene,

E is a simple communication

G represents O,

R3and R4are the same or different and each represents hydrogen or alkyl and

Q represents carboxy or a group represented by the formula (22), and R10represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy rigmarolish groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Specific examples of preferable compounds among the heterocyclic compounds represented by the formula (1)include the following compounds (1) to (32):(1) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid,

(2) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid,

(3) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid,

(4) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid,

(5) 1-oxide, 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine,

(6) 2-{4-[N-(4,5-di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic acid,

(7) 7-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]heptane acid,

(8) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid,

(9) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy}acetic acid,

(10) 2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid,

(11) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butylochki}acetic acid,

(12) 2-{4-[N-(2,3-diphenylpyridine-6-yl)-N-methylamino]butylochki}acetic acid,

(13 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid,

(14) 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid,

(15) 2-{4-[N-(4,5-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid,

(16) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(p-toluensulfonyl)ndimethylacetamide,

(17) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(isopropylphenyl)ndimethylacetamide,

(18) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(trifloromethyl)ndimethylacetamide,

(19) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(o-toluensulfonyl)ndimethylacetamide,

(20) N-(benzazolyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(21) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(22) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-methoxybenzenesulfonyl)ndimethylacetamide,

(23) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-permentantly)ndimethylacetamide,

(24) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(2-thiophenesulfonyl)ndimethylacetamide,

(25) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(26) N-(N,N-dimethylaminomethyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(27) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(morpholine-4-ylsulphonyl)ndimethylacetamide,

(28) 2-{4-[N-(5,6-given pyrazin-2-yl)-N-isopropylamino]butylochki}-N-(pyrrolidin-1-ylsulphonyl)ndimethylacetamide,

(29) phenyl ester N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(30) N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(31) sodium salt of N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid, and

(32) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(methylsulphonyl)ndimethylacetamide.

Heterocyclic compounds represented by the following General formula (1z), in which the substituents correspond to any one of the following cases (I) to (V) (hereinafter also referred to as heterocyclic compounds (1z))are new compounds which have not been described.

(I)

R91and R92are the same or different, and each represents optionally substituted aryl, the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro, Y9represents N or N→O, Z9represents N or CR96and R96represents hydrogen, alkyl or halogen,

And9represents NR97, O, S, SO, SO2or ethylene, and R97represents hydrogen, alkyl, alkenyl or cycloalkyl,

D9is alkylene or albaniles, which is optionally substituted by hydroxy, or a9and D9are connected to each other to form divalent group represented by the following formula (2z):

m is an integer from 0 to 2, k is an integer 2 or 3 and n is an integer from 0 to 4,

E9represents a phenylene or a simple bond, or D9and E9are connected to each other to form divalent group represented by the following formula (3z):

(represents a simple bond or double bond)

w is an integer from 0 to 2 and x is 0 or 1,

G9represents O, S, SO, SO2or C(R98)(R99and R98and R99are the same or different and each represents hydrogen or alkyl,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, monoalkylammonium, dialkylammonium or a group represented by the following formula (22z):

R910is the battle amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro;

(II)

R91and R92are the same or different, and each represents optionally substituted aryl, the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro,

Y9represents CR95, Z9represents N or CR96and R95and R96are the same or different and each represents hydrogen, alkyl or halogen,

And9represents SO or SO2,

D9is alkylene or albaniles, which is optionally substituted by hydroxy, or a9and D9connected to others is g other to form divalent group, represented by the following formula (2z):

m is an integer from 0 to 2, k is an integer 2 or 3 and m is an integer from 0 to 4,

E9represents a phenylene or a simple bond, or D9and E9are connected to each other to form divalent group represented by the following formula (3z):

(represents a simple bond or double bond),

w is an integer from 0 to 2 and x is 0 or 1,

G9represents O, S, SO, SO2or C(R98)(R99and R98and R99are the same or different and each represents hydrogen or alkyl,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, monoalkylammonium, dialkylammonium or a group represented by the following formula (22z):

R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic what groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro;

(III)

R91and R92are the same or different, and each represents optionally substituted aryl, the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro,

Y9represents CR95, Z9represents N or CR96and R95and R96are the same or different and each represents hydrogen, alkyl or halogen,

And9represents NR97, O, S, or ethylene, and R97represents hydrogen, alkyl, alkenyl or cycloalkyl,

D9is albaniles, or And9and D9are connected to each other to form divalent group represented by the following formula (2z):

m is an integer from 0 to 2, k is an integer 2 or 3, and n is an integer from 0 to 4,

E9represents a phenylene or a simple link or D 9and E9are connected to each other to form divalent group represented by the following formula (3z):

(represents a simple bond or double bond),

w is an integer from 0 to 2 and x is 0 or 1,

G9represents O, S, SO, SO2or C(R98)(R99and R98and R99are the same or different and each represents hydrogen or alkyl,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, monoalkylammonium, dialkylammonium or a group represented by the following formula (22z):

R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, di is alkylamino, carboxy, cyano and nitro;

(IV)

R91and R92are the same or different, and each represents optionally substituted aryl, the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro,

Y9represents CR95, Z9represents N or CR96and R95and R96are the same or different and each represents hydrogen, alkyl or halogen,

And9represents NR97, O, S, or ethylene, and R97represents hydrogen, alkyl, alkenyl or cycloalkyl,

D9is alkylene, which is optionally substituted by hydroxy,

E9represents a phenylene,

G9represents O, S, SO, SO2or C(R98)(R99), and R98and R99are the same or different and each represents hydrogen or alkyl,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, monoalkylammonium, dialkylammonium or group performance is undertaken by the following formula (22z):

R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro, and

(V)

R91and R92are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro,

Y9represents CR95, Z9represents N or CR96and R95and R96each represents hydrogen,

And9represents NR97and R97represents hydrogen, alkyl, alkenyl or cycloalkyl,

D9is alkylene, which is not necessary C is substituted hydroxy,

E9is a simple communication

G9represents Oh,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, monoalkylammonium, dialkylammonium or a group represented by the following formula (22z):

and R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Among the new heterocyclic compounds (1z)described above, the preferred compounds are the following compounds in which the substituents correspond to any one of the following case (i) to (iii):

(i)

R91and R92are the same or different, and each represents optionally substituted FeNi and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9and Z9match any of the following cases (1) and (2):

(1) Y9represents N, and Z9represents N or CH and

(2) Y9represents N→O, and Z9represents CH,

And9represents NR97and R97represents hydrogen, alkyl or cycloalkyl,

D9is alkylen,

E9represents a simple bond,

G9represents O, S, SO, SO2or C(R98)(R99), and R98and R99each represents hydrogen,

R93and R94are the same or different and each represents hydrogen or alkyl, and

Q9represents carboxy, alkoxycarbonyl, tetrazolyl or a group represented by the formula (22z), R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio of alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro;

(ii)

R91and R92are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9represents CH and Z9represents N or CH,

And9represents NR97and R97represents hydrogen, alkyl or cycloalkyl,

D9is alkylen,

E9represents a simple bond,

G9represents Oh,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl or a group represented by the formula (22z), R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, harilal the La, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro, and

(iii)

R91and R92are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9and Z9match any of the following cases (1) and (2):

(1) Y9represents N or CH, and Z9represents N or CH and

(2) Y9represents N→O, and Z9represents CH,

And9represents NR97and R97represents hydrogen, alkyl or cycloalkyl,

D9is albaniles,

E9represents a simple bond,

G9represents O, S, SO, SO2or C(R98)(R99), and R98and R99each represent hydrogen,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl or a group represented by the formula (22z), R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, n is necessarily replaced by aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Among the new heterocyclic compounds (1z)described above, the preferred compounds are the following compounds, in which R91and R92are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9and Z9match any of the following cases (1) and (2):

(1) Y9represents N, and Z9represents CH and

(2) Y9represents CH and Z9represents N or CH,

And9represents NR97and R97represents hydrogen or alkyl,

D9is alkylen,

E9represents a simple bond,

G9represents Oh,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9is a carb is XI, tetrazolyl or a group represented by the formula (22z), R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Among the new heterocyclic compounds (1z)described above, particularly preferred compounds are the following compounds, in which R91and R92are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9represents N, and Z9represents CH,

And9represents NR97and R97represents alkyl,

D9is alkylen,

E9represents a simple bond,

G9represents Oh,

R93and R94 are the same or different, and each represents hydrogen or alkyl,

Q9represents carboxy or a group represented by the formula (22z), R910represents amino, monoalkylamines, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heterocyclic group, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, halogenoalkane, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamines, dialkylamino, carboxy, cyano and nitro.

Specific examples of preferable compounds among the new heterocyclic compounds (1z)described above include the following compounds (1) to (32):

(1) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid,

(2) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid,

(3) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid,

(4) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid,

(5) 1-oxide, 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine,

(6) 2-{4-[N-(4,5-di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic sour is,

(7) 7-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]heptane acid,

(8) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid,

(9) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy}acetic acid,

(10) 2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid,

(11) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butylochki}acetic acid,

(12) 2-{4-[N-(2,3-diphenylpyridine-6-yl)-N-methylamino]butylochki}acetic acid,

(13) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid,

(14) 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid,

(15) 2-{4-[N-(4,5-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid,

(16) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(p-toluensulfonyl)ndimethylacetamide,

(17) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(isopropylphenyl)ndimethylacetamide,

(18) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(trifloromethyl)ndimethylacetamide,

(19) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(o-toluensulfonyl)ndimethylacetamide,

(20) N-(benzazolyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(21) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(22) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropyl what Ino]butylochki}-N-(4-methoxybenzenesulfonyl)ndimethylacetamide,

(23) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-permentantly)ndimethylacetamide,

(24) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(2-thiophenesulfonyl)ndimethylacetamide,

(25) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(26) N-(N,N-dimethylaminomethyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(27) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(morpholine-4-ylsulphonyl)ndimethylacetamide,

(28) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(pyrrolidin-1-ylsulphonyl)ndimethylacetamide,

(29) phenyl ester N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(30) N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(31) sodium salt of N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid, and

(32) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(methylsulphonyl)ndimethylacetamide.

The present invention is described in detail later.

Examples of "alkyl" include unbranched or branched alkyl having from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Especially preferred is alkyl having from 1 d is 4 carbon atoms.

Examples of the alkyl part of the "halogenoalkane", "arylalkyl", "alkylthio", "alkoxyalkyl", "alkylsulfonyl", "monoalkylamines", "dialkylamino", "monoalkylphenol" and "dialkylamino" include the above-described alkali.

Examples of "alkoxy" include unbranched or branched alkoxy having from 1 to 6 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, n-hexyloxy, etexilate. Especially preferred is an alkoxy having from 1 to 4 carbon atoms.

Examples of the alkyl part of the "alkoxycarbonyl" and "alkoxyalkyl" described above include alkyl.

Examples of "alkenyl include unbranched or branched alkenyl having from 2 to 6 carbon atoms, e.g. vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. Especially preferred is alkenyl having 3 or 4 carbon atoms.

Examples of "cycloalkyl include cycloalkyl having from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Especially preferred is cycloalkyl having 5 to 7 carbon atoms.

Examples of "halogen" include Automator, chlorine, bromine and iodine.

Examples of "aryl" include aryl having 6 to 10 carbon atoms, for example, phenyl, 1-naphthyl and 2-naphthyl. Especially preferred is phenyl.

Examples of the aryl part of the "arylalkyl and aryloxy" include the above-described aryl.

Examples of "alkylene include unbranched or branched alkylene having from 1 to 8 carbon atoms, for example, methylene, ethylene, 1-methylation, 2-mutilation, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethine and octamethylene. Especially preferred is alkylene having from 3 to 6 carbon atoms, more preferred is alkylene having 4 carbon atoms.

Examples of "Alcanena include unbranched or branched albaniles having from 2 to 8 carbon atoms, for example, ethenylene, 1-propanole, 2-propanole, 1-butylen, 2-butylen, 3-butylen, 1-penttinen, 2-penttinen, 3-penttinen, 4-penttinen, 4-methyl-3-penttinen, 1-hexarelin, 2-hexarelin, 3-hexarelin, 4-hexarelin, 5-hexarelin, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-hoktanyan, 2-hoktanyan, 3-hoktanyan, 4-hoktanyan, 5-hoktanyan, 6-hoktanyan and 7-hoktanyan. Especially preferred is albaniles having from 3 to 6 carbon atoms, more preferred is albaniles having 4 carbon atoms.

Examples of "heterotic the practical group include the following groups (1) and (2).

(1) Examples of the heterocyclic group include 5 - or 6-membered aromatic ring having from 1 to 4 heteroatoms selected from nitrogen atoms, oxygen and sulfur, or such a ring condensed with the benzene ring and the nitrogen atoms and sulfur can form the oxide, when the atom of the ring is a nitrogen atom or a sulfur atom. Examples include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-indolyl, 2-furanyl, 3-furanyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothiazol, 1,3-oxazol-2-yl, 4-isoxazolyl, 2-thiazolyl, 5-thiazolyl, 2-benzothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazole-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl and 1,3,5-triazine-2-yl.

(2) Examples of the heterocyclic group include a group 4-8-membered saturated ring which optionally has 1 to 4 identical or different atoms of nitrogen, oxygen and sulfur, or such a ring condensed with the benzene ring and the nitrogen atoms and sulfur can form the oxide, when the atom of the ring is a nitrogen atom or a sulfur atom. Examples include piperidine, piperazinil, 3-methylpiperazin-1-yl, homopiperazin, morpholino, thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl and 2-tetrahydrofuranyl.

Compounds of the present invention can be obtained, for example, the method described is passed below.

In the following way in the case when the original product has a Deputy, who may be unsuitable for the reaction (for example, hydroxy, amino or carboxy), the original product is usually used in the reaction, previously protected by a protective group (for example, methoxymethyl, 2-methoxyethoxymethyl, benzyl, 4-methoxybenzyl, triphenylmethyl, 4,4'-dimethoxytrityl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, palolem, tetrahydropyranyl or tert-butyldimethylsilyl) in a known manner. After completion of the reaction, the protective group can be removed by a known method such as catalytic reduction, the treatment with alkali or acid treatment.

Method 1 (Getting heterocyclic compounds (1A), where a represents NR7, O, or S-heterocyclic compound (1))

where a1represents NR7, O or S; L represents a removable group, such as halogen, mesilate or tosyloxy, Y, Z, R1, R2, R3, R4, D, E, G and Q have the meanings indicated in the General formula (1).

Heterocyclic compound (1A) can be obtained by the interaction of the compound (4) with compound (5). This interaction is usually done with the use of redundant connections (5) or Foundation in the absence of solvent or in pochtaservice. The amount of compound (5) is from 1 to 20 moles, preferably from 1 to 10 moles, per mole of the compound (4). Examples of the base include organic amine (e.g. pyridine, triethylamine, triethanolamine, N-methyldiethanolamine, N,N-diisopropylethylamine or triisopropanolamine), metal hydride (e.g. sodium hydride) and an inorganic base (e.g. potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide). The solvent is not specifically limited if it does not participate in the reaction, and examples include ethers such as tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene, and mixtures of such solvents. The reaction temperature varies depending on the type of the source material and the substrate and the reaction temperature, but usually it ranges from 0°to 300°C. the reaction Time varies depending on the type of starting material and the reaction temperature, but preferably it ranges from 30 minutes to 100 hours.

Method 2 (Separate receive heterocyclic compounds (1A))

where a1and L have the meanings indicated above, and Y, Z, R1, R2, R3, R4, D, E, G and Q are C is achene, specified in the General formula (1).

Heterocyclic compound (1A) can be obtained by the interaction of the compound (6) (including tautomer) with compound (7). This interaction is carried out in an organic solvent (e.g. ethers such as tetrahydrofuran and diethyl ether; Amidah, such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene, and mixtures of such solvents) in the presence of a base. Used the base is the same as the reason described in method 1. The amount of compound (7) is from 1 to 10 moles, preferably 1 to 2 moles, per mole of the compound (6). The reaction temperature varies depending on the type of source material and the substrate, but typically it ranges from 0 to 150°C. the reaction Time varies depending on the type of source material and the substrate and the reaction temperature, but preferably it ranges from 30 minutes to 24 hours.

Method 3 (Getting heterocyclic compounds (1b), where a represents NR7, O or S, and G represents About in heterocyclic compound (1))

where a1and L have the meanings indicated above, and Y, Z, R1, R2, R3, R4, D, E and Q have values, ukasannyi General formula (1).

Stage 1

Compound (9) can be obtained by the interaction of the compound (4) with compound (8). This interaction can be performed in the same manner as in method 1.

Stage 2

Heterocyclic compound (1b) can be obtained by the interaction of the compound (9) with compound (10). This interaction can be performed by a known method, for example, the way B.P. Czech et al. (Tetrahedron, 41, 5439 (1985)), method A. Takahashi et al. (J. Org. Chem., 53, 1227 (1988)) or the method N.A. Meanwell et al. (J. Med. Chem., 35, 3498 (1992)).

Method 4 (the Individual receiving heterocyclic compounds (1b), where a represents NR7, O or S, and G represents About in heterocyclic compound (1))

where a1and L have the meanings indicated above, and Y, Z, R1, R2, R3, R4, D, E and Q have the meanings indicated in the General formula (1).

Stage 1

Compound (9) can be obtained by the interaction of the compound (6) (including tautomer) with compound (11). This interaction can be performed in the same manner as in method 2.

Stage 2

Heterocyclic compound (1b) can be obtained by the interaction of the compound (9) with compound (10) in the same way as in stage 2 of the method 3.

Method 5 (Getting heterocyclic compounds (1C), where E represents a simple bond, and G represents O or S in heterocyclic connection is to (1))

where G1represents O or S, a and L have the above values, and Y, Z, R1, R2, R3, R4, D and Q have the meanings indicated in the General formula (1).

Heterocyclic compound (1C) can be obtained by the interaction of the compound (12) compound (13). This reaction is carried out using a base in the absence of solvent or in a suitable solvent. Used the base is the same as the reason described in method 1. Solvent used is not specifically limited if it does not participate in the reaction, and examples include ethers such as tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; water; and mixtures of such solvents. When using additives, such as catalysts migration phases, such as bromide hexadecyltrimethylammonium, and iodides such as sodium iodide, the reaction sometimes proceeds easily. The reaction temperature varies depending on the type of source material, but it usually ranges from 0°to 100°C. the reaction Time varies depending on the type of starting material and the reaction temperature, but preferably, it ranges from 3 minutes to 24 hours.

