Triazine compounds, method of their production, pharmaceutical compositions on their basis, the method of treatment and intermediate substances

 

(57) Abstract:

The invention relates to new triazinyl compounds of formulas Ia and Ib:

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or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment. Compounds of formulas Ia and Ib have anti-inflammatory activity and may find application in medicine. The invention relates also to pharmaceutical compositions, methods of obtaining new compounds, methods of treatment of inflammatory diseases and intermediate substances. 5 c. and 2 C.p. f-crystals, 1 table.

The invention relates to triazinyl compounds, in particular biphenylamine, biphenylmethanol and biphenyldicarboxylic compounds, to processes for their preparation, to their use as medicaments and to their containing pharmaceutical compositions.

In particular, the invention relates to (4-hydroxy-3-(aryl)phenyl)azaelea soedinenii or (4-hydroxy-3-(aryl)phenyl) what if, intended for use as a drug, for example, for the treatment or prevention of inflammatory diseases, in particular inflammatory or obstructive diseases of the Airways such as asthma.

Hereinafter, the invention features a pharmaceutical composition containing (4-hydroxy-3-(aryl)phenyl)aziridine connection or (4-hydroxy-3-(aryl)phenyl) arylcarboxamide in free form or in the form of a pharmaceutically acceptable acid salt additive, for example, in combination with a pharmaceutically acceptable diluent or carrier.

In addition, according to the invention features the use of (4-hydroxy-3-(aryl)phenyl)sariling connection or (4-hydroxy-3-(aryl)phenyl)arylcarboxamide in free form or in the form of a pharmaceutically acceptable acid salt additive in the manufacture of medicaments for the treatment or prevention of inflammatory diseases, in particular inflammatory or obstructive diseases of the Airways such as asthma.

According to the invention it is also proposed a method for the treatment or prevention of inflammatory diseases, in particular inflammatory or obstructive diseases of the respiratory tract (4-hydroxy-3-(aryl)phenyl)arylcarboxamide in free form or in the form of a pharmaceutically acceptable acid salt additive to the patient, requiring such therapy.

(4-hydroxy-3-(aryl)phenyl)azaelia connection or (4-hydroxy-3-(aryl)phenyl)arylcarboxamide according to the invention and their pharmaceutically acceptable form in the form of an acid additive salt later in the description briefly designated as "agents of the invention". In these compounds, 4-hydroxy-fragment refers to (optionally fluoro-substituted)alkoxygroup, for example (fluorescent0-3- )1-C4alkoxygroup, for example methyl, ethyl, deformity or trifluoromethyl, 3-aryl fragment denotes a mono - or bicyclic fragment having at least one aromatic ring, such as azaril, for example pyridyl,1-C4alkylpyridine or chinoline; aromatic 2,5-cyclohexadiene-3,4-ridin-1-yl, for example benzofurazanyl or benzofuranyl; or phenyl, preferably appropriately substituted, for example, meta and/or para-substituted (I) one or two substituents selected from the group comprising nitro, carbarnoyl, halogen (for example chloro), trifluoromethyl, alkoxy (for example, C1-C4alkoxy), dialkoxy (for example, tios1-C4alkoxy), alkylsulfate (for example, C1-C4alkylsulfate), alkylsulfonyl (for example, C1-C4

The agents according to the invention include compounds that are well known, but for which the pharmaceutical activity was not described or not anticipated. So, for example, Jin and others (Macromol. Symp. (1995), 96 [International Conference on Liquid Crystal Polymers 1994], 125-134) described methyl-4'-methoxy-3'-vinylbiphenyl-4-carboxylate is starecheski materials in the form of complex sobolifera. The Buu-Hoi and others (J. Org. Chem. 21, [1956] , 136-138) describes how to obtain 2-(6-methoxybiphenyl-3-yl)quinoline and its analogues, optionally substituted in the quinoline ring stands or phenyl in position 3 and/or carboxypropyl in position 4 and described (J. Org. Chem. 2, [1964], 762-763) obtaining 2-(6,2'-dimethoxybiphenyl-3-yl)quinoline and its analogues, optionally substituted in the quinoline ring stands in position 3 and/or carboxypropyl in position 4. The Buu-Hoi and co-authors have not observed any practical value and the activity of these quinoline compounds. In the Belgian patent 652320 on the name of the company Du Font described by receiving 5-(6-methoxybiphenyl-3-yl)-2-methylthiazole as an intermediate product upon receipt 5,5'-diphenyldichlorosilane of sensitizers emulsions of silver halide for use in the field of photography.

Thus, the invention relates to (4-hydroxy-3-(aryl) phenyl)azaelea connection or (4-hydroxy-3-(aryl)phenyl)arylcarboxamide, for example, in which fragments of the 4-hydroxy, 3-aryl, Azarel, arylcarboxylic have the above values, provided

that 3-aryl fragment does not denote an unsubstituted phenyl when a piece of arylcarboxylic denotes phenyl-4-carboxylic acid or phenyl-4-METI fragment does not denote an unsubstituted phenyl or 2-methoxide-1-yl, when

sarily fragment denotes unsubstituted 2-quinoline or 2-quinoline, substituted stands or phenyl in position 3 and/or carboxypropyl in position 4,

or their pharmaceutically acceptable acid additive salts.

New connections specified in this part of the invention, intended to qualify as "agents of the invention".

The agents according to the invention may be in free form or in the form of a pharmaceutically acceptable acid salt additive. Pharmaceutically active acid additive salts for use according to the invention include, for example, hydrochloride, oxalates and fumarate.

In particular, the invention relates to an agent according to the invention, a 4-(hydroxy)-3-[phenyl-(or 2,5-cyclohexadiene-3,4-ridin-1-yl)]phenylethenyl or 4-(hydroxy)-3-[phenyl-(or 2,5-cyclohexadiene-3,4-ridin-1-yl)]generallyconsidered in free form or in the form of a pharmaceutically acceptable acid salt additive. Optional 3-phenyl fragment is substituted, for example 3 - or 4-substituted. 2,5-Cyclohexadiene-3,4-ridin-1-ilen fragment preferably is a 2,5-cyclohexadiene-3,4-N-ridin-1-ilen fragment, preferably aromatic. Predpodtitelno denotes pyridine, for example, 4-pyridine, imidazopyridine, for example 6-imidazo[1,2-a]pyridine, or benzamid, for example 3 - or 4-benzamide. Preferably arylcarboxylic fragment represents phenylcarbene, for example phenyl-3 - or-4-carboxy. For example, the agents according to the invention include [2-(C1-C4alkoxy)biphenyl-5-yl]pyridine, [2-(C1-C4alkoxy)biphenyl-5-yl] benzamide or [2-(C1-C4alkoxy)biphenyl-5-yl] phenylcarbamate, and biphenylyl fragment is an optional 3'- and/or 4,substituted or optional 3',4'-fused aromatic ring, preferably a compound of formula Ia or formula Ib:

< / BR>
< / BR>
where in the formula la W represents N or C-CO-R, where R is a HE, O-C1-C6alkyl or NR3R4where R3and R4that may be the same or different values, denote H or C1-C6alkyl, or

in the formula Ib Az denotes azzarello group containing one or more nitrogen atoms, such as quinoline, athineon, indole, imidazopyridine, for example, imidazo[1,2-a]pyridine,

and in both formulas Ia and Ib R1stands WITH1-C4alkyl, preferably methyl; R2denotes phenyl fragment, e.g. the er, chloro), trifluoromethyl, C1-C4alkoxy, cyano or phenoxy or R5and R6together form a bridge having a length of 3-5 atoms, where the atoms of the bridge are selected from the group comprising S, O, N and S, for example-och2O-, or propylene; or R2denotes a 2,5-cyclohexadiene-3,4-ridin-1 silt fragment, for example, of formula III:

< / BR>
where R7and R8together form an aromatic bridge, having a length of 3-5 atoms, where the atoms of the bridge are selected from the group comprising S, O, N and S, for example, =N-O-N=;

in free form or in the form of a pharmaceutically acceptable acid additive salt.

