Imidazo-kannelirovannye iso - and heterocyclic compounds and method of production thereof

 

(57) Abstract:

Use as highly efficient receptor antagonists angiotensin-2. The essence of the invention: imidazo-kannelirovannye ISO - and heterocyclic compounds and how they are received by alkylation of the corresponding imidazopyridine suitable alkylating ageton. 2 S. and 1 C.p. f-crystals, 1 table.

The invention relates to imidazo - annelirovaniya ISO - and heterocyclic compounds, method of their production and to the means on the basis of them.

From EP-A 399 731, EP-A 399 732, EP-a 400 835 and EP-434 038 known imidazo - kannelirovannye, aromatic compounds such as antagonists of angiotensin II receptors. However, none of these publications do not describe compounds that have cyclically substituted phenyl ring as a substituent at the nitrogen of imidazole ring and a heterocycle, annelirovannymi with imidazole ring, similarly, little is known compounds bearing kannelirovannye with imidazole homoeroticism hydrocarbons and simultaneously biphenylene group on the nitrogen atom of the imidazole; as unknown no connection to biphenylenes group are the rest of the sulfonylurea or sulfonylurea the rest.

At present in the receptors of angiotensin II, both in vivo and also in vitro.

The invention relates to compounds of the formula

< / BR>
the symbols have the following meaning:

X means a monocyclic residue with 3, 4 or 5 atoms in the ring or a bicyclic residue from 8-10 atoms in the ring which may be partially or fully be gidrirovanny and in which one or more CH or CH2-groups can be replaced by N, NH or O;

R(1)

1. (C1-C10)-alkyl,

2. (C3-C10)-alkenyl,

3. (C3-C10)-quinil,

4. OR (6)

5. (C3-C8-cycloalkyl,

6. (C4-C10-cycloalkenyl,

7. (C5-C10)-cycloalkylcarbonyl,

8. (C5-C10-cycloalkylcarbonyl,

9. (CH2/m-B-(CH2)n-R(7)

10. benzyl,

11. the remainder determined under the number 1. 2. 3 or 9, which monogamist with CO2R(6)

12. The remainder determined under number 1. 2. 3, or 9, where 1 until all H atoms replaced by fluorine, or

13. The remainder determined under number 10, which phenyl is substituted by 1 or 2 identical or different residues from the series comprising halogen, (C1-C4-alkoxy and nitro; R(2), R(3), R(4) and R(5) are the same or different and mean:

1. Bogorodica, carboxyl, (C1-C4-alkoxycarbonyl;

2. linear or branched, if necessary substituted, containing up to 6 C-atoms, alkyl, alkanniny, CNS or allylthio - remainder;

3. aryl, arylalkyl or killkenny residue in which the alkyl or alkanniny Deputy, unbranched or branched and has up to 6 C-atoms, and aryl Deputy means monocyclic residue with 5 or 6 atoms in the ring or condensed rings of 8 to 14 atoms in the ring, containing one or more heteroatoms like 0, N or S and which may be, if necessary, replaced,

< / BR>
R(6)

1. hydrogen

2. (C1-C8)-alkyl,

3. (C3-C8-cycloalkyl,

4. phenyl,

5. benzyl or

6. defined in paragraph (2 residue, in which from 1 until all H atoms replaced by fluorine;

1(7)

1. hydrogen

2. (C1-C8)-alkyl,

3. (C3-C8-cycloalkyl,

4. (C2-C4)-alkenyl or

5. (C2-C4)-quinil;

R(8) R(9) R(10) R(11) or the same or different and mean:

1. hydrogen

2. (C1-C6)-alkyl or (C1-C6)-alkenyl, unsubstituted or replacement of the sludge, where the alkyl residue is a monocyclic 5 or 6 atoms in the ring or a bicyclic 8-10 atoms in the ring, if necessary, contains one or more heteroatoms like O, N and S, and substituted by 1 or 2 identical or different residues from the series: halogen, hydroxy, hydroxyl, nitro, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C4-alkanoyl, (C1-C4)-alkanoyloxy and CO2/R (6);

or

R(8) R(9) R(10) R(11) together with bearing N-atom form a 2 - to 8-membered ring that is saturated or ninasimone may contain another heteroatom selected from the group of N, O and S, and unsubstituted or substituted with halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)alkenyl, (C1-C4)-alkyloxy and CO2R(6),

or

R(10) R(11), or the same or different, denote an acyl residue containing up to 6 C-atoms, or (C1-C6)-alkyl or (C6-C12)-aryl residue, which can be, if necessary substituted with halogen or (C1-C6)-alkyl residues; L (C1-C3) alcander;

R(12) R(13) is the same or different and mean:

1. hydrogen

2. halogen,

3. nitro,

4. (C1-C4) and is 5 to 10 atoms in the ring; which can be monocyclic or bicyclic, and where up to 9 ring atoms are C-atoms, which is substituted or is substituted by up to 6 mainly up to 3 identical or different residues R(14) R(15),

or

2. biphenylyl the remainder, which is not substituted or is substituted by up to 4, mainly up to 2 identical or different residues R(14) R(15), and "A" however, it is substituted by at least one residue as defined for R(15) PP 18. 19. 28. 40 or 42, and q is zero, R(14)-1. halogen,

2. oxo,

3. nitroso,

4. nitro,

5. amino,

6. cyano,

7. hydroxyl,

8. (C1-C6)-alkyl,

9. (C1-C4-alkanoyl,

10. (C1-C4-alkanoyloxy,

11. CO2R(6),

12. methanesulfonamido,

13. triftormetilfullerenov,

14. -CO-NH-OR (16)

15. -CO2-NR (17)R (18),

16. -CH2-OR (18),

17. (C1-C4-heteroaryl-(CH2)q- mostly 1-tetrazolyl,

18. (C7-C13-aroyl,

< / BR>
21. (C6C12)-aryl;

R15means:

1. hydrogen

2. (C1-C6)-alkyl,

3. (C3-C8-cycloalkyl

4. (C6-C12)-aryl,

5. (C7-C13-aroyl,

9. CO2R (6)-

10. halogen,

11. cyano,

12. nitro,

13. NR (17) R (18),

14. hydroxyl,

15. -CO-NH-CHR (19) -CO2R (6),

16. sulfo,

17. -SO3R (6),

18. -SO2-NR (18)-CO-NR (17) R (16), -SO20-NR (18) -CO-O-R (17), -SO2N(CO-O-R) (17))2or-SO2-NR (18) -CS-R (17) R (16)

19. -NR (18) -CO-NR (17) -SO2-CH2-R (18),

20. -WITH(CF3)2HE

21. phosphonooxy,

22. RHO3H2,

23. -NH-PO(OH)2,

24. -S(O)LR (17),

25. -CO-R (20),

< / BR>
< / BR>
31. 5-tetrazolyl-NH-CO-,

32. -CO-NH-NH-SO2CF3,

< / BR>
< / BR>
39. -CO-NH-SO2-R (6),

40. -SO2-NH-CO-R (17),

41. defined in paragraph (4 residue, substituted by 1 or 2 identical or different residues from the series: halogen, cyano, nitro, R (17) R (18) and hydroxyl;

42. R together with R (14) means-CO-NH-SO2-; R (16) R (17) is the same or different

1. hydrogen

2. (C1-C6)-alkyl,

3. (C3)-C8-cycloalkyl,

4. (C6)-C12)-aryl, preferably phenyl,

5. (C6-C10)-aryl-(C1-C4)-alkyl,

6. (C1-C9-heteroaryl, which may be partially or fully be gidrirovanny, mostly 2-pyrimidinyl, 1-piperidinyl or hinokitiol;

7. (C3-C are the same or different residues from the series: hydroxyl, methoxy, nitro, cyano, CO2R (6), trifluoromethyl, -NR (25) R (26)

< / BR>
9. (C1-C9-heteroaryl- (C1-C3)-alkyl, and the heteroaryl portion may be partially or fully be gidrirovannah,

10. defined 2 residue, in which from 1 until all H atoms may be replaced by fluorine,

11. (C2-C6)-alkenyl,

12. (C3-C8)-cycloalkenyl,

13. (C3-C8)-cycloalkenyl-(C1-C3)-alkyl,

14. (C3-C8-cycloalkyl-(C1-C4)-alkyl,

15. (C6-C10)-aryl-(C3-C6)-alkenyl,

16. (C1-C9)-hetaryl-(C3-C6)-alkenyl,

17. (C3--C6)-quinil,

18. (C6-C10)-aryl(C3-C6)-quinil,

19. (C1-C9-heteroaryl-(C3-C6)-quinil,

20. The rest of the formula , and R (16) cannot have the meaning specified in paragraph 20.

Stereocenter can be both R-and S-configuration

21. R (16) R (17) together with bearing N-atom form heteroaryl, which also may be partially or fully be gidrirovanny.

R (18)

1. Hydrogen

2. (C1-C6)-alkyl,

3. (C3-C8-cycloalkyl,

4. (C6- heteroaryl;

R (19)

1. hydrogen

2. (C1-C6)-alkyl,

3. (C3-C8-cycloalkyl,

4. phenyl or

5. benzyl;

R (20)

1. hydrogen;

2. (C1-C6) alkyl,

3. (C3-C8-cycloalkyl

4. phenyl-(CH2)q-,

5. OR (19)

6. P (25) P (26) or

< / BR>
R (21) means cyano, nitro or CO2R (18);

R (22) means CO2R (6) or CH2CO2R (6);

R (23) means hydrogen, halogen, (C1-C4) alkyl or (C1-C4-alkoxyl;

R (24) denotes hydrogen, (C1-C4) alkyl or phenyl;

R (25) R (26) the same or different and mean:

1. hydrogen

2. (C1-C4)-alkyl,

3. phenyl,

4. benzyl or

5. methylbenzyl;

I mean NR (23), or CH2;

In the mean Oh, NR (18) or S;

T means:

1. simple link,

2. - -

3. -CH2-

4. -O-,

5. -S-,

6. -NR (28)-,

7. -CO-NR (28)-,

8. -NR (28) -CO-,

9. -O-CH2-,

10. -CH2-O-,

11. -S-CH2-,

12. -CH2-S-,

13. -NH-CR (27) R (29)-,

14. -NR (28) -SO2-,

15. -SO2-NR (28)-,

16. -CR (27) R (29) -NH-,

17. -CH=CH-,

18. -CF=CF-,

19. -CH=CF

20. -CF=CH-,

21. -CH2-CH2-,

22. -CF2-CF2,

5)-alkyl, phenyl, allyl or benzyl;

R (28) means hydrogen, (C1-C6)-alkyl, benzyl or allyl;

R (30) means: 1. R (27) R (28),

2. ureido,

3. toureiro,

4. toluene-4-sulfonyl or

5. benzosulfimide;

R (31) R (32) the same or different and mean (C1-C4)-alkyl,

or together (CH2)q;

Q means: CH2, NH, O or S;

n means an integer from 1 to 5;

m means an integer from 0 to 3;

means an integer from 1 to 10;

r is zero, 1 or 2;

as well as their physiologically compatible salts.