Method 6 (Getting heterocyclic compounds (1E), where G is a SO, or heterocyclic compounds (1f), where G is a SO2in heterocyclic compound (1))

where A, Y, Z, R1, R2, R3, R4, D, E and Q have the meanings indicated in the General formula (1).

Heterocyclic compound (1E) can be obtained by oxidation of heterocyclic compounds (1d) [the compound in which G is a S-heterocyclic compound (1)], obtained by any method described above or below. This reaction can be carried out in a suitable solvent (the solvent is not specifically limited if it does not participate in the reaction, and examples of it include amides such as N,N-dimethylformamide and N,N-dimethylacetamide; hydrocarbons, such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; alcohols, such as methanol and ethanol; organic acids such as acetic acid and triperoxonane acid; water; and mixtures of such solvents) at a temperature of from -20 to 100°in the presence of oxidizing agent (e.g., hydrogen peroxide, peracetic acid, metaperiodate, m-chloroperoxybenzoic acid, halogen or N-chlorosuccinimide). The reaction time varies depending on the type of the original products is a and the oxidizing agent and the reaction temperature, but preferably, it ranges from 30 minutes to 24 hours. The amount of oxidizing agent preferably ranges from 1 to 10 moles per mole of heterocyclic compounds (1d).

Heterocyclic compound (1f) can be obtained by oxidation of heterocyclic compounds (1d) or heterocyclic compounds (1E). This reaction can be carried out in the same solvent as described above, in the presence of an oxidizing agent. Examples of the oxidizing agent include hydrogen peroxide, peracetic acid, peroxosulfates potassium permanganates and perborate sodium. The reaction temperature and reaction time are the same as the temperature and reaction time, as described above.

When the product receives a mixture of heterocyclic compounds (1E) and heterocyclic compounds (1f), heterocyclic compound (1E) and the heterocyclic compound (1f) can, respectively, to separate from the mixture and clean conventional methods of separation and purification, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography or thin-layer chromatography.

Method 7 (Getting heterocyclic compounds (1h), where a is a SO, or heterocyclic compounds (1i), where a represents the SO2in heterocyclic compound (1))

where Y, Z, R1, R2, R3, R4, D, E, G and Q have the meanings indicated in the General formula (1).

Heterocyclic compound (1h) can be obtained by oxidation of heterocyclic compounds (1g) [connection, where A is a S-heterocyclic compound (1)], obtained by any method described above. This reaction can be performed in the same way as when receiving heterocyclic compounds (1E) of the heterocyclic compounds (1d) in method 6.

Heterocyclic compound (1i) can be obtained by oxidation of heterocyclic compounds (1g) or heterocyclic compounds (1h). This reaction can be performed in the same way as when receiving heterocyclic compounds (1f) of the heterocyclic compounds (1d) or heterocyclic compounds (1E) in method 6.

When the product receives a mixture of heterocyclic compounds (1h) and heterocyclic compounds (1i), heterocyclic compound (1h) and heterocyclic compound (1i) can be respectively separate from the mixture and clean conventional methods of separation and purification, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography or thin-layer chromatography.

Method 8 (Getting heterocyclic compounds (1j), g is e a represents the ethylene in the heterocyclic compound (1)).

where L1represents a halogen, M represents-CH=CH - or-C≡and Y, Z, R1, R2, R3, R4, D, E, G and Q have the meanings indicated in the General formula (1).

Stage 1

Compound (16) can be obtained by the interaction of the compound (14) with compound (15). This reaction can be carried out in a suitable solvent at a temperature of from 20 to 150°in the presence of a catalyst. As the solvent there can be used, for example, polar solvents such as acetonitrile and N,N-dimethylformamide; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as benzene and toluene; basic solvents such as triethylamine and piperidine, and mixtures of such solvents. As catalyst there may be used, for example, palladium catalysts such as dichloro(triphenylphosphine)palladium and tetrakis(triphenylphosphine)palladium and a metal halide such as copper iodide and copper bromide. The reaction time varies depending on the starting material, catalyst and reaction temperature, but it usually takes from 30 minutes to 48 hours. The amount of compound (15) is from 1 to 10 moles, preferably 1 to 3 moles, per mole of the compound (14).

Using the connection (14) and akinrolabu, al is analalava, alkylzinc or alkalizing connection (16) can be obtained in a known manner. Examples of such method include a method Y. Akita et al. (Chem. Pharm. Bull., 34, 1447 (1986), Heterocycles, 23, 2327 (1985)).

Stage 2

Heterocyclic compound (1j) can be obtained by catalytic reduction of compound (16). The compound (1j) can be obtained by the interaction with hydrogen at normal pressure or a predetermined pressure at a temperature of from 20 to 50°in a suitable solvent in the presence of a catalyst. Examples of the catalyst which can be used include platinum catalyst and a palladium catalyst. The mass ratio of the catalyst to the compound (16), preferably approximately from 10 to 50%. The solvent is not specifically limited if it does not participate in the reaction, and examples include water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetic acid and mixtures of such solvents.

Alternatively, the heterocyclic compound (1j) can be obtained directly from the compound (14) according to the method of T. Watanabe et al. (Heterocycles, 29, 123 (1989)).

Method 9 (Getting heterocyclic compounds (1k), where a represents ethylene and G represents About in heterocyclic compound (1))

where L1is a Gal who gene M represents-CH=CH - or-C≡and Y, Z, R1, R2, R3, R4, D, E, G and Q have the meanings indicated in the General formula (1)

Stage 1

The compound (18) can be obtained by the interaction of the compound (14) with compound (17). This reaction can be performed in the same way as in stage 1 way 8.

Stage 2

The compound (19) can be obtained by catalytic reduction of compound (18). This reaction can also be conducted in the same manner as in stage 2 of the method 8.

Stage 3

Heterocyclic compound (1k) can be obtained by the interaction of the compound (19) with compound (10). This reaction can also be conducted in the same manner as in stage 2 of the method 3.

Method 10 (Getting heterocyclic compounds (1n), where Q represents carboxy in heterocyclic compound (1))

where R13represents alkyl and A, Y, Z, R1, R2, R3, R4, D, E and G have the meanings indicated in the General formula (1)

Heterocyclic compound (1n) can be obtained by hydrolysis of heterocyclic compounds (1m)obtained by the method described above. This reaction is carried out in a suitable solvent in the presence of acid or base. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and when the minimum level used bases include inorganic bases, such as sodium hydroxide and potassium hydroxide. Examples of the solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; water and mixtures of such solvents. The reaction temperature varies depending on the starting material and catalyst, but it usually ranges from -10 to 100°C. the reaction Time varies depending on the starting material, catalyst and reaction temperature, but it usually takes from 30 minutes to 5 hours.

Method 11 (Obtaining heterocyclic compounds (1R), where Q is a carbarnoyl, monoalkylammonium, dialkylammonium or a group represented by the formula (22) in the heterocyclic compound (1))

where R11and R12are the same or different and each represents hydrogen, alkyl, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted aryloxyalkyl or optionally substituted heterocyclic sulfonyl and A, Y, Z, R1, R2, R3, R4, D, E and G have the meanings indicated in the General formula (1).

Heterocyclic compound (1P) can be obtained by the interaction of heterocyclic compounds (1n) or reaction is capable derived from compound (20). Examples of the reactive derivative of heterocyclic compound (1n) include reactive derivatives commonly used in the amidation, for example, halogenmethyl acid (the acid chloride acid or bromohydrin acid), mixed acid anhydride, imidazole and active amide. When using carboxylic acids heterocyclic compounds (1n) the reaction is carried out at a temperature of from -20 to 100°using a condensing agent (for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethylthiophosphate and diphenylphosphinite) in the presence or in the absence of a base (e.g. organic bases such as triethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene). Solvent used is not specifically limited if it does not participate in the reaction, and examples include ethers such as tetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; NITRILES such as acetonitrile and propionitrile; hydrocarbons, such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane, and mixtures of such solvents. In this case you can also use additives (for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide). Time R the shares vary depending on the type of the condensing agent and the reaction temperature, but, preferably, it ranges from 30 minutes to 24 hours. The number of compounds (20) and a condensing agent, preferably, is from 1 to 3 moles per mole of heterocyclic compounds (1n). When using gelegenheid acid as the reactive derivative of heterocyclic compound (1n), the reaction is carried out at a temperature of from -20 to 100°using the same base and solvent as bases and solvents described above. The reaction time varies depending on the type of gelegenheid acid and the reaction temperature, but preferably, it ranges from 30 minutes to 24 hours. The number of connections (20)preferably ranges from 1 to 3 moles per mole of gelegenheid acid.

Method 12 (Getting heterocyclic compounds (1r), where Q is a CONHSO3H in heterocyclic compound (1))

Stage 1

The compound (1q) can be obtained by the interaction of the compound (1n) or its reactive derivative with ammonia. The reaction can be conducted in the same manner as in method 11.

Stage 2

The compound (1r) can be obtained by using the compound (1q), obtained in stage 1, by a known method (Tetrahedron, 39, 2577 (1983), Tetrahedron, 56, 5667 (2000), J. Org. Chem., 50, 3462 (1985), J. Chem. Soc., Perkin Trans. I, 649 (1988)), for example, by dissolving 2-PI is oline in a halogenated solvent, the addition of chlorosulfonic acid and the addition of the compound (1q). The reaction temperature and reaction time vary depending on the source material, but the reaction is preferably carried out at a temperature from -50 to 100°With the passage of time from 30 minutes to 5 hours.

Connection from (4) to (20), used as starting product in these reactions, are known compounds or can be obtained by a known method or a method described in the reference examples.

Compounds of the present invention can be isolated from the above reaction mixture and purify the conventional methods of isolation and purification, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography or thin-layer chromatography.

Compounds of the present invention can be used as a medicinal product in free base form or acid, but can also be used after the formation of pharmaceutically acceptable salts in a known manner. When the compounds of the present invention are basic examples of the salt include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and organic acid salts such kamakana acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, naphthalenesulfonate acid and camphorsulfonic acid.

When the compounds of the present invention are acidic, examples of the salt include alkali metal salts such as sodium salt and potassium salt, and salts of alkaline earth metals such as calcium salt.

Compounds of the present invention may exist as geometric isomers (Z-form and S-form) and these isomers and their mixtures are also included in the present invention.

Compounds of the present invention can exist in the form of compounds having an asymmetric carbon, and these optical isomers and racemic forms are also included in the present invention. The optical isomer can be obtained from racemic form, obtained as described above, the separation of optical isomers by using an optically active acid (e.g. tartaric acid, dibenzoyltartaric acid, almond acid or 10-camphorsulfonic acid) using the basicity of racemic forms or by using a pre-obtained optically active compounds as a source cont the KTA.

Compounds of the present invention are excellent receptor agonists PGI2discover inhibitory effect on platelet aggregation, vasodilator action, bronchodilatory effect, inhibitory effect on the deposition of lipids and inhibitory effect on the activation of leukocytes, as shown in the following examples, tests, and are also characterized by low toxicity. Therefore, the compounds of the present invention can be used as a preventive or therapeutic agent for the treatment of transient ischemic (TIA), diabetic neuropathy, diabetic gangrene, peripheral vascular disease (for example, obliterating arteriosclerosis, intermittent claudication, peripheral arterial embolism, diseases associated with vibration, and disease, Raynaud's disease), systemic lupus erythematosus, reocclusion or restenosis after percutaneous intraluminal coronary angioplasty (RTSA), arteriosclerosis, thrombosis (e.g. acute cerebral thrombosis), diabetic nephropathy, hypertension, pulmonary hypertension, ischemic diseases (e.g., cerebral infarction and myocardial infarction), angina (e.g., stable angina and unstable angina), glomerulonephritis, diabetics the Oh nephropathy, allergies, asthma, ulcers, bedsores, restenosis after intervention in the coronary artery, such as atherectomy and permanent residence of the stent, and thrombocytopenia caused by dialysis. Compounds of the present invention can also be used as an agent to accelerate gene therapy or therapy that is associated with the development of blood vessels, such as transplantation of autologous bone marrow cells.

When the compounds of the present invention are used as drugs, they can be administered to a mammal, including a human, alone or in a mixture with pharmaceutically acceptable, non-toxic inert carrier, for example, in the form of a pharmaceutical composition containing the compound in the amount of 0.1% to 99.5%, preferably from 0.5% to 90%.

As the carrier can be used one or more auxiliary agents for ready preparative forms such as solid, semi-solid or liquid diluent, filler and other auxiliary agents for medicinal ready preparative forms. Preferably, the pharmaceutical composition is injected in the form of a standard dosage forms. The pharmaceutical composition may be introduced into the tissue or intravenously, orally, topically (subcutaneously), or rectally. Needless to say that the use of the drug is its form, suitable for any route of administration described above. It is preferable, for example, oral administration.

Although it is desirable that the dose can be adjusted depending on conditions of the patients, including age and body weight, route of administration, nature and severity of the disease, as well as a daily dose, the amount of the active ingredient for an adult is usually from 0.01 mg to 1000 mg, preferably from 0.1 to 100 mg

In some cases, a lower dose may be sufficient or may require a higher dose. Usual dose given once or several times as dose divided into portions.

The BEST WAY of carrying out the INVENTION

The present invention is hereinafter described in more detail with reference to examples of the preparation in the reference examples, examples, examples and tests, but the present invention is not limited to this.

Reference example 1

4-(Isopropylamino)-1-butanol

4-Amino-1-butanol in the number 100,40 g was dissolved in a mixed solvent of 108 ml of acetone and 160 ml of ethanol, and after addition of 2.1 g of platinum oxide (IV) the hydrogenation is carried out under a pressure of 2 to 3 psi for 48 hours. The catalyst is removed by filtration of the reaction solution and the filtered product concentrate, while receiving 147,64 g of the desired compound in the form of colorless maslany is that substance.

Reference example 2

4-(Cyclopentylamine)-1-butanol

In the same manner as in reference example 1, except that Cyclopentanone is used instead of acetone to obtain a pale yellow oily substance.

Reference example 3

4-(Cyclohexylamino)-1-butanol

In the same manner as in reference example 1, except that cyclohexanone is used instead of acetone to obtain colorless crystals having a melting point of from 48 to 50°C.

Reference example 4

4-(Aminomethyl)-1-butanol

Stage 1

4-(Formylamino)-1-butanol

4-Amino-1-butanol in an amount of 10 g was dissolved in 100 ml of ethanol and add to 13.6 ml ethylformate. After heating the mixture while boiling under reflux for 18 hours the solvent is evaporated under reduced pressure, thus obtaining to 13.29 g of the desired compound as a pale yellow oily substance.

Stage 2

4-(Aminomethyl)-1-butanol

Aluminosilicate in the number 6,36 g are suspended in 100 ml of tetrahydrofuran and added dropwise a solution to 13.29 g of 4-(formylamino)-1-butanol in 50 ml of tetrahydrofuran at a rate that makes it possible to calm the boiling under reflux. After boiling the mixture under reflux for 1.5 hours, the reaction solution is cooled with ice and added dropwise, in the specified order, 6.3 ml in the water, 6.3 ml of aqueous 15% sodium hydroxide solution and 18.9 ml of water, followed by stirring for 30 minutes. Insoluble matter is removed by filtration and the solvent in the filtrate is evaporated under reduced pressure. The residue is evaporated under reduced pressure, thus obtaining of 6.73 g of the desired compound as colorless oily substance. Boiling point: from 84 to 85°C/16 mm Hg.

Reference example 5

(±)-3-(2-Pyrrolidinyl)-1-propanol

Stage 1

Methyl ether (±)-N-benzyloxycarbonyl-2-pyrrolidinecarboxylic acid

To a solution of 28,83 g (±)-N-benzyloxycarbonyl-2-pyrrolidinecarboxylic acid in 180 ml of N,N-dimethylformamide add 23,23 g of potassium bicarbonate and 10.8 ml of methyliodide. After stirring at room temperature for 15 hours, the reaction solution was diluted with water and then extracted twice with diethyl ether. After the extract was washed with aqueous 5% Hydrosulphite solution of sodium and water and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, thus obtaining 26,52 g of the desired compound as a yellowish oily substance.

Stage 2

(±)-N-Benzyloxycarbonyl-2-formylpyridine

To a solution of 12.00 g methyl ester (±)-N-benzyloxycarbonyl-2-pyrrolidinecarboxylic acid in 50 ml of dry dichloromethane in the atmosphere and the heat at -70° C or lower are added dropwise 50 ml of hydride diisobutylaluminum (1 M solution in toluene), followed by stirring for 2 hours. To the reaction solution are added dropwise 230 ml of 1 N. hydrochloric acid and the mixture is then warmed to room temperature and extracted with diethyl ether. The extract is washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 4,72 g of the desired compound as colorless oily substance.

Stage 3

Ethyl ether (±)-3-(N-benzyloxycarbonylamino-2-yl)acrylic acid

60%sodium hydride in number 376 mg washed with hexane to remove the oily component and suspended in 10 ml of anhydrous tetrahydrofuran and then at room temperature is added dropwise a solution 2,11 g diethylethylenediamine in 2 ml of anhydrous tetrahydrofuran. After stirring for 10 minutes dropwise over approximately 10 minutes, add a solution of 2.00 g (±)-N-benzyloxycarbonyl-2-formylpyridine in 5 ml of anhydrous tetrahydrofuran, followed by stirring for additional 30 minutes. The reaction solution was poured into water, extracted with diethyl ether and dried over magnesium sulfate and then the solvent is pariwat under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 1.86 g of the desired compound as colorless oily substance.

Stage 4

(±)-3-(N-Benzyloxycarbonylamino-2-yl)-2-propen-1-ol

To a solution of 1.86 g of ethyl ether (±)-3-(N-benzyloxycarbonylamino-2-yl)acrylic acid in 15 ml of dry dichloromethane in an argon atmosphere at -70°or lower added dropwise to 12.9 ml hydride diisobutylaluminum (1 M solution in toluene), followed by stirring for one hour. To the reaction solution are added dropwise 60 ml of 1 N. hydrochloric acid and the mixture is then warmed to room temperature and extracted with diethyl ether. The extract is washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 0.75 g of the desired compound as colorless oily substance.