Most preferably R2selected from the group comprising 3-nitrophenyl, 3-(trifluoromethyl)phenyl, 3-tianfeng, 3 - or 3,4-haloethanol (for example, 3-chlorophenyl or 3-chloro-4-forfinal), indan-5-yl, benzofuran-5-yl and 1,3-benzo[d]dioxolane-5-yl.

Thus, the compounds of formula I include:

1. 4-[2-(methoxy)biphenyl-5-yl]pyridine,

2. 4-[2(methoxy) -3'-(nitro) - biphenyl-5-yl]pyridine,

3. 4-[2(methoxy) -3'-(trifluoromethyl)biphenyl-5-yl]pyridine,

4. 4-[2-(methoxy)-3',4'-(propylene) - biphenyl]pyridine,

5. 4-[4-(methoxy)-3-(benzofurazan-5-yl)phenyl]pyridine,

6. 4-[2-(methoxy)-3'-(cyan)biphenyl-5-yl]pyridine,

7. 4-[2-(methoxy)-3'(chlorine) is a biphenyl-5-yl]pyridine,

10. 4-[2-(methoxy)-4'-(phenoxy)biphenyl-5-yl]pyridine,

11. 4-[2-(methoxy)-3'-(chloro)'-4'-(fluoro)biphenyl-5-yl] pyridine,

12. 4'-methoxy-3'-(benzofurazan-5-yl)[1,1'-biphenyl]-4-carboxamid,

13. ethyl ester of 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl]-4-carboxylic acid,

14. ethyl ester of 4'-methoxy-3',-(3-nitrophenyl)[1,1,-biphenyl]-3-carboxylic acid,

15. ethyl ester of 4'-methoxy-3-methyl-3'-(3-nitrophenyl) [1,1,-biphenyl]-4-carboxylic acid,

16. ethyl ester of 3'-(5-benzofurazanyl)-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid,

17. 2,2-dimethylpropionic ether 3'-(5-benzofurazanyl)-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid,

18. 3'-(5-benzofurazanyl)-4'-methoxy[1,1'-biphenyl]-4-carboxylic acid,

19. 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl]-3-carboxylic acid

20. 4'-methoxy-3-methyl-3'-(3-nitrophenyl)[1,1'-biphenyl] -4-carboxylic acid,

21. 3'-(5-benzofurazanyl)-4'-methoxy [1,1'-biphenyl] -4-carboxylic acid,

22. 4'-methoxy-3'-(3-chlorophenyl)[1,1'-biphenyl]-4-carboxylic acid,

23. 4'-methoxy-3'-(3-tianfeng)[1,1,-biphenyl]-4-carboxylic acid,

24. 4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl]-4-carboxamid,

25. 4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl]-3-carboxamid,

26. 4'-methoxime,

28. 6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a] pyridine in free form or in the form of a pharmaceutically acceptable acid additive salts, such as hydrochloride.

The compounds of formula I are preferably obtained by interaction of the compounds of formula I,a or formula I,b:

< / BR>
< / BR>
where X denotes a halogen (preferably bromine) or a leaving group, such as tin or boron-containing group (preferably- (OH)2), a R1, W and Z have the meanings stated for formula Ia and Ib, with acceptable activated aryl, such as arylalkenes, or arylboronic acid, for example, with the compound of the formula IIA or IIIa:

< / BR>
< / BR>
where Y denotes a halogen (preferably bromine) or a leaving group, such as tin or boron-containing group (preferably- (OH)2), and R-groups have the meanings indicated for formula II and III;

and allocation of the resulting compounds according to the invention, for example, of formula Ia or Ib in free form or in the form of an acid additive salt. Preferably one of the radicals X or Y denotes a halogen, for example bromine, and the other denotes a leaving group, such as-B(OH)2. Acceptable reaction conditions may include conducting the in (preferably three-ortho-tolylphosphino or three 2-furifosmin), base, such as sodium carbonate, in a solvent such as toluene, acetonitrile or DMF), and/or a suitable catalyst such as palladium-based catalyst. The reaction should be carried out in the temperature range from ambient temperature to the boiling point of the solvent, for example from 20 to 150oWith, preferably 70-90oC.

New intermediate products, primarily formulas I,a and I,b, fall under the scope of the invention. Compounds of formula I,a and I,b can be obtained by the reaction of a combination type of Suzuki reaction or Steele, for example, between the derivative 4-alkoxyamino acid and appropriately substituted ganodermataceae system, or alternatively can be obtained from 4-kalaidjian and the corresponding Grignard reagent, for example, the interaction of 4-bromopyridine with the compound of the formula R1O-C6H4-MgBr, where R1has the above meanings, in the presence of an appropriate catalyst, for example Nickel catalyst, to obtain 4-arylpyrimidine, which is then halogenous, for example, interaction with Br2obtaining the compounds of formula I,and or I,b, where X denotes halogenation with alkyllithium, for example, butyllithium, with subsequent interaction with alkylboron, for example triethylborane, obtaining the compounds of formula I,and or I,b, in which X represents-B(OH)2. The compounds of formula IIA or IIIa can be obtained similarly by halogenation of aryl, for example by synthesized, optionally with subsequent replacement of the halogen on the leaving group, such as-B(OH)2.

Example 1: 4-[2-(methoxy)biphenyl-5-yl]pyridine

a) 4-(4-methoxyphenyl)pyridine

The solution containing bromide 4-methoxybenzylamine obtained from 4-bromoanisole (150 g to 0.80 mole) and magnesium (20 g, or 0.83 mol) in anhydrous tetrahydrofuran (300 ml), filtered, cooled to -10oWith and carefully add to the mix a mixture containing chloride bis(triphenylphosphine)Nickel(II) (1.5 g, 2.25 mmole) and the hydrochloride of 4-bromopyridine (65 g, 0,334 mol) in anhydrous tetragidrofurane (300 ml), with 10oC in argon atmosphere. After adding 50% of the Grignard reagent is an intense exothermic reaction and the temperature of the mixture maintained within the range of 50-60oWith during the entire subsequent process of adding, using a cooling bath of ice-methanol. Upon completion of the addition the mixture is stirred taymouth methyl tert-butyl ether (500 ml) and extracted with 5 M hydrochloric acid (g ml). The combined extracts washed with methyl tert-butyl ether), alkalinized (aqueous NaOH) and extracted with methyl tert-butyl ether (4x300 ml). The combined extracts are dried (Na2SO4) and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from methyl tert-butyl ether-cyclohexane, receiving 4-(4-methoxyphenyl)pyridine as a colorless crystalline solid, tPL94-96oC.