Alkyl, alkenyl and quinil can be linear or branched. The corresponding applies to derived from them remains, as alkanoyl or alkoxy.

Under cycloalkyl see also substituted by alkyl ring. (C6-C12)-Aryl is, for example, phenyl, naphthyl, or biphenyl, preferably phenyl. The relevant matters to produce from them remains, as aroyl or aralkyl.

Under (C1-C9) heteroaryl see, in particular, residues, which are manufactured from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent the volume of the condensation site of bicyclic residues (as in indolizinyl) can be N-atom.

This for example, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, eradiating, indolyl, indazoles, hinely, yosinori, phthalazine, honokalani, hintline, cinnolines.

Under bellrowan heterobicycle Academy of Sciences, which made the rest And, you know, in particular, bicyclic system with 8-10 atoms in the ring, with up to 9 atoms of the ring is C-atoms, of which two are located next to each other atom represent a General integral part of both rings. One or both of these rings are formally produced from benzene, in which one or more CH groups are replaced by N, O+and S+and/or in which two adjacent CH groups [in the formation of five-membered aromatic ring] is replaced by S, NH or O.

"A" is, for example, the remainder of benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, cinoxacin, heatline, cinnoline, benzthiazole, benzothiazol-1,1-dioxide, coumarin, chromane, benzoxazole, benzisothiazole, benzodiapine of benzotriazole, benzotriazine, benzoxazine imidazo-pyridine, imidazopyrimidines, imidazopyridine, it is Tcl EN can also be partially or fully gidrirovanny. Mostly, however, the ring remains an aromatic, and benzenediamine heterobicycle is an especially preferred.

In the case of S-containing and/or partially saturated residues Bicycle, for example, may also be oxo-substituted, as is the case in the rest of benzo-1,2,3-triazinone.

Linking "And" performs from isoctliteral or heterocyclic part at about zero through alcander-bridge L, and when q is 1 through a single connection to the group

< / BR>
Under ISO - or heterocycle HN2from which is mono - or bicyclic residue X, see, for example, the remainder of cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, Cycloheptane, benzene, naphthalene, furan, thiophene, pyrrole, pyridine, pyridazine, pyrimidine, piperidine, piperazine, research, indole, indazole, oxazole, etoxazole, quinoline, isoquinoline, benzothiophene, benzofuran, benzothiazole, benzoxazole, imidazopyridine, imidazopyrimidines and foramerican. Halogen is fluorine, chlorine, bromine and iodine.

Under physiologically compatible salts of the compounds of formula 1 understand both their organic and inorganic salts, as they are described in Remington's Pharmaceuti cal Sciences, I. Edition page 1418 (1985).

what are the salts of sodium, potassium, calcium and ammonium; for the main group of salt with hydrochloric acid, sulfuric acid, phosphoric acid, carboxylic acids or sulphonic acids such as acetic, citric, benzoic, maleic, fumaric, tartaric, p-toluensulfonate acid.

Preferred compounds of formula II are:

< / BR>
in which the symbols have the following meaning:

L(1), L(2), L(3), and L(4):

1. -CH2-,

2. -SN=

3. the remainder determined under number 2, and 1 or 2 methine groups are replaced by nitrogen; preferably L(4) N,

R(1)

1. (C1-C10)-alkyl,

2. (C3-C10)-alkenyl

3. (C3-C10)-quinil,

4. (C3-C8-cycloalkyl,

5. benzyl or

6. benzyl, which is substituted as described above;

R (2) and R (3) are the same or different and represent:

1. hydrogen

2. hydroxyl,

3. halogen,

4. linear or branched (C1-C6)-alkyl residue, unsubstituted or substituted by one or more identical or different substituents from the series: halogen, hydroxyl, (C1-C4-alkoxy, (C1-C4)-alkylthio, mercapto;

5. -CO2R (6);

T means a simple bond, -0-, -CO-, NHCO -, or-och21
-C7)-alkyl, (C3-C7)-alkenyl or (C3-C7)-quinil;

R (12) R (13) the same or different and mean

hydrogen and (C1-C4) alkyl;

R (14) means: 1. (C1-C4) alkyl,

2. (C1-C4-alkoxy,

3. cyano,

4. amino,

5. nitro,

6. fluorine, chlorine or bromine,

7. (C1-C4-heteroaryl CH2;

8. (C1-C4)-alkanoyloxy,

9. (C1-C4-alkanoyl,

10. benzoyl or

11. tetrazolyl;

R (15) means:

1. (C1-C4)-alkyl,

2. (C6-C12)-aryl,

3. (C1-C3-alkanoyloxy,

4. (C1-C4-alkoxy,

5. (C1-C9-heteroaryl, mostly 5-tetrazolyl,

6. cyano,

7. nitro,

8. hydroxy,

9. SO3R (6),

10. chlorine, bromine,

11. CO2R (6),

12. CO-NH-R (19),

13. WITH-R (20),

14. SO2-NR (18) -CO-NR (17) R (16),

15. SO2-NR (18)-CO-O-R (17) or SO2N (CO-OR) 17))2< / BR>
16. CO-R (19) -CH2H

17. (C1-C4) alkyl CO2N,

18. N-CO-NH-SO2-CH2-R (19),

< / BR>
23. R (14) c R (15) together-CO-NH-SO2;

L-CH2-;

R (18) hydrogen;

R (25) R (26), independently on the x2">

The invention also concerns the method of producing compounds of formula 1, which is characterized in that compounds of the formula III

< / BR>
in which R (1),

R (2), R (3), R (4), R (5) and X have the above meanings, alkylate using compounds of the formula IV

< / BR>
in which L, q, R (12) R (13) and a have the above meanings, and U represents a volatile group, if necessary, temporarily introduced protective group again otscheplaut, and the resulting compounds of formula 1 optionally transferred to their physiologically compatible salts.

Suitable volatile groups U are preferably nucleofugal group (see Angew Chem. 7 (1960), as the halogen, o-eluwankulama, mesilate or triplet.

Ways of getting prestudy formula III are known from U.S. patent 4 880 8044, patent Germany 3 911 603, European patents: EP-A-399 731, EP-A-399 732, EP-a-400 835, EP-a-400 974, EP-A-415 886, EP-A-420 237, EP-A-425 921 and EP-A-434 038.

For the alkylation of compounds of formula III are suitable, for example, corresponding benzylchloride, benzalconium, benzyl-mesylates or benzyl triflate or appropriate alkylhalogenide, -tozilaty-meliloti or triflate. Obtaining these compounds is, in itself, in a known manner, for example by palaeosalinity, see for example, J. Org, Chemk. 44, 4733 (1979) and Helv. Chim. Acta 62, 2661 (1979).

Synthesis of benzimidazole derivatives, benzothiophene, imidazo-pyridine, imidazo-pyrimidine with CH3group core is carried out according to R. P. Dickson et al in y. Med. Chem. 29, 1937 (1986), E. Abinente en al in y. Heterocuclic Chem. 26, 1875, (1989), A. Koubsock et al in y Org. Chem. 41, 3399 (1976) and according to F. Santer et al in Mh Chem. 99, 715 (1968).

Biphenylene derivatives can be synthesized, for example, based on the derivatives of arylboronic acid by binding with substituted aryl halides using catalysts of transition metals, in particular palladium. Corresponding reactions are described by R. B. Milleret al (Organometallics 1984, 3, 1261) or A. Zuzuki et al (Synthetic Commun 11 (7)- 513 (1981)).

Sulfonylurea derivatives of the formula (I) can be obtained from the corresponding sulfonamides of the formula (I) by reacting esters harpalinae acid or by interaction with dimethyldicarbonate and bases, such as potassium carbonate, in an inert solvent at temperatures up to the boiling point of the respective solvent.

Derivatives of sulfonylurea (I) can be obtained by choice or from the corresponding sulfonamides of the formula (I) by reacting with isocyanate is for example, the sulfoxide or sulfonylureas formula (I) by affecting the appropriate amine in an inert, high-boiling solvent, such as toluene, at temperatures up to the boiling point of the respective solvent.

The remainder sulfonamida can be obtained, if necessary, on the basis of the amino group, by rearrangement Meerwein. For this amine hydrochloride first diasterous, and then, in the presence of a copper catalyst, enter into interaction with the sulfur dioxide in glacial acetic acid. Subsequent exposure to ammonia leads to the sulfonamide group.

The alkylation is carried out in principle by known methods in the same way.

Imidazo-annualrevenue derivatives of the formula III metallorum, for example, in the presence of a base. The preferred base is metal hydrides of the formula MN as lithium hydride, sodium or potassium hydride, for example, dimethylformamide or dimethyl sulfoxide as the solvent, or a metal alcoholate of the formula R, and R means methyl, ethyl, tert-butyl, and the reaction is carried out in the corresponding alcohol, dimethylformamide or dimethyl sulfoxide. Educated thus salts of imidazo the dominant reagent.

