Substituted azoles and method of production thereof

 

(57) Abstract:

Usage: as the antagonists of the angiotensin-II-receptor. The inventive substituted azoles f-crystals I and the way they are received by the interaction of the compounds f-crystals II with compound f-ly III, followed by protective groups. Radicals have the appropriate values. Connection structure f-ly I, II, III. 2 S. p. f-crystals.

From EP-A-324 377, EP-A-253 310; EP-A-288 733 and EP-A-323 841 known as derivatives, imidazoles, pyrrole, pyrazole or triazole and their use as antagonists of the Angiotensin-II-receptor.

New substituted azoles in this invention are the highest-impact antagonists angiotensin-II-receptor and in vivo and in vitro. The invention relates to compounds of the formula I

R in which

a) X, Y, Z, equal or different and denote N or CR2,

b) R1means

1. (C2-C10)-alkyl

2. (C3-C10)-alkenyl

3. (C3-C10)-quinil

4. OR3< / BR>
5. (C3-C8-cycloalkyl

6. (C4-C10-cycloalkenyl

7. (C5-C10)-cycloalkylcarbonyl

8. (C5-C10-cycloalkylcarbonyl

9. -(CH2)m-B-(CH2)n-R4
13. in paragraph (b) 10. certain radical, in which the phenyl is substituted by 1 or 2 identical or different radicals from the series halogen, (C1-C4)-alkoxy or nitro;

(C) R2means

1. hydrogen

2. halogen-free

3. nitro,

4. CvF2v+1< / BR>
5. pentafluorophenyl

6. cyano

7. phenyl

8. phenyl-(C1-C3)-alkyl

9. (C1-C10)-alkyl

10. (C3-C10)-alkenyl

11. phenyl-(C2-C6)-alkenyl

12. 1-imidazol-(CH2)m-

13. 1,2,3-triazole-(CH2)n-

14. tetrazol-(CH2)m-

15.-(CH2)o-1-CHR7-OR5< / BR>
16. -(CH2)o-O-CO-R3< / BR>
17. -(CH2)o-S-R6< / BR>
18. -S(O)r-R6< / BR>
19. -CH=CH-(CH2)m-CHR3-OR6< / BR>
20. -CH2=CH-(CH2)m-CO-R6< / BR>
21. -CO-R8< / BR>
22. -CH=CH-(CH2)m-O-CO-R7< / BR>
23. -(CH2)m-CH(CH3)-CO-R8< / BR>
24. -(CH2)o-CO-R8< / BR>
25. -(CH2)o-O--NR-R9< / BR>
26. -(CH2)o-NR7--OR9< / BR>
27. -(CH2)o-NR7-CO-OTHER9,

28.O-NO2,

32. -CH2-N3,

33. -(CH2)n-NO2,

34. -CH=N-NR5R7,

35. phthalimido(CH2)n-,

36. -(CH2)NH

37. -(CH2CF3< / BR>
38. -(CH2)n- NN

39. -(CH2)o- NN

40. phenyl-SO2-NH-N=CH-

41. -CH=N-NH

42. -(CH2)n-SO2-NR7-CO-NR6R9,

43. -(CH2)o-SO2R9,

44. one of the paragraphs (C) 7. or 8. certain radical, which is substituted in the phenyl with 1 or 2 identical or different radicals from the series halogen, hydroxy, methoxy, trifloromethyl, CO2R3or phenyl.

46. in paragraph (C) 13. certain radical, which is substituted by 1 or 2 identical or different radicals from the series of methoxycarbonyl and (C1-C4)-alkyl,

d) R3means

1. hydrogen

2. (C1-C8)-alkyl

3. (C3-C8-cycloalkyl

4. phenyl

5. benzyl or

6. in paragraph (d) 2. certain radical, where from 1 to all H atoms replaced by fluorine

e) R4means

1. hydrogen

2. (C1-C6)-alkyl

3. (C3-C8-cycloalkyl

4. (C2-C4)-alkenyl or

5. (C2-C4)-quinil

f) R5on or

5. benzil

g) R6means

1. hydrogen

2. (C1-C6)-alkyl

3. (C3-C8-cycloalkyl

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

5. benzil

6. (C1-C9-heteroaryl, which may be partially or fully be gidrirovanny, preferably 2-pyrimidinyl

7. (C1-C4-alkanoyl

8. one in paragraph (g) 4. or 6. certain radical, substituted by 1 or 2 identical or different radicals from the series halogen, hydroxy, methoxy, nitro, cyano, CO2R3and trifloromethyl, NR11R12or