b) 4-(3-bromo-4-methoxyphenyl)pyridine

Bromine (26,0 g, 163 mmole) is added to a stirred solution of 4-(4-methoxyphenyl)pyridine (13,6 g of 73.5 mmole) in acetic acid (500 ml) and incubated at 60oC for 72 h the mixture is Then evaporated to dryness under reduced pressure, the residue is treated with an aqueous ammonia (400 ml, 6 M) and extracted with ethyl acetate (CH ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 95% methyl tert-butyl ether/4.5% methanol/0.5% aqueous NH3(25%) and recrystallized from simple ether-cyclohexane, receiving 4-(3-bromo-4-methoxyphenyl)pyridine as a pale BR> A mixture containing 4-(3-bromo-4-methoxyphenyl)pyridine (1,32 g, 5 mmol), phenylboronic acid (to 0.67 g, 5.5 mmole), tri-ortho-tolylphosphino (0.152 g, and 0.50 mmole), palladium(II) acetate (0,056 g, 0.25 mmole), sodium carbonate (1.06 g, 10 mmol) and water (10 ml) in dimethylformamide (20 ml), kept under stirring at 80oC for 3 hours the mixture is Then treated with water (100 ml) and extracted with ethyl acetate (CH ml). The combined extracts are washed (saturated NaCI solution), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 98% ethyl acetate/1,8% ethanol/0.2% aqueous NH3(25%)) to give 4-[4-methoxy-3-(phenyl)phenyl] pyridine base. The base was dissolved in diethyl ether (5 ml), treated with methanolic solution of Hcl (excess), evaporated to dryness under reduced pressure and recrystallized from isopropanol-diethyl ether, receiving hydrochloride 4-[2-(methoxy)-(1,1-biphenyl)-5-yl]pyridine as a pale yellow crystalline solid, tPL180-200oWith that has the following physical specifications:

1H-NMR ( DMSO-d6): the 3.89 (s, 3H), 7,35 (d, J=8.7 Hz, 1H), 7,39 (d, J=7.2 Hz, 1H), 7,45 (dd, J=7,1 Hz, J=7,2 Hz, which measures 2: 4-[2-(methoxy)-3'-(nitro) - biphenyl-5-yl]pyridine

This connection get analogously to example 1, using 3-(nitro)phenylboronic acid instead of phenylboronic acid, getting mentioned in the title compound, tPL145-150oC.

Example 3: 4-[2-(methoxy)-3'-(trifluoromethyl)biphenyl-5-yl]pyridine

This connection get analogously to example 1, using 3-(trifluoromethyl)phenylboronic acid instead of phenylboronic acid, getting mentioned in the title compound as hydrochloride, tPL103-106oC.

Example 4: 4-[2-(methoxy)-3',4'-(propylene) - biphenyl]pyridine

a) Indan-5-baronova acid

A solution of n-utility in hexane (13,2 ml, 1.6 M, 21 mmol) is added to a stirred solution of 5-bromoindene (1.06 g, 4 mmole) in anhydrous tetrahydrofuran (30 ml) at -75oC in argon atmosphere. The mixture is stirred for 30 min at -65oC, then treated with triethylborane (of 3.07 g, 21 mmol) and stirred for 60 min at -50oC. the Resulting mixture was allowed to warm to 0oC, and then treated with saturated aqueous ammonium chloride (60 ml) and extracted with ethyl acetate (CH ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, getting neocidin soviat from ethyl acetate-hexane, getting indan-5-Bronevoy acid as a colourless crystalline solid.

b) 4-[2-(methoxy)-3',4'-(propylene) - biphenyl]pyridine

According to the method described in example 1B, but using indan-5-Bronevoy acid instead of phenylboronic acid get crude product, which was purified using chromatography (silica gel, 98% ethyl acetate/1,8% ethanol/0.2% aqueous NH3(25%)) to give 4-[2-(methoxy)-3',4'-(propylene) - biphenyl] pyridine base. The base is dissolved in acetone (5 ml), treated with methanolic solution of Hcl (excess), evaporated to dryness under reduced pressure and recrystallized from isopropanol-simple broadcast receiving hydrochloride 4-[2-(methoxy)-3',4'-(propylene) - biphenyl]pyridine as a pale yellow crystalline solid, tPL185-205oWith that has the following physical specifications:

1H-NMR ( DMSO-d6): to 2.06 (m, 2H), 2.91 in (m, 4H), of 3.07 (s, 3H), 7,27-to 7.32 (m, 2H), 7,33 (d, J=8.7 Hz, 1H), 7,41 (s, 1H), to 7.93 (d, J=2.5 Hz, 1H), 8,07 (dd, J= 8.7 Hz, J=2.5 Hz, 1H), 8,42 (d, J=6.0 Hz, 2H) and 8,86 (d, J=6.0 Hz, 2H).

Example 5: 4-[4-(methoxy)-3-(5-benzofurazanyl)phenyl] pyridine

a) (5-benzofurazanyl)baronova acid

According to the method described in example 4A, but using 5-bromobenzophenone, receiving (5-benzofurazanyl)baronova acid in the form of a crystalline solid beige color, tPL> 300oC, which has the following physical specifications:

1H-NMR ( DMSO-d6+D2O): 3,66 (s, 3H), to 7.84 (d, J=9.1 Hz, 1H), 7,95 (d, J=9.1 Hz, 1H) and of 8.37 (s, 1H).

b) 4-[4-methoxy-3-(5-benzofurazanyl)phenyl]pyridine

According to the method described in example 1B, but using (5-benzofurazanyl)Bronevoy acid instead of phenylboronic acid get crude product, which was purified using chromatography (silica gel, 98% ethyl acetate/1,8% ethanol/0.2% aqueous NH3(25%), and after recrystallization from etelaat-hexane receive 4-[4-methoxy-3-(5-benzofurazanyl)phenyl]pyridine in the form of a crystalline solid beige color, tPL187-192oC.

Example 6: 4-[2-(methoxy)-3'-cyan(1,1,-biphenyl)-5-yl]pyridine

a) 2-Methoxy-5-(4-pyridinyl)phenylboronic acid

A solution of n-utility in hexane (1.7 ml, 2.5 M, 4.25 mmole) is added to a stirred solution containing 4-(3-bromo-4-methoxyphenyl)pyridine (Example 1B; 1.06 g, 4 mmole) and triethylborane (0,62 g, 4.2 mmole) in anhydrous tetrahydrofuran (20 ml) at -85oC in argon atmosphere. The mixture is stirred for 15 min the atom (h ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from ethyl acetate-hexane, obtaining 2-methoxy-5-(pyridin-4-yl)phenylboronic acid in the form of a crystalline solid beige color, tPL194-200oWith that has the following physical specifications:

1H-NMR ( DMSO-d6): 3,88 (s, 3H), 7,13 (d, J=8.7 Hz, 1H), 7,68 (d, J=6,1 Hz, 2H), 7,88 (s, 1H), a 7.85 (dd, J=8.7 Hz, J=2.4 Hz, 1H), of 7.97 (d, J=2.4 Hz, 1H) and at 8.60 (d, J=6,1 Hz, 2H).

b) 4-[2-(methoxy)-3,-cyan(biphenyl)-5-yl]pyridine

A mixture containing 3-bromobenzonitrile (of 0.91 g, 5.0 mmol), 2-methoxy-5-(4-pyridinyl)phenylboronic acid (0.50 g, 2.3 mmole), tri-ortho-tolylphosphino (0.152 g, and 0.50 mmole), palladium(II) acetate (0,056 g, 0.25 mmole), sodium carbonate (1,59 g, 15 mmol) and water (15 ml) in dimethylformamide (46 ml), kept under stirring at 80oC for 5 hours the mixture is Then treated with water (100 ml) and extracted with ethyl acetate (CH ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, ethyl acetate) to obtain 4-[4-m methanolic solution of Hcl (excess), evaporated to dryness under reduced pressure and recrystallized from ethanol-simple broadcast receiving hydrochloride 4-12-(methoxy)-3'-cyan(biphenyl)-5-yl] pyridine as a pale yellow crystalline solid, tPL142-150oC.