An alternative possibility for deprotonation of imidazole derivatives is, for example, the reaction of interaction with potassium carbonate in DMF or DMCO.

The reaction of the interaction is carried out at temperatures below room temperature up to the boiling temperature of the reaction mixture, mainly in the range between +20oC and the boiling temperature of the reaction mixture, for about from 1 to 10 hours

Proposed according to the invention the compounds of formula 1 have an antagonistic effect on the angiotensin II receptor and therefore can be used to treat hypertension, dependent on angiotensin II.

Possible applications are in the treatment of diseases such as heart failure, cardio-protection, myocardial infarction, cardiac hypertrophy, atherosclerosis, nephropathy, renal failure, and cardiovascular diseases of the brain, as transistor ischemic attacks and cerebral hemorrhage.

Renin is a proteolytic enzyme from the class aspartate that as a result of different stimuli (volume reduction, lack of sodium, stimulation of b-receptors) oculoglandular cells of the kidneys is excreted in the circle credne thanks "angiotensin converting enzyme" (ACE) is translated in angiotensin-II. Antiotensin II plays an essential role in blood pressure regulation, as it directly increases blood pressure because of angiospasm. Additionally, it stimulates the secretion of aldosterone from the adrenal gland and thus increases the through suppression excretion of sodium and extracellular fluid volume, which in turn, contributes to high blood pressure.

Postreceptor action is stimulation phosphoinositol sharing (allocation of CA2+), activation of protein kinase C, and promote hormonal receptor-dependent AMR.

The affinity of compounds of the formula I to angiotensin II receptor can be determined by measuring the displacement of125I-angiotensin II-or 3H-angiotensin II receptors in the area glomerulosa membranes of adrenal glands of cattle. For this purpose, the prepared membranes are suspended in buffer at pH 7.4. In order to prevent the degradation of the radio during incubation, add Aprotinin, an inhibitor of catalase. Additionally used in approximately 1400 CPM tracer with specific activity 74 q (mmol) sold by the company "Amershan Buchler" and the amount of receptor protein that binds 50% from the a + Aprotinin; 50 μl of buffer with angiotensin II or without him or receptor antagonist and 50 µl of tracer. After an incubation period of 60 min, at a temperature of 25oWith bound and free radioligand separated by filtration analysis using whatmann filter (R) GFIC on SkadronR(Skatron) memory cells.

Nonspecific binding is prevented by treating the filters with 0.3% polyethylenimine, pH 10 (Sigma, N 3143). Based on measurements of radioactivity in a gamma scintillation counter to determine the intensity of the displacement radioligand receptor. IC50values, which indicate the concentration of the inhibitor, in order to displace 50% of the ligand, are determined according to hem. et al. Theor. Biol, 59, 253 (1970). For compounds of formula (I) they are in the range of 1x10-41x10-9M

Alternatively, to determine the affinity of the compounds of formula I to the receptor of angiotensin-II in the measurement result of the displacement of1251-angiotensin-II or3N-angiotensin-II prepararsi receptors of various organs (liver, lungs, adrenal glands, brain, and so on).

For this purpose, the prepared membranes are suspended in incubation buffer (20 mm Tris) containing 135 mm NaCl, 10 mm KCl, 10 mm M the bacitracin 0.1 mm) and with radioactively marked by angiotensin-II and various concentrations of the tested compounds is incubated for 90 min at a temperature of 25oC. then bound and free radio-ligand separated by filtering through microtechnological filter (JF 51, Schleicher Schiill) on the memory cells (SKATRON).

Measurement-related receptor radioactivity on the filters by beta or gamma spectrometer determine the degree of displacement of radioligand recepta tested compounds. The intensity of the displacement radioligand receptor tested compounds indicated through the IC50, i.e. the concentration of inhibitor, which displaces 50% of the associated radioligand receptor. The calculation of the IC50-values is carried out via the PC-software (LIGAND, G. A. Mcpherson 1985, Elsinier-BiosoFT, 68 Hills Road, Cambridge CB 2ILA, UK). Measured for compounds of formula (I) IC50values are in the range of 1x10-5to 1x10-11M

To determine the antagonistic action of the compounds of formula (I) in vivo their inhibitory effect on induced by angiotensin II raises blood pressure can be measured on demyelinated Spragne Dawley - rats (Mollegard, Danemark). Blood pressure is measured on vta rotis. Intravenous is in the vein of the penis. After preparation of the animal and a 20-minute lie is 0, 30 and 100 ng of angiotensin-II in 0.1 ml of an aqueous solution at intervals of 5 minutes the compounds of formula (I) dissolved in distilled water, possibly adding 10% ethanol and/or bases(pH<10) or acid (pH>3), and injected in doses 1-300 μg/rq/ kg intravenously or 5-100 µg/kg intraduodenally.

When intraduodenal injection of angiotensin-II carried out in 20, 40 and 60 min, while intravenously is carried out successively with an interval of 10 minutes of the Compounds of formula (I) are particularly effective in the range of 1-300 mg/kg intravenously or 5 are 300 mcg/kg intraduodenally.

The invention relates also to a pharmaceutical composition comprising the compounds of formula I and other biologically active substances, such as diuretics or nesteroidnykh anti-inflammatory, biologically active substances. The compounds of formula (I) can also be used as diagnostics for the renin-angiotensin-system.

The pharmaceutical preparations contain an effective amount of the active substance of the formula (I) and possible other active substances together with inorganic or organic medium used for pharmaceutical purposes. Applied the t from the species of warm-blooded body weight, age and kind introduction.

The pharmaceutical preparations of the present invention receive by known methods dissolving, mixing, granulating or drazhirovanija.

For oral use, the active compounds are mixed with the usual additives, as carriers, stabilizers or inert diluents, and through the normal process methods in natural forms of administration, such as tablets, pills, detachable capsules, aqueous alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, fumarate magnesium or starch, especially corn starch. Thus it is possible to carry out the preparation in the form of dry or wet granulate. As oily carriers or solvents can be considered, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous and intravenous administration of the active compounds or their physiologically compatible salts, preferably, together with the usual agents such as agents, dissolving, emulsifying agents, or other spymania, for example, water, physiological saline solution or alcohols, e.g. ethanol, propandiol or glycerol; it is also sugar solutions such as glucose or mannitol solutions, or a mixture of various of the aforementioned solvents.

According to the above method have been defined, for example, compounds of examples 1, 2, 3, 15, 19, 27, 31 and 51, the following IC50values:

P R I m e R IC50/nM/

1 78

2 65

3 149

15 0,8

19 0,74

27 1,1

31 0,48

51 1,8

List of abbreviations:

DCl desorption-chemical ionization

DMF N,N-dimethylformamide

HER ethylacetat

FAB Fast Atom Bombardment-fast atom bombardment

h hour (time)

Ner n-heptane

Min minute (min)

NBS N-bromosuccinimide

RT, room temperature

Example 1

2-n-Butyl-1-/2-carboxy-3-chloro-benzo/b/thiophene-6-yl/ methyl/-1H-benzimidazole-7-carboxylic acid

(a) Amide 2-carboxy-6-nitro-benzoic acid

30 g (0,155 mol) of anhydride 3-nitrophilous acids contribute portions in 180 ml of concentrated ammonia solution and the resulting solution was heated under stirring for 45 minutes at a temperature of 100oC. Evaporated on a rotary evaporator, double-distilled Weta sucked off and dried in vacuum over P2O5. Get to 31.8 g of target compound.

Melting point: 180oWITH

Rf /SiO2CH2Cl2/CH3OH 1:1/ 0,3

MS/DCI/ 211 /M + J/

b) 2-Amino-3-nitro-benzoic acid

31 g /0.147 mol of the compound from example 1A are dissolved in 50 4 n sodium liquor and 100 ml of water, add 150 ml of a solution of sodium hypochlorite /excess in relation to KI starch paper/ and the resulting solution was heated for 60 minutes at a temperature of 100oC. After the reaction is cooled, diluted with 250 ml of a saturated solution of Na2CO3- and 400 ml of a saturated solution of KN2PO4- set the pH value of the solution 3 with 4n Hcl /concentrated Hcl and the product extracted three times with 500 ml ethyl acetate. After drying over MgSO4, concentration and stirring with diisopropyl ether obtain 18 g of the target compound.

Melting point:188 194oWITH

Rf /SiO2CH2CI2/CH3OH 1:1/ 0,7

MS /DCI/ 183 /M+H/

c). Methyl ester 2-amino-3-nitro-1-benzoic acid

18 g /99 mmol/ Compound from example 1b/ in 200 ml of methanol with 20 ml of thionyl chloride is stirred for 48 h at boiling temperature under reflux.SUB>2CO3three times extracted with ethyl acetate, the combined organic phases are washed with diluted aqueous Na2CO4and saturated NaCl solution, dried over Na2SO4and concentrate. Chromatographic analysis on SiO2with the help of HER/ner 9:1 and 7:33 yields of 11.5 g of the target compound. Melting point: 86-88oWITH

Rf /SiO2EE/Hep 1:1/ 0,5

Ms /DCI/ 197 /M + H/

d Methyl ester 2-/M-/n-pentanol/amino/-3-nitro benzoic acid

7 g /35.5 mmol/ compound from example 1 in 50 ml of acid chloride of valerianic acid for 1 h at 110oC. Concentrated to dryness, the residue in ether is treated for 30 min with activated charcoal, filtered, concentrated and subjected to chromatographic purification on SiO2through HER/Hep 2:8. Obtain 5.8 g of the target compound.