9. (C1-C9-heteroaryl-(C1-C3)-alkyl, in this part of heteroaryl may be partially or fully gidrirovannah.

h) R7means

1. hydrogen

2. (C1-C6)-alkyl

3. (C3-C8-cycloalkyl

4. (C6-C12)-aryl-(C1-C6)-alkyl, preferably benzyl

5. phenyl or

6. (C1-C9-heteroaryl

i) R8means

1. hydrogen

2. (C1-C6)-alkyl

3. (C3-C8-cycloalkyl

4. phenyl-(CH2)q-,

5. OR5,

6. NR11R12or

7. -N

j) R9means

1. (The SUB> or

6. in paragraph (j) 1. certain radical, where from 1 to all of hydrogen atoms substituted by fluorine

k) R10means cyano, nitro or CO2R7;

l) R11and R12the same or different and mean

1. hydrogen

2. (C1-C4)-alkyl

3. phenyl

4. benzyl or

5. -methylbenzyl

m) D mean NR13, O, or CH2;

n) R13means hydrogen, (C1-C4)-alkyl or phenyl

Oh) And means the radical of a heterocycle with 5 to 10 ring atoms, which may be mono - or bicyclic and where up to 9 ring atoms are C-atoms which may be substituted up to 6, preferably up to 3 identical or different radicals R14or -(CH2)n-1-(CHR6-CH2)o-1-R15and which may be unsaturated or partially gidrirovanny;

R) R14means

1. halogen-free

2. oxo

3. nitroso

4. nitro

5. amino

6. cyano

7. hydroxy

8. (C1-C6)-alkyl

9. (C1-C4-alkanoyl

10. (C1-C4)-alkanoyloxy

11. CO2R3,

12. methanesulfonamido

13. triftormetilfosfinov

14. -CO-NH-OR9,

15. -SO2-NR6F7,

18. (C7-C13-aroyl

19. -CH2-NQ

20. -[CH]-NQ

21. (C6-C12)-aryl

q) R15means

1. hydrogen

2. (C1-C6)-alkyl

3. (C3-C8-cycloalkyl

4. (C6-C12)-aryl

5. (C7-C13-aroyl

6. (C1-C4)-alkoxy

7. (C1-C4)-alkanoyloxy

8. (C1-C9-heteroaryl

9. CO2R3,

10. halogen

11. cyano

12. nitro

13. NR6R7< / BR>
14. hydroxy

15. -CO-NH-CHR5-CO2R3,

16. sulfa

17. -SO3R3,

18. -SO2-NR7-CO-NR6R9,

19. -NR7-CO-NR6-SO2-CH2-R5< / BR>
20. -C(CF3)2OH,

21. phosphonooxy

22. RHO3H2,

23. -NH-PO(OH)2,

24. -S(O)2R6,

25. -CO-R8,

26. -CO-NR6R9,

27. -CR20(OH),-PO(OH)2,

28. in paragraph (p) 20. certain radical

29. -SO2-NH-S

30. -NH-CO CO2H

31. -O-(CH2]n-NQ

32. 5-tetrazolyl-NH-CO-,

33. -CO-NH-NH-SO2CF3,

34. -CO

35. R7< / BR>
36. CF3< / BR>
37. NH

38. -T

39. -N

40. -CO-NH-SO2-R19or

41. in paragraph (q) 4R6R7and hydroxy;

r) B means O, NR7or S;

s) W denotes O or S;

t) L means (C1-C3)-alcander;

u) R16means CO2R3or CH2CO2R3;

v) R17means hydrogen, halogen, (C1-C4)-alkyl or (C1-C4)alkoxy;

w) R18means hydrogen, (C1-C4)-alkyl or phenyl;

x) R19means

1. (C1-C8)-alkyl

2. (C3-C8-cycloalkyl

3. phenyl

4. benzyl or

5. in paragraph (x) 1. certain radical, where one to all the H atoms replaced by fluorine or chlorine;

y) T means

1. simple link

2. - -

3. -CH2-

4. -O-

5. -S-

6. NR21-,

7. -CO-NR21-,

8. -NR21-CO-,

9. -O-CH2-,

10. -CH2-O-,

11. -S-CH2-,

12. -CH2-S-,

13. -NH-CR20R22-,

14. -NR21-SO2-,

15. -SO2-NR21-,

16. -CR20R22-NH-,

17. -CH=CH-

18. -CF=CF

19. -CH=CF

20. -CF=CH-

21. -CH2-CH2-

22. -CF2-CF2-,

23. -CH(OR3)-

24. -CH(OCOR5)-

25. or

26. C

z) R20and R22the same or different and mean hydrogen, (Cnil or allyl;

b') means 1.