These compounds have a similar way, using the appropriate approach formulated above.

Example 7: Hydrochloride 4-[2-(methoxy)-3'-(chloro) - biphenyl-5-yl]pyridine, tPL156-210oC.

Example 8: 4-[2-(methoxy)-3',4'-(methylenedioxy)biphenyl-5-yl]pyridine, tPL168-171oC.

Example 9: Hydrochloride 4-[2-(methoxy)-3'-(phenoxy)biphenyl-5-yl] pyridine, tPL184-204oC.

Example 10: Hydrochloride 4-[2-(methoxy)-4'-(phenoxy)biphenyl-5-yl]pyridine, tPL173-218oC.

Example 11: Hydrochloride 4-[2-(methoxy)-3'-(chloro)-4'-(fluoro)biphenyl-5-yl] pyridine, tPL115oC.

The compounds of formula I containing benzamide or phenolcarboxylic instead of pyridyl get the same way.

Example 12: 4'-methoxy-3'-(benzofurazan-5-yl)[1,1,-biphenyl]-4-carboxamid

a) Ethyl ester of 4'-methoxy[1,1,-biphenyl]-4-carboxylic acid

A mixture containing ethyl ester 4-bromobenzoyl acid (23,6 g, 103 mmole), 4-detoxicated cesium (30.0 g, 200 mmol) in 1,2-dimethoxyethane (300 ml), kept under stirring at 85oC for 3 hours the mixture is Then treated with water (500 ml) and extracted with ethyl acetate (CH ml). The combined extracts are washed (saturated NaCI solution), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 5% ethyl acetate/95% cyclohexane) to give ethyl ester of 4'-methoxy[1,1,-biphenyl]-4-carboxylic acid as a colourless crystalline solid, tPL103-104oC.

These compounds have a similar way, using the corresponding esters of brombenzene acid and arylboronic acid:

ethyl ester of 4'-methoxy[1,1,-biphenyl]-3-carboxylic acid,

ethyl ester of 4'-methoxy-3-methyl[1,1,-biphenyl]-3-carboxylic acid.

b) Ethyl ester of 3,-bromo-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid

A solution of bromine (14.6 g, 91,3 mmole) in carbon tetrachloride (100 ml) is added to a stirred mixture of ethyl ether 4'-methoxy[1,1,-biphenyl]-4-carboxylic acid (23,4 g, 91,3 mmole) and silica gel (100 g particle size 0,040-0,063 mm; Merck 1.093 its the silica gel was removed by filtration. The filtrate is washed with aqueous sodium bicarbonate solution (200 ml, 1 M), and then aqueous sodium thiosulfate solution (50 ml, 2 M), dried (Na2SO4), filtered and evaporated to dryness under reduced pressure, obtaining the crude product which is recrystallized from simple ether-cyclohexane, obtaining the ethyl ester of 3'-bromo-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid as a colourless crystalline solid, tPL114-115oC.

These compounds have a similar way, using the corresponding esters:

ethyl ester of 3'-bromo-4'-methoxy[1,1,-biphenyl]-3-carboxylic acid, tPL88-90oWITH,

ethyl ester of 3'-bromo-4'-methoxy-3-methyl[1,1'-biphenyl] -4-carboxylic acid, tPL84-87oC.

in) 3,-Bromo-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid

A mixture containing ethyl ester of 3'-bromo-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid (28.8 g, 86 mmol) and aqueous sodium hydroxide solution (35 ml, 2 M) in ethanol (690 ml), kept under stirring at 90oC for 2 h Then cooled mixture is acidified with hydrochloric acid (200 ml, 1 M) and the resulting precipitate filtered and dried, obtaining 3'-bromo-4'-methoxy[1,1 is profilemy ether 3,-bromo-4,-methoxy[1,1'-biphenyl]-4-carboxylic acid

A mixture containing 3'-bromo-4'-methoxy[1,1,-biphenyl]-4-carboxylic acid (19.2 g, 62.5 mmole) and dimethylformamide (0.1 ml) in toluene (200 ml), treated with stirring at 20oWith oxalylamino (11,0 ml, 126 mmol). The mixture is then incubated at 50oC for 1 h, then evaporated to dryness under reduced pressure. The resulting crude acid chloride is dissolved in anhydrous tetrahydrofuran (250 ml) and added dropwise to a stirred solution of tert-butyl lithium in tetrahydrofuran (obtained by slow addition of 32.5 ml of n-utillity to the solution containing 23,5 ml of anhydrous tert-butanol in 200 ml of anhydrous tetrahydrofuran at 20oC). The mixture is stirred for a further 2 h, then treated with saturated aqueous ammonium chloride (400 ml) and extracted with ethyl tert-butyl ether (CH ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 20% ethyl acetate in cyclohexane) and recrystallized from ethyl tert-butyl ether-hexane, obtaining 2,2-dimethylpropyl the STV.

d) 4-(3-Bromo-4-methoxyphenyl)benzamide

According to the method described in example 1B, but using 4-(4-methoxyphenyl)benzamide instead of 4-(4-methoxyphenyl)pyridine receive a 4-(3-bromo-4-methoxyphenyl)benzamide in the form of a crystalline solid beige color, tPL246-250oC.

e) 4'-Methoxy-3'-(benzofurazan-5-yl)[1,1,-biphenyl]-4-carboxamid

According to the method described in example 5B, but using 4-(3-bromo-4-methoxyphenyl)benzamide instead of 4-(3-bromo-4-methoxyphenyl)pyridine get the crude product, which was purified using chromatography (silica gel, ethyl acetate) and recrystallized from ethanol-ethyl acetate, getting mentioned in the title compound in the form of a crystalline solid beige color, tPL235-255oC.

Example 13: Ethyl ester of 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl]-4-carboxylic acid

A mixture containing ethyl ester of 3'-bromo-4'-methoxy[1,1'-biphenyl]-4-carboxylic acid (26,6 g, 79,3 mmole), 3-nitrophenylarsonic acid (21.2 g, 127 mmol), tri-ortho-tolylphosphino (of 2.51 g, compared to 8.26 mmole), palladium(II) acetate (0,91 g of 4.05 mmole), potassium carbonate (21,9 g, 159 mmol) and water (100 ml) in dimethylformamide (400 ml), stand under stirring at 60oWith the tech who shat (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 10% ethyl acetate in cyclohexane) to give ethyl ester of 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl] -4-carboxylic acid as a colourless crystalline solid, tPL106-108oC.

These compounds have a similar way, using the corresponding esters of brombenzene acid and arylboronic acid.

Example 14: Ethyl ester of 4'-methoxy-3'-(3-nitrophenyl) [1,1'-biphenyl]-3-carboxylic acid, tPL87-89oC.

Example 15: Ethyl ester of 4'-methoxy-3-methyl-3'-(3-nitrophenyl)[1,1,-biphenyl]-4-carboxylic acid, tPL88-90oC.

Example 16: Ethyl ester of 3'-(5-benzofurazanyl)-4'-methoxy[1,1,-biphenyl] -4-carboxylic acid, tPL166-168oC.

Example 17: 2,2-Dimethylpropionic ether 3'-(5-eovpaa)-4'-methoxy[1,1'-biphenyl]-4-carboxylic acid, tPL131-136oC.