Melting point: 66-69oWITH

Rf/SiO2EE/Hep 1:1 with 0.4

Ms /DCI/ 281 /M + H/

e) 6-Bromo-methyl-3-chloro-2-methoxycarbonyl-benzo/b/- thiophene

2.5 g /10.4 mmol/ X-chloro-2-methoxycarbonyl-6-methylbenzo/b/thiophene/ received according to J, Org.Chem. 41, 3399 /1976/ refluxed in 150 ml of chlorobenzene with 1,87 NBS and 420 mg of dibenzoylperoxide within 5 hours After the distillation of chlorobenzene in a rotary evaporator UB>2SO3and a saturated solution is dried over Na2SO4and concentrate. Chromatography on SiO2with the help of HER/ner 1:2 give 2.28 g of the target compound.

Melting point: 143 145oWITH

Rf /SiO2/, EE/ner 1:20/ 0,3 -

MS /DCI/ 319, 321 /M+H/.

f) Methyl ether 2-/N-/n-pentanol/-//3-chloro-2 - methoxycarbonylbenzyl/b/-thiophene-6-yl/methyl/ /amino-3-nitrobenzoic acid/

800 mg /2,86 mmol/ compound from example 1d/dissolved in 5 ml of abs. DMF, mixed with K2CO3the number of 395 mg) and the mixture stirred for 10 min at room temperature. Was added dropwise a solution of 913 mg of the compound from example 1 in 20 ml of abs. DMF, and the reaction solution is stirred over night at room temperature. DMF is removed then in vacuum, the residue is treated IT, ITS phase is washed with water, diluted with saturated solution of NaHCO3and a saturated solution of NaCl, dried over Na2SO4and concentrate. Chromatography on SiO2with the help of HER/ner 1:2 give 860 mg of the title compound.

Rf /SiO2EE/Hep 1:2 0,3

MS /FAB/ 519 /M + H/.

g) /Methyl ester of 2-N-butyl-1-//3-chloro-2-methoxycarbonylbenzyl/b /thiophene-6-yl/methyl/-1H-benzimidazole-7-carboxylic acid

450 mg /0.85 mmol/ connect the Ute. The filtrate is concentrated to dryness, the resulting residue in 10 ml of HER/isopropanol /1:1/, and 10 ml of saturated Hcl ITS solution is stirred for 30 minutes at a temperature of 50oC. After concentration and crystallization from methanol obtain 190 mg of the target compound.

Melting point: 167-170oC (decomposition)

Rf /SiO2CH2CI2/ CH3OH /NH4OH 49/ 1 /0,1/ 0,3

MS /DCI/ 471 /M + H/

h) 2-H-Butyl-1-//2-carboxy-3-chloro-benzo/ b /thiophene-6-yl/ methyl/-1H-benzimidazole-7-carboxylic acid

185 mg /0,39 mmol/ compound from example 1g/ dissolved in 10 ml of ethanol was added 1 ml of N2O and 1 ml conc. NaOH, and the resulting solution was stirred for 3h at room temperature. The ethanol is removed in vacuo, set the pH of the aqueous solution 3 by means of glacial acetic acid, and the precipitated precipitate is sucked off. After drying in high vacuum, receive 100 mg of the target compound as white crystals. Melting point: > 260oC.

Rf /SiO2EE/CH3OH 2/1 0,18

Ms /FAB/ 443 /M + H/

Example 2

2-N-Butyl-1-//3-carboxy-2-phenyl-imidazole/1,2-a/pyridine-7-yl/-methyl/-1H-benzimidazole-7-carboxylic acid

Ethyl ester

a) 2-Benzoyl-2-bromo-acetic acid

25 ml (0.144 mol). ,5 ml of bromine, and the brown solution is stirred for 1 h at 5oC, for 3 h at room temperature and for 2 hours at a temperature of 60oC. Carry out concentration to dryness, the residue treated HER, the solution washed with 10% solution of Na2SO3a saturated solution of NaCI dried over MgSO4, concentrated and dried in high vacuum. Get 38 g of the title compound in the form of oil red.

Rf /SiO2EE/Hep 1/6/ 0,28.

MS /DCI/ 271, 273 /M + H/.

b) Ethyl ester of 7-methyl-2-phenyl-imidazo /1,2-a/ pyridine-3-carboxylic acid

38 g /0.14 mol of the compound from example 2A/ and 15.2 g of 2-amino-4-methyl-pyridine is stirred in ethanol for 8 h at boiling temperature under reflux. Concentrate to dryness, the residue was diluted with a saturated solution of Na2CO3repeatedly extracted with HER, the combined organic phases are washed with saturated NaCl solution, dried over Na2SO4and concentrate. Chromatography on SiO2with HER/Hep 2:1 give 12.2 g of the target compound.

Rf /SiO2EE/Hep 2:1/ 0,3

MS /DCI) 281 /M + H/

c) Ethyl ester of 7-bromomethyl-2-phenyl-imidazo/1,2-a/ pyridine-3-carboxylic acid

3 g /10,7 mmol/ Saedinenie 1E. Obtain 1.2 g of the target compound.

Rf /SIO2EE/Hep 1/2 0,2

Ms /DCI/ 359, 361 /M + H/.

d) Methyl ester 2-/N-/n-pentanol/-//3-etoxycarbonyl-2-phenyl-imidazo/1,2-a/-pyridin-7-yl /methyl/amino-3-nitro-benzoic acid

300 mg /2,85 mmol /compound from example 1d/, of 1.03 g of the compound from example 2C) and 400 mg2CO3subjected to interaction according to the method indicated in example 1f). Obtain 520 mg of the target compound.

Rf /SiO2; EE /Hep 1:1/ 0,2

MS/FAB/ 559 /M + H/

e) Methyl ester of 2-n-butyl-1-//3-etoxycarbonyl-2-phenyl-imidazo/1,2-a/pyridine - 7-yl/-methyl/-1H-benzimidazole-7-carboxylic acid

400 mg /0.71 mmol/ Compound from example 2d is subjected to interaction by the method specified in example 1g/. After precipitation from methanol by diethyl ether to obtain 250 mg of the target compound.

Melting point: 217 220oC (decomposition)

Rf /SiO2EE-Hep 9/1/ 0,5

MS /DCI/ 511 /M + H/

h) 2-n-Butyl-1-//3-carboxy-2-phenyl-imidazo/1,2-a/pyridine-7-yl/methyl/ 1H-benzimidazole-7-carboxylic acid

230 mg /0.45 mmol/ Compound from example 1E/ omelet according to the method indicated in example 1h. Get 117 g of target compound as white crystals.

Temperature p is H-butyl-1-//3-carboxy-2-phenyl-imidazole/1,2-a/pyrimidine-7-yl/methyl/-1H-benzimidazole-7-carboxylic acid

a) Ethyl ester of 7-methyl-2-phenyl-imidazo(1,2-a) pyrimidine-3-carboxylic acid

The target connection receive in accordance with the method described in example 2b, of the compounds indicated in example 2A, and 2-amino-4-methylpyrimidine.

Rf /SiO2EE/ Hep 2:1 0,2

/DCl/ 282 /M + H/.

b) Ethyl ester of 7-bromomethyl-2-phenyl-imidazo/1,2-a/pyrimidine-3-carboxylic acid.

Obtaining this compound is carried out according to the method indicated in example 2; 2 g /7,11 mmol/ compound from example 3A obtain 510 mg of the target compound.

Rf /SiO2EE/Hep 1:2/ 0,2

MS /FAB/ 360, 362 /M + H/.

C) Methyl ester 2-/N-/n-pentanol/-//3-etoxycarbonyl-2-phenyl-imidazo /1,2-a) pyrimidine-7-yl/methyl/amino-3-nitrobenzoic acid

Obtaining this compound is carried out according to the method of example 1f/. From 435 mg /1.55 mol of the compound from example 1d/ and 558 g of compound from example 3b obtain 550 mg of the target compound.

Rf /SiO2EE/Hep 2:1/ 0,2

Ms /DCl/ 560 /M + H/.

b) Methyl ether /2-n-butyl-1-//3-etoxycarbonyl-2-phenylimidazo/1,2-a/pyrimidine-7-yl/-methyl/-1H-benzimidazole-7-carboxylic acid.

This connection get as indicated in example 1g) method; this to beige.

Melting point: 185-187oWITH

Rf /SiO2EE/Hep 1:1/ 0,2

MS /FAB/ 512 /M + H/

e) 2-n-Butyl-1-/3-carboxy-2-phenyl-imidazo/1,2-a/pyrimidine-7-yl/methyl/-1H-benzimidazole-7-carboxylic acid

Obtaining this compound is produced according to the method indicated in example Ih). From 45 mg (0,99 mmol) of the compound from example 3d) obtain 31 mg of the target compound.

Melting point: > 260oWITH

Rf/SiO2HER/CH3OH/ 0,1

MS/FAB/470 /M + H/

Example 4

2-n-Butyl-3-/2-carboxy-3-chloro-benzo/b/thiophene-6-yl/methyl/-3H - imidazo/4,5-b/pyridine

a) 2-n-Butyl-3H-imidazo/4,5-b/pyridine

10 g /to 91.6 mmol/ 2,3-Diaminopyridine and 27.4 g valerianic acid is stirred for 18 hours at a temperature of 170oC. After the reaction was diluted with 100 ml of CH2CI2and washed with a saturated solution of NaHCO3, water and saturated NaCl solution, dried over Na2SO4and concentrate. Chromatography on SIO, SIS2with the help of HER/Hep 20:1 to give 9.7 g of the target compound.

Melting point: 103oC

Rf/SiO2EE/CH3OH 20:1/ 0,3

MS/DCl/ 176/ M + H/.

b) 2-n-Butyl-3-//3-chloro-2-methoxycarbonyl-benzo/b/ thiophene-6-yl/methyl/-3H-imidazo/4,5-b/pyridine

300 0,94 mg /mmol/ Conn is e 8 h at room temperature. Concentrate to dryness, the residue treated her, HER solution is washed with water, diluted aqueous SO4, a saturated solution of NaHCO3and saturated NaCI solution, dried over Na2SO4and concentrate. Chromatography on SiO2through HER/ner 1:1 gives 130 mg of the target compound in the form of a powder slightly yellow in color.