2. ureido

3. tririga

4. toluene-4-sulfonyl or

5. benzosulfimide

C') R24and R25the same or different and mean (C1-C4)-alkyl or together stand for -- (CH2)q-;

d') R26and R27the same or different and mean

1. hydrogen

2. halogen

3. nitro

4. (C1-C4)-alkyl or

5. (C1-C2)-alkoxy

e') Q means CH2, NH, O or S;

f') m is a whole number from 0 to 5;

g') n is a whole number from 1 to 5;

h') o whole number from 1 to 10;

i') q is 0 or 1;

j') r is 0, 1 or 2 or

k') v whole number from 1 to 6; and their physiologically compatible salts.

Alkyl, alkenyl or quinil can be straight-chain or branched. The same thing is to learn from these radicals, as alkenyl or alkoxy.

Under cycloalkyl are also alkyl substituted rings.

(C6-C12)-aryl is, for example, phenyl, naphthyl or biphenyl, preferably phenyl. The same thing is to learn from these radicals, as aroyl or aralkyl.

Under (C1-C9-heteroaryl understood, in particular, radicals which are derived from phenyl or naphthyl, to the above may also be 1 or both of the atom designated condensation of a bicyclic radical (as in Indochinese) N-atom. This is, for example, furanyl, tiny, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, chincarini, hintline, indolinyl.

Under the heterocycle EN2, from which it is derived radical And, see, for example, the radical of furan, thiophene, imidazole, pyrazole, triazole, oxazole, isoxazol, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, indazole, quinoline, isoquinoline, phthalazine, Hinckley, heatline, cinnoline, benzothiophene, benzofuran, coumarin, chromane, benzthiazole, benzoxazole, benzisothiazole, benzoxazine, benzthiazide, imidazopyridine, imidazopyrimidines, imidazo - pyrazine, imidazopyridine, imidazolidine, imidazothiazole, imidazolidinone, pyrazolidine, properidine, thienopyridine, oxazolopyridine, oxazolopyridine and pyrrolopyrimidine. If the heterocycle is partially gidrirovanny, radical remains preferably aromatic.

Binding And is isoctliteral or heterocyclic part through alcander-bridge L.

Under physiologically compatible salts of the compounds of formula I is the basis of physical and chemical stability and solubility among the acidic group is preferable among others, sodium, potassium and ammonium salts; among the main groups among the other salts with hydrochloric acid, sulfuric acid, phosphoric acid, carboxylic acid or acid and acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, p-toluensulfonate. Preferred compounds of formula I, where

a) X=N,Y represents CR2Z means CR2< / BR>
b) X is CR2Y=N and Z=CR2< / BR>
C) X is CR2Y=CR2Z=N or

d) X, Y, and Z as needed means N, with

(C) is particularly preferable.

Further preferred compounds of formula (I), in which

a) R1means

1. (C3-C10)-alkyl

2. (C3-C10)-alkenyl

3. (C3-C10)-quinil

4. (C3-C8-cycloalkyl

5. benzyl or

6. benzyl, which is as defined above substituted.

b) R2means

1. hydrogen

2. halogen

3. nitro

4. CvF2v+1< / BR>
5. pentafluorophenyl

6. cyano

7. phenyl

8. phenyl-(C1-C3)-alkyl

9. (C3-C10)-alkyl

10. (C3-C10)-alkenyl

11. phenyl-(C2-C6)- IS(CH2)m-

15. -(CH2)o-1-CHR7-OR5< / BR>
16. -(CH2)o-O-COR3< / BR>
17. -COR8< / BR>
18. -(CH2)o-CO-R8< / BR>
19. -S(O)rR6< / BR>
20. -CH=CH-(CH2)m-CHR3-OR6< / BR>
21. -CH2=CH-(CH2)m-CO-R8< / BR>
22. -(CH2)o-NH-CO-OR9< / BR>
23. -(CH2)o-NH-SO2-R9< / BR>
24. -(CH2)nF

25. -(CH2)o-SO3R9< / BR>
26. -(CH2)n-SO2-NH-CO-NR6R9or

27. one in PP. b) 7. 8. 9. 10. or 15 specific radical, which as above stated in paras. (C) 44. 45. or 46; as required for such a radical definitely substituted;

(C) R8means hydrogen; and (C1-C5)-alkyl, OR5or NR11R12or morpholino;

d) T means

1. Simple link

2. - -

3. -NR21-

4. -CH2-CH2-

5. -O-CO-

6. -O-CH2-

7. -CH2-O-

8. -S-CH2-

9. -CH2-S-

10. -NH-CH2-

11. -CH2-NH - or

12. -CH=CH - and the other radicals and variables are as defined above.