Stage 5

(±)-3-(2-Pyrrolidinyl)-1-propanol

(±)-3-(N-Benzyloxycarbonylamino-2-yl)-2-propen-1-ol in the amount of 0.73 g dissolved in 7 ml of ethanol and after adding 200 mg of 5% palladium on coal mixture is heated to 35°and hydronaut at atmospheric pressure for 8 hours. The catalyst was removed by filtering the reaction solution, and the filtrate concentrated under decreased the pressure, while receiving 0.34 g of the desired compound as a pale yellow oily substance.

Reference example 6

6-Chloro-2,3-diphenylpyridine

Stage 1

1-Oxide, 2,3-diphenylpyridine

2,3-Diphenylpyridine in the amount of 1 g was dissolved in chloroform and added 1.4 g of 70% m-chloroperoxybenzoic acid, followed by stirring at room temperature for 15 hours. After washing the reaction solution is aqueous 5% potassium carbonate solution and saturated salt solution and drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, thus obtaining 1.3 g of crude crystals. The crude crystal was washed with diisopropyl ether, thus obtaining 922 mg of the desired compound as colorless crystals having a melting point of 167 to 170°C.

Stage 2

6-Chloro-2,3-diphenylpyridine

To 922 mg of 1-oxide, 2,3-diphenylpyridine add 3 ml of phosphorus oxychloride, followed by stirring at 100°C for 15 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate and then washed with aqueous 5% potassium carbonate solution and saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 428 mg of the desired connection is placed in the form of an oily substance.

Reference example 7

(±)-1-(2-Pyrrolidinyl)-4-(2-tetrahydropyranyloxy)Bhutan

Stage 1

(±)-1-(N-Benzyloxycarbonylamino-2-yl)-4-(2-tetrahydropyranyloxy)-1-butene

In argon atmosphere, the suspension 6,76 g of bromide 3-(2-tetrahydropyranyloxy)propyltrichlorosilane in 30 ml of dry tetrahydrofuran is cooled with ice and added dropwise to 8.7 ml of n-utility (1.6 M solution in hexane). After stirring for 15 minutes the ice bath is removed and the mixture is continuously stirred for one hour. Dropwise at room temperature, add a solution of 2.70 g (±)-N-benzyloxycarbonyl-2-formylpyridine obtained in step 2 of reference example 5 in 15 ml of dry tetrahydrofuran, followed by stirring for 2 hours. The reaction solution is cooled with ice and add aqueous saturated solution of ammonium chloride and, after extraction with diethyl ether, the extract washed with saturated salt solution and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 3,40 g of the desired compound as colorless oily substance.

Stage 2

(±)-1-(2-Pyrrolidinyl)-4-(2-tetrahydropyranyloxy)Bhutan

(±)-1-(N-Benzyloxycarbonylamino-2-yl)-4-(2-tetrahydropyranyloxy)-1-butene in the count is the number 3,40 g dissolved in 30 ml of ethanol and add 600 mg of 5% palladium on coal. The mixture is heated to a temperature of from 35°C to 40°and hydronaut at normal pressure for 24 hours. The catalyst was removed by filtering the reaction solution, and the filtrate concentrated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 1.42 g of a mixture of the desired connection and (±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)-1-butene in the form of a pale yellow oily substance. To a solution of the mixture formed in 14 ml of methanol, add 200 mg of 5% palladium on coal. The mixture hydronaut at 2 ATM and a temperature of 30°C to 40°C for 2 hours. Conduct further processing and purification, while receiving 1,43 g of the desired compound as a pale yellow oily substance.

Reference example 8

3-(Methoxyethoxy)-N-methylbenzylamine

Stage 1

3-(Methoxyethoxy)benzaldehyde

A solution of 100 g of 3-hydroxybenzaldehyde and 214 ml of N-ethyldiethanolamine in 800 ml of dichloromethane is cooled with ice and add dropwise a solution to 68.4 ml chloromethylmethylether ester in 200 ml of dichloromethane. After stirring for one hour the ice bath removed and the mixture is continuously stirred at room temperature over night. The reaction solution was washed in turn aqueous 10% sodium hydroxide solution and 10% citric acid and dried over magnesium sulfate and then the races is oritel is evaporated under reduced pressure. The residue is evaporated under reduced pressure, thus obtaining 81.3 g of the desired compound as colorless oily substance. Boiling point: 125-127°C/10 mm Hg.

Stage 2

3-(Methoxyethoxy)-N-methylbenzylamine

5% platinum on coal suspended in 10 ml of methanol and add a solution of 3.00 g of 3-(methoxyethoxy)benzaldehyde in 10 ml of methanol and 2.1 ml of 40% methylamine (solution in methanol). After heating up to 30°C at 2 ATM for 22 hours add hydrogen. The catalyst was removed by filtering the reaction solution, and the filtrate concentrated. The residue is purified column chromatography on silica gel, thus obtaining of 2.51 g of the desired compound as a yellowish oily substance.

Reference example 9

1-[3-(Benzyloxy)phenyl]-2-(methylamino)ethane

Stage 1

1-[3-(Benzyloxy)phenyl]-2-(formylamino)ethane

To the solution at 8.60 g of 2-[3-(benzyloxy)phenyl]ethylamine in 50 ml ethanol add 4.6 ml of ethylformate and the mixture is heated to boiling under reflux for 18 hours. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel, thus obtaining to 4.81 g of the desired compound as a pale orange oily substance.

Stage 2

1-[3-(Benzyloxy)phenyl]-2-(methylamino)ethane

Aluminosilicate in the amount of 1.07 g suspended in 20 ml of tetrahydrofuran is on and dropwise at room temperature add a solution 4,78 g of 1-[3-(benzyloxy)phenyl]-2-(formylamino)ethane in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and then heated to boiling under reflux for 2 hours. The reaction solution is cooled with ice, and in the order added dropwise 1 ml water, 1 ml of aqueous 15% sodium hydroxide solution and 3 ml of water, followed by stirring for 30 minutes. The insoluble solid is removed by filtration and the solvent in the filtrate is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining of 3.46 g of the desired compound as a pale yellow oily substance.

Reference example 10

1-Methylamino-4-(methoxyethoxy)indan

Stage 1

4-(Methoxyethoxy)-indane

To a solution of 4.12 g of 4-hydroxy-1-indanone and 7.3 ml of N-ethyldiethanolamine in 30 ml of dichloromethane is added dropwise under stirring and cooling with ice added to 2.3 ml chloromethylmethylether ether. The ice bath removed and the mixture is continuously stirred over night. The reaction solution was diluted with diethyl ether, washed with water, aqueous 10% citric acid solution and aqueous 5% sodium hydroxide solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, thus obtaining to 4.23 g of the desired compound as light orange crystals having a melting point of from to 54° C.

Stage 2

1-Methylamino-4-(methoxyethoxy)indan

To a solution of 1.00 g of 4-(methoxyethoxy)-1-indanone in 10 ml of ethanol is added to 2.8 ml of 40% methylamine (solution in methanol) and 367 mg of cyanoborohydride sodium. Under stirring at room temperature, added dropwise with 0.55 ml of acetic acid and the mixture is heated to boiling under reflux for 4 hours. The reaction solution is cooled in the air, mixed with water and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel, thus obtaining and 0.61 g of the desired compound in the form of a dark green oily substance.

Reference example 11

tert-Butyl ester 2-(4-bromobutyrate)acetic acid

Stage 1

4-(2-Tetrahydropyranyloxy)-1-butanol

To a solution of 100.0 g of 1,4-butanediol and 20 ml of 3,4-dihydro-2H-Piran in 80 ml dichloromethane and 140 ml of tetrahydrofuran, add 1.8 g of p-toluensulfonate pyridinium. After stirring at room temperature for 18 hours the solvent is evaporated under reduced pressure. The residue is extracted three times with diethyl ether after addition of saturated salt solution. After washing the extract with water and drying over magnesium sulfate the solvent is evaporated, thus obtaining 35,98 g ask what about the crude product as colorless oily substance.

Stage 2

tert-Butyl ester 2-[4-(2-tetrahydropyranyloxy)butylochki]acetic acid

4-(2-Tetrahydropyranyloxy)-1-butanol in the number 35,98 g dissolved in 300 ml of benzene and then add 33,95 g of hydrosulphate of Tetra-n-butylamine and 300 ml of aqueous 40% solution of potassium hydroxide. With vigorous stirring under ice cooling are added dropwise to 10.5 ml of tert-butylbromide, so that the internal temperature was in the range from 5 to 10°With or below. After stirring for 45 minutes in the ice bath removed and the mixture is stirred at room temperature for one hour. The reaction solution was diluted with water and then extracted with diethyl ether. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 36,21 g of the desired compound as colorless oily substance.

Stage 3

tert-Butyl ester 2-(4-hydroxybutyrate)acetic acid

To a solution of 36,21 g tert-butyl ester 2-[4-(2-tetrahydropyranyloxy)butylochki]acetic acid in 360 ml of methanol add 47,77 g monohydrate p-toluensulfonate acid. After stirring at room temperature for 30 minutes the reaction solution is neutralized water dissolve the ohms of sodium bicarbonate and the solvent is evaporated under reduced pressure. The residue is diluted with water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 17,02 g of the desired compound as colorless oily substance.

Stage 4

tert-Butyl ester 2-(4-bromobutyrate)acetic acid

To a solution of 17,02 g tert-butyl ester 2-(4-hydroxybutyrate)acetic acid in 400 ml of dichloromethane add 24,04 g of triphenylphosphine and 31.78 g tetrabromide carbon. After stirring at room temperature for one hour the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 16,95 g of the desired compound as colorless oily substance.

Reference example 12

5,6-Diphenyl-2-(ethylamino)pyrazin

2-Chloro-5,6-diphenylpyrazine in the amount of 1.00 g add to 18.7 ml of 2 M ethylamine in methanol and the mixture is subjected to interaction in a sealed tube at 80°C for 16 hours. After cooling, optionally, add 12 ml of 2 M solution of ethylamine in methanol, followed by continuous stirring in a sealed tube at 90°C for 17.5 hours and additionally stirred at room temperature for 46 hours is. After evaporation of the solvent under reduced pressure the residue is purified column chromatography on silica gel, thus obtaining 531 mg of the desired compound as pale yellow crystals having a melting point of from 121 to 123°C.

Reference example 13

2 Allylamino-5,6-diphenylpyrazine

To a solution of 1.00 g of 2-chloro-5,6-diphenylpyrazine in 10 ml of methanol added 2.14 g of allylamine and the mixture is subjected to interaction in a sealed tube at 80°With over 41 hours, followed by stirring at room temperature for 54 hours. After evaporation of the solvent under reduced pressure the reaction solution is mixed with water, extracted with chloroform, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 330 mg of the desired compound as light yellow crystals having a melting point of from 97 to 100°C.

Reference example 14

tert-Butyl ester 2-[4-chloro-(Z)-2-butene-1-yloxy)]acetic acid

Stage 1

(Z)-4-(2-Tetrahydropyranyloxy)-2-butene-1-ol

1,4-Butanediol in an amount of 50 g was dissolved in 200 ml of tetrahydrofuran and added 280 mg of p-toluensulfonate pyridinium and under ice cooling are added dropwise a solution obtained by dissolving 10,27 g of 3,4-dihydro-2H-Piran 50 m is tetrahydrofuran. After the temperature is returned to room temperature, the reaction solution is stirred for 21 hours. The solvent is evaporated under reduced pressure and the residue extracted with diethyl ether after the addition of water. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure, thus obtaining 7,05 g of the desired crude product as colorless oily substance.

Stage 2

tert-Butyl ester 2-[4-(2-tetrahydropyranyloxy)-(Z)-2-butene-1-yloxy)]acetic acid

(Z)-4-(2-Tetrahydropyranyloxy)-(Z)-2-butene-1-ol in the amount of 6.00 g dissolved in 10 ml of benzene and added 1.18 g of hydrosulphate of Tetra-n-butylamine and 10 ml of aqueous 50% sodium hydroxide solution and added dropwise to 6.75 ml of tert-butylbromide with stirring under ice cooling. After 10 minutes the temperature returns to room temperature and the reaction solution is stirred for one hour. The solution is extracted with diethyl ether after addition of ice water. The extract is washed with saturated salt solution and the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining a 1.00 g of the desired compound as colorless oily substance.

Stage 3

tert-Buti the new ester 2-[4-hydroxy-(Z)-2-butene-1-yloxy)]acetic acid

To a solution of 1.00 g of tert-butyl ester 2-[4-(2-tetrahydropyranyloxy)-(Z)-2-butene-1-yloxy)]acetic acid in 30 ml of methanol added 88 mg p-toluensulfonate pyridinium and the mixture is heated to boiling under reflux for 3 hours. The solvent is evaporated under reduced pressure and the reaction solution is extracted with ethyl acetate after addition of water. After the extract is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, to thereby obtain 420 mg of the desired compound as an oily substance.

Stage 4

tert-Butyl ester 2-[4-chloro-(Z)-2-butene-1-yloxy)]acetic acid

To a solution of 420 mg of tert-butyl ester 2-[4-hydroxy-(Z)-2-butene-1-yloxy]acetic acid in 10 ml of N,N-dimethylformamide added to 1.00 g of 2,4,6-collidine and 350 mg of lithium chloride. With stirring under ice cooling are added dropwise of 0.64 ml methanesulfonanilide, followed by stirring at room temperature for 2 hours. The reaction solution is extracted with ethyl acetate after addition of ice water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 350 mg of the desired compound as colorless oily substance.

Reference note the R 15

Methyl ester 2-[4-chloro-(E)-2-butene-1-yloxy]acetic acid

Stage 1

Methyl ester 2-[3-formyl-(E)-2-propen-1-yloxy]acetic acid

To a solution of 1.57 g of methyl ester of 2-[4-hydroxy-(Z)-2-butene-1-yloxy]acetic acid in 157 ml of benzene type of 7.90 g celite and 4,87 g Harrogate pyridinium, followed by stirring the mixture at room temperature for 23 hours. Insoluble matter is removed by filtration and the solvent in the filtrate is evaporated under reduced pressure. After dissolution in ethyl acetate, the insoluble matter is removed by filtration through celite, while receiving 311 mg of the desired crude product as a brown oily substance.

Stage 2

Methyl ester 2-[4-hydroxy-(E)-2-butene-1-yloxy]acetic acid

To a solution of 311 mg of methyl ester of 2-[3-formyl-(E)-2-propen-1-yloxy]acetic acid in 10 ml of methanol add 149 mg of sodium borohydride, followed by stirring at room temperature for 4.5 hours. The solvent is evaporated under reduced pressure and the residue extracted with ethyl acetate after addition of ice water. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure, thus obtaining 187 mg of the desired crude product as an oily substance.

Stage 3

milovy ester 2-[4-chloro-(E)-2-butene-1-yloxy)]acetic acid

In the same way as in stage 4 of reference example 14, except that the methyl ester of 2-[4-hydroxy-(E)-2-butene-1-yloxy)]acetic acid is used instead of tert-butyl ester 2-[4-hydroxy-(Z)-2-butene-1-yloxy)]acetic acid, receive the desired colorless oily substance.

Reference example 16

1-Oxide, 2,3-diphenyl-5-(methylamino)pyrazine

To 1.00 g of 1-oxide 5-chloro-2,3-diphenylpyrazine add 20 ml of 40% methylamine in methanol and the mixture is subjected to interaction in a sealed tube at room temperature for 15 hours. The reaction solution is extracted with ethyl acetate after addition of water. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting crude crystal was washed with diisopropyl ether, thus obtaining 536 mg of the desired compound as light yellow crystals having a melting point of from 145 to 147°C.

Reference example 17

4,5-Diphenyl-2-(methylamino)pyrimidine

Stage 1

3-(Dimethylamino)-1,2-diphenyl-2-propen-1-he

Benzylpenicillin in the amount of 25.00 g mixed with 92 ml of dimethylacetal N,N-dimethylformamide and the mixture is then heated to boiling under reflux for one hour. Almost all of dimethylacetal N,N-dimethylformamide is evaporated under reduced pressure and the precipitated crystals are washed the Ute diethyl ether. After drying receive 31,40 g of the desired compound as light yellow crystals having a melting point of 128 to 130°C.

Stage 2

4,5-Diphenyl-2-(methylamino)pyrimidine

To 20 ml of xylene type of 10.00 g of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-it, of 6.90 g of the hydrochloride of 1-methylguanine and to 8.70 g of potassium carbonate and the mixture is then heated to boiling under reflux for 13 hours using a partial condenser hot irrigation with water separator Dean-stark. The reaction solution is extracted with ethyl acetate after addition of water, dried over anhydrous magnesium sulfate and then the solvent is evaporated. The crude crystal was washed with diisopropyl ether and dried, thus obtaining 6,51 g of the desired compound as light yellow crystals having a melting point of 136 to 138°C.

Reference example 18

4,5-Di-p-tolyl-2-(methylamino)pyrimidine

Stage 1

N-Methoxy-N-methyl-p-toluamide

To a solution of 10.00 g of p-trouillard in 300 ml of dichloromethane add 6,94 g of the hydrochloride of N,O-dimethylhydroxylamine. The reaction solution is cooled with ice and added dropwise 11.5 ml of pyridine. After completion of adding dropwise, the mixture is stirred at room temperature for one hour and the solvent is evaporated under reduced pressure. The residue is mixed with water, extracted dieti the new ether and then washed in sequence with 10% hydrochloric acid, water and aqueous saturated sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate the solvent is evaporated under reduced pressure, thus obtaining the 10.40 g of the desired compound as colorless oily substance.

Stage 2

1,2-Di-p-tolerate-1-he

In an argon atmosphere a solution of the 10.40 g of N-methoxy-N-methyl-p-toluamide in 100 ml of tetrahydrofuran is cooled with ice and added dropwise 4-methylbenzylamine (solution obtained by dissolving or 10.60 g α-chloro-p-xylene and of 1.94 g of magnesium in 85 ml of tetrahydrofuran). After stirring for one hour, slowly add 100 ml of 10% hydrochloric acid. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the crude crystal was washed with diisopropyl ether and then dried under reduced pressure, thus obtaining 8,43 g of the desired compound as colorless crystals having a melting point of from 93 to 100°C.

Stage 3

4,5-Di-p-tolyl-2-(methylamino)pyrimidine

In the same way as in stages 1 and 2 of reference example 17, except that 1,2-di-p-tolerate-1-use it instead of benzylpenicillin, the desired compound obtained as pale yellow crystals having a melting point of from to 162° C.