Melting point: 127 129oC.

Rf/SiO2HER/assistant 1:1/ 0,2

MS /DCI/ 414 /M + H/

c) 2-n-Butyl-3-//2-carboxy-3-chloro-benzo/b/thiophene-6-yl/methyl/-3H-imidazo/ 4,5-b/pyridine

117 mg /0.28 mmol/ Compound from example 4b/ enter into interaction by the method specified in example 1h. Obtain 107 mg of the target compound in the form of white powder.

Melting point: > 260oWITH

Rf/SiO2EE/CH3OH A 2:1/ 0,3

MS /FAB/ 400 /M + H/

Example 5

2-n-Butyl-3-//3-carboxy-2-phenyl-imidazo/1,2-a/pyridine-7 Il/-methyl-3H-imidazo/4,5-b/pyridine

a) 2-n-Butyl-3-//3-etoxycarbonyl-2-phenyl-imidazo/1,2/and/ pyridine-7-yl/methyl/-3H-imidazo/4,5-b/pyridine

The target connection receive according to the method indicated in example 4b, from the compounds of examples 2C and 4A/.

MS /DCl/ 454 /M + H/

b/ 2-n-Butyl-3-//3-carboxy-2-phenyl-imidazo/1,2-a/pyridine-7-yl/ methyl/-3H-imidazo/4,5-b/p is P CLASS="ptx2">

MS /FAB/ 426 /M + H/

Example 6

2-n-Butyl-3-//3-carboxy-2-phenyl-imidazo/1,2-a/pyrimidine-7-yl/-methyl/-3H-imidazo/4,5-b/pyridine

a) 2-n-Butyl-3-//3-etoxycarbonyl-2-phenyl-imidazo/1,2-piridin-7-yl/methyl-3H-imidazo/4,5-b/pyridine

This compound is obtained from the compounds of examples 3b /4A and/ by way of example 4b/.

MS /DCl/ 455 /M + H/

b) 2-n-Butyl-3-//3-carboxy-2-phenyl-imidazo/1,2-a/pyrimidine-7 - yl/-methyl/-3H-imidazo/4,5-pyridine

The target compound is obtained from the compound of example 6A according to the reaction of interaction described in example 1h.

MS /FAB/ 427 /M + H/

Example 7.

2-n-Butyl-3-/2-/4-were/-3-/1H-tetrazol-5-yl/-imidazo/4,5-b/ pyridinyl/-3H-imidazo/4,5-b/pyridine

a) 2-4-Methyl-phenyl/-imidazo/4,5-pyridine

8.6 g (91,4 mmol) of 2-Aminopyridine and 7.7 g (45,7 mol) chloromethyl-p-triketone /received according hem.Iett. 1990, 1125-1128/ is stirred for 45 minutes at a temperature of 130oC. After the reaction solution was diluted with CH2CI2, washed with water and saturated NaCl solution, dried over MgSO4and concentrate. Chromatography on SiO2through HER/Hep 4:1 1:1 gives 6.8 g of the target compound.

Melting point: 142 144oWITH

Rf /SiO2/, EE/Hep 1:1/ 0,2

MS (DCI)SUB> at 0oWith mixed with 3.6 ml RO3the reaction solution is then stirred for 30 minutes at room temperature and at 0oWith added dropwise a solution of 6.8 g /32,7 mmol/ compound from example 7a/ compound from example 7a/. After 2 h stirring at 60oTo carry out the concentration, the residue is mixed with a solution of 20 g of NaOH in 200 ml of N2O, stirred for 1 h at boiling temperature under reflux and the precipitate is sucked off, dropped out after cooling in an ice bath. Recrystallization from ethanol gives 5.5 g of the target compound.

Melting point: 168-171oWITH

Rf /SiO2EE/Hep 8:2/ 0,4

MS /DCl/ 237/ M + H/

C) 3-Oximino-2-/4-methyl-phenyl/-imidazo/4,5-pyridine

2 g /of 8.47 mmol/ Compound of example 7b/ in 30 ml of methanol is mixed with solution of 883 mg of hydroxylamine hydrochloride and 1.04 u sodium acetate in 65 ml of water. The reaction solution is stirred for 5 h at room temperature and 1 h at boiling temperature under reflux. The methanol is removed in a rotary evaporator, then diluted with water, and precipitated after cooling, the precipitate is sucked off. After drying over P2O5in high vacuum, get 2,04 g of target compound. Melting point: 202-2062CO3and saturated NaCl solution, dried over MgSO4and concentrate. Recrystallization from diisopropyl ether /EE network of 1.9 g of the target compound.

Melting point: 133 144oC.

Rf /SiO2EE/Hep 1 1/ 0,2

MS /DCl/ 234 /M + H/

e) 2-/4-methyl bromide-phenyl/-3-cyano-imidazo/4,5-pyridine

Obtaining this compound is carried out according to the method indicated in example 1E. From 1.7 g of the compound from example 7d obtain 1.73 g of the target compound.

Melting point: 182 186oC.

Rf/SiO2EE/Hep 1:1 0,2

MS/SCl/ 312 /314 / M + H/

f/ 2-n-Butyl-3-/3-cyano-2-/4-were/-imidazo/4,5-pyridinyl/-3H, imidazo/4,5-b/pyridine

The target compound is obtained from the compounds of examples 4A and 7th /in accordance with the method specified in example 4b/.

Ms /DCl/ 407 /M + H/

g/ 2-n-Butyl-3-/2-/4-were/-3-/1H-tetrazol-5-yl/imidazo/4,5-pyridinyl//-3H-imidazo/4,5-b/pyridine

210 ml /0.51 mmol/ Compound from example 7f/ stirred in 5 ml of toluene with 308 mg trimethyllysine within 3 days when the fact is saturated KF solution and 0.2 ml F4/50%/nogo stirred for 2 days at room temperature. Diluted through HER, filtered, separating the organic phase of the filtrate, washed with N2Oh and a saturated solution of NaCI dried over Na2SO4and concentrate. Chromatography on SiO2through HER/CH3OH 3:1 give 110 mg of the target compound.

MS /FAB/ 450 /M + H/.

Example 8.

2-n-Butyl-1-/2-/4-were/-3-/1H-tetrazol-5-yl/- imidazo/4,5-pyridinyl/-1H-benzimidazole-7-carboxylic acid

a) Methyl ester 2-/N-/n-pentanol/-3-cyano-2-/4-were/imidazo-/4,5-pyridinyl/-amino-3-nitro-benzoic acid

This compound is obtained from the compounds mentioned in examples 1d and 7e/, in accordance with the method described in example 1f/. Of 730 mg /2.34 mmol/ compound from example 7E/ and 655 mg /2.34 mmol/ compound from example 1d/ receive 988 mg of the target compound.

Melting point: 128 131oWITH

Rf/SiO2EE/Hep 8:2/ 0,3

MS/DCl/ 512 /M + H/

b/ Methyl ester of 2-n-butyl-1-/3-cyano-2-/4-were/-imidazo/4,5-pyridinyl/-1H-benzimidazole-7-carboxylic acid

The target compound is obtained from the compound of example 8A/ according to the method indicated in example 1g/.

Rf/SiO2CH is-5-yl/imidazo/4,4-pyridinyl/-1H-benzimidazole-7 carboxylic acid

157 mg /0.34 mmol/ Compound from example 8b/ enter into interaction by the method specified in example 7g/; obtain 88 mg of the target compound.

Melting point: 120-155oWITH

Rf/SiO2CH2Cl2/CH2OH 8:2/ 0,3

MS/FAB/ 507 /M + H/

d/ 2-n-Butyl-1-/2-/4-were/3-/H-tetrazol-5-yl/-imidazo /4,5-pyridinyl/-1H-benzimidazole-7-carboxylic acid

The target compound is obtained from the compound of example 8b according to the method described in example 1h/.

Rf/SiO2CH2Cl/CH3OH/CH3COOH/H2O 20:15:2:4 0,8 ///1 MS/FAB/ 493 /M + H/

Example 9

5,7-Dimethyl-2-ethyl-3-/2-carboxy-3-chloro-benzo/b/thiophene-6-yl/-methyl/3H-imidazo/4,5-b/pyridine

a/ 5,7-Dimethyl-2-ethyl-3-//3-chloro-2-methoxycarbonyl-benzo/b/ thiophene-6-yl/methyl/3H-imidazo/4,5-b/pyridine

500 mg /2.8 mmol/ 5,7-Dimethyl-2-ethyl-3H-imidazole/4,5-b/ pyridine/known from EP-a 400 974/ in an atmosphere of argon in 10 ml of abs. DMF is mixed with 165 mg of NaH /50%/; to the reaction solution after 30 min stirring, add 900 mg /2.8 mmol/ compound from example 4b/, and within 2 h and stirred at room temperature. The reaction solution is mixed with water, extracted through IT, combined IT extracts washed with water and saturated NaCl solution, dried over tion.

Rf/SIO2EE/CH315:1/ 0,3

MS/DCl/ 414 /M + H/

b/ 5,7-Dimethyl-2-ethyl-3-//2-carboxy-3-chloro-benzo/b/thiophene-6-yl-methyl/-3H-imidazo/4,5-b/pyridine

680 mg /1,64 mmol/ Compound from example 9a transform according to the method indicated in example 1L. Obtain 570 mg of the target compound.