Especially preferred compounds of formula (I), in which

a) R1means (C3-C7)-alkyl, (C3- F2v+1c v=1, 2, or 3

4. pentafluorophenyl

5. -S(O)rR6< / BR>
6. (CH2)o-1-CHR7-OR5< / BR>
7. (CH2)o-O-CO-R3< / BR>
8. -COR8< / BR>
9. -(CH2)o-CO-R8< / BR>
10. -CH2-NH-CO-R8< / BR>
11. -(CH2)o-NH-SO2-R9< / BR>
12. -CH=CH-CHR3-OR6< / BR>
13. tetrazolyl-(CH2)m-

14. -(CH2)nSO2-NH-CO-NR6R9< / BR>
15. -(CH2)o-SO3R9or in this case substituted hydroxy (C1-C5)-alkyl, preferably hydroxymethyl;

(C) R3means hydrogen or (C1-C4)-alkyl;

d) R6means hydrogen, (C1-C4)-alkyl, (C1-C4-alkanoyl or preferably (C2-C9-heteroaryl;

e) R7means hydrogen, (C1-C4)-alkyl, (C1-C9-heteroaryl or (C6-C12)-aryl-(C1-C4)-alkyl;

f) R8means hydrogen, (C1-C4)-alkyl, OR5or morpholino;

g) R9means CF3, (C1-C6)-alkyl or phenyl;

h) R14means

1. (C1-C4)-alkyl

2. (C1-C4)-alkoxy

3. cyano

4. amino

5. nitroso
-C9-heteroaryl-CH2-

13. (C1-C4)-alkanoyloxy

14. (C1-C4-alkanoyl

15. benzoyl

16. -CH2-NQ

17. -NH-CO-R7or

18. tetrazolyl

i) means R15< / BR>
1. (C1-C4)-alkyl

2. (C6-C12)-aryl

3. (C1-C3)-alkanoyloxy

4. (C1-C4)-alkoxy

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

6. cyano

7. nitro

8. hydroxy

9. -S(O)rR6< / BR>
10. -SO3R3< / BR>
11. chlorine

12. bromine

13. benzoyl

14. -CO2R3< / BR>
15. -CO-NH-R6< / BR>
16. -NR6R7< / BR>
17. -CO-R8< / BR>
18. -SO2-NR6R7,

19. -(CH2CO)q-NQ

20. -O-(CH2)3-NQ

21. -SO2-NH-CO-NR6R9.< / BR>
22. -PO3H2,

23. -CO-CHR5-CO2H,

24. -NH-CO-NH-SO2-CH2-R5,

25. 5-tetrazolyl-NH-CO-,

26. -SO2-NH-S

27. -CO-N

28.R7< / BR>
29. CF3< / BR>
30. NH

31. -T

32. -NH-CO CO2H

33. -CO-NH-SO2-R19or

34. in i) 2. certain radical substituted as defined above.

j) Q means CH2, NH or O;

k) R18means water is passed as indicated above.

Especially preferred are the compounds of formula (I), the symbols R2, R9, R14, R15, Z, X, Y have the following meanings:

R2chlorine, bromine, -S(O)rR6, -COR8or;

R9(C1-C6)-alkyl;

R14tetrazolyl;

R15-CO2-R3, -SO2-NR6R7, -SO2-NH-CO-NR6R9or-NH-CO-NH-SO2-CH2-R5; Z is N

X, Y both signify CR2;

q zero

L CH2;

The invention also concerns the method of producing compounds of the formula I, characterized in that compounds of the formula (II)

R (II)

where R1X, Y and Z, as defined above, is alkylated with compounds of formula III

U-L-(O) (III) where L, A and q are defined above and U is tsepliaeva group, in this case, temporarily introduced protective group again otscheplaut and the compounds of formula (I) transferred to their physiologically compatible salts.

Suitable spare groups U are mostly groups such as halogen, o-toluensulfonate, mesilate or triphala (see chem. (1960) 71). The method of obtaining compounds of formula (II) are known from US-4 355 044, EP-A-324 377 EP-A-323 841. Other methods are described in G. L'abbe (hem. Rev. , 345 (1969); T. Srodsky ("The ch what persons comes from the derivative of the oxime of 1-cyanophlyctis-acid-2, as a result of which after recovery of the reaction are known from the literature reducers and attach mercapto-compounds to the nitrile group using protective groups preliminary stage, which can be cyclosiloxane in the imidazole. For the cyclization stage can be used, among other things, a mixture of l5and dimethylaminopyridine (DMAR), POCl3and SOCl3and their mixtures with DMAR.