Example 18: 3'-(5-eovpaa)-4'-methoxy[1,1'-biphenyl]-4-carboxylic acid

A mixture containing ethyl ester of 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl] -4-carboxylic acid (1.88 g, 5 mo for 3 hours Then the cooled mixture is acidified with hydrochloric acid (100 ml, 1 M) and the resulting precipitate filtered and dried, obtaining 3'-(5-benzofurazanyl)-4'-methoxy[1,1,-biphenyl] -4-carboxylic acid as a colourless crystalline solid, tPL270-274oC.

These compounds have a similar way, using the corresponding esters.

Example 19: 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl]-3-carboxylic acid, tPL223-228oC.

Example 20: 4,-methoxy-3-methyl-3'-(3-nitrophenyl)[1,1,-biphenyl]-4-carboxylic acid, tPL278-281oC.

Example 21: 3'-(5-benzofurazanyl)-4'-methoxy[1,1,-biphenyl]-4-Kabanova acid, tPL> 300oC.

Example 22: 4'-methoxy-3'-(3-chlorophenyl)[1,1'-biphenyl]-4-carboxylic acid, tPL250-252oC.

Example 23: 4'-methoxy-3'-(3-tianfeng)[1,1,-biphenyl]-4-carboxylic acid, tPL280-285oC.

Example 24: 4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl]-4-carboxamid

A solution of trimethylaluminum in toluene (10 ml, 2 M) is added dropwise within 30 min to a stirred suspension of ammonium chloride (1.07 g, 20 mmol) in toluene (20 ml) at 5oC in argon atmosphere. The mixture is stirred oil acid (1.65 g, 4.3 mmole) in toluene (40 ml) and stirred at 60oC for 18 hours, the Cooled mixture is washed with hydrochloric acid (50 ml, 5 M), and then saturated aqueous sodium chloride (50 ml), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by crystallization from ethyl acetate-ethyl tert-butyl ether, receiving 4'-methoxy-3'-(3-nitrophenyl)[1,1,-biphenyl] -4-carboxamide in the form of a colorless crystalline solid, tPL201-205oC.

These compounds have a similar way, using the corresponding esters.

Example 25: 4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl]-3-carboxamid, tPL118-120oC.

Example 26: 4,-methoxy-3-methyl-3'-(3-nitrophenyl)[1,1'-biphenyl] -4-carboxamid, tPL179-184oC.

Example 27: N-methyl-4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl] -4-carboxamid

According to the method described in example 24, but using methylamine hydrochloride instead of ammonium chloride obtain the crude product, which was purified using chromatography (silica gel, 50% ethyl acetate in cyclohexane), and after recrystallization from tetrahydrofuran-cyclohexane on what about solids, tPL171-172oC.

Representative imidazopyridine compound was obtained as follows.

Example 28: 6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine

a) 5-(2-Hydroxyphenyl)benzofurazan

A mixture containing 5-bromobenzophenone (11,94 g, 60 mmol), 2-hydroxyphenylarsonic acid (9,10 g, 66 mmol), tri-ortho-tolylphosphino (1,82 g, 6 mmol), palladium(II) acetate (0,672 g, 3 mmole), potassium carbonate (12.4 g, 90 mmol) and water (90 ml) in dimethylformamide (180 ml), incubated with stirring at 80oC in argon atmosphere for 30 minutes the mixture is Then treated with water (300 ml) and extracted with ethyl acetate (CH ml). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 20%-100% ethyl acetate in cyclohexane), and recrystallized from ethyl acetate-hexane, obtaining 5-(2-hydroxyphenyl)benzofuran in the form of a light yellow crystalline solid, tPL166-169oC.

b) 5-(3-Bromo-6-hydroxyphenyl)benzofurazan

A mixture containing 5-(2-hydroxyphenyl)benzofurazan (11.2 g, 52,8 mmole) and tribromo the e 18 PM The solvent is evaporated under reduced pressure, obtaining a residue which is treated with water (300 ml) and extracted with ethyl acetate (CH ml). The combined extracts are washed (saturated NaCI solution), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from ethyl acetate-hexane, obtaining 5-(3-bromo-6-hydroxyphenyl)benzofuran in the form of a light yellow crystalline solid, tPL179-181oC.

C) 5-(3-Bromo-6-methoxyphenyl)benzofurazan

Stir the mixture containing 5-(3-bromo-6-hydroxyphenyl)benzofurazan (to 8.70 g, 30 mmol), potassium carbonate (14,42 g, 90 mmol) and methyliodide 30 and 2.83 ml, 45 mmol) in dimethylformamide (100 ml), incubated with stirring at 18oC for 16 hours the mixture is Then treated with water (600 ml) and extracted with ethyl acetate (CH ml). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from methyl tert-butyl ether-hexane, obtaining 5-(3-bromo-6-methoxyphenyl)benzofuran in the form of a crystal is 1,2-a]pyridine

A mixture containing 6-bromoimidazo[1,2-a]pyridine (2,36 g, 12 mmol), hexamethylditin (5.0 g, 15.3 mmole), triphenylphosphine (496 mg, 1.89 mmole) and bis(dibenzylideneacetone)palladium(0) (270 mg, of 0.47 mmole) in toluene (120 ml), incubated with stirring at 118oC in argon atmosphere for 6 hours the mixture is Then treated with an aqueous solution of potassium fluoride (300 ml, and 0.50 M) and extracted with toluene (g ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 50% ethyl acetate in cyclohexane) to give 6-(tributylstannyl)imidazo[1,2-a]pyridine as a colourless oil.

d) 6-[4-Methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a] pyridine

A mixture containing 5-(3-bromo-5-methoxyphenyl)benzofurazan (2,44 g, 8 mmol), 6-(tributylstannyl)imidazo[1,2-a]pyridine (2.2 g, of 7.9 mmole), triphenylphosphine (336 mg, of 1.28 mmole) and bis(dibenzylideneacetone)palladium(0) (186 mg, of 0.32 mmole) in dimethylformamide (60 ml), incubated with stirring at 125oC in argon atmosphere for 36 hours the Solvent is evaporated under reduced pressure, obtaining the crude product, which was purified using chromatography (silica gel, 95% atlasphere, getting 6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine as a pale yellow crystalline solid,PL190-196oC.

The agents according to the invention, as defined above, for example, of formula Ia or Ib, in particular the examples, in free form or in the form of a pharmaceutically acceptable acid additive salt proably pharmacological activity and are useful as pharmaceuticals, e.g. for therapy in the treatment of the following in the description of diseases and conditions.

In particular, the agents according to the invention show inhibitory activity against inhibitory cyclic nucleotide phosphodiesterase (PDE), the election in respect of isoenzyme type IV.

The agents according to the invention have anti-inflammatory, prevents increased reactivity of the Airways and bronchodilatory properties. In addition, they possess immunosuppressive, inhibiting the secretion of TNF and other pharmacological activities that may be shown on the standard test methods described in the examples below.

A. Inhibition of PDE4: analysis of the inhibition of recombinant isoenzyme PDE4A, PDE4B, PDE4C and PDE4D

Cell Signal, 1994; 6: 793-812), rat PDE4B (as described in Colicelli and others, Proc. Natl. Acad. Sci. USA 1989; 86: 3599-3903), human PDE4C (as described by Engels and others, FEBS Lett., 1995; 358: 305-310) and human PDE4D (as described by Baecker and other Gene, 1994; 138: 253-256), clone or extrachromosomal expressing the yeast vector (PDE4C, PDE4D), or by integrating (PDE4A, PDE4B; one copy) in the locus RAR strain of Saccharomyces cerevisiae lacking both genes PDE yeast wild type. Yeast strains expressing the PDE4 isoenzymes are grown in 1 l cultures at 30oWith, pellitero (precipitated by centrifugation and stored frozen until homogenization.