Reference example 19

5-(Benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene

Stage 1

5-(Benzyloxy)-1-tetralone

To a solution of a 4.86 g of 5-hydroxy-1-tetralone in 50 ml of acetonitrile add 5,13 g benzylbromide and to 6.22 g of potassium carbonate and the mixture is heated to boiling under reflux for 4 hours. Insoluble matter is removed by filtration and the filtrate concentrated. The residue is purified column chromatography on silica gel, thus obtaining 6,62 g of the desired compound as a pale yellow oily substance.

Stage 2

5-(Benzyloxy)-2-(methoxycarbonyl)-1-tetralone

In an argon atmosphere of 2.09 g of 60% sodium hydride are suspended in 30 ml of anhydrous dioxane and add 11,51 g dimethylcarbonate. Under stirring with heating on an oil bath at a temperature of from 80 to 85°With dropwise over the course of approximately one hour add to 6.58 g of 5-(benzyloxy)-1-tetralone in 15 ml of dioxane. After stirring for one hour the reaction solution is cooled with ice and added dropwise 52 ml of aqueous 1 n solution of acetic acid. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining of 7.95 g is a need for the constituent compounds in the form of a light yellow oily substance.

Stage 3

5-(Benzyloxy)-1-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen

A solution of 7.95 g of 5-(benzyloxy)-2-(methoxycarbonyl)-1-tetralone in 80 ml of methanol is cooled with ice and five servings of added 0.97 g of sodium borohydride. After stirring for 30 minutes the ice bath is removed and the mixture is additionally stirred for 30 minutes. The reaction solution was diluted with ice water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 5,96 g of the desired compound as colorless oily substance.

Stage 4

5-(Benzyloxy)-2-(methoxycarbonyl)-3,4-dihydronaphthalene

To a solution 5,96 g of 5-(benzyloxy)-1-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene in 23 ml of anhydrous pyridine add 4,37 g p-toluensulfonate. After stirring with heating at 70°C for 3 hours optional add 0,72 g p-toluensulfonate, followed by stirring for 1.5 hours. The reaction solution is extracted with diethyl ether after addition of ice water. The extract is washed in sequence with water, 10% hydrochloric acid, water and aqueous saturated solution guide is carbonate sodium and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining and 2.79 g of the desired compound as colorless crystals having a melting point of 64 to 67°C.

Stage 5

5-(Benzyloxy)-2-(hydroxymethyl)-3,4-dihydronaphthalene

In an argon atmosphere to a solution and 2.79 g of 5-(benzyloxy)-2-(methoxycarbonyl)-3,4-dihydronaphthalene in 30 ml of dry dichloromethane is added dropwise 24 ml (1 M solution in toluene) hydride diisobutylaluminum at -70°C or lower, followed by stirring for 20 minutes. To the reaction solution are added dropwise 26 ml of aqueous 10% sodium hydroxide solution and after heating at room temperature the mixture is extracted with diethyl ether. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 2.25 g of the desired compound as colorless crystals having a melting point of from 59 to 61°C.

Stage 6

5-(Benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene

In an argon atmosphere to a solution to 1.82 g of 5-(benzyloxy)-2-(hydroxymethyl)-3,4-dihydronaphthalene and 0.55 g of 4-(dimethylamino)pyridine in 30 ml of dichloromethane type of 1.43 g of p-toluensulfonate. After adding dropwise ,2 ml of triethylamine, the mixture is stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water and then extracted with diethyl ether. The extract is washed in sequence with 5% hydrochloric acid, water and aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 1.06 g of the desired compound as colorless oily substance.

Reference example 20

1-Bromo-4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]Bhutan

A solution of 1.50 g of 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol and 1.18 g of triphenylphosphine in 20 ml of dichloromethane is cooled with ice and add 1,49 g tetrabromide carbon. After stirring for one hour the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 1.18 g of the desired compound as a yellow oily substance.

Reference example 21

5,6-Bis-(4-methoxyphenyl)-2-chloropyrazine

In the same way as when receiving 2-chloro-5,6-diphenylpyrazine described in the document (J. Am. Chem. Soc., 74, 1580 (1952)), receive the requested connection. Melting point: from 126 to 127°C.

In the same manner as in reference example 21, receive the following connections:

5,6-bis-(4-forfinal)2 is operatin (melting point: 91 to 92° C)

2-chloro-5,6-di-p-tollerson (melting point: from 112 to 117°).

Reference example 22

Isopropylcarbonate

With stirring under ice cooling to a solution of saturated ammonium in 40 ml of anhydrous tetrahydrofuran is slowly added dropwise 1,126 ml isopropylacetanilide. After stirring under ice cooling for 3 hours, the insoluble matter is removed by filtration and then the solvent is evaporated under reduced pressure. To the resulting oily substance is added diethyl ether and the precipitated crystals are collected by filtration and then dried under reduced pressure, thus obtaining 0.71 g of the desired compound in the form of yellowish crystals having a melting point of from 56 to 59°C.

Reference example 23

4-Methoxybenzenesulfonamide

In the same manner as in reference example 22, except that 4-methoxybenzenesulfonamide used instead of isopropylacetanilide, the desired compound obtained as colorless crystals having a melting point of from 110 to 112°

Reference example 24

4-Forbindelsesfaneblad

In the same manner as in reference example 22, except that 4-forbindelsesfaneblad used instead of isopropylacetanilide, the desired compound obtained as colorless crystals having the ku melting from 123 to 125° With

Reference example 25

2-Thiophenesulfonyl

In the same manner as in reference example 22, except that 2-thiophenesulfonyl used instead of isopropylacetanilide, the desired compound obtained as colorless crystals having a melting point of 144 to 145,5°

Reference example 26

Morpholine-4-ylsulphonyl

Mix of 5.00 g of sulphonamide, 4.09 g of the research and 5 ml of 1,2-dichloroethane and the mixture is heated with stirring on an oil bath at 120°C for 11 hours. The reaction solution is cooled in air to room temperature and the crystals are washed with diethyl ether, washed with methanol and then dried under reduced pressure, thus obtaining 5,98 g of the desired compound in the form of brownish crystals with a melting point of from 158 to 161°C.

Reference example 27

Pyrrolidin-1-ylsulphonyl

In the same manner as in reference example 26, except that pyrrolidin used instead of the research, the desired compound obtained as brown crystals having a melting point of from 94 to 97°

Reference example 28

Phenyl ether sulfamic acid

The solution to 4.98 g of phenol in 9 ml of toluene are added dropwise 7,49 g chlorosulfonylisocyanate in 5 ml of toluene at an internal temperature of 45°With or below. After adding a drop of the mixture is heated on an oil bath at 110° C and continuously stirred for 12 hours. The reaction solution is cooled with ice and the insoluble matter is removed by filtration and then the filtrate is heated on an oil bath at 40°C. With vigorous stirring slowly added dropwise 1.2 ml of water. The reaction solution is cooled with ice and the precipitated crystals are collected by filtration, washed with toluene and then dried under reduced pressure, thus obtaining 6,46 g of the desired compound as colorless crystals having a melting point of from 78 to 80°C.

Example 1

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid

Stage 1

4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol

Mix 30 g of 2-chloro-5,6-diphenylpyrazine and 131,22 g of 4-(isopropylamino)-1-butanol and the mixture is then heated with stirring at 190°C for 10 hours. The reaction solution was cooled down, poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified column chromatography on silica gel, thus obtaining 22,96 g of the desired compound as colorless crystals having a melting point of 102 to 103°C.

Stage 2

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid

4-[N-(5,6-Diphenylene the Jn-2-yl)-N-isopropylamino]-1-butanol in the number 22.84 to g are dissolved in 160 ml of benzene and type of 10.73 g of hydrosulphate of Tetra-n-butylamine and 160 ml of 40% aqueous solution of potassium hydroxide. With vigorous stirring under ice cooling are added dropwise of 10.73 g of tert-butylbromide so as to regulate the internal temperature in the range from 5 to 10°C. After stirring for 45 minutes in the ice bath removed and the mixture is stirred at room temperature for one hour. The reaction solution was diluted with water and then extracted with diethyl ether. The extract is washed with water and dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 21,70 g of the desired compound as a pale yellow oily substance.

1H-NMR (CDCl3) δ: 1,27 (6N, e), 1,48 (N, C), 1,55-1,90 (4H, m), of 3.45 (2H, t)to 3.58 (2H, t), of 3.95 (2H, s), 4,82 (1H, quintet), 7,17-to 7.50 (10H, m), of 8.00 (1H, s)

Example 2

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-cyclopentylamine]butylochki}acetic acid

In the same manner as in example 1, except that 4-(cyclopentylamine)-1-butanol is used instead of 4-(isopropylamino)-1-butanol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,48 (N, C), 1,63-1,79 (10H, m), 1,98 is 2.00 (2H, m), of 3.48 (2H, t), of 3.57 (2H, t), of 3.95 (2H, s), 4,66 was 4.76 (1H, m), 7,20-of 7.48 (10H, m), 8,02 (1H, s)

Example 3

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-cyclohexyl what Ino]butylochki}acetic acid

In the same manner as in example 1, except that 4-(cyclohexylamino)-1-butanol is used instead of 4-(isopropylamino)-1-butanol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,16-1,90 (14N, m, 1,48 (N, C)of 3.48 (2H, t), of 3.57 (2H, t), of 3.95 (2H, s), 4,25 is 4.35 (1H, m), 7,21-7,49 (10H, m), to 7.99 (1H, s)

Example 4

tert-Butyl ester 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid

In the same manner as in example 1, except that 2-chloro-5,6-di-p-tollerson used instead of 2-chloro-5,6-diphenylpyrazine, the desired compound obtained as a yellow oily substance.

1H-NMR (CDCl3) δ: 1,24-1,29 (6N, m, 1,48 (N, C), 1,68 is 1.75 (4H, m), 2,32 (3H, s), of 2.33 (3H, s), 3,42 (2H, t), of 3.57 (2H, t), of 3.95 (2H, s), 4,79 (1H, quintet), 7,03-to 7.09 (4H, m), 7.24 to 7,29 (2H, m), 7,34-7,38 (2H, m), of 7.96 (1H, s)

Example 5

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid

In the same manner as in example 1, except that 2-chloro-5,6-diphenylpyridine used instead of 2-chloro-5,6-diphenylpyrazine and 4-(methylamino)-1-butanol is used instead of 4-(isopropylamino)-1-butanol, provided that the reaction temperature of stage 1 regulate in the range from 100 to 150°C, the desired compound obtained as a light brown oily product.

1H-NMR (CDCl3)δ : 1,47 (N, C), 1,60-1,80 (4H, m), of 3.12 (3H, s), of 3.56 (2H, t), 3,66 (2H, t)to 3.92 (2H, s), of 6.52 (1H, DD), 7,10-7,53 (11H, m)

Example 6

tert-Butyl ester 2-{4-[N-(3-chloro-5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid

In the same manner as in example 1, except that 2,3-dichloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-diphenylpyrazine, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,20-1,30 (6N, m), 1,40-1,50 (N, m), 1,50-1,80 (4H, m), 3,41-3,51 (4H, m)to 3.89 (2H, s), 4,37 (1H, quintet), 7,20 is 7.50 (10H, m)

Example 7

tert-Butyl ester 2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid

In the same manner as in example 1, except that 3-chloro-5,6-di-p-tolyl-1,2,4-triazine is used instead of 2-chloro-5,6-diphenylpyrazine, provided that the reaction temperature of stage 1 regulate at 80°and the reaction time regulate to 40 minutes, the desired compound obtained as a yellowish brown oily substance.

1H-NMR (CDCl3) δ: 1,31 (6N, e), 1,48 (N, s), 1.60-to 1,90 (4H, m), 2,35 (6N, (C), 3,50-3,70 (4H, m), of 3.95 (2H, s), 5,10 (1H, m), 7,11 (4H, d), 7,40 (4H, DDD)

Example 8

tert-Butyl ester 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid

In the same manner as in example 1, except that 3-chloro-5,6-diphenyl-1,2,4-triazine is used instead of 2-chloro-56-diphenylpyrazine, provided that the reaction temperature of stage 1 regulate up to 80°and the reaction time regulate up to 30 minutes, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,32 (6N, e), 1,47 (N, s), 1.60-to 1,90 (4H, m), 3,50-3,70 (4H, m), of 3.95 (2H, s), 5,11 (1H, m), 7,25-of 7.55 (10H, m)

Example 9

tert-Butyl ester 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid

Stage 1

4-[N-(5,6-Di-p-tollerson-2-yl)-N-methylamino]-1-butanol

To a solution of 3.00 g of 2-chloro-5,6-di-p-tollerating and 1.57 g of 4-(methylamino)-1-butanol and 15 ml of N,N-dimethylformamide type of 2.26 g of potassium carbonate. After heating with stirring at 100°C for 26 hours the reaction solution is extracted with diethyl ether after addition of ice water. The extract is washed in sequence with water and saturated salt solution and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel and the resulting crystals are washed with diisopropyl ether, thus obtaining 2.76 g of the desired compound as colorless crystals having a melting point of from 94 to 96°C.

Stage 2

tert-Butyl ester 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid

In the same way as in stage 2 use the and 1, except that use 4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]-1-butanol obtained in stage 1, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, C), 1,59-1,90 (4H, m), 2,32 (3H, s), of 2.33 (3H, s), and 3.16 (3H, s), 3,55 (2H, t), 3,66 (2H, t), 3,93 (2H, s), 7,00-7,10 (4H, m), 7,20-7,40 (4H, m), to 7.99 (1H, s)

Example 10

tert-Butyl ester 2-[4-{N-[5,6-bis-(4-methoxyphenyl)pyrazin-2-yl]-N-methylamino}butylochki]acetic acid

In the same way as in example 9, except that 5,6-bis-(4-methoxyphenyl)-2-chloropyrazine used instead of 2-chloro-5,6-di-p-tollerson, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, s), 1.60-to of 1.85 (4H, m), and 3.16 (3H, s), of 3.56 (2H, t), 3,66 (2H, t), of 3.80 (3H, s), 3,81 (3H, s), of 3.94 (2H, s), 6.75 in-6,85 (4H, m), 7,26-7,46 (4H, m), of 7.96 (1H, s),

Example 11

tert-Butyl ester 2-[4-{N-[5,6-bis-(4-forfinal)pyrazin-2-yl]-N-methylamino}butylochki]acetic acid

In the same way as in example 9, except that 5,6-bis-(4-forfinal)-2-chloropyrazine used instead of 2-chloro-5,6-di-p-tollerson, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, C), 1,61-1,90 (4H, m), 3,17 (3H, s), of 3.56 (2H, t)to 3.67 (2H, t), 3,93 (2H, s), 6,91-7,03 (4H, m), 7,26 was 7.45 (4H, m), 8,01 (1H, s)

Example 12

tert-Butyl ester 2-{4-[N-(5,6-diphenyl-3-METI pyrazin-2-yl)-N-methylamino]butylochki}acetic acid

In the same way as in example 9, except that 2-chloro-5,6-diphenyl-3-methylpyrazine used instead of 2-chloro-5,6-di-p-tollerson, the desired compound obtained as light yellow crystals having a melting point of from 48 to 51°C.

Example 13

tert-Butyl ester 2-{2-[1-(5,6-diphenylpyrazine-2-yl)piperidine-4-yl]ethoxy}acetic acid

In the same way as in example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and 2-(piperidine-4-yl)ethanol is used instead of 4-(methylamino)-1-butanol, connection required to receive in the form of yellowish crystals having a melting point of from 104 to 106°C.

Example 14

tert-Butyl ether (±)-2-{3-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]propyloxy}acetic acid

In the same way as in example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and (±)-3-(2-pyrrolidinyl)-1-propanol is used instead of 4-(methylamino)-1-butanol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3)δ: 1,47 (N, C), 1,50-2,20 (8H, m), 3,40 of 3.75 (4H, m), 3,93 (2H, s), 4,15-4,30 (1H, m), 7,20 is 7.50 (10H, m), of 7.90 (1H, s)

Example 15

tert-Butyl ester 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid

In the same way as in example 9, for the claim is ucheniem, 3-chloro-5,6-diphenyl-1,2,4-triazine is used instead of 2-chloro-5,6-di-p-tollerson, provided that the reaction temperature of stage 1 adjust to room temperature and the reaction time adjust up to 3 hours, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, s), 1.60-to 1,90 (4H, m)to 3.34 (3H, s), of 3.57 (2H, t), 3,86 (2H, t), of 3.94 (2H, s), 7,25-of 7.55 (10H, m)

Example 16

tert-butyl ether (±)-2-{4-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]butylochki}acetic acid

Stage 1

(±)-1-[1-(5,6-Diphenylpyrazine-2-yl)pyrrolidin-2-yl]-4-(2-tetrahydropyranyloxy)Bhutan

In the same way as in stage 1 of example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and (±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)butane is used instead of 4-(methylamino)-1-butanol, connection required to receive in the form of yellowish crystals having a melting point of from 94 to 96°C.

Stage 2

(±)-4-[1-(5,6-Diphenylpyrazine-2-yl)pyrrolidin-2-yl]-1-butanol

To a solution of 1.25 g (±)-1-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]-4-(2-tetrahydropyranyloxy)butane in 13 ml of methanol is added 0.52 g of monohydrate p-toluensulfonate acid, followed by stirring at room temperature for 3 hours. The reaction solution is alkalinized by adding water feast upon the frame of solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure, to thereby obtain 1.10 g of the desired compound as a pale yellow oily substance.

Stage 3

tert-Butyl ether (±)-2-{4-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]butylochki}acetic acid

In the same way as in step 2 of example 1, except that use (±)-4-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]-1-butanol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3)δ: 1,30-of 2.20 (10H, m), 1,47 (N, C), 3,42 of 3.75 (4H, m)to 3.92 (2H, s), 4,08-4,20 (1H, m), 7,20 is 7.50 (10H, m), 7,89 (1H, s)

Example 17

tert-Butyl ether (±)-2-{2-[1-(5,6-diphenylpyrazine-2-yl)piperidine-3-yl]ethoxy}acetic acid

Stage 1

(±)-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-1-(5,6-diphenylpyrazine-2-yl)piperidine

In the same way as in stage 1 of example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and (±)-3-[2-(tert-butyldimethylsilyloxy)ethyl]piperidine is used instead of 4-(methylamino)-1-butanol, receive the requested connection.