Oxidation of tizaidine into the corresponding sulfones, sulfoxy occurs preferably through percolate in suitable solvents, such as dichloromethane.

For alkylation of azoles of the formula II are suitable, for example, corresponding benzylchloride, -tozilaty, -mesylates, triflate or relevant alcalali - gendy, -tozilaty, -mesylates or triflate.

Obtaining these compounds is known by, for example, halogenoalkanes corresponding methyl preliminary stages. Here principally used N-bromosuccinimide, see J. Org.Chem. , 4733 (1979) and Helv. Chim. Acta , 2661 (1979).

The alkylation is known method.

Derived Azola formula (II) metallised, for example, in the presence of a base. The preferred core is metaloxide formula MOR, thus R is stands, ethyl, t-bootrom and the reaction is carried out in the corresponding alcohol, DMF or DMSO.

Educated thus salt Azola dissolved in an aprotic solvent type DMF or DMSO and mixed with the required amount of alkylating reagent.

An alternative possibility of deprotonation derivatives Azola network exchange reaction with potassium carbonate in DMF or DMSO.

Getting tetrazole is a known method from the corresponding NITRILES with azegami, for example, trialkyl - sunniside or sodium azide.

The exchange reaction is carried out at temperatures below room temperature up to the boiling temperature of the reaction mixture for from 1 to 10 hours

Proposed invention the compounds of formula I have an antagonistic effect on angiotensin-II-receptor and can therefore be used for therapy associated with angiotensin-II hypertension. You can also use in heart failure, cardioprotective, myocardial infarction, hypertrophy of the heart, arterial sclerosis, renal disease, kidney failure, and cardiovascular diseases of the brain, as transistor ischemic attack and stroke.

Renin is proteolytically stimulation (low sodium, stimulation of receptors). There he it Decapeptide angiotensin-1 released from the liver angiotensinogen. He translates by "angiotensin converting enzyme" (ACE) to angiotensin-P. Angiotensin-P plays a significant role in the regulation of blood pressure, as it directly increases blood pressure by reducing blood vessels. Additionally, it stimulates the secretion of aldosterone of the adrenal gland and thus increases the through binding allocation sodium extracellular fluid volume, which in turn contributes to high blood pressure.

The action of receptors, in addition, is to stimulate the exchange phosphoinositol, activation of protein kinase C and the relief camp-dependent hormone receptors.

The affinity of compounds of the formula I to angiotensin-II-receptor can be determined by measurement125l-angiotensin-P or3N-angiotensin-P-eviction receptors in the area glomerulosa membranes of bovine adrenal gland. For this purpose, the prepared membrane suspendered in buffer at pH 7.4. To prevent the degradation associated radioactive atoms during incubation, added aprotein inhibitor of peptidases. Additionally used approximately 14000 with whom AutoRAE binds 50% of tracer. The reaction is started by adding 50 ml of membrane suspension to a mixture of 100 l buffer + Aprotinin; 50 l of buffer with or without angiotensin-P or antagonist of the receptor and 50 l of tracer. After a period of incubation of 60 min at 25aboutWith bound and free radioactive atoms are separated by filtration through Whatmann filter on the collection of cells Shatron. Non-specific compounds are removed using a filter with 0.3% polyethylenimine pH 10 (Sigma N 3143). Measurement of radioactivity in a gamma scintillation counter determines the strength of the penetration of radioactive atoms in the receptor. The value of the iC50that means the concentration of the inhibitor to displace 50% of the atoms is determined by Chem. et. al. J. Theor. Biol. , 253 (1970). For compounds of formula I it lies in the area of 1x10-41x10-9M

To determine the antagonistic action of the compounds of formula I can be measured by their effect on induced by angiotensin-P increase in blood pressure. As the drug is Na-thiobarbital Trapanal, Ryk guloley in the dosage of 100 mg/kg i.p. which is administered intravenously in the vena Jugularis. Blood pressure is measured in A. carotis. Before these animals pre-treated with pentolinium (10 mg/kg i. m.), to reach the shaft intravenously. The dose is 0.5 g/kg of the compounds of formula I are dissolved in Aqua. dest and in dosages of 0.1 to 1.0 and 100 mg/kg administered intravenously or vnutriaortalina.

The compounds of formula I are particularly effective in the area of 0.1-100 mg/kg. the Invention relates also to a pharmaceutical composition comprising compounds of formula I and other biologically active substances, as, for example, diuretic or nesteroidnyi antiflammatory biologically active substances. The compounds of formula I can be used also for diagnostic systems of the renin-angiotensin.