MS /DCl/ 400 /M + H/

Example 10

5,7-Dimethyl-2-ethyl-3-//3-carboxy-2-phenyl-imidazo/1,2-a/ pyridine-7-yl/methyl/-3H-imidazo/4,5-b/pyridine

and/ 5,7-Dimethyl-2-ethyl-3-//3-etoxycarbonyl-2-phenyl-imidazo /1,2-a/-birdin-7-yl/methyl/-3H-imidazo/4,5-b/pyridine

Obtaining this compound is the same as given in example 9a, from 5,7-dimethyl-2-ethyl-3H-imidazo /4,5-b/pyridine is obtained according to EP-a 400 974/ and compounds from example 2C/. From 280 mg /0.78 mmol/ compound from example 2C/ obtain 160 mg of the target compound.

Rf/SiO2HER / 0,2

MS/FAB/ 454 /M + H/.

b/ 5,7-Dimethyl-2-ethyl-3-//3-carboxy-2-phenyl-imidazo/1,2 - a/ pyridine-7-yl/methyl/-3H-imidazo/4,5-b/pyridine

The target compound is obtained from the compound of example 10b/ by the method specified in example 1L/.

MS /FAB/ 426 /M + H/

Example 11

5,7-Dimethyl-2-ethyl-3-//2-/4-were/-3-/1H-tetrazol-5-yl/imidazo/ 4,5-pyridinyl/-3H-imidazo/4,5-b/pyridine

and/ 5,7-Dimethyl-2-ethyl-3-/3-cyano-2-/4-Matildas/4,5-b/pyridine/ obtained according to EP-a 400 974/ and compounds from example 7E/

MS/DCI/ 407 /M + H/

b/ 5,7-Dimethyl-2-ethyl-3-//2-/4-were/-3-/1H - tetrazol-5-yl/imidazo/4,5-pyridinyl/-3H-imidazo/4,5-b/pyridine

The target compound is obtained from the compound from example 11a/ according to the method indicated in example 7g/.

MS/FAB/ 450 /M + H/.

Example 12

3-//2'-Aminomethylphenol/carbonemissions-biphenyl-4-yl/-methyl/-5,7-dimethyl-2-ethyl-3H-imidazo/4,5-b/pyridine

a) Sulfonamides

of 51.6 g (0.3 mol) 0-Bromoaniline in argon atmosphere dobavlayet to a solution consisting of 100 ml of concentrated Hcl and 30 ml of glacial acetic acid; at a temperature of 10oWith added dropwise a solution of 22.4 g of nitrite in 30 ml of water, and the reaction solution is stirred for 60 min at -5oC. the resulting solution was added dropwise to saturated SO2to a solution of 7 g uCl2x 2H2O and 0.5 g uCl in 300 ml of glacial acetic acid, the mixture after 60 min of stirring at room temperature is poured into a mixture of ice/water, extracted with ether, the ether extracts washed with saturated solution of NaHCO3and with water, dried over MgSO4and concentrate. Received sulfurylchloride connection number and 67.8 g in 500 ml of acetone, cooled, mixed with 300 ml of concentrated ammonia. After myauth H2O, and dried in high vacuum. The target compound without further purification used in the next reaction.

b/ 2-N,N-Dimethylbenzenesulfonamide

0,236 mol of Compound from example 12A in 150 ml of abs. DMF 40 ml of N,N-dimethylformamidine stirred for 2 h at room temperature. The reaction solution was poured into 200 ml of a 5% solution of NaHSO4with ice /1: 1/, the precipitation is sucked off, washed with H2and dried in vacuum. Get 67 g of target compound.

Rf /SiO2EE/Hep 1:1/ 0,1

MS/DCI/ 291 /M + N/

c/ 4'-Methyl-biphenyl-2-N,N-dimethylbenzenesulfonamide

To 11 g /of 37.9 mmol/ compound from example 12b, 1 g of triphenylphosphine, 8 g of Na2CO3in 150 ml of toluene and 40 ml of H2O add, in argon atmosphere, first 420 mg Pd/OAC/2and then to 5.66 g of 41.9 mmol /tolylboronic acid in 100 ml ethanol.

Now boiled for 4 h, then concentrated and treated with 500 ml of IT and 500 ml of H2O. the Resulting precipitate is filtered off, and is characterized as the target connection. ITS phase is separated, dried over Na2SO4and concentrate. Chromatography on SiO2using IT gives further number of target compounds;

Total yield: 7,ltname

The target compound is produced from compound 12 with a /by way of example 1K/. Of 3.8 g /13.5 mmol/ compound 12 is obtained 1.2 g of the target compound.

Rf/SiO2HER/Hep 2:1/ 0,2

MS/DCI/ 381 /383/ M + H/

e/ 5,7-dimethyl-3-//2'-N,N-dimethylbenzenesulfonamide-4-yl /-methyl/-2-ethyl-3H-imidazo-4:5-o/pyridine

The target compound is obtained from the compound of example 12d and 5,7-dimethyl-2-ethyl-3H-imidazo/4,5-o/pyridine according to the method of example 9a. Of 3.2 g of compound 12d obtain 1.1 g of the target compound;

Rf/SiO2HER/CH310:1/ 0,2

MS/FAB/: 476 /M + H/

f/ /5,7-Dimethyl-2-ethyl-3-//2'-sulfonatophenyl-4-yl/methyl/ 3H-imidazo/4,5-b/pyridine

0.6 g /1,26 mmol/ Compound from example 12E /boil/ under reflux in 20 ml of ethanol with 10 ml of concentrated Hcl solution for 45 minutes, the Ethanol is removed in vacuo, neutralized by saturated NaHCO3using the solution of NaHSO4install approximately pH 5-6 and extracted through IT. ITS phase is dried /Na2SO4and concentrate, and obtain 380 mg of the target compound.

RF/SiO2EE/Hep 5:1/ 0,5

MS/FAB/: 421 /M + H/.

g/ 5,7-Dimethyl-2-ethyl-3-//2'-ethoxycarbonylmethylene-4-yl/-methyl/-3H-imidazo/4,5-b/pyridine

0,52 is mg /2.4 mmol/ ethyl ether of Harborview acid is refluxed for 3 hours After cooling to room temperature, mixed with 10% solution of NaHSO4, extracted with HER and the organic phase is dried over MgSO4. Concentration and chromatography on SiO2using IT as additionally separated by give 250 mg of the target compound.

Rf/SiO2EE/ 0,2

MS/FAB/ 493 /M + H/

h/ 3-//2'-Aminomethylphenol/carbonemissions-biphenyl-4 - yl/methyl//-5,7-dimethyl-2-ethyl-3H-imidazo/4,5-b/pyridine

80 mg /0,16 mmol/ Compound from example 12g and 50 μl of the phenethylamine refluxed in 5 ml of abs. toluene in an argon atmosphere for 1.5 hours After concentration and chromatography on SiO2through HER/CH3OH 10: 1 will receive 70 mg of target compound after freeze-drying, in the form of amorphous powder,

Rf/SiO2EE/CH2OH 10:1/ 0,4

MS/FAB/ 568 /M + H/

Example 13

3-//2'-/Aminoethylthiomethyl/-carbonylmethyl-biphenyl-4-yl/-methyl/-5,7-dimethyl-2-ethyl-3H-imidazo/4,5-b/pyridine

The target connection receive according to the method of example 12h of the compound from example 12g and cyclohexylethylamine; obtained from 80 mg /0.16 mmol) of the compound from example 12 g/ 90 mg of target compound after freeze-drying in the form of an amorphous solid.

Rf/SiO2,-dimethyl-2-ethyl-3H-imidazo/4,5-b/pyridine

The target connection receive according to the method of example 12h of the compound from example 12g/ and cyclohexylethylamine; obtained from 80 mg /0,16 mmol/ compound from example 12g 90 mg of target compound after freeze-drying in the form of an amorphous solid.

Rf/SiO2EE/ 0,3

MS/FAB/ 560 /M + H/

Example 14

3-//2'-/Dimethylamine/carbonemissions-biphenyl-4-yl/-5,7-dimethyl-2-ethyl-3H-imidazo//4,5-b/pyridine

The target connection receive according to the method of example 12h from the compound of example 12g and diallylamine. Receive 60 mg of target compound from 80 mg/0,16 mmol/connections example 12g) as amorphous solids.

Rf/SiO2HER/CH3OH 10:1/ 0,2

MS/FAB/ 544 /M + H/

Example 15.

3-//2'-/N, N-Diallylbarbituric-aminosulfonyl-biphenyl-4-yl/methyl/-5,7-dimethyl-2-ethyl-3H-imidazo/4,5-b/pyridine

100 mg /0.23 mmol/ Compound of example 12f /in 10 ml of abs. DMF) in an argon atmosphere with 66 mg /0.46 mmol/ K2CO3and 57 mg (0.47 mmol) allyl ether of Harborview acid is boiled for 45 minutes After concentration, processing IT, wash IT-phase using a 10% solution of Na2HSO4, drying /MgSO4/ and chromatography on SiO2through ITS receive 70 mg Clevo is//2'-/N, N-Dimensionsional/aminosulfonyl-biphenyl-4-yl/-5,7-dimethyl-2-ethyl-3H-imidazo/4,5-b/pyridine

This connection receive according to the method of example 15 from the compound of example 12f and benzyl ether of Harborview acid. Of 100 mg /0.23 mmol/ connections 12f/ receive 70 mg of the target compound.

Rf /SiO2EE/ 0,2

MS/FAB/ 689 /M + H/

Example 17

3-//2'-/Cyclohexyloxycarbonyl/aminosulfonyl-biphenyl - /-4-yl/-5,7-dimethyl-2-ethyl-imidazo/4,5-b/pyridine

The target compound is obtained from the compound of example 12f and cyclohexylmethanol ether Harborview acid according to the method of example 15, and amide and ether used but in equimolar ratio.

Rf/SiO2; methyl-tert.-butyl ether/ 0,2

MS/FAB/, 561 /M + H/

Example 18

5,7-Methyl-2-ethyl-3-//2'-ethoxycarbonyl/aminosulfonyl-biphenyl-4-yl/methyl/-3H-imidazo/4,5-b/pyridine

The target compound is obtained from the compound of example 12 and ethyl ether of Harborview acid according to the method of example 17.