Homogenization: Pelletierine yeast (5 ml) are suspended in 50 ml buffer (10 mm Tris-hydroxyethylaminomethyl, 1 mm ethylenediaminetetraacetic acid, 1 mg/ml leupeptin and pepstatin And 175 mg/ml phenylmethylsulfonyl, 1 mm dithiothreitol, pH 7.4 with Hcl). After centrifugation for debris add 15 g of glass granules (diameter 425-600 mm, acid washed, company Sigma Chemical Co.), rinsed with buffer. To this suspension was added 1 ml of buffer and 60 mg cholamidopropyl acid and the suspension is intensively stirred for 4 h at 4oC. Yeast cells break down (disintegrate), evaluating microscopy (phases is ristow glass funnel, the homogenate was collected by suction and washed glass beads buffer total volume of 15 ml of Cell fragments are separated from cytosol by centrifugation (2000xg, 10 min, 4oC). Debris resuspended in 15 ml of buffer and evaluated for PDE activity together with the cytosol.

Analysis of PDE: Protocol analysis based on two-stage method described by Thompson and others (Adv. Second Messenger Phosphoproteun Res. 1979; 10: 69-92), modified for 96-well microtiter plates. In General, the enzyme is dissolved in a buffer for homogenization (see above) to the total hydrolysis of the substrate in the process of analysis was 10-30%. To initiate the reaction, 25 ml of the diluted enzyme is added to 25 ml of substrate ([3H]-cyclic amp, 1.25 mm 740 Bq) and 75 ml of inhibitor (see below). After incubation for 30 min at 37oWith reaction, stop using baths with hot water (65oC, 5 min). Tablets cooled on ice and incubated for 10 min at 37oWith 25 ml of 5'-nucleotidase (from the venom of the snake, from oiophaghus hannah, the company Sigma Chemical Co. , 0.1 mg/ml in water). Unreacted substrate is separated from [3H] -adenosine by successively adding the aliquot volume (100+50+50 ml with 5 min intervals) 30% (about. /about.) suspension of Dowex 1x2 (acetate form on 96-well tablets with scintillation solid phase (LumaPlate, Canberra Packard), using an automatic pipette (type Hamilton MicroLab 2200), dried (at least 4 h at 50oC) and count radioactivity (counter type, Canberra Packard TopCount).

Inhibitors: Royal solutions of inhibitors are prepared in dimethyl sulfoxide (DMSO) and diluted with water/DMSO, receiving 7 concentrations are selected so that they evoked inhibition in the range from 30% to 70%. The concentration of DMSO in the analysis process support constant at 50 ml/ml.

Determination of the parameters of inhibition. The concentration at which inhibition occurs by 50% (IC50), and the slope of the dose-response (hill coefficient) determined from the graphs of the dependence of inhibition on the concentration using nonlinear equalization using the least squares method using logarithmic equations with two parameters. The results are expressed as the negative logarithm of the concentration of inhibitor at which there is 50% inhibition (IC50) (in moles/l; pIC50). Estimate 95% confidence intervals and expressed as pL and pU (negative decimal logarithm of the lower and upper confidence limits, respectively). Concentrations that cause the Todd agents according to the invention mainly inhibit PDE isoenzymes type IV, showing minor action in respect of the isoenzymes of types 1, 2, 3 and 7. In the group of PDE isoenzymes type IV (i.e., the PDE isoenzymes type IV from a to D) agents according to the invention is mainly manifested by the electoral ingibirovanie of isoenzyme D PDE type IV compared with inhibition of isozymes 4A, 4B and 4C PDE type IV.

B. anti-Inflammatory activity: Inhibition of activation of eosinophils formyl-MetLeuPhe (fMLP)

Purified human eosinophils (104/well in 0.2 ml HBSS) stimulate fMLP (1 μm) in the presence of lucigenin (25 μm). Inhibition of the oxidation potential (as measured by the changes chemiluminescence) is determined by the curve dose-response, using a logarithmic equation.

The agents according to the invention show activity when tested by the methods a and B in concentrations of from 0.001 to 5 μm, typically in concentrations in the range of small nanomolar concentrations.

C. Effect on allergen-induced pulmonary eosinophilia

Treatment of rats Brown Norway inhaled antigen (ovalbumin, OA) causes of pulmonary eosinophilia after a maximum of 48 hours after treatment. In addition to the evaluation of cases of eosinophilia, the activation status of these cells can be determined with esteem experiment determine the inhibition agents according to the invention accumulation of eosinophils in the lungs.

Ovalbumin (10 μg/ml) mix (1 hour on ice in mixer with aluminum hydroxide (10 mg/ml) and injected subcutaneously together with vaccine Century pertussis (0.25 ml/specimen, intraperitoneally) to male rats Brown Norway (weighing about 200 g). The OA injection with adjuvant repeated after 15 and 21 days. On the 28th day of sensitized animals enclosed in plastic tubes and exhibit within 1 hour of OA in aerosol form (3.2 mg/ml), using only the nasal treatment system. After 48 h kill animals with phenobarbital (250 mg/kg, intraperitoneally). Light washed using 3 aliquot volume (4 ml) solution Khanka (tenfold HBSS, 100 ml; EDD, 100 mm, 100 ml; HEPES 1 M, 10 ml; 1 l of water), the resulting cells are arranged into groups, smears air-dried and stained for differentiation of cell types. Cells are identified and counted using oil immersion (1000-fold increase). Counting at least 500 cells per smear and determine the total number of all cell types.

Test the connection, enter vnutritrahealno for 1 h before and 24 h after injection of OA.

In untreated animals, the treatment of OA induces an increase in all types of cells in BAL fluid 24 h after injection. Preliminary Wed BAL-fluid depending on the dose of the compound compared with the untreated control variant. The number of cells of other leukocytes (macrophages, neutrophils) also decreases.

Given their anti-inflammatory activity, their impact on increased airway reactivity and their profile in relation to the inhibition of PDE isoenzymes, in particular their activity as selective inhibitors of PDE type IV, the agents according to the invention are suitable for treating, in particular for prophylactic treatment of obstructive or inflammatory Airways disease. So, for example, with constant and regular administration over extended periods of time the agents according to the invention are suitable for successful protection from recurrent bronchostenosis or other symptomatic effects accompanying obstructive or inflammatory airway disease, or to control, reduce or reverse the development of the basic status of such disease.

Given their probalities activity, the agents according to the invention is suitable as bronholiticheskih means, for example, for the treatment of chronic or acute bronchostenosis, for example, for symptomatic treatment of obstructive or inflammatory Airways disease.

In accordance with the above, the invention also includes:

A. the Way

a) treatment increased airway responsiveness,

b) increasing the lumen of the bronchi or bronchioles or, in particular,

in the treatment of obstructive or inflammatory Airways disease in a patient, ordaudio for such treatment, and this method includes the introduction to the patient an effective amount of an agent according to the invention.

Obstructive or inflammatory airway disease, which fall under the scope of the invention include asthma, pneumoconiosis, chronic obstructive disease of the Airways or lungs (OSDP or OSL) and respiratory distress syndrome in adults (rdsw), as well as exacerbation of increased reactivity of the Airways in the treatment of other medication, such as aspirin, or therapy with the use of-agonists.

The invention is applicable for the treatment of asthma of any type or origin, including congenital and primarily purchased asthma. It is applicable for treatment of allergic (atopic/mediated by immunoglobulin E (IgE)) asthma. It is also applicable to the treatment diatopically asthma, including, for example, br types of non-allergic asthma. It is also applicable for the treatment of syndrome startrange breathing children (children, early asthma).