The pharmaceutical preparations contain an effective amount of biologically active substances of formula I and other biologically active substances together with inorganic or organic pharmaceuticals substance carrier. The application may be intranasal, intravenous, subcutaneous or oral. The dosage of the biologically active substance depends on the characteristics of blood, weight, age and species introduction.

The pharmaceutical preparations of the proposed invention are well-known methods in the form of solutions, mixtures, granules or pills. For oral use, the active compounds are mixed with the usual form of suitable forms of introduction, as tablets, pills or oil solutions. As inert carriers may be used, for example, gum-Arabicas, magnesium, magnesium carbonate, potassium phosphate, lactose, glucose, fumarate magnesium or starch, especially corn. This preparation may be in the form of dry and wet granulate. As oily substances carriers or solvents can be considered, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

For subcutaneous or intravenous use active compounds or their physiologically compatible salts, preferably with the usual substances, as a solvent mediator, emulsifiers or other auxiliary substances in solutions, suspensions or emulsions. As solvents can be considered: water, physiological saline solution or alcohols, for example ethanol, propandiol or glycerol, in addition, solutions of sugars glucose or mannitol, as well as a mixture of various of the aforementioned solutions.

List of abbreviations:

DMF N,N-dimethylformamide

NBS N-bromosuccinimide

AIBN, azobis-isobutyronitrile

El electron impact

DCl Direkteinlap chemische lonisation

RT bedroom is evil-1-yl)methyl]phenyl}imida - zo- [1,2-a]pyridine-3-carboxylic acid

a) 2-bromo-3-p-tolyl-3-oxo-propionic acid ethyl ester (Aelv. Chim Acta , 2205 (1974) of 20.4 g of 3-p-tolyl-3-oxo-propionic acid ethyl ester was dissolved in 20 ml of CCL4. A solution of 6 ml of bromine is added dropwise in 30 ml of CCL4when -5aboutC. After incubation for 1 h at -5aboutWith stirred 3 h at 20aboutC, then 1 h at 60aboutC. the Solvent is removed. The named product is applied on the raw material. Exit 34,

b) Ethyl ester of 2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid.

5.7 g (20 mmol) of the compound from step 1a) and 3.76 g (40 mmol) of 2-aminopyridine is boiled in 50 ml of absolute EtOH 4 h in the reverse flow, then mixed at RT overnight. After thickening is placed in a 1N solution of NaHCO3and extracted 3 times with CH2CL2. After drying over Na2SO4thickens. Product raw chromatographies on SiO2c EtOAc/ n-heptane(1, 2). After crystallization is obtained from n-heptane 4.1 g of product with a melting point of 88aboutC; MS (DCl) + 281 (M+H).

c) Ethyl ester of 2-(4-methyl bromide-phenyl)-imidazole(1,2-a)pyridine-3-carbon-howl acid.

3 g (about 10.7 mmol) of the compound from step 1b) is boiled in 20 ml of CCL4with 2.1 g (to 11.8 mmol) of NBS and 200 mg of benzoyl peroxide 4 h in the reverse flow. After ohlazhdeniya> and thickens. Chromatography in a silicon gel with EtoAc /n-heptane (0,8:1,2) as solvent gives 1.5 g of the named product as colorless crystals; melting point 131aboutC. MS (DCl):359+361 (M+H).

d) Ethyl ester 2-{4-[(2-n-butyl-4-chloro-5-formyl-imidazol-1-yl)methyl] phenyl} imidazo (1,2-a)pyridine-3-carboxylic acid ().

0,72 g (2 mmol) of compound 1c), and 0.37 g (2 mmol) of 2-n-butyl-4-chloro-imidazole-5-aldehyde (from EP-A-324 377), and 0.3 g (2.2 mmol) of potassium carbonate are mixed in 10 ml of dry DMF for 3 h at RT. After placing it in the water extracted EtOAc (2 times). Related organic phases are washed 3 times with water and 1 ml of saturated common salt solution, dried with Na2SO4and gathering. Chromatography on silicon gel gives 0.8 g of these compounds, and 0.04 g of the isomer 5-chloro-2-formyl .

:1H-NMR (270 z, CDCl3): 9,78 (s, 1H); 9,39 (d, 1H); 7,74 (d, 1H), of 7.70 (d, 1H), 7,43 (dt, 1H); to 7.09 (d, 2H); 7.03 is (dt, 1H); 5,63 (s, 1H); 4,32 (q, 2H); to 2.67 (m, 2H); 1,7 (m, 2H); 1,4 (m, 2H); to 1.22 (t, 3H); 0,9 (t, 3H) ppm Rf(SiO2; EtOAc/ n-heptane (1:2)=0,16.