Rf/SiO2EE/ 0,2

MS/FBA/ 493 /M + H/

Example 19

2-n-Butyl-1-//2'-ethoxycarbonylmethyl-biphenyl-4-yl/methyl-1H-benzimidazol-7-carboxylic acid

and/ Methyl ether 2-/N-/n-pentanol/-2'-N,N-dimethylbenzenesulfonamide-bifani,2 mmol/ compound from example 12 d and 11.7 g /84,6 mmol/ K2CO3in 200 ml of abs. DMF for 24 h at room temperature. After concentrating to dryness, the residue treated HER, the solution washed three times with H2Oh, 1 times solution SO4/25%/ once with saturated solution of NaHCO3and once with saturated NaCl solution, dried over MgSO4and concentrate. Oily residue gives, after crystallization from HER/ diisopropyl ether, 7,9 the target compounds. Chromatography of the concentrated mother liquor on SiO2using n-heptane /HER (2/3) gives more of 2.54 g of the target compound.

Melting point: 148 152oC.

Rf/SiO2, n-heptane /2:8/ 0,33

MS /FAB/ 581 /M + H/

b/ Methyl ether 2-/N-/n-pentanol/-//2'-N,N-dimethylbenzenesulfonamide-biphenyl-4-yl/ methyl/amino/-3-amino-benzoic acid

10.4 g /17,9 mmol/ Compound from example 19a hydronaut in 800 ml of methanol for 3 h in the presence of Raney Nickel. The catalyst is filtered off, the filtrate is concentrated to dryness, the residue is dried in high vacuum. Get to 9.9 g of the target compound as an amorphous foam.

Rf /SiO2CH2CI2/CH3OH 95:5/ 0,3

MS /FAB/ 551 /M + H/

c/ Methyl ester of 2-n-butyl-1-//2'-sulfonatophenyl-4-yl/Manolo with 90 ml of concentrated hydrochloric acid for 3 hours at the boiling temperature under reflux. The solvent is evaporated, the remaining solution set using 6N NaOH solution pH of about 5-6, the aqueous solution extracted three times by means of CH2Cl2combined organic phases are washed with saturated NaCl solution and dried over MgSO4. Recrystallization from ITS network 8,16 g of target compound as white crystals.

Melting point: 192 195oWITH

Rf/SiO2EE/n-heptane 8:2/ 0,38

MS/FAB/ 478 /M + H/

Alternative target compound is also obtained from the compound of example 19a by this method. When this is obtained from 100 mg /0,19 mmol/ connections 19a of 60 mg of the target compound.

d/ Methyl ester of 2-n-butyl-1-//2'-dimethylbenzenesulfonamide-biphenyl-4-yl/methyl/-1H-benzimidazol-7-carboxylic acid

150 mg /0.18 mmol/ Compound from example 19b in the atmosphere of argon in 10 ml of a mixture of isopropanol /EE/ /1:1/ 10 ml of saturated HCl EE solution is left to stand overnight at room temperature. Concentrated, the residue is treated CH2CI2CH2CI2the phase is washed with a saturated solution of Na2CO3water and saturated NaCI solution and dried on MgSO4. Concentration and drying in a high vacuum gives 138 mg target si ether 2-n-butyl-1-//2'-ethoxycarbonylmethylene-4-yl/-1H-benzimidazol-7-carboxylic acid

3.25 g /for 6.81 mmol/ Compound from example 19 and 170 ml /1,36 mmole/ DMAP in 12 ml of abs. pyridine in an argon atmosphere at 0oWith mixed with 1,53 g /13,6 mmol/ tert. -potassium butyl and after 10 min of stirring at the same temperature is mixed with 0,65 ml /for 6.81 mmol/ ethyl ether of Harborview acid. Stirred over night at room temperature. Then in the solution under ice cooling set an acidic reaction using 25% solution SO4and multiple extracted with HER. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4and concentrate. Chromatography on SiO2by CH2CI2/CH3OH/NH39:1:0.1 to/ give 1.8 g of the target compound as an amorphous foam.

Rf/SiO2; CH2CI2/ CH3OH/CH3COOH 9:1:0,2/ 0,71

MS /FAB/ 550 /M + H/

f/ 2-N-Butyl-1-//2'-ethoxycarbonylmethyl-biphenyl-4-yl/methyl/-1H-benzoimidazol-7-carboxylic acid

Obtaining the target compound from the compound of example 19th is carried out according to the method indicated in example 1h.

Rf/SiO2CH2CI2/CH3OH/CH3COOH 9:1:0,2/ 0,64

MS /FAB/ 536 /M + H/

Example 20

2-n-Butyl-1-//2'-n-propylenecarbonate incorporatedsolvang-biphenyl-4-yl/ methyl/-1H-benzimidazol-7-carboxylic acid

100 mg /0,21 mmol/ Compound from example 19 with 8 ml of abs. acetone with 90 mg /0.6 mmol/ K2CO3in 24 ál /0.25 mmol/ h-propositionthe for 2 h refluxed. After cooling the solution by adding 2 NHCl establish a pH of approximately 1, and repeatedly extracted by CH2CI2. The combined organic phases are washed once with H2O and once with saturated NaCI solution, dried over MgSO4and concentrate. Recrystallization from HER give 107 mg of the target compound.

Melting point: 150-152oC.

Rf/SiO2; CH2CI2/CH3OH/NH39:1:0,2/ 0,24

MS /FAB/ 563 /M + H/.

b/ 2-n-Butyl-1-//2'-n-propylbenzenesulfonyl-biphenyl - /-4-yl/methyl/-1H-benzimidazole-7-carboxylic acid

The target compound is obtained from the compound from example 20A according to the method indicated in example 1h. From 38 mg /0.07 mmol/ compound of example 20 and receive 30 mg of target compound as an amorphous foam.

Rf /SiO2CH2CI2/CH3OH/CH3COOH 9:1:0,2/ 0,2

MS /FAB/ 549 /M + H/

Example 21

2-n-Butyl-1-//2'-isopropylaminocarbonyl-biphenyl-4-yl/methyl/-1H-benzimidazole-7-carboxylic acid is for 8 h in an autoclave at a temperature of 80oC. the Reaction solution was concentrated, and the residue chromatographic on SiO2with the help of CH2CI2/CH3OH/ 95:5/. Obtain 38 mg of the target compound as an amorphous foam.

Rf/SiO2CH2Cl2/CH3OH/CH3COOH 9:1:0,2/ 0,35

Ms /FAB/ 549 /M + H/

Example 22

2-n-Butyl-1-//2'-allylaminogeldanamycin-biphenyl-4-yl/-methyl/-1H-benzimidazol-7-carboxylic acid

a/ Methyl ester of 2-n-butyl-1-//2'-allylaminogeldanamycin-biphenyl-4-yl/-methyl-1H-benzimidazol-7-carboxylic acid

The target compound is obtained from the compound of example 19 according to the method of example 20 and in the application arylisocyanate instead of n-propositionthe. Of 150 mg /0.31 mmol/ compound from example 19 (C) obtain 136 mg of the target compound.

Melting point; 142 145oC.

Rf/SiO2CH2CI2/CH3OH/NH39:1:0,2/ 0,19

MS/FAB /561/ M + H/

b/ 2-n-Butyl-1-//2'-allylaminogeldanamycin-biphenyl-4-yl/ methyl-1H-benzimidazole-7-carboxylic acid

Obtaining this compound is carried out according to the method of example 1h and 123 mg /0.22 mmol/ connections 22 and obtain 73 mg of the target compound.

Melting point: 220oWITH

Rf/SiO2CH
and/ Methyl ester of 2-n-butyl-1-//2'-ethylenediaminetetra-biphenyl-4-yl/ -methyl/-1H-benzimidazole-7-carboxylic acid

The target compound is obtained from the connection specified in example 19 (C), by interacting with utilitarianism according to the method of example 20.

Melting point: 182oC.

Rf/SiO2CH2CI2/CH3OH/NH39:1:0,2/ 0,22

MS /FAB/ 549 /M + H/

b/ 2-n-Butyl-1-//2'-ethylenediaminetetra-biphenyl-4-yl/methyl/-1H-benzimidazole-7-carboxylic acid

This compound is obtained from the compound of example 23 and according to the method described in example 1h.

Melting point: > 220oWITH

Rf/SiO2CH2CI2/CH3COOH 9:1:0,2/ 0,35

MS/FAB/ 535 /M + H/

Example 24

2-n-Butyl-1-//2'-cyclopropanecarbonitrile-biphenyl-4-yl/methyl-1H-benzimidazole-7-carboxylic acid

and/ Methyl ester of 2-n-butyl-1-//2'-cyclopropanecarbonitrile-biphenyl-4-yl/methyl-1H-benzimidazole-7-carboxylic acid

139 GM /0.29 mmol/ Compound from example 19c/ in an atmosphere of argon in 2 ml of abs. DMSO with 35 mg /0.88 mmol/ powdered of NaC and 67 mg /0.32 mmol/ 2,2,2-trichloro-N-cyclopropylmethyl-ndimethylacetamide /from Cyclops is up on the ice, acidified with 2n Hcl and the precipitated precipitate is sucked off. After recrystallization from HER obtain 69 mg of the target compound.

Melting point: 158-161oWITH

Rf/SiO2, n-heptane/EE/ 2:8/ 0,23

MS /FAB/ 575 /M + H/

b/ 2-n-Butyl-1-//2'-cyclopropanecarbonitrile-biphenyl-4-yl/methyl-1H-benzimidazole-7-carboxylic acid

The target compound is obtained from the compound of example 24 and by the method specified in example 1h.

Melting point: 234 236oWITH

Rf/SiO2CH2CI2/CH3OH/CH3COOH 9:1:0,2/ 0,28

MS /FAB/ 561 /M + H/.