Stage 2

(±)-2-[1-(5,6-Diphenylpyrazine-2-yl)piperidine-3-yl]ethanol

To a solution of 1.20 g of 3-[2-(tert-butyldimethylsilyloxy)ethyl]-1-(5,6-diphenylpyrazine-2-yl)piperidine in 6 ml of tetrahydrofuran, add 5.0 ml of 1 M peridotite-n-butylamine in tetrahydrofuran. After stirring at room temperature for 2 hours the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining of 0.77 g of the desired compound as a pale yellow amorphous substance.

Stage 3

tert-Butyl ether (±)-2-{2-[1-(5,6-diphenylpyrazine-2-yl)piperidine-3-yl]ethoxy}acetic acid

In the same way as in step 2 of example 1, except that use (±)-2-[1-(5,6-diphenylpyrazine-2-yl)piperidine-3-yl]ethanol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,48 (N, C), 1,53-1,99 (7H, m), 2,80 (1H, DD), 3,05 (1H, TD), 3,63 (2H, t), of 3.96 (2H, s), 4,28-to 4.38 (2H, m), 7,21-of 7.48 (10H, m), 8,17 (1H, s)

Example 18

Methyl ester of (R)-2-[3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]acetic acid

Stage 1

(R)-3-{2-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-1-hydroxyethyl}phenol

In the same way as in stage 1 of example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and L-phenylephrine is used instead of 4-(methylamino)-1-butanol, the desired compound obtained as a light brown amorphous substance.

Stage 2

Methyl ester of (R)-2-[3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]acetic acid

To a solution 066 g (R)-3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-1-hydroxyethyl}phenol and 0.28 g of methylpropanoate in 10 ml of acetonitrile, add 2 mg of potassium iodide and 0.28 g of potassium carbonate and the mixture is heated to boiling under reflux in for 4 hours. Insoluble matter is removed by filtration and filtet concentrated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 0.55 g of the desired compound as a pale orange amorphous substance.

1H-NMR (CDCl3) δ: totaling 3.04 (3H, s), 3.75 to 4,01 (2H, m), of 3.78 (3H, s), 4,63 (2H, s), 5,02-5,17 (2H, m), 6,79-6,85 (1H, m), 7,00-7,05 (2H, m), 7,20-7,50 (11N, m), 8,10 (1H, s)

Example 19

Methyl ester 2-[3-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}phenoxy]acetic acid

Stage 1

1-{[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]methyl}-3-(methoxyethoxy)benzene

In the same way as in stage 1 of example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and 3-(methoxyethoxy)-N-methylbenzylamine used instead of 4-(methylamino)-1-butanol, the desired compound obtained as colorless crystals having a melting point of from 109 to 111°C.

Stage 2

3-{[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]methyl}phenol

To a suspension of 0.91 g of 1-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-3-(methoxyethoxy)benzene in 10 ml of methanol is added 2 ml of an 18% solution of hydrogen chloride in methanol. After stirring at room temperature for 2 hours optional add 1 ml of an 18% solution of hydrogen chloride in methanol and the mixture is continuously stirred for one the th hour. After evaporation of the solvent under reduced pressure the reaction solution is neutralized by adding aqueous saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The crude crystal was washed with diethyl ether and then dried, thus obtaining 0.66 g of the desired compound as colorless crystals having a melting point of from 156 to 157°C.

Stage 3

Methyl ester 2-[3-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}phenoxy]acetic acid

In the same way as in step 2 of example 18, except that the use of 3-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}phenol, the desired compound obtained as colorless crystals having a melting point of from 132 to 134°C.

Example 20

Methyl ester 2-[3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]ethyl}phenoxy]acetic acid

Stage 1

1-(Benzyloxy)-3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]ethyl}benzene

In the same way as in stage 1 of example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and 1-[3-(benzyloxy)phenyl]-2-(methylamino)ethane is used instead of 4-(methylamino)-1-butanol, the desired compound obtained as light yellow crystals having a melting point of from 78 to 78.5 per°C.

Stage 2

3-{2-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]ethyl}phenol

To 1,17 g 1(of gasoline is hydroxy)-3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]ethyl}benzene add 12 ml of ethanol and 6 ml of hydrochloric acid followed by heating with stirring at 80° C for 17 hours. The reaction solution is cooled in air to room temperature, neutralized aqueous saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The crude crystal was washed with diisopropyl ether and then dried, to thereby obtain 0.87 g of the desired compound as light yellow crystals having a melting point of from 158 to 161°C.

Stage 3

Methyl ester 2-[3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]ethyl}phenoxy]acetic acid

In the same way as in step 2 of example 18, except that the use of 3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]ethyl}phenol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: to 2.94 (2H, t), of 3.12 (3H, s), with 3.79 (3H, s), 3,85 (2H, t), 4,59 (2H, s)6,70-6,91 (3H, m), 7.18 in-7,50 (11N, m), 8,02 (1H, s)

Example 21

1-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-4-(ethoxycarbonylmethoxy)indan

Stage 1

1-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-4-(methoxyethoxy)indan

In the same way as in stage 1 of example 9, except that 2-chloro-5,6-diphenylpyrazine used instead of 2-chloro-5,6-di-p-tollerating and 1-methylamino-4-(methoxyethoxy)indan used instead of 4-(methylamino)-1-butanol, Tr is the necessary connection receive in the form of a light yellow oily substance.

Stage 2

1-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-4-hydroxyine

1-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-4-(methoxyethoxy)indan in the amount of 220 mg dissolved in 2 ml of 25% solution of hydrogen chloride in ethyl acetate, followed by stirring at room temperature for 3 hours. After adding water, the reaction solution is neutralized aqueous saturated solution of sodium bicarbonate and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 167 mg of the desired compound as a pale yellow oily substance.

Stage 3

1-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-4-(ethoxycarbonylmethoxy)indan

In the same way as in step 2 of example 18, except that the use of 1-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-4-hydroxyine, the desired compound obtained as a light yellow oily substance.

Example 22

Methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid

In an argon atmosphere to a solution of 763 mg of 5,6-diphenyl-2-(methylamino)pyrazine in 4 ml of N,N-dimethylformamide added 140 mg of 60% sodium hydride, followed by stirring at 80°C for 30 minutes. The reaction solution is cooled with ice and honey is i.i.d. add 657 mg of methyl ester of 2-(4-bromobutyrate)acetic acid in 2 ml of N,N-dimethylformamide. After removing the ice bath, the mixture is stirred at room temperature for 14 hours. The reaction solution is mixed with ice water and extracted with ethyl acetate, and after washing the extract with saturated salt solution and drying over anhydrous magnesium sulfate the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 240 mg of the desired compound as a pale yellow oily substance.

1H-NMR (CDCl3) δ: 1,65-of 1.85 (4H, m), 3,18 (3H, s)to 3.58 (2H, t), 3,68 (2H, t), of 3.75 (3H, s)4,06 (2H, s), 7,20 is 7.50 (10H, m), 8,03 (1H, s)

Example 23

Ethyl ester of 7-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]heptane acid

In the same way as in example 22, except that ethyl ester ethyl-7-bromoheptanoate acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: of 1.25 (3H, t), of 1.30 and 1.80 (8H, m), 2,28 (2H, t), 3,17 (3H, s), 3,61 (2H, t), of 4.12 (2H, square), 7,20 is 7.50 (10H, m), 8,02 (1H, s)

Example 24

Methyl ester of 8-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]octane acid

In the same way as in example 22, except that the methyl ester 8-bromooctanoate acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired connection is tion obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,20-1,40 (5H, m), 1,50-1,75 (5H, m)to 2.29 (2H, t), 3,17 (3H, s), of 3.60 (2H, t), 3,66 (3H, s), 7,20 is 7.50 (10H, m), 8,01 (1H, s)

Example 25

Methyl ester of 9-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]nonanalog acid

In the same way as in example 22, except that the methyl ester of 9-brennannovak acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,20-1,40 (8H, m), 1,50-1,75 (4H, m)to 2.29 (2H, t), 3,17 (3H, s), of 3.60 (2H, t), 3,66 (3H, s), 7,20 is 7.50 (10H, m), 8,01 (1H, s)

Example 26

Ethyl ester of 6-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]hexanoic acid

In the same way as in example 22, except that the ethyl ester of 6-Bromhexine acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: of 1.24 (3H, t), 1,30-1,50 (2H, m), 1,60-1,80 (4H, m), is 2.30 (2H, t), and 3.16 (3H, s), 3,62 (2H, t), of 4.12 (2H, square), 7,20 is 7.50 (10H, m), 8,01 (1H, s)

Example 27

Tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butylochki}acetic acid

In the same way as in example 22, except that 5,6-diphenyl-2-(ethylamino)pyrazin used instead of 5,6-diphenyl-2-(methylamino)pyrazine and tert-butyl ester 2-(4-bromobutyl the XI)acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: of 1.25 (3H, t), 1,47 (N, s), 1.60-to of 1.85 (4H, m), 3,55-3,70 (6N, m), 3,93 (2H, s), 7,20 is 7.50 (10H, m), of 8.00 (1H, s)

Example 28

tert-Butyl ester 2-{4-[N-allyl-N-(5,6-diphenylpyrazine-2-yl)amino]butylochki}acetic acid

In the same way as in example 22, except that 2-allylamino-5,6-diphenylpyrazine used instead of 5,6-diphenyl-2-(methylamino)pyrazine and tert-butyl ester 2-(4-bromobutyrate)acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, s), 1.60-to of 1.85 (4H, m), 3,55-3,70 (4H, m), 3,93 (2H, s), 4,05-of 4.25 (2H, m), 5,15-and 5.30 (2H, m), 5,80-x 6.15 (1H, m), 7,2-to 7.50 (10H, m), to 7.99 (1H, s)

Example 29

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy}acetic acid

In the same way as in example 22, except that tert-butyl ester 2-[4-chloro-(Z)-2-butene-1-yloxy]acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a brown oily product.

1H-NMR (CDCl3) δ: 1,48 (N, C), and 3.16 (3H, s)to 3.92 (2H, s), 4,24 (2H, d), 4,37 (2H, d), the ceiling of 5.60-5,90 (2H, m), 7,20 is 7.50 (10H, m), with 8.05 (1H, s)

Example 30

Methyl ester 2-{4-[N-(5,6-diphenylene the Jn-2-yl)-N-methylamino]-(E)-2-butene-1-yloxy}acetic acid

In the same way as in example 22, except that the methyl ester of 2-[4-chloro-(E)-2-butene-1-yloxy]acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily product.

Example 31

1-Oxide, 2,3-diphenyl-5-{N-[4-(tert-butoxycarbonylamino)butyl]-N-methylamino}pyrazine

In the same way as in example 22, except that 1-oxide, 2,3-diphenyl-5-(methylamino)pyrazine used instead of 5,6-diphenyl-2-(methylamino)pyrazine and tert-butyl ester 2-(4-bromobutyrate)acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,48 (N, C), 1,60-1,80 (4H, m), 3,11 (3H, s), 3,50-the 3.65 (4H, m), of 3.94 (2H, s), 7,15-7,40 (10H, m), of 7.75 (1H, s)

Example 32

tert-Butyl ester 2-{4-[N-(4,5-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid

In the same way as in example 22, except that 4,5-diphenyl-2-(methylamino)pyrimidine used instead of 5,6-diphenyl-2-(methylamino)pyrazine and tert-butyl ester 2-(4-bromobutyrate)acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl 3) δ: 1,47 (N, s), 1.60-to 1,90 (4H, m), 3,24 (3H, s), of 3.57 (2H, t), of 3.77 (2H, t), 3,93 (2H, s), 7,10 was 7.45 (10H, m), with 8.33 (1H, s)

Example 33

tert-Butyl ester 2-{4-[N-(4,5-di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic acid

In the same way as in example 22, except that 4,5-di-p-tolyl-2-(methylamino)pyrimidine used instead of 5,6-diphenyl-2-(methylamino)pyrazine and tert-butyl ester 2-(4-bromobutyrate)acetic acid is used instead of the methyl ester of 2-(4-bromobutyrate)acetic acid, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, s), 1.60-to 1,90 (4H, m), 2,32 (3H, s), of 2.34 (3H, s), 3,23 (3H, s), of 3.56 (2H, t), and 3.72 (2H, t), 3,93 (2H, s), 6,99-7,11 (6N, m), 7,34 (2H, d), of 8.28 (1H, s)

Example 34

tert-Butyl ester 2-{4-[(5,6-diphenylpyrazine-2-yl)thio]butylochki}acetic acid

To a solution of 500 mg of 5,6-diphenyl-2-pyrazinyl in 20 ml of acetone add 321 mg of sodium carbonate and dropwise under stirring and cooling with ice add a solution of 556 mg of tert-butyl methyl ether 2-(4-bromobutyrate)acetic acid in 2 ml of acetone, followed by stirring at room temperature for 24 hours. The solvent is evaporated under reduced pressure and then the residue is mixed with water and extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate and then dissolve Italy is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 701 mg of the desired compound as a pale yellow oily substance.

1H-NMR (CDCl3) δ: 1,47 (N, s), 1.70 to a 2.00 (4H, m), and 3.31 (2H, t), 3,55 (2H, t)to 3.92 (2H, s), 7,20 is 7.50 (10H, m), 8,44 (1H, s)

Example 35

5-(tert-Butoxycarbonylmethyl)-2-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalen

Stage 1

5-(Benzyloxy)-2-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-3,4-dihydronaphthalene

In an argon atmosphere 0.97 g of 60% sodium hydride suspended in anhydrous N,N-dimethylformamide and in the form of three servings of added 0.97 g of 5,6-diphenyl-2-(methylamino)pyrazine. After stirring at 80°C for 30 minutes the reaction solution is cooled with ice and added dropwise a solution of 0.97 g of 5-(benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene in 5 ml of anhydrous N,N-dimethylformamide. After stirring for 30 minutes the reaction solution was diluted with ice water and then extracted with diethyl ether. The extract is washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining of 1.81 g of the desired compound as a pale yellow amorphous substance.

Stage 2

2-{[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]methyl}-5-hydroxy-1,2,3,4-tetrahydro fralin

To 800 mg of 5-(benzyloxy)-2-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-3,4-dihydronaphthalene add 18 ml of ethanol, 15 ml of ethyl acetate and 80 mg of 10% palladium on coal, and after the mixture hydronaut at 3 ATM at room temperature for 31 hours the reaction continued at 30°C for 23 hours. The catalyst was removed by filtration and the filtrate is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 443 mg of the desired compound as a pale yellow oily substance.

Stage 3

5-(tert-Butoxycarbonylmethyl)-2-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalen

To a solution of 413 mg of 2-[N-(5,6-diphenylpyrazine-2-yl)-N-methyl(aminomethyl)]-5-hydroxy-1,2,3,4-tetrahydronaphthalene and 210 mg of tert-butylbromide in 10 ml of acetonitrile is added a catalytic amount of potassium iodide and 163 mg of potassium carbonate and the mixture is heated to boiling under reflux for 4 hours. Insoluble matter is removed by filtration and the filtrate concentrated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 423 mg of the desired compound as a pale orange oily substance.

1H-NMR (CDCl3) δ: 1,40-1,60 (1H, m), 1,48 (N, C)1,95-3,15 (6N, m), 3,24 (3H, s), 3,53-of 3.80 (2H, m), 4,51 (2H, s), of 6.52 (1H, d), 6,72 (1H, d),? 7.04 baby mortality (1H, t), 7,1-to 7.50 (10H, m), of 8.06 (1H, s)

Example 36

Methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid

Mix of 1.17 g of 1-bromo-4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butane, 0.29 grams of methylthioribose, and 0.46 g of potassium carbonate, a catalytic amount of potassium iodide and 27 ml of acetonitrile and the mixture is refluxed for 4 hours. Insoluble matter is removed by filtration and the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 1.19 g of the desired compound as light yellow crystals having a melting point of 64 to 67°C.

Example 37

Methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid

A solution of 600 mg of methyl ester of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid obtained in example 36, in 10 ml of dichloromethane is cooled with ice and add 329 mg, 70% m-chloroperoxybenzoic acid. After stirring under ice cooling for 2 hours, the reaction solution was diluted with aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on Sealy is agile, while receiving 385 mg of the desired compound in the form of yellowish crystals having a melting point of 128 to 130°C.

Example 38

Methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid

In accordance with column chromatography on silica gel in example 37 obtain 163 mg of the desired compound as light yellow crystals having a melting point of from 123 to 125°C.

Example 39

tert-Butyl ester 2-[4-(5,6-diphenylpyrazine-2-sulfinil)butylochki]acetic acid

With stirring under ice cooling to a solution of 350 mg of tert-butyl ester 2-{4-[(5,6-diphenylpyrazine-2-yl)thio]butylochki}acetic acid obtained in example 34, in 5 ml of chloroform added 191 mg, 70% m-chloroperoxybenzoic acid, followed by stirring for 2 hours. The reaction solution is mixed with 20 ml of 0.2 n sodium hydroxide solution, extracted with chloroform and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 145 mg of the desired compound as a pale yellow oily substance.

1H-NMR (CDCl3) δ: 1,46 (N, s), 1.70 to of 2.20 (4H, m), 3,05 is 3.40 (2H, m), 3,55 (2H, DD), to 3.92 (2H, s), 7,20-of 7.55 (10H, m), 9,16 (1H, s)

Example 40

tert-Butyl ester 2-[4-(5,6-diphenylpyrazine-2-sulfonyl)Buti is oxy]acetic acid

To a solution of 350 mg of tert-butyl ester 2-{4-[(5,6-diphenylpyrazine-2-yl)thio]butylochki}acetic acid obtained in example 34, in 5 ml of chloroform added 421 mg, 70% m-chloroperoxybenzoic acid, followed by stirring at room temperature for 19 hours. The reaction solution is mixed with 20 ml of 0.2 n sodium hydroxide solution, extracted with chloroform and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 380 mg of the desired compound as colorless crystals having a melting point of from 88 to 90°C.

Example 41

tert-Butyl ester 2-[5-(5,6-diphenylpyrazine-2-yl)pentyloxy]acetic acid

Stage 1

5,6-Diphenyl-2-[5-(2-tetrahydropyranyloxy)-1-penten-1-yl]pyrazin

To the solution was 1.58 g of 2-chloro-5,6-diphenylpyrazine in 10 ml of triethylamine added 1.20 g of 5-(2-tetrahydropyranyloxy)-1-pentene, 208 mg dichlorobis(triphenylphosphine)palladium(II) and 56 mg of copper iodide(I), followed by stirring the mixture in an argon atmosphere at 80°C for 8 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in diethyl ether and then the insoluble matter is removed by filtration through celite. After evaporation of the solvent under reduced pressure the residue is purified column chromatography the raffia on silica gel, while receiving 1,79 g of the desired compound as a brown oily substance.