:1H-NMR (270 MHz, CDCl3): to 9.93 (d, 1H), 9,39 (d, 1H), 7,78 (d, 2H); 7,72 (m, 1H); 7,46 (dt, 1H); was 7.08 (d, 2H); 7,02 (dt, 1H); USD 5.76 (s, 2H); or 4.31 (q, 2H); in 2.68 (m, 2H); to 1.75 (m, 2H); 1,4 (m, 2H); 1,25 (t, 3H); 0,9 (t, 3H) ppm Rf (SiO2; EtOAc/n-heptane 1:1)=0,08.

e) 2-{ 4-[(2-n-Butyl-4-chloro-5-formyl-imidazol-1-yl)assume 5 ml of ethanol and 1.2 ml of 1N NaOH for 18 hours at RT (under nitrogen). After dilution with a 10% solution KN2RHO4extracted with EtOAc 3 times. After washing with saturated salt solution, dried with Na2SO4and thickens. Product raw crystallized from isopropyl ether. Obtain 0.16 g of the named compound as colourless crystals, melting point 120-123aboutC.

MS(DCl): 437 (M+H).

P R I m e R 2. 2-{4-[(2-n-Butyl-4-chloro - 5-hydroxymethyl-imidazol-1-yl)methyl]phenyl}-imidazo(1,2-acid.

a) ethyl ester of 2-{4-[(2-n-butyl-4-chloro-(5-hydroxymethyl-imidazol-1-yl)me-til]phenyl}imidazo( 1,2-a new acid.

0.28 g of the compound from example 1d) mixed 45 min with 0.25 g of sodium hydride in 10 ml of ethanol. After dilution 1N NaOH extracted 2 times with EtOAc. After washing the organic phase with saturated salt solution, dried with Na2SO4and thickens. Get 0,22 g of the named product.

1H NMR (270 MHz, CDCl3): 9,4 (dt, 1H); of 7.75 (d, 2H); 7,73 (dt, 1H); 7,46 (dt, 1H); 7,05 (m, 3H); 5,3 (s, 2H); 4.5 m (s, 2H); to 4.3 (q, 2H); 2,6 (m, 2H); 1,7 (m, 2H); to 1.48 (m, 2H); 1,25 (t, 3H); 0,9 (t, 3H) ppm. MS (FAB): 467 (M+H).

b) 2-{ 4-[(2-n-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl)methyl]phenyl} imidazo(1, 2-a)pyridine-3-carboxylic acid.

0,22 g of the compound from example 2A), share in 5 ml FL the melting point 173-175aboutC. MS (FAB): 439 (M+H).

P R I m e R 3. 2-{4-[(2-n-Butyl-5-carboxy-4-chloro-imidazol-1-yl)methyl] phenyl}them - data(1,2-a)pyridine-3-carboxylic acid.

a) ethyl ester of 2-{4-[(2-n-butyl-4-chloro-5-ethoxycarbonylmethyl-1-yl)me - til]phenyl}imidazo(1,2-a)pyridine-3-Carbo - new acid.

0.28 g (0.6 mmol) of the compound from example 1d) are dissolved in 5 ml of ethanol. Add 0.15 g of sodium cyanide, further 53 glacial acetic acid and 1.25 g of manganese dioxide. After 32 h of stirring at RT is extracted, washed with ethanol and the filtrate is condensed. After placing in water is installed with 2% hydrochloric acid to pH 3-4 and extracted with CH2CL2. After drying the organic phase with Na2SO4thickens. Product raw is used without further purification.

b) 2-{ [(4-n-Butyl-5-carboxy-4-chloro-imidazol-1-yl)methyl] phenyl}imidazo(1,2-a)PI - recyclate.

Product raw from 3A) was stirred 48 h at RT with 2 ml of 1N. NaOH in 3 ml of ethanol. After thickening, placed in the water and with 2% Hcl is set to pH 3. After saturation with sodium chloride salt with CH2CL2extracted, dried with Na2SO4and thickens. Product raw purified on a silica gel with CH2CL2/MeOH 2:1. Get 40 mil}imida - zo(1,2-a)pyrimidine-3-carboxylic acid.

a) Ethyl ester of 2-(4-methyl-phenyl)-imidazo(1,2-a)pyrimidine-3-carboxylic acid.