The invention is applicable to treatment of pneumoconiosis any type or origin, including, for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and bissines.

The invention is applicable to treatment OSDP or OSL, including chronic bronchitis, emphysema or related shortness of breath.

The invention is also applicable to the treatment of bronchitis of any type or origin, including acute, arachidonyl, catarrhal, chronic, lobar or purulent tuberculous bronchitis.

In view of their activity as selective inhibitors of allocation of TNF - (tumor necrosis factor), the agents according to the invention is also suitable for down-regulation or inhibition of the excretion of TNF-, for example, for the treatment of diseases or conditions that are caused by the release of TNF - or TNF - a plays the role of a mediator, for example, diseases or conditions, the etiology of which includes or contains a pathology, for example, spam, excessive or unregulated secretion of TNF-, in particular for the treatment of cachexia or endotoxic shock and for the treatment of AIDS [cf. data th with pathological secretion of TNF - or with pathological levels of TNF - a in serum, regardless of origin, including cachexia, resulting, for example, bacterial, viral or parasitic infection or the result of deprivation or exhaustion humoral or other organic, such as the kidney function. He, for example, is applicable for the treatment of cancer, malaria and permalloy cachexia, cachexia resulting from dysfunction of the pituitary, thyroid or thymus, and uremic cachexia. He, in particular, is effective for the treatment of AIDS-related cachexia, such as cachexia resulting from or associated with HIV infection.

The method according to the invention is also applicable for the treatment of septic shock, such as shock, which is the result of a bacterial infection, for example, toxic or endotoxic shock. In this regard, it should be noted that the invention relates to a method of treating septic shock, and conditions resulting from or have symptoms of septic shock, for example rdsw (respiratory distress syndrome of adults). The method according to the invention is also applicable to other acute inflammatory conditions, such as severe burns, meningitis and pneumonia.

The method according to the invention, kometenmelodie or control the development of such disease.

Given their profile in relation to the inhibition of PDE isoenzymes and/or inhibiting the excretion of TNF-, as well as their immunosuppressive activity, the agents according to the invention are also suitable as immunosuppressants, for example, for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases in which occur voplotilsya processes or that have an inflammatory component or aetiology, or as anti-inflammatory of Agatov for the treatment of inflammatory diseases, in particular for the treatment of inflammatory disease are autoimmune reaction or which has an autoimmune component or aetiology.

Examples of such diseases to which the invention is applicable, include autoimmune haematological disorders (e.g. hemolytic anemia, gipoplasticheskaya anemia, this anemia erythrocytes and idiopathic thrombocytopenia), systemic lupus erythematosus, polyhedric, scleroderma, granulomatous's granulomatosis, dermatomyositis, chronic active hepatitis, severe pseudoparalysis myasthenia syndrome Stevens-Johnson, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative to titlenow pneumonia, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Owain (front and rear), dry (sicca) keratoconjunctivitis and vernally keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with nephrotic syndrome or without it, e.g. including idiopathic nephrotic syndrome or nephropathy minimal change), as well as inflammatory and/or hyperproliferative skin diseases, such as psoriatic atopic dermatitis, pemphigoid and, in particular, contact dermatitis, such as allergic contact dermatitis.

The agents according to the invention is particularly suitable for the treatment of arthritis and other rheumatic or inflammatory diseases, primarily for the treatment of rheumatoid arthritis.

Compounds according to the invention also have indications for use as immunosuppressants to prevent rejection of the graft, for example to maintain allogeneic transplants of organs, or so forth, for example, transplants of kidney, liver, lung, heart, heart-lung, intestine, bone marrow, skin or cornea.

Given their anti-inflammatory activity, in particular, in otnosheniyami diseases, e.g. eosinophilia, in particular associated with eosinophilia diseases of the Airways (e.g. involving abnormal eosinophil infiltration of lung tissue), including hypereosinophilia, affecting the respiratory tract and/or lungs, as well as, for example, associated with eosinophilia of respiratory diseases that are caused or accompanied by the syndrome Leffler, eosinophilic pneumonia, parasitic (in particular, matatalino) infestation (including tropical eosinophilia), bronchopulmonary Aspergillus, polyarthritis nodosa (including syndrome Churg-Strauss), the eosinophilic granulomas and associated with eosinophilia disorders of the respiratory tract, caused by a reaction to medication.

Given their profile in relation to the inhibition of PDE isoenzymes, in particular their profile as selective inhibitors of PDE type IV, the agents according to the invention, also suitable as inhibitors of PDE type IV, for example, for the treatment of diseases associated with decrease of calcium in the tissues, in particular degenerative diseases of bones and joints, caused by the reduction of calcium, in particular osteoporosis. In this regard, they are also suitable for the treatment of allergic inflammatory sabesto vasodilator agents for example, for the treatment of angina, hypertension, congestive heart failure and multi-infarct dementia, and to treat other conditions, which shows the inhibition of PDE type IV, such as depression, conditions and disorders characterized by impairment in cognitive function, including Alzheimer's disease, Parkinson's disease and stroke.

Because of their synergistic ability to interact with immunosuppressants and/or anti-inflammatory drugs, the agents according to the invention are also suitable as chotherapeutic agents for use in combination with these drugs, such as amplifiers therapeutic activity of these drugs or as a means to reduce the required dose or potential side effects of such drugs. Medicines that can be used in conjunction with the agents according to the invention, include, for example, cyclopeptide, cyclopeptide or macrolide immunosuppressants or anti-inflammatory medicines, such as medicines belonging to the class of cyclosporine, such as cyclosporine a or G, drugs such as tecnologie drug class glucocorticoids. Diseases for which it may be applied such combined therapy include, for example, any disease or condition that requires immunosuppressive or anti-inflammatory medication, such as described above in the description. In particular, the agents according to the invention is suitable for use in the above joint therapy, for example, for the purposes of immunosuppressive, anti-inflammatory or anti-asthma treatment, for example, to achieve the effects of cyclosporine, such as cyclosporine a, a sparing-effects caused by macrolide or steroids.

In accordance with the invention also features:

B. the Way

a) down-regulation or inhibition of the excretion of TNF-,

b) inhibiting the activity of PDE isoenzyme type IV,

C) implementation of immunosuppression,

g) treatment of inflammatory diseases or

d) the treatment of any specific condition or disease specified above, the patient, ordaudio for such treatment, and this method includes the introduction to the patient an effective amount of an agent according to the invention.

The present invention also refers to:

Century Agay the tvii with any of the above method or for the treatment of any of the above diseases or conditions, for example, specified in sections a and B.

The dose used in the practical implementation of the invention, obviously, vary depending, for example, from a particular disease or condition to be treated, in particular from the applied agent according to the invention, the route of administration and the desired therapy. In General, however, satisfactory results, for example, in the treatment of the above diseases can be obtained by oral dose in the range from 0.01 to 2.0 mg/kg For larger mammals, for example humans, the recommended daily dose for oral administration should correspond to a range from about 0.75 to 150 mg, and it is usually applied once or divided into daily doses for two or four injection or in the form of a continuous release. Thus, suitable standard dosage forms for oral administration comprise from about 0.2 to 75 or 150, for example from about 0.2 or 2.0 to 50, 75 or 100 mg of the agent according to the invention together with a pharmaceutically acceptable diluent or carrier.