Stage 2

5,6-Diphenyl-2-(5-hydroxy-1-penten-1-yl)pyrazin

To a solution of 1,79 g of 5,6-diphenyl-2-[5-(2-tetrahydropyranyloxy)-1-penten-1-yl]pyrazine in methanol added 1.13 g of p-toluensulfonate pyridinium and the mixture is heated to boiling under reflux for 30 minutes. The reaction solution was poured into ice water with stirring, extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure the resulting crystals are recrystallized from isopropyl ether, thus obtaining a 1.00 g of the desired compound as yellow crystals having a melting point of from 88 to 90°C.

Stage 3

5,6-Diphenyl-2-(5-hydroxypentanal-1-yl)pyrazin

To a solution of 400 mg of 5,6-diphenyl-2-(5-hydroxy-1-penten-1-yl)pyrazine in 20 ml of ethanol, add 80 mg of 5% palladium on coal and the mixture hydronaut at 30°C for 5 hours. After further adding 40 mg of 5% palladium on coal hydrogenation continued for one hour. The catalyst is removed by filtration of the reaction solution through celite and the filtrate dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure, thus obtaining 398 mg of the desired compound as a yellow oily substances is STV.

Stage 4 tert-Butyl ester 2-[5-(5,6-diphenylpyrazine-2-yl)pentyloxy]acetic acid

In the same way as in step 2 of example 1, except that 5,6-diphenyl-2-(5-hydroxypentanal-1-yl)pyrazin used instead of 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol, the desired compound obtained as a light yellow oily substance.

1H-NMR (CDCl3)δ: 1,40-2,00 (6N, m, 1,48 (N, C)of 2.92 (2H, t), of 3.54 (2H, t), of 3.95 (2H, s), 7,20 is 7.50 (10H, m), 8,46 (1H, s)

Example 42

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid

tert-Butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid in the amount of 21,07 g dissolved in 200 ml of methanol and add 60 ml of 1 n sodium hydroxide solution. After the mixture is heated at the boil under reflux for 2 hours, the solvent is evaporated under reduced pressure and the residue is dissolved in water. After washing with diethyl ether the aqueous layer was neutralized with 60 ml of 1 N. hydrochloric acid and then extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure and then the residue was washed with diisopropyl ether, thus obtaining 15,82 g of the desired compound.

Elemental analysis (for C25H29N3O3)

Calc. (%): C, OF 71.58; H, 6,97; N, 10,02.

Nai is prohibited (%): C, 71,66; N, 7.03 IS; N, 9,92.

Example 43

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-cyclopentylamine]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-cyclopentylamine]butylochki}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 101 to 103°C.

Elemental analysis (for C27H31N3O3)

Calc. (%): C, 72,78; N, 7,01; N, 9,43.

Found (Percent): C, 72,20; N, 7,26; N, 9,17.

Example 44

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-cyclohexylamino]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-cyclohexylamino]butylochki}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 130 to 131°C.

Elemental analysis (for C28H33N3O3)

Calc. (%): C, 73,18; N, 7,24; N, 9,14.

Found (Percent): C, 73,03; N, 7,34; N, 8,97.

Example 45

2-{4-[N-(5,6-Di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid, the desired compound obtained as light yellow is kristallov, having a melting point of from 155 to 156°C.

Elemental analysis (for C27H33N3O3)

Calc. (%): C, 72,62; N, 7,22; N, 9,41.

Found (Percent): C, 72,61; N, At 7.55; N, 9,12.

Example 46

Sodium salt of 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid

After tert-butyl ester 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid hydrolyzing in the same manner as in example 42, the resulting 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid is treated with the same amount of 1 n sodium hydroxide solution, thus obtaining the desired compound as a pale brown amorphous substance.

Elemental analysis (for C24H25N2O3Na·0,4 H2O)

Calc. (%): C, 68,69; N, OF 6.20; N, 6,68.

Found (Percent): C, 68,69; N, 6,36; N, 6,36.

Example 47

2-{4-[N-(3-Chloro-5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid

tert-Butyl ester 2-{4-[N-(3-chloro-5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid in the amount of 218 mg dissolved in 2 ml of 1,4-dioxane and add 2 ml of 1 N. hydrochloric acid, followed by stirring at 80°C for one hour. The mixture is additionally stirred at 110°C for 4 hours. The reaction solution is neutralized 1 N. a solution of sodium hydroxide and then extracted with ethyl acetate. E is strict dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The resulting crude crystal was washed with a mixture solvent of hexane-ethyl acetate (4:1), while receiving 120 mg of the desired product in the form of grey crystals having a melting point of 136 to 138°C.

Elemental analysis (for C25H28ClN3O3)

Calc. (%): C, 66,14; N, TO 6.22; N, 9,26.

Found (Percent): C, 66,10; N, 6,32; N, 9,05.

Example 48

2-{4-[N-(5,6-Di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid, the desired compound obtained as yellow crystals having a melting point of from 119 to 121°C.

Elemental analysis (for C26H32N4O3)

Calc. (%): C, 69,62; N, 7,19; N, 12,49.

Found (Percent): C, 69,44; N, 7,15; N, 12,45.

Example 49

2-{4-[N-(5,6-Diphenyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid

In the same way as in example 47, except that using tert-butyl ester 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid, the desired compound obtained as yellow crystals having a melting point of 128 to 130°C.

Elemental analysis (for C24H28N4O3)

Calc. (%): C, 68,55; N, OF 6.71; N, 13,32.

Found (Percent): C, 68,44; N, Only 6.64; N, 13,21.

When the EP 50

2-{4-[N-(5,6-Di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid, the desired compound obtained as light yellow crystals having a melting point of 161 to 162°C.

Elemental analysis (for C25H29N3O3)

Calc. (%): C, OF 71.58; H, 6,97; N, 10,02.

Found (Percent): C, 71,46; N, 6,97; N, To 9.91.

Example 51

2-[4-{N-[5,6-Bis-(4-methoxyphenyl)pyrazin-2-yl]-N-methylamino}butylochki]acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-[5,6-bis-(4-methoxyphenyl)pyrazin-2-yl]-N-methylamino]butylochki}acetic acid, the desired compound obtained as light yellow crystals having a melting point of 128 to 130°C.

Elemental analysis (for C25H29N3O5)

Calc. (%): C, 66,50; N, 6,47; N, 9,31.

Found (Percent): C, 66,42; N, 6,36; N, 9,18.

Example 52

2-[4-{N-[5,6-Bis-(4-forfinal)pyrazin-2-yl]-N-methylamino}butylochki]acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-[4-{N-[5,6-bis-(4-forfinal)pyrazin-2-yl]-N-methylamino}butylochki]acetic acid, the desired compound obtained as light yellow crystals, having the point is the melting point of 116 to 118° C.

Elemental analysis (for C23H23F2N3O3)

Calc. (%): C, 64,63; N, 5,42; N, 9,83.

Found (Percent): C, 64,76; N, The 5.45; N, Being 9.61.

Example 53

Sodium salt of 2-{4-[N-(5,6-diphenyl-3-methylpyridin-2-yl)-N-methylamino]butylochki}acetic acid

After tert-butyl ester 2-{4-[N-(5,6-diphenyl-3-methylpyridin-2-yl)-N-methylamino]butylochki}acetic acid hydrolyzing in the same manner as in example 42, the resulting 2-{4-[N-(5,6-diphenyl-3-methylpyridin-2-yl)-N-methylamino]butylochki}acetic acid is treated with the same amount of 1 n sodium hydroxide solution, thus obtaining the desired compound as a brownish amorphous substance.

Elemental analysis (for C24H26N3O3Na·0,4 H2O)

Calc. (%): C, 66,32; N, 6,21; N, 9,67.

Found (Percent): C, 66,59; N, To 6.67; N, 9,63.

Example 54

2-{2-[1-(5,6-Diphenylpyrazine-2-yl)piperidine-4-yl]ethoxy}acetic acid

In the same way as in example 42, except that using tert-butyl ester 2-{2-[1-(5,6-diphenylpyrazine-2-yl)piperidine-4-yl]ethoxy}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 173 to 174°C.

Elemental analysis (for C25H27N3O3)

Calc. (%): C, 71,92; N, OF 6.52; N, 10,06.

Found (Percent): C, 71,62; N, 6,53; N, 9,79.

Example 55

(±)-2-{3-[1-(5,6-Diphenylpyrazine-2-yl)p is Raiden-2-yl]propyloxy}acetic acid

In the same manner as in example 42, except that using tert-butyl ether (±)-2-{3-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]propyloxy}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 137 to 139°C.

Elemental analysis (for C25H27N3O3)

Calc. (%): C, 71,92; N, OF 6.52; N, 10,06.

Found (Percent): C, 72,01; N, 6,56; N, 9,80.

Example 56

2-{4-[N-(5,6-Diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid

In the same way as in example 47, except that using tert-butyl ester 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 108 to 110°C.

Elemental analysis (for C22H24N4O3)

Calc. (%): C, 67,33; N, 6,16; N, OF 14.28.

Found (Percent): C, 67,38; N, To 6.22; N, 14,22.

Example 57

(±)-2-{4-[1-(5,6-Diphenylpyrazine-2-yl)pyrrolidin-2-yl]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ether (±)-2-{4-[1-(5,6-diphenylpyrazine-2-yl)pyrrolidin-2-yl]butylochki}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 138 to 140°C.

Elemental analysis (for C26H29N3 O3)

Calc. (%): C, 72,37; N, 6,77; N, 9,74.

Found (Percent): C, 72,35; N, 6,85; N, 9,50.

Example 58

(±)-2-{2-[1-(5,6-Diphenylpyrazine-2-yl)piperidine-3-yl]ethoxy}acetic acid

In the same manner as in example 42, except that using tert-butyl ether (±)-2-{2-[1-(5,6-diphenylpyrazine-2-yl)piperidine-3-yl]ethoxy}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 139 to 140°C.

Elemental analysis (for C25H27N3O3)

Calc. (%): C, 71,92; N, OF 6.52; N, 10,06.

Found (Percent): C, 71,99; N, 6,60; N, 10,00.

Example 59

(R)-(+)-2-[3-{2-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]acetic acid

In the same manner as in example 42, except that use methyl ester (R)-2-[3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 158 to 159°C.

[α]D20: +40,86 (=0,465, methanol)

Elemental analysis (for C27H25N3O4)

Calc. (%): C, 71,19; N, OF 5.53; N, WHICH 9.22.

Found (Percent): C, 71,21; N, To 5.58; N, 9,17.

Example 60

2-[3-{[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]methyl}phenoxy]acetic acid

In the same manner as in example 42, except that use methyl ester 2-[3-{[N-(5,6-d is phenylpiperazin-2-yl)-N-methylamino]methyl}phenoxy]acetic acid, the desired compound obtained as yellowish crystals having a melting point of 182 to 187°C.

Elemental analysis (for C26H23N3O3)

Calc. (%): C, 73,39; N, THE 5.45; N, 9,88.

Found (Percent): C, 73,26; N, Vs. 5.47; N, 9,83.

Example 61

2-[3-{2-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]ethyl}phenoxy]acetic acid

In the same manner as in example 42, except that use methyl ester 2-[3-{2-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]ethyl}phenoxy]acetic acid, the desired compound obtained as yellowish crystals having a melting point of 174 to 176°C.

Elemental analysis (for C27H25N3O3)

Calc. (%): C, 73,79; N, 5,73; N, 9,56.

Found (Percent): C, 73,43; N, 5,79; N, To 9.32.

Example 62

4-(Carboxymethoxy)-1-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]indan

In the same manner as in example 42, except that the use of 1-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-4-(ethoxycarbonylmethoxy)indan, the desired compound obtained as light yellow crystals having a melting point of 182 to 184°C.

Elemental analysis (for C28H25N3O3)

Calc. (%): C, 74,48; N, TO 5.58; N, 9,31.

Found (Percent): C, 74,06; N, 5,70; N, Which Is 9.09.

Example 63

Sodium salt of 2-[4-(5,6-diphenylpyrazine-2-yloxy)butoxy]acetic acid

Stage 1

1-(5,6-Diphenylpyrazine-2-yloxy)-4-(2-tetrahydro what Iranians)Bhutan

4-(2-Tetrahydropyranyloxy)-1-butanol in the number of 1.57 g dissolved in 20 ml of tetrahydrofuran, and under ice cooling added 360 mg of 60% sodium hydride, followed by stirring at room temperature for 1.5 hours. The mixture is refluxed for 30 minutes and then cooled with ice and add a 2.00 g of 5-chloro-2,3-diphenylpyrazine. After stirring for 40 minutes, the mixture is heated to 80°C, stirred at the same temperature for 4.5 hours and then stirred at room temperature for 88 hours. The reaction solution is mixed with ice water, extracted with ethyl acetate and then washed with a saturated solution of salt. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure, thus obtaining 2,39 g of the desired compound as an oily substance.

Stage 2

4-(5,6-Diphenylpyrazine-2-yloxy)-1-butanol

1-(5,6-Diphenylpyrazine-2-yloxy)-4-(2-tetrahydropyranyloxy)butane in amounts 2,39 g dissolved in methanol and add 1,53 g p-toluensulfonate pyridinium and the mixture is then refluxed for 30 minutes. The reaction solution is cooled, poured into ice water with stirring and then extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure, the floor is th at this 1,74 g of the desired compound as colorless crystals, having a melting point of from 93 to 95°C.

Stage 3

Sodium salt of 2-[4-(5,6-diphenylpyrazine-2-yloxy)butoxy]acetic acid 4-(5,6-diphenylpyrazine-2-yloxy)-1-butanol in an amount of 500 mg dissolved in 3 ml of tert-butanol and added 420 mg of tert-butoxide potassium and then a solution of 222 mg of Chloroacetic acid in 1 ml of tert-butanol are added during the boiling under reflux. After adding 3 ml of tert-butanol mixture is refluxed for 15 hours. After add ice water, regulate pH to 4 with 1 N. hydrochloric acid, the reaction solution is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting oily substance is dissolved in a solvent, benzene:methanol = 4:1 and excess 2 M trimethylsilyldiazomethane (solution in hexane) is added with methyl ether complex. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel, thus obtaining 88 mg of the ether in the form of an oily substance. The ester is dissolved in 1 ml of methanol and add 1 ml of 1 n sodium hydroxide solution followed by boiling under reflux for one hour. After evaporation of the solvent under reduced pressure the solvent is mixed with water, the industry is up with ethyl acetate, neutralize 1 ml of 1 N. hydrochloric acid and then extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting oily substance was dissolved in methanol and add the same amount of 1 n sodium hydroxide solution and then the solvent is evaporated under reduced pressure, while receiving 60 mg of the desired compound as a colorless amorphous substance.

Elemental analysis (for C28H25N3O3·1,1 H2O)

Calc. (%): C, 62,88; N, TO 5.56; N, 6,67.

Found (Percent): C, 63,07; N, The 5.51; N, 6,28.

Example 64

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid

In the same manner as in example 42, except that use methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid, receive the requested connection.

Elemental analysis (for C23H25N3O3)

Calc. (%): C, 70,57; N, 6,44; N, OF 10.73.

Found (Percent): C, 70,44; H, 6.42 Per; N, At 10.64.

Example 65

7-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]heptane acid

In the same manner as in example 42, except that the use of methyl ester of 7-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]heptane acid, the desired compound obtained as colorless crystals having a melting point of from 114 to 118°C.

elementry analysis (for C 24H27N3O2·0,2 H2O)

Calc. (%): C, 73,33; N, 7.03 IS; N, 10,69.

Found (Percent): C, 73,32; N, 7,06; N, 10,41.

Example 66

8-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]octanoic acid

In the same manner as in example 42, except that the use of methyl ester of 8-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]octane acid, the desired compound obtained as colorless crystals having a melting point of 116 to 117°C.

Elemental analysis (for C25H29N3O2)

Calc. (%): C, 74,41; N, 7,24; N, 10,41.

Found (Percent): C, 74,16; N, Of 7.25; N, 10,29.

Example 67

9-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]novanova acid

In the same manner as in example 42, except that the use of the methyl ester of 9-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]nonanalog acid, the desired compound obtained as colorless crystals having a melting point of from 103 to 105°C.

Elemental analysis (for C26H31N3O2·0,3 H2O)

Calc. (%): C, 73,83; N, 7,53; N, TO 9.93.

Found (Percent): C, 73,80; N, At 7.55; N, 9,65.

Example 68

6-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]hexanoic acid

In the same manner as in example 42, except that the use of ethyl ester of 6-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]hexanoic acid, the desired compound obtained as colorless crystals having a melting point of 159 to 160° C.

Elemental analysis (for C23H25N3O2)

Calc. (%): C, 73,58; N, OF 6.71; N, 11,20.

Found (Percent): C, 73,16; N, PC 6.82; N, Br11.01.

Example 69

Sodium salt of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butylochki}acetic acid

Using tert-butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butylochki}acetic acid carboxylic acid is obtained in the same manner as in example 42, and the resulting carboxylic acid is treated with the same amount of 1 n sodium hydroxide solution, thus obtaining the desired compound as a pale yellow amorphous substance.

Elemental analysis (for C24H26N3O3Na·1H2O)

Calc. (%): C, 64,71; N, 6,34; N, 9,43.

Found (Percent): C, 64,88; N, Of 6.25; N, 9,16.

Example 70

Sodium salt of 2-{4-[N-allyl-N-(5,6-diphenylpyrazine-2-yl)amino]butylochki}acetic acid

Using tert-butyl ester 2-{4-[N-allyl-N-(5,6-diphenylpyrazine-2-yl)amino]butylochki}acetic acid carboxylic acid is obtained in the same manner as in example 42, and the resulting carboxylic acid is treated with the same amount of 1 n sodium hydroxide solution, thus obtaining the desired compound as a colorless amorphous substance.

Elemental analysis (for C25H26N3O3Na·0,7 N2O)

Calc. (%): C, 66,42; N, 6,11; N, 9,29.

Found%: C, 66,31; N, 5,97; N, 8,98.

Example 71

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy}acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 148 to 150°C.

Elemental analysis (for C23H23N3O3)

Calc. (%): C, 70,93; N, 5,95; N, 10,79.

Found (Percent): C, 70,71; N, 6,00; N, 10,67.