Example 25

2-n-Butyl-3-//2'-ethoxycarbonylmethyl-biphenyl-4-yl/methyl-3H-imidazo-/4,5-b/ /5,4-b/-pyridine

a/ 2-n-Butyl-3-//2'-N, N-dimethylbenzenesulfonamide-biphenyl-4-yl/methyl/-3H-imidazo-/4,5-b/ /5,4-b/-pyridine

The target compound is obtained from the compounds mentioned in examples 4 and 12 d according to the method described in example 4 b. Purification is accomplished by chromatography on SiO2with the help of HER/CH3OH 20:1 as solvent and crystallization from HER/diisopropyl ether. Melting point: 205-211oC.

Rf/SiO2EE/CH3OH 20:1/ 0,15

MS /FAB/ 476 /M + H/

b/ 2-n-Butyl-3-//2'-sulfonatophenyl-4-yl/methi chromatography on SiO2with the help of HER/CH3HE is 20:1 as solvent.

Rf/SiO2EE/CH3OH 20:1/ 0,39

MS /FAB/ 421 /M + H/

c/ 2-n-Butyl-3-//2' -ethoxycarbonylmethyl-biphenyl-4-yl/ methyl-3H-imidazo/4,5-b/ / /5,4-b/ pyridine

1 g /2,38 mmol/ Compound from example 25b/ in an atmosphere of argon in 25 ml of abs. dimethoxyethane with 1 g of activated /drying in high vacuum at 150o3 h/ molecular sieve 4 , 0.66 g2CO3and 232 μl of ethyl ether of Harborview acid is refluxed for 6 hours, After cooling, mixed with 100 ml of 10% solution KN2PO4/pH approximately 4/, is shaken out three times with HER, merged ITS extracts are dried over Na2SO4and concentrate. Chromatography on SiO2/EE/CH3HE is 20:1/ give 0.5 g of the target compound.

Melting point: 172oWITH

Rf/SiO2EE/CH3OH 20:1/ 0,3

MS/FAB/ 493 /M + H/

Example 26

2-n-Butyl-3-//2'-isopropylaminocarbonyl-biphenyl-4-yl/methyl/-3H-imidazo/4,5-b/ / /5,4-b/pyridine

The target compound is obtained from 100 mg /0.2 mmol/ compound from example 25 with after boiling at reflux for 3 h with 209 μl /2,44 mmol/ Isopropylamine in 5 ml of toluene, concentration and chromatography H1/ 0,36

Ms /FAB/ 506 /M + H/

Example 27

2-n-Butyl-3-//2'-allylaminogeldanamycin-biphenyl-4-yl-/methyl-3H-imidazo/4,5-b/ / /5,4-b/pyridine

The target compound is obtained by interaction of the compounds of example 25 b/ s arylisocyanates similar to the method described in example 20.

Melting point: 121oWITH

Rf/SiO2HER/CH3HE IS 20:1/ 0,26

MS/FAB/ 504 /M + H/

Example 28

2-n-Butyl-3-[/2'-n-propylbenzenesulfonyl-biphenyl-4-yl/-methyl]-3H-imidazo-/4,5-b/ / /5,4-b/ pyridine

150 mg /0.3 mmol/ compound of example 25C/ 5 ml toluene with 295 μl /3.6 mmol/ n-Propylamine refluxed for 3 h

Carry out the concentration, and the residue is subjected to chromatography on SiO2/ITS/. Receive 90 mg of the target compound.

Melting point: 137 138oC.

Rf/SiO2EE/ 0,2

MS /FAB/ 506/ M + H/

Example 29

2-n-Butyl-3-//2'-benzyloxycarbonylamino-biphenyl-4-yl/methyl-3H-imidazol-/4,5-b/ / /5,4-b/ pyridine

The target compound is obtained from the compound of example 25 b and benzyl ether of Harborview acid according to the method described in example 25 C.

Melting point: 85oWITH

Rf/SiO2EE/CH3OH 20:1 0,29

MS is the AOR-/4,5-b/pyridine

a/ 2-Ethyl-7-methyl-3H-imidazo/4,5-b/pyridine

10 g /65.3 mmol/ 2-Amino-4-methyl-3-nitropyridine subjected to hydrogenation in 40 ml of tetrahydrofuran and 40 ml of methanol in the presence of Nickel Raney. The catalyst is filtered off, the solvent is removed, the residue is mixed with ethanolic HCl and usageprice 2,3-diamino-4-methyl-pyridine-hydrochloride sucked off. 7 g of the hydrochloride is dissolved in 57 g of polyphosphoric acid and from 28.5 g R2O5and 28.5 g of N3PO4/85-Noah// mixed with some of 1.26 ml of propionic acid and the solution is stirred for 2 hours at a temperature of 100oC. After cooling, poured into ice water, alkalinized in the additive Na2CO3and repeatedly extracted with HER. The combined ITS-phases are washed with a saturated solution of NaCl, dried over Na2SO4concentrate and the residue chromatographic on SiO2/EE/ CH3OH 5:1/. Gain of 4.2 g of the target compound.

Rf/SiO2EE/CH35:1/ 0,4

MS /DCl/ 162 /M + H/

b/ 3-//2'-N,N-Dimethylbenzenesulfonamide-biphenyl-4-yl/methyl/-2-ethyl-7-methyl-imidazo/4,5-b/pyridine

3.1 g /(Jn 19: 26 mmol/ Compound from example 30 and and 9.15 g /(Jn 19: 26 mmol/ compound from example 12 d /75%/ 200 ml abs. DMF in the presence of 2.6 g /a 19.6 mmol/ K2CO2Cl2CH2Cl2the solution is washed with water, dried over Na2SO4and concentrate. Chromatography on SiO2/EE/ CH3OH /20:1/ give 2.8 g of the target compound. Melting point: 168 170oC.

Rf/EE/CH3OH 20:1/ 0,13

MS /FAB/ 462 /M + H/

with/ 2-Ethyl-7-methyl-3-//2'-sulfonatophenyl-4-yl/-methyl-imidazo /4,5-b/pyridine

2.8 g /6,06 mmol/ Compound from example 30b is transferred to the target compound (2.2 g) according to the method described in example 19 C.

Melting point: 211-212oWITH

Rf/SiO2HER/CF3HE/ 0,35

MS /FAB/ 407 /M + H/

b/ 2-Ethyl-7-methyl-3-[(2'-n-propylbenzenesulfonyl-4-yl) -methyl-imidazo/4,5-b/pyridine

The target compound is obtained from the compound of example 30 and n-propositionthe according to the method of example 20. Of 70 mg /0,172 mmol/ connections 30 to obtain 43 mg of the target product.

Melting point: 215-220oWITH

Rf/SiO2EE /CH320:1/ 0,36

MS /FAB/ 492 /M + H/

Example 31

2-Ethyl-3-//2'-ethylenediaminetetra-biphenyl-4-yl/methyl-7-methyl-imidazo/4,5-b/pyridine

The target compound is obtained from the compound of example 30 and utilizationof according to the method of example 20 a. melting point: 240 245oWITH

Rf is Il/-2-ethyl-7-methyl-imidazo/4,5-b/pyridine

Obtaining the target compound is carried out by a reaction between the compounds of example 30C arylisocyanates by way of example 20A.

Melting point: 216 219oWITH

Rf/SiO2HER/ 0,13

MS /SAB/ 490 /M + H/

Example 33

2-Ethyl-3-//2'-methoxycarbonylaminophenyl-biphenyl-4-yl)methyl/-7-methyl-imidazo/4,5-b/pyridine

100 mg /0,245 mmol/ Compound from example 30 to mix with 171 mg /1,24 mmole/ K2CO3, 62 μl /of 0.62 mmol/ dimethylcarbonate and 25 mg of DMAP in 10 ml dietilaminoetilovogo ether for 2 h at boiling temperature under reflux. Then carry out the distillation, the residue is mixed with a solution of HER/KN2PO4the organic phase is separated and washed twice with a solution of KH2PO4. Drying over Na2SO4, concentration and chromatography on SiO2give 44 mg of the target compound.

Rf/SiO2EE/ 0,15

MS/FAB/: 465 /M + H/.

Listed in the table examples of the formula Y get like that shown in examples 1 33 methods of the described structural elements:

e

1. Imidazo-kannelirovannye ISO - and heterocyclic compounds of General formula I

< / BR>
where X is a monocyclic residue with 4 atoms in the ring, in which one or different, hydrogen, carboxyl, C1C6-alkyl, C1C4-alkoxycarbonyl;

L C1C3-alcander;

And the rest of bicyclic heterocycle with 9 atoms in the ring containing 1 atom S or 1 3 N atom, substituted residues R4and R5or biphenylyl residue, substituted by identical or different residues R4and R5and As necessarily substituted by at least one residue R5;

R4halogen, 2-tetrazolyl, -SO2NH2, cyano;

R5hydrogen, C1C4-alkyl, alkoxycarbonyl, carboxyl, -SO2-NHCONR6R7, -SO2-NHCOOR7, -SO2-N(COOR7)2, -SO2N=CHN(CH3)2, phenyl, were;

R6, R7the same or different, hydrogen, C1- C4- alkyl, C3WITH8-cycloalkyl-C1WITH4-alkyl, phenyl-C1WITH4-alkyl, C2- C6alkenyl or R6and R7form together with supporting their nitrogen atom of heteroaryl, which may be partially or fully gidrirovanny,

as well as their physiologically compatible salts.

2. The method of obtaining the compounds of formula I

< / BR>
where the radicals take the values defined for formula I, p. 1, otlichalis jirout compound of formula III

U L A,

where A and L have the above meanings;

U tsepliaeva group, if necessary temporarily introduced protective group,

again otscheplaut with the separation of the target product in free form or as physiologically acceptable salt.

3. The compound of formula I on p. 1, showing an antagonistic effect on the angiotensin II receptor.

 

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