When applying for the treatment of chronic or obstructive diseases of the respiratory tract, for example Aline to vary, for example, depending on the specific disease or condition-specific agent used according to the invention, the specific route of administration (for example, by using either a dry powder form for inhalation or otherwise) and the desired action. However, in General, the recommended daily dose for inhalation is in the range from approximately 2.5 to approximately 130,0 µg/kg/day, for example in the range from about 13.0 to about 60,0 mg/kg/day. For larger mammals, for example humans, the recommended daily dose for administration by inhalation, for example, for the treatment of asthma should be in the range of from about 0.2 to 10 mg, for example from 1 to 5 mg, and it is usually applied as a single dose or divided into 2 or 3 separate doses for administration throughout the day. Acceptable dose for the introduction, therefore, must be in the range of from about 200 mg to about 3.3 mg with the introduction of 3 times a day preferably with a device for inhalation of a dry powder in the form of a series consisting of 2-8 dowani with each introduction.

The agents according to the invention can also be entered using any other appropriate means, for example by INF is for the treatment of autoimmune diseases of the eye; dermal, i.e., topically on the skin, for example, for the treatment of dermatitis or psoriasis, or rectally, such as using enemas or suppositories, for example, for the treatment of inflammatory bowel disease. Acceptable doses for applications such ways should usually be 10-100 times lower than the doses required for oral administration.

Pharmaceutical compositions comprising the agents according to the invention, can be obtained using conventional solvents or excipients, or using methods well known in the field of herbal medicines. For example, dosage forms for oral administration may be tablets, capsules, etc., Composition for dermal application may be in the form of creams, ointments, gels and transdermal delivery systems, such as plaques, in addition to inert solvents or carriers can also contain agents that enhance penetration through the skin and is also known in this field.

Compositions for inhalation can be a spray or other intended for spraying the composition, and the composition in the form intended for inhalation dry powders with a solvent or without him for suggesting the inhalation in the form of a dry powder agents according to the invention can be applied in the form of a pharmaceutically acceptable acid salt additive. This compound in salt form is usually pulverized, for example, using an air nozzle or ceramic mill with obtaining finely ground powder for inhalation, for example, with an average particle diameter of approximately 2-3 microns.

Preferably, at least 90% of the product had an average particle diameter less than 7.8 μm, more preferably less than 4.8 μm. To ensure receipt of acceptable and appropriate to the product, suitable for administration via inhalation in the form of a dry powder, it may be preferable to carry out the grinding of the active substance, pre-mixed with a suitable environment carrier, which can be used by inhalation, for example, lactose, in the cold.

In accordance with the above, the invention also relates to pharmaceutical compositions containing the agent according to the invention together with a pharmaceutically acceptable diluent or carrier, for example, for use in any of the methods described above.

The compounds were tested using the test method (inhibition of PDE4D) and test method (anti-inflammatory). The result is
< / BR>
where in the formula la W represents N or C-CO-R, where R is a HE, O-C1-C6alkyl or NR3R4where R3and R4that may be the same or different values, denote H or C1-C6alkyl,

or in formula Ib Az denotes imidazopyridine, for example, imidazo[1,2-a] pyridine,

and in both formulas Ia and Ib R1stands WITH1-C4alkyl, preferably methyl;

R2denotes phenyl fragment, e.g., of formulas II

< / BR>
where R5and R6independently of one another denote H, nitro, halogen (e.g. chloro), trifluoromethyl, C1-C4alkoxy, cyano or phenoxy; or R5and R6together form a bridge, which represents an O-CH2-O-, or propylene;

or R2denotes a 2,5-cyclohexadiene-3,4-ridin-1 silt fragment, for example, formula III

< / BR>
where R7and R8together form an aromatic bridge of the formula =N-O-N=;

in free form or in the form of a pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, selected from the group including

4-[2-(methoxy)biphenyl-5-yl] pyridine,

4-[2-(methoxy)-3'-(nitro) - biphenyl-5-yl] pyridine,

4-[2-(methoxy)-3'-(trifluoromethyl)biperiden,

4-[2-(methoxy)-3'-(cyan)biphenyl-5-yl]pyridine,

4-[2-(methoxy)-3'-(chloro) - biphenyl-5-yl]pyridine,

4-[2-(methoxy)-3,,4'-(methylenedioxy)biphenyl-5-yl]pyridine,

4-[2-(methoxy)-3'-(phenoxy)biphenyl-5-yl]pyridine,

4-[2-(methoxy)-4'-(phenoxy)biphenyl-5-yl]pyridine,

4-[2-(methoxy)-3'-(chloro)-4'-(fluoro)biphenyl-5-yl]pyridine,

4'-methoxy-3'-(benzofurazan-5-yl)[1,1'-biphenyl]-4-carboxamid,

ethyl ester of 4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl] -4-carboxylic acid,

ethyl ester of 4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl] -3-carboxylic acid,

ethyl ester of 4'-methoxy-3-methyl-3'-(3-nitrophenyl)[1,1'-biphenyl]-4-carboxylic acid,

ethyl ester of 3'-(5-benzofurazanyl)-4'-methoxy[1,1'-biphenyl]-4-carboxylic acid,

2,2-dimethylpropionic ether 3'-(5-benzofurazanyl)-4'-methoxy [1,1'-biphenyl] -4-carboxylic acid,

3'-(5-benzofurazanyl)-4'-methoxy [1,1'-biphenyl]-4-carboxylic acid,

4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl]-3-carboxylic acid

4'-methoxy-3-methyl-3'-(3-nitrophenyl)[1,1'-biphenyl]-4-carboxylic acid,

3'-(5-benzofurazanyl)-4'-methoxy[1,1'-biphenyl]-4-carboxylic acid,

4'-methoxy-3'-(3-chlorophenyl)[1,1'-biphenyl]-4-carboxylic acid,

4'-methoxy-3'-(3-tianfeng)[1,1'-biphenyl]-4-carboxylic acid,

4'-methoxy-the STI-3-methyl-3'-(3-nitrophenyl)[1,1'-biphenyl]-4-carboxamid,

N-methyl-4'-methoxy-3'-(3-nitrophenyl)[1,1'-biphenyl]-4-carboxamid,

6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine

in free form or in the form of a pharmaceutically acceptable acid additive salt.

3. Pharmaceutical composition having anti-inflammatory activity containing compound under item 1 in the form of the free compounds or in the form of a pharmaceutically acceptable acid additive salt.

4. Method for the treatment or prevention of inflammatory diseases, including the introduction of an effective amount of the compounds under item 1 in free form or in the form of a pharmaceutically acceptable acid additive salt to a patient in need of such therapy.

5. The method according to p. 4, wherein the inflammatory disease is an inflammatory or obstructive airway disease.

6. A method of obtaining a connection on p. 1, including the interaction of the compounds of formula I or formula I (b:

< / BR>
< / BR>
where X denotes a halogen or a leaving group, a R1, W and Z have the values listed in paragraph 1, with activated aryl compound of the formula IIA or IIIa:

< / BR>
< / BR>
where Y denotes a halogen (preferably bromine) or departing/SUB> and R8have the values listed in paragraph 1,

and isolation of the resulting compound in free form or in the form of a pharmaceutically acceptable acid additive salt.

7. The compound of formula I a or I b

< / BR>
< / BR>
where X is halogen (preferably bromine) or a leaving group, such as tin or boron-containing group (preferably- (OH)2), a R1, W and Z have the values listed in paragraph 1, provided that when X represents bromine and R1denotes methyl, W denotes C-COOCH3when X denotes chlorine or bromine and R1denotes methyl, ethyl, propyl or butyl, and W denotes C-COOH, when X represents chlorine and R1denotes methyl, W denotes C-SOON2CH3or-SOON2CH2CH3.

 

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