Example 72

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-methylamino]-(E)-2-butene-1-yloxy}acetic acid

In the same manner as in example 42, except that use methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(E)-2-butene-1-yloxy}acetic acid, the desired compound obtained as light yellow crystals having a melting point of 128 to 130°C.

Elemental analysis (for C23H23N3O3·0,2 H2O)

Calc. (%): C, 70,28; N, 6,00; N, 10,69.

Found (Percent): C, 70,33; N, 5,94; N, 10,46.

Example 73

1-Oxide, 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine

In the same manner as in example 42, except that use 1-oxide, 2,3-diphenyl-5-{N-[4-(tert-butoxycarbonylamino)butyl]-N-methylamino}pyrazine, the desired compound obtained as colorless Cree is of metal, having a melting point of from 185 to 190°C.

Elemental analysis (for C23H25N3O4)

Calc. (%): C, 67,80; N, 6,18; N, 10,31.

Found (Percent): C, 67,54; N, 6,18; N, 10,15.

Example 74

2-{4-[N-(4,5-Diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(4,5-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid, receive the requested connection.

Elemental analysis (for C23H25N3O3)

Calc. (%): C, 70,57; N, 6,44; N, OF 10.73.

Found (Percent): C, 70,59; H, 6.42 Per; N, 10,80.

Example 75

2-{4-[N-(4,5-Di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[N-(4,5-di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic acid, receive the requested connection.

Elemental analysis (for C25H29N3O3)

Calc. (%): C, OF 71.58; H, 6,97; N, 10,02.

Found (Percent): C, 71,72; N, Of 6.96; N, 10,13.

Example 76

2-{4-[(5,6-Diphenylpyrazine-2-yl)thio]butylochki}acetic acid

In the same manner as in example 42, except that using tert-butyl ester 2-{4-[(5,6-diphenylpyrazine-2-yl)thio]butylochki}acetic acid instead of the tert-butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}of uksosn the th acid, the desired compound obtained as light yellow crystals having a melting point of 86 to 88°C.

Elemental analysis (for C22H22N2O3S)

Calc. (%): C, 66,98; N, 5,62; N, 7,10.

Found (Percent): C, 66,81; N, To 5.57; N, 7,47.

Example 77

5-(Carboxymethoxy)-2-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalen

In the same manner as in example 42, except that using 5-(tert-butoxycarbonylmethyl)-2-{[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalen, the desired compound obtained as light yellow crystals having a melting point of from 212 to 213°C.

Elemental analysis (for C30H29N3O3·0,2 H2O)

Calc. (%): C, 74,57; N, 6,13; N, 8,70.

Found (Percent): C, 74,26; N, To 6.19; N, To 8.41.

Example 78

Sodium salt of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio]acetic acid

Using methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid carboxylic acid is obtained in the same manner as in example 42, and the resulting carboxylic acid is treated with the same amount of 1 n sodium hydroxide solution to obtain the desired compound as a brownish amorphous substance.

Elemental analysis (for C25H28N3O2SNa·0.5 N2O)

Calc (%): C, 64,36; N, OF 6.26; N, 9,01.

Found (Percent): C, 64,14; N, Equal To 6.05; N, 8,90.

Example 79

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid

In the same manner as in example 42, except that use methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid, the desired compound obtained as yellowish crystals having a melting point of from 117 to 120°C (decomposition).

Elemental analysis (for C25H29N3O3S)

Calc. (%): C, 66,49; N, 6,47; N, 9 : 30 A.M.

Found (Percent): C, 66,14; N, 6,47; N, 8,97.

Example 80

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid

In the same manner as in example 42, except that use methyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid, the desired compound obtained as yellowish crystals having a melting point of from 183 to 185°C.

Elemental analysis (for C25H29N3O4S·0,2 H2O)

Calc. (%): C, 63,73; N, OF 6.29; N, 8,92.

Found (Percent): C, 63,64; N, 6,23; N, 8,66.

Example 81

Sodium salt of 2-[4-(5,6-diphenylpyrazine-2-sulfinil)butylochki]acetic acid

In the same way as in example 47, except that using tert-butyl ester 2-[4-(5,6-diphenylpyrazine-2-sulfinil)butylochki]acetic acid, 2-4-(5,6-diphenylpyrazine-2-sulfinil)butylochki]acetic acid is obtained in the form of a pale yellow oily substance. 125 mg of the resulting oily substance was dissolved in methanol and after the addition of 0.30 ml of 1 n sodium hydroxide solution, the solvent is evaporated under reduced pressure. The remainder utverjdayut by adding isopropanol and diethyl ether, washed with diethyl ether and then dried, to thereby obtain 73 mg of the desired compound as a pale yellow amorphous substance.

Elemental analysis (for C22H21N2O4SNa·1,5H2About·0.5 s3H8O)

Calc. (%): C, 57,66; N, USD 5.76; N, 5,72.

Found (Percent): C, 58,30; N, 5,10; N, The 5.45.

Example 82

2-[4-(5,6-Diphenylpyrazine-2-sulfonyl)butylochki]acetic acid

In the same way as in example 47, except that using tert-butyl ester 2-[4-(5,6-diphenylpyrazine-2-sulfonyl)butylochki]acetic acid, the desired compound obtained as light yellow crystals having a melting point of from 123 to 125°C.

Elemental analysis (for C22H22N2O5S)

Calc. (%): C, 61,96; N, 5,20; N, 6,57.

Found (Percent): C, Of 61.95; H, A 5.25; N, 6,41.

Example 83

Sodium salt of 2-[5-(5,6-diphenylpyrazine-2-yl)pentyloxy]acetic acid

In the same manner as in example 42, except that tert-butyl ester 2-[5-(5,6-diphenylpyrazine-2-yl)pentyloxy]acetic acid is used instead of tert-butyl ester 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-Isopropylamine is]butylochki}acetic acid, 2-[5-(5,6-diphenylpyrazine-2-yl)pentyloxy]acetic acid is obtained as an oily substance. The resulting oily substance is treated with the same amount of 1 n sodium hydroxide solution, thus obtaining the desired compound as a pale brown amorphous substance.

Elemental analysis (for C23H23N2O3Na·0,5H2O)

Calc. (%): C, 67,80; N, 5,94; N, 6,88.

Found (Percent): C, 68,03; N, To 6.22; N, 6.48 In.

Example 84

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(methylsulphonyl)ndimethylacetamide

In an argon atmosphere to a solution of 300 mg of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid obtained in example 42, in 5 ml of anhydrous tetrahydrofuran added 128 mg of 1,1'-carbonyldiimidazole and after stirring at room temperature for 30 minutes, the mixture is heated at the boil under reflux for 30 minutes. After air cooling to room temperature, add 69 mg methanesulfonamide. After stirring for 10 minutes, added dropwise to 0.11 ml of 1,8-diazabicyclo[5.4.0]-7-undecene. After stirring at room temperature overnight, the reaction solution was diluted with water and then extracted with diethyl ether. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure and then about who headed the remainder of the purified column chromatography on silica gel, while receiving 272 mg of the desired compound.

Elemental analysis (for C26H32N4O4S)

Calc. (%): C, 62,88; N, OF 6.49; N, 11,28.

Found (Percent): C, 63,06; N, 6,47; N, 10,98.

Example 85

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(p-toluensulfonyl)ndimethylacetamide

To a solution of 500 mg of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid obtained in example 42, in 5 ml of anhydrous tetrahydrofuran add 214 mg of 1,1'-carbonyldiimidazole and after stirring at room temperature for 30 minutes, the mixture is heated at the boil under reflux for 30 minutes. After air cooling to room temperature, add 206 mg p-toluensulfonate. After stirring for 10 minutes, added dropwise to 0.18 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. After stirring at room temperature over night almost all the solvent is evaporated under reduced pressure. The residue is mixed with water and then neutralize 1 N. hydrochloric acid. The reaction solution is extracted with ethyl acetate and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel, thus obtaining 460 mg of the desired compound.

Elemental analysis (for C32H36N4O4S)

Calc. (%): C, 6,11; N, 6,34; N, 9,78.

Found (Percent): C, 67,04; N, 6,37; N, 9,65.

Example 86

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(isopropylphenyl)ndimethylacetamide

In the same manner as in example 85, except that isopropylcarbonate used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C28H36N4O4S)

Calc. (%): C, 64,10; N, 6,92; N IS 10.68.

Found (Percent): C, 64,19; N, 6,97; N, To 10.62.

Example 87

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(trifloromethyl)ndimethylacetamide

In the same manner as in example 85, except that triftormetilfullerenov used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C26H29F3N4O4S·1,2 N2O)

Calc. (%): C, 54,57; N, OF 5.53; N, 9,79.

Found (Percent): C, 54,41; N, 5,22; N, 9,45.

Example 88

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(o-toluensulfonyl)ndimethylacetamide

In the same manner as in example 85, except that o-toluensulfonate used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C32H36N4O4S)

Calc. (%): C, 67,11; N, 6,34; N, 9,78.

Found (Percent): C, 66,95; N, 6,32; N, 9,59.

Example 89

N-(Benzazolyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropyl what Mino]butylochki}ndimethylacetamide

In the same manner as in example 85, except that benzosulfimide used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C31H34N4O4S)

Calc. (%): C, 66,64; N, 6,13; N, THERE IS A 10.03.

Found (Percent): C, 66,66; N, 6,12; N, 9,99.

Example 90

N-(4-Chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide

In the same manner as in example 85, except that 4-chlorobenzenesulfonamide used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C31H33ClN4O4S)

Calc. (%): C, 62,77; N, 5,61; N, 9,45.

Found (Percent): C, 62,99; N, To 5.58; N, 9,50.

Example 91

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-methoxybenzenesulfonyl)ndimethylacetamide

In the same manner as in example 85, except that 4-methoxybenzenesulfonamide used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C32H36N4O5S·0.6 N2O)

Calc. (%): C, 64,11; N, OF 6.25; N, 9,35.

Found (Percent): C, 63,86; N, 5,95; N, 9,39.

Example 92

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-permentantly)ndimethylacetamide

In the same manner as in example 85, except that 4-forbindelsesfaneblad used instead of p-toluol is lonarid, receive the requested connection.

Elemental analysis (for C31H33FN4O4S)

Calc. (%): C, 64,56; N, 5,77; N, 9,72.

Found (Percent): C, 64,36; N, 5,88; N, 9,56.

Example 93

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(2-thiophenesulfonyl)ndimethylacetamide

In the same manner as in example 85, except that 2-thiophenesulfonyl used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C29H32N4O4S2)

Calc. (%): C, 61,68; N, 5,71; N, 9,92.

Found (Percent): C, 61,70; N, 5,78; N, 9,76.

Example 94

N-(Aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide

In the same manner as in example 85, except that the sulphonamide used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C25H31N5O4S)

Calc. (%): C, 60,34; N, 6,28; N, 14,07.

Found (Percent): C, 60,09; N, 6,27; N, 14,04.

Example 95

N-(N,N-Dimethylaminomethyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide

In the same manner as in example 85, except that N,N-dimethylsulfone used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C27H35N5O4S)

Calc. (%): C, 61,69; N, OF 6.71; N, 13,32.

Found (percent): C, 61,60; N, Only 6.64; N, 1324.

Example 96

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(morpholine-4-ylsulphonyl)ndimethylacetamide

In the same manner as in example 85, except that morpholine-4-ylsulphonyl used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C29H37N5O5S)

Calc. (%): C, 61,36; N, TO 6.57; N, 12,34.

Found (Percent): C, 61,11; N, 6,59; N, A 12.03.

Example 97

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(pyrrolidin-1-sulfonyl)ndimethylacetamide

In the same manner as in example 85, except that pyrrolidin-1-sulfonamide used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C29H37N5O4S)

Calc. (%): C, 63,13; N, 6,76; N, 12,69.

Found (Percent): C, 63,11; N, To 6.78; N, 12,49.

Example 98

Phenyl ether [2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid

In the same manner as in example 85, except that phenyl ether sulfamic acid is used instead of p-toluensulfonate receive the requested connection.

Elemental analysis (for C31H34N4O5S)

Calc. (%): C, 64,79; N, 5,96; N, 9,75.

Found (Percent): C, 64,93; N, 6,01; N, 9,59.

Example 99

2-{4-[N-(5,6-Diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide

In 20 ml of anhydrous those who of rageragerage dissolved 1.50 g of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid and add 0,500 ml of triethylamine and then 0,376 ml atilglukuronida under stirring and cooling with ice. After stirring under ice cooling for 45 minutes, add a saturated solution of ammonia in 20 ml of tetrahydrofuran, followed by stirring for one hour. After removing the ice bath and stirring at room temperature for 18 hours, evaporated almost all of the solvent. The residue is mixed with water and then extracted with ethyl acetate. The extract is washed in sequence aqueous saturated solution of sodium bicarbonate, 1 N. a solution of sodium hydroxide and water and dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue was washed with diethyl ether and then dried under reduced pressure, to thereby obtain 1.19 g of the desired product.

Elemental analysis (for C25H30N4O2)

Calc. (%): C, 71,74; N, 7,22; N, 13,39.

Found (Percent): C, 71,79; N, 7,30; N, 13,34.

Example 100

Sodium salt of N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid

In an argon atmosphere a solution of 1,443 g of 2-picoline in 1.7 ml of 1,2-dichloroethane is cooled to -10°C. dropwise at a temperature of 0°or lower is added dropwise a solution of chlorosulfonic acid in 3.5 ml of 1,2-dichloroethane and after stirring for 15 minutes add 712 mg of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide. The reaction of the races is a thief heated to 75° C and cooled in air to room temperature after stirring for 2 hours. The reaction solution was diluted with dichloromethane and then washed in sequence water of 0.6 M sodium hydrosulphate and water. The reaction solution is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (chloroform-methanol), while receiving 798 mg of N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid.

Elemental analysis (for C25H30N4O5SN·0,5 CHCl3)

Calc. (%): C, 54,86; N, THE 5.51; N, 10,04.

Found (Percent): C, 54,72; N, The 5.51; N, 9,84.

Example 101

1 ml of a mixed solution of ethanol and water (1:1) dissolve 100 mg of the compound obtained in example 100, and add 0,200 ml of 1 n sodium hydroxide solution. After evaporation of the solvent mixture utverjdayut mixed solution of ethanol and methanol and the solid collected by filtration and then dried under reduced pressure, thus obtaining 49 mg specified in the title compound as a colourless solid.

Elemental analysis (for C25H29N4O5SNa·1,5 H2O)

Calc. (%): C, 54,83; N, OF 5.89; N, 10,23.

Found (Percent): C, 54,39; N, Of 5.48; N, 10,07.

The test example 1

Test of inhibition of aggregation trom acetow person

Blood collected from healthy human volunteers in an aqueous solution of triacrylate, centrifuged at 200 x g for 10 minutes and the upper layer emit to obtain plasma rich in platelets (PRP). Residual blood, containing added trinatriytsitrat, centrifuged at 1500 x g for 10 minutes and the supernatant collected as plasma-depleted platelets (PPP). The number of platelets in PRP set about to 300,000/µl using PPP. Platelet aggregation is measured by aggregometry. 280 μl of PRP added to the cuvette and incubated at 37°C for one minute and then add 10 μl solution of the test compounds (obtained by dissolving the test compounds in a 1.5-fold molar amount of sodium hydroxide solution and dilution water) and the mixture is additionally incourt for 2 minutes. Then add 10 ál of aqueous solution of adenosine diphosphate (ADP) to establish a final concentration of 1 x 105M and induce and within 7 minutes watching platelet aggregation. The percentage inhibition is calculated from the ratio of the percent aggregation adding the test compound to the percent aggregation by adding water instead of the solution of the test compound (control). The test compound are added to achieve a final concentration in the range of 10-8up to 10-4M, Velicina IC 50determine the percent inhibition of aggregation at each concentration. The results are shown in table 1.

It is obvious that the compounds of the present invention significantly inhibit platelet aggregation in human PRP.

Table 1

Inhibition of aggregation of human platelets
Test connectionIC50(µm)
Example 420,2
Example 430,8
Example 460,5
Example 480,4
Example 640,2
Example 650,3
Example 730,2

Example 740,8
Example 750,2
Example 780,3

The test example 2

Test of inhibition of binding3N-iloprost with membranes of human platelets

Membranes of human platelets with 100 µg of protein suspended in 200 μl of 50 mm buffer Tris-HCl (pH 7.4)containing 10 mm MgCl2, 1 mm EGTA and 5 nm3N-iloprost, and then incubated at 37°C for 10 minutes with 5 μm unlabeled by iloprost or compound (1 μm) example is 64. Membranes of platelets collected on a glass filter and the radioactivity was measured after washing four times with 50 mm buffer Tris-HCl. The compound (1 μm) of example 64 inhibits binding3N-iloprost 85%.

The test example 3

The increase in the concentration of camp in human platelets

The washed suspension of human platelets in the amount of 500 ál (2 x 108/ml)containing each concentration of the compound of example 64, incourt at 37°C for 10 minutes and exposed to ultrasound after adding 1 M solution perchloro acid. After processed by the ultrasound solution is centrifuged and the supernatant neutralized aqueous 1 M solution of potassium bicarbonate, his centrifuged again and produce a supernatant. The concentration of camp in the supernatant determined by ELISA method. As shown in table 2, the amount of camp in platelets is increased by the connection of example 64 concentration dependent manner.

Table 2

Increasing the amount of camp in human platelets
The concentration of the compound of Example 64(nm)camp

(pmol/108platelets)
103,7
306,7
10020,7
300 28,5
100039,4
300035,3

As is evident from the examples of tests 1-3, the compounds of the present invention inhibit platelet aggregation on the basis of their antagonistic activity for receptor PGI2.

Example 4 testing

Test the toxicity of a single dose in mice

The compound of example 42 oral was administered to mice (including three mice per group) at doses of 10, 30 or 100 mg/kg as a result, no deaths.

The compound of example 64 oral was administered to mice (five mice per group) at a dose of 300 mg/kg as a result, no deaths.

The test example 5

Testing method of inhibiting platelet aggregation Ex vivo in monkeys

The compound of example 84 oral introduced two abacadabra monkeys (Macaca fascicularis, male, age 3 to 5) at the dose of 0.3 or 1 mg/kg Before entering or after 2, 4 and 8 hours after injection the blood was collected (4.5 ml each) using a cylinder for injection containing water of 3.8% solution of citric acid in the amount of 1/10 of the volume of blood that must be assembled. Blood containing citric acid solution, centrifuged at 200 x g for 10 minutes and the lower layer was collected as PRP. In addition, the remaining blood was centrifuged at 1500 x g for 10 minutes and supernatant was collected as RRR μl of PRP was added to a cuvette and incubated at 37° C for one minute and then to induce platelet aggregation was added 10 μl of a solution of ADP (5 to 30 μm). The percentage of platelet aggregation was measured by aggregometry (PM8C, Mebanix, Tokyo) using PPP as the blind experience and the percentage of inhibition of platelet aggregation was determined by comparing the percentage of inhibition prior to the introduction of compounds with percentage inhibition after administration of the compounds according to the following equation. The results are shown in table 3.

The percentage inhibition of platelet aggregation (%) = 100 - (percentage of aggregation after administration of the compound)/(the percentage of aggregation prior to the introduction of compound) x 100.

Table 3

The percentage of inhibition of aggregation in platelets monkeys (%)
Time after administration (h)The dose of a compound of example 84

(mg/kg)
0,31
22863
43440
81952

It is evident that the compound of example 84 firmly inhibits platelet aggregation in a dose-dependent manner from 2 to 8 hours after dosing and efficacy of the medicinal product is stored for an extended period BP is like.

An example of the finished formulation 1

Tablets (tablets for internal use)

Ready preparative form, having a weight of 200 mg per pill

The compound of example 4020 mg
Corn starch88 mg
Crystalline cellulose80 mg
Calcium salt of carboxymethylcellulose10 mg
Light anhydrous silicic acid1 mg
Magnesium stearate1 mg

The mixed powders obtained in accordance with the above prepared preparative form, extruded, while receiving tablets for internal use.

An example of the finished formulation 2

Tablets (tablets for internal use)

Ready preparative form, having a weight of 120 mg per pill

The compound of example 511 mg
Lactose60 mg
Corn starch30 mg
Crystalline cellulose20 mg
Hydroxypropylcellulose7 mg
Magnesium stearate2 mg
/p>

The mixed powders obtained in accordance with the above prepared preparative form, extruded, while receiving tablets for internal use.

Example of finished formulations of 3

Tablets (tablets for internal use)

Ready preparative form, having a weight of 180 mg per pill

The compound of example 63100 mg
Lactose45 mg
Corn starch20 mg
Hydroxypropylcellulose of low substitution9 mg
Polyvinyl Speer (partially saponified)5 mg
Magnesium stearate1 mg

The mixed powders obtained in accordance with the above prepared preparative form, extruded, while receiving tablets for internal use.

INDUSTRIAL APPLICABILITY

The compound of the present invention can be used as a therapeutic agent such as an inhibitor of coagulation of platelets, because it shows antagonistic activity for receptor PGI2and also has low toxicity.

1. Agonist receptor PGI2that includes the heterocyclic compound represented by the following about the soup formula (1), or its salt as an active ingredient

where R1and R2are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy;

Y represents N, N→O or CR5Z represents N or CR6and R5and R6are the same or different and each represents hydrogen, alkyl or halogen;

And represents NR7and R7represents hydrogen, alkyl, alkenyl or cycloalkyl;

D represents alkylene or albaniles, which is optionally substituted by hydroxy, or a and D are connected to each other to form divalent group represented by the following formula (2):

r is an integer from 0 to 2, q is an integer 2 or 3 and t is an integer from 0 to 4;

E is a phenylene or a simple link or D and E are connected to each other to form divalent group represented by the following formula (3):

(represents a simple bond or double with the IDE);

u is an integer from 0 to 2, and v is 0 or 1;

G represents O, S, SO, SO2;

R3and R4are the same or different and each represents hydrogen or alkyl;

Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, or a group represented by the following formula (22):

R10represents amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, morpholine, pyrrolidine and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

2. Agonist receptor PGI2according to claim 1, where in formula (1) R1and R2are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y and Z correspond to any of the following cases (1) and (2):

(1) Y represents N or CH, and Z represents N or CH and

(2) Y is N→O, and Z represents CH,

And represents NR7and R7represents hydrogen, alkyl or cycloalkyl

D represents alkylene or albaniles,

E represents a simple bond,

G represents O, S, SO, SO2,

R3and R4are the same or different and each represents hydrogen or alkyl, and

Q represents carboxy, alkoxycarbonyl, tetrazolyl or a group represented by the formula (22), and R10represents amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, morpholine, pyrrolidine and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

3. Agonist receptor PGI2according to claim 1, where in formula (1) R1and R2are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y and Z correspond to any of the following cases (1) and (2):

(1) Y is N and Z represents CH and

(2) Y represents CH and Z represents N or CH,

And represents NR7and R7represents hydrogen or alkyl,

D represents alkylene,

E represents a simple bond,

G represents O,

R3and R4are the same or different and each represents hydrogen or alkyl,

Q represents carboxy, tetrazolyl or a group represented by the formula (22), and R10represents amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, morpholine, pyrrolidine, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

4. Agonist receptor PGI2according to claim 1, where in formula (1) R1and R2are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y is N and Z represents CH,

And represents NR7and R7represents alkyl,

D represents alkylene,

E represents a simple bond,

G represents O,

R3and R4are the same or different and each represents hydrogen or alkyl, and

Q represents carboxy or a group, p is redstavlennye formula (22), and

R10represents amino, dialkylamino,

hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, morpholine, pyrrolidine and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

5. Agonist receptor PGl2according to claim 1, where the heterocyclic compound is a compound selected from the group consisting of the following compounds (1) to (32):

(1) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki}acetic acid,

(2) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid,

(3) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid,

(4) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid,

(5) 1-oxide, 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methyl-amino}pyrazine,

(6) 2-{4-[N-(4,5-di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic acid,

(7) 7-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]heptane acid,

(8) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid,

(9) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy}acetic acid,

(10) 2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}UKS who scurry acid,

(11) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butylochki}acetic acid,

(12) 2-{4-[N-(2,3-diphenylpyridine-6-yl)-N-methylamino]butylochki}acetic acid,

(13) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid,

(14) 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid,

(15) 2-{4-[N-(4,5-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid,

(16) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(p-toluensulfonyl)ndimethylacetamide,

(17) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(isopropylphenyl)ndimethylacetamide,

(18) 2-{4-N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(trifloromethyl)ndimethylacetamide,

(19) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(o-toluensulfonyl)ndimethylacetamide,

(20) N-(benzazolyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(21) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(22) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-methoxybenzenesulfonyl)ndimethylacetamide,

(23) 2-{4-N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-permentantly)ndimethylacetamide,

(24) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(2-thiophenesulfonyl the l)ndimethylacetamide,

(25) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(26) N-(N,N-dimethylaminomethyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(27) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(morpholine-4-ylsulphonyl)ndimethylacetamide,

(28) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(pyrrolidin-1-ylsulphonyl)ndimethylacetamide,

(29) phenyl ester N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(30) N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(31) sodium salt of N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl] sulfamic acid, and

(32) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(methylsulphonyl)ndimethylacetamide.

6. Inhibitor of platelet aggregation, comprising the heterocyclic compound according to any one of claims 1 to 5, or its salt as an active ingredient.

7. Therapeutic agent for obliterating arteriosclerosis, comprising the heterocyclic compound according to any one of claims 1 to 5, or its salt as an active ingredient.

8. Therapeutic agent for intermittent claudication, including the heterocyclic compound according to any one of claims 1 to 5, or its salt in image quality is as active ingredient.

9. Therapeutic agent for peripheral arterial embolism, including the heterocyclic compound according to any one of claims 1 to 5, or its salt as an active ingredient.

10. Heterocyclic compound represented by the following General formula (1z), or its salt

where the substituents corresponds to any one of the following cases (I) and (II):

(I)

R91and R92are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy;

Y9represents N or N→O, Z9represents N or CR96and R96represents hydrogen, alkyl or halogen,

And9represents NR97and R97represents hydrogen, alkyl, alkenyl or cycloalkyl,

D9is alkylene or albaniles, which is optionally substituted by hydroxy, or a9and D9are connected to each other to form divalent group represented by the following formula (2z):

m is an integer from 0 to 2, k is an integer 2 or 3 and n is an integer from 0 to 4,/p>

E9represents a phenylene or a simple bond, or D9and E9are connected to each other to form divalent group represented by the following formula (3z):

(represents a simple bond or double bond)

w is an integer from 0 to 2 and x is 0 or 1,

G9represents O, S, SO, SO2,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, alkoxycarbonyl, tetrazolyl, carbarnoyl, or a group represented by the following formula (22z):

R910represents amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, morpholine, pyrrolidine and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy;

(II)

R91and R92represent phenyl or p-tolyl,

Y9represents CH, Z9represents N or CH,

And9represents NR97and NR97represents methyl,

D9the stand is made by a butylene,

E9represents a simple bond,

G9represents Oh,

R93and R94represent hydrogen, and

Q9represents carboxy or tert-butoxycarbonyl;

including the following case:

R91and R92represent p-tolyl and Y9represents CH.

11. Heterocyclic compound of claim 10 or its salt, where in the formula (1z) substituents correspond to the following cases:

R91and R92are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9and Z9match any of the following cases (1) and (2):

(1) Y9represents N, and Z9represents N or CH and

(2) Y9represents N→O, and Z9represents CH, And9represents NR97and R97represents hydrogen, alkyl or cycloalkyl,

D9is alkylen, E.9represents a simple bond,

G9represents O, S, SO, SO2,

R93and R94are the same or different, and each present is employed, a hydrogen or alkyl, and

Q9represents carboxy, alkoxycarbonyl, tetrazolyl or a group represented by the formula (22z), R910represents amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, pyrrolidine, morpholine and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

12. Heterocyclic compound of claim 10 or its salt, where in the formula (1z) R91and R92are the same or different, and each represents optionally substituted phenyl and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9represents N,

Z9represents CH,

And9represents NR97and R97represents hydrogen or alkyl,

D9is alkylen,

E9represents a simple bond,

G9represents Oh,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy, tetrazolyl or a group represented by the formula (22z), R910is the th amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted phenyl, optionally substituted, aryloxy or optionally substituted thienyl, pyrrolidine, morpholine, and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

13. Heterocyclic compound of claim 10 or its salt, where R31and R92are the same or different, and each represents optionally substituted phenyl, and the substituents are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl and alkoxy,

Y9represents N, and Z9represents CH,

And9represents NR97and R97represents alkyl,

D9is alkylen,

E9represents a simple bond,

G9represents Oh,

R93and R94are the same or different and each represents hydrogen or alkyl,

Q9represents carboxy or a group represented by the formula (22z), R910represents amino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted f the Nile, optionally substituted, aryloxy or optionally substituted thienyl, pyrrolidine, morpholine and the substituents of the alkyl, aryl, aryloxy or heterocyclic groups are the same or different, and from 1 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy.

14. Heterocyclic compound of claim 10 or its salt, where the heterocyclic compound is selected from the following compounds (1) to (32):

(1) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-methylamino]butylochki} acetic acid,

(2) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]butylochki}acetic acid,

(3) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetic acid,

(4) 2-{4-[N-(5,6-di-p-tollerson-2-yl)-N-isopropylamino]butylochki}acetic acid,

(5) 1-oxide, 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazin,

(6) 2-{4-[N-(4,5-di-p-tolylboronic-2-yl)-N-methylamino]butylochki}acetic acid,

(7) 7-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]heptane acid,

(8) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylthio}acetic acid,

(9) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-methylamino]-(Z)-2-butene-1-yloxy} acetic acid,

(10) 2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazine-3-yl)-N-isopropylamino]butylochki}acetic acid,

(11) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-ethylamino]butyl) - Rev. XI}acetic acid,

(12) 2-{4-[N-(2,3-diphenylpyridine-6-yl)-N-methylamino]butylochki}acetic acid,

(13) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylsulfonyl}acetic acid,

(14) 2-{4-[N-(5,6-diphenyl-1,2,4-triazine-3-yl)-N-methylamino]butylochki}acetic acid,

(15) 2-{4-[N-(4,5-diphenylpyridine-2-yl)-N-methylamino]butylochki}acetic acid,

(16) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(p-toluensulfonyl)ndimethylacetamide,

(17) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(isopropylphenyl)ndimethylacetamide,

(18) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(trifloromethyl)ndimethylacetamide,

(19) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(o-toluensulfonyl)ndimethylacetamide,

(20) N-(benzazolyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(21) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(22) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-methoxybenzenesulfonyl)ndimethylacetamide,

(23) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(4-permentantly)ndimethylacetamide,

(24) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(2-thiophenesulfonyl)ndimethylacetamide,

(25) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isoprop the laminitis]butylochki}ndimethylacetamide,

(26) N-(N,N-dimethylaminomethyl)-2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}ndimethylacetamide,

(27) 2-{4-N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(morpholine-4-ylsulphonyl)ndimethylacetamide,

(28) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(pyrrolidin-1-ylsulphonyl)ndimethylacetamide,

(29) phenyl ester N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(30) N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl]sulfamic acid,

(31) sodium salt of N-[2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}acetyl] sulfamic acid, and

(32) 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butylochki}-N-(methylsulphonyl)ndimethylacetamide.

15. Therapeutic agent for pulmonary hypertension, including a heterocyclic compound according to any one of claims 1 to 5, or its salt as an active ingredient.



 

Same patents:

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine of the following general formulae: (IA)

and (IB) wherein R1 means and , or -NH(CH2)2OH, -NR3C(O)CH3 or -NR3C(O)-cyclopropyl; R2 means methyl or chlorine atom; R3 means hydrogen atom or methyl; R means hydrogen atom or -(CH2)2OH; n = 1 or 2, and their pharmaceutically acceptable acid-additive salts. Also, invention describes a medicinal agent possessing effect of agonist of NK-1 receptors based on these compounds. Proposed compounds show good affinity degree to NK-1 receptors and can be used in treatment or prophylaxis of diseases associated with these receptors.

EFFECT: valuable medicinal properties of compounds and agent.

10 cl, 1 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes using compound of the general formula (I): wherein R1 means hydrogen atom or radical -X-Y-R4 wherein -X-Y- means a bond, radical -CO-O-, -CO-NH- or -CS-NH-; R4 means alkyl, cycloalkyl or aralkyl; R2 means aryl possibly substituted 4 times with halogen atom, alkyl, alkoxyl or aryl; R3 means hydrogen atom, or a pharmaceutically acceptable salt for preparing a medicinal agent designated for effect as a modulator of sodium channels. Also, invention describes a medicinal agent and pharmaceutical composition comprising compound of the formula (I)M given in the invention description as an active component. Modulators of sodium channels are used in therapy for withdrawal or prophylaxis of pain, migraine, post-operative pains, in epilepsy treatment and in other cases.

EFFECT: valuable medicinal properties of compounds.

13 cl, 26 ex

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

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

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

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of benzimidazole of general formulae (IV)

and

For compounds of the formula (IV): R represents hydrogen atom, (C1-C10)-alkyl and others; D represents phenyl or azaphenyl; n = 0; A, B and Q represent hydrogen atom, (C1-C10)-alkyl and others; Z represents a bond, (C1-C6)-alkylene or -CH2O-; R1 represents hydrogen atom, (C1-C10)-alkyl and others; R2 represents hydrogen atom. For compounds of the formula (IVA): n = 0; Z represents a bond, -CH2-, -CH2O-, -CH2CH2-; R represents hydrogen atom or (C1-C10)-alkyl; R1 represents hydrogen atom, (C3-C12)-cycloalkyl, benzyl and others; R2 represents hydrogen atom. Compounds of formulae (IV) and (IVA) possess affinity with respect to nociceptin and μ-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

18 cl, 5 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to derivatives of 1,2-dihydropyridine of the general formula (I)

,

their salts or hydrates wherein Q means oxygen atom (O); R1, R2, R3, R4 and R5 are similar or different of one another and each radical means hydrogen atom, halogen atom, (C1-C6)-alkyl group or group represented by the formula: -X-A (wherein X means a simple bond, (C1-C6)-alkylene group); A means (C6-C14)-aromatic hydrocarbocyclic group or 5-14-membered aromatic heterocyclic group. Also, invention describes a method for preparing compounds and pharmaceutical composition. Compounds possess the strong inhibitory effect on AMPA receptors and/or kainate receptors.

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

99 cl, 1 tbl, 414 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

Ionic liquids ii // 2272043

FIELD: organic chemistry.

SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.

EFFECT: improved and valuable properties of ionic liquids.

3 ex

FIELD: organic chemistry, agriculture and veterinary.

SUBSTANCE: invention relates to triazine derivatives of formula I

wherein R1 is thienyl substituted with phenyl substituted with C1-C6-haloalkyl or C1-C6-haloalkoxy; or phenyl optionally substituted with one or two halogen, C1-C6-alkyl, C1-C6-haloalkoxy, substituted C2-C6-alkenyl, etc; or unsubstituted or monosubstituted phenoxy, wherein substituent is selected from group containing halogen, C1-C6-alkyl, C1-C6-haloalkyl or C1-C6-haloalkoxy; R2 is hydrogen or optionally substituted C1-C6-alkyl, wherein substituent is selected from group containing NO2 and C1-C6-alkylthio; A is direct bond; R5 is C1-C6-alkyl; R6 is hydrogen, C1-C6-alkyl or -C(=O)-R5; X1 is halogen and C1-C6-alkyl; X2 and X3 independently hydrogen, halogen and C1-C6-alkyl; with the proviso, that radical A-R1 and phenyl group are not in vicinal position relatively to one another in triazine ring; X1 is not Cl or F when X2 and X3 are hydrogen and R1 is phenyl, 2-fluorophenyl, p-fluorophenyl or 3-chlorophenyl. Also disclosed are composition containing compound of formula I as active ingredient and method for controlling of pests and ticks. Said method includes treating of pests and ticks or occupation places thereof with compound of formula I.

EFFECT: compounds and compositions with high controlling activity in regard to parasites on plants and warm-blooded animals.

5 cl, 9 tbl, 9 ex

The invention relates to the field of chemistry of heterocyclic compounds, namely the derivative of 1,2,4-triazinones with astragalina and herbicide activities that can be used in agriculture

The invention relates to new compounds of the formula (I), where R0- phenyl, R1- phenyl, heteroaryl, lower alkyl which may be substituted or unsubstituted, R2substituted or unsubstituted phenyl, lower alkyl, R3is hydrogen, acyl group, sulfonylurea group, X and Y independently represent a nitrogen atom or a carbon atom, Z is methylene group

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

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