5.7 g of the compound ISA) is heated with 10 g of 2-aminopyrimidine 30 min at 130aboutC. After cooling, is placed in CH2CL2and washed 6 times with water. After drying over Na2SO4thickens. Product raw purified on a silica gel with EtOAc as ratories. Gain of 3.45 g of the named compound as colourless crystals, melting point. MS (DCl): 282 (M+H).

b) Ethyl ester of 2-(4-methyl bromide-phenyl)imidazo(1,2-a)pyrimidine-3-carbon - howl acid.

3,3 g of compound from 4A) is boiled in reverse flow with 2.4 g of NBS and 230 mg of benzoyl peroxide in 35 ml of CCL44 o'clock Processing takes place as described in example 1C). MS (DCl): 360+362 (M+H).

c) 2-{ 4-[(2-n-Butyl-4-chloro-5-formyl-imidazol-1-yl)methyl] phenyl}imidazo(1,2-a) pyrimidine-3-carboxylic acid ethyl ester.

Get as described in example 1d) from the compound of example 4B) MS/(FAB) 466 (M+H).

d) 2-{ 4-[(2-n-Butyl-4-chloro-5-formyl-imidazol-1-yl)methyl] phenyl}imidazo(1,2-a) pyrimidine-3-carboxylic acid.

Get as described in example 1E) from the compound of example 4C) MS (FAB) 438 (M+H).

Examples of formula 1A, are shown in table.1, 2, were obtained by the way, leads tetrazolyl)-imidazo(1,2-a)pyridine.

a) -bromo-2-tolyl-acetonitrile.

of 15.9 g (0.1 mol) 3-p-tolyl-3-oxo-propionitrile (J. Amer.Chem. Soc.,990 (1974)) are dissolved in 20 ml of CCL4.

P R I m e R 52. 2-{4-[(3-Methoxymethyl-5-n-propyl-1,2,4-trizol-4-yl)methyl]phenyl}-imidazo(1,2 - a)picolata.

and) 2-{4-[(3-Methoxymethyl-5-n-propyl-1,2,4-trizol-4-yl)methyl]phenyl}imidazo(1,2-a )percolate ethyl ester.

Is obtained from 2 mmol of the compound from example 1C) and 2 mmol of 3-methoxymethyl-5-n-propyl-1,2,4-triazole (known from EP-A-323 842) in this way (example 1d). MS (DCl): 434 (M+H).

b) 2-{4-[(3-Methoxymethyl-5-n-propyl-1,2,4-triazole-4-yl)methyl]phenyl}imidazo- (1,2-a)pyridine-3-carboxylic xlot.

Obtained from the compound from example 52a) by the method indicated in example 1E). MS (DCl): 406 (M+H).

P R I m e R 53. 2-{4-[(3-Methoxymethyl-5-n-butyl-pyrazole-1-yl)methyl]phenyl}imida - zo(1,2-a)pyridine-3-carboxylic acid.

A solution of 6 ml of bromine is added dropwise in 30 ml of CCL4if -10aboutC. Stirred 1 h at -8aboutWith, then 3 h at 20aboutC, then 1 h at 60aboutC. the Solvent is removed. Product named raw is used on.

b) 3-cyano-2-(4-methyl-phenyl)-imidazo(1,2-a)pyridine.

value of 4.76 g (20 mmol) of the compound from 41A) and 3.76 g (40 mmol) 2-aminoe the gel with EtIAc/n-heptane (1:3). Obtain 3.6 g of the product as oil. MS (DCl): 234 (M+H).

c) 2-(4-methyl bromide-phenyl)-3-cyano-imidazo(1,2-a)pyridine.

of 2.34 g (10 mmol) of the compound from 41b) together with 2 g of NBS dissolved in 20 ml of chlorobenzene. After adding 200 mg of benzoyl peroxide in 20 ml of chlorobenzene. After adding 200 ml of benzoyl peroxide is heated for 90 min at 120aboutC. After cooling is sucked away and the filtrate is washed 2 times with 1N solution of NaHCO3. The organic phase is dried over Na2SO4and thickens. Chromatography on SiO2(EtOAC/n - heptane 1: 2) gives a named connection. MS (DCl): 312+314 (M+H).

d) 2-{ 4-[(2-n-Butyl-4-chloro-5-formyl-imidazol-1-yl)methyl] phenyl}-3-cyano-them-data (1,2

0,63 g (2 mmol) of the compound from 41p), and 0.37 g (2 mmol) of 2-n-butyl-4-chloro-imidazole-5-aldehyde, and 0.3 g of Na2CO3react analogously to example 1d). Obtain 7 g of the above compound in the form of oil. MS (DCl): 418 (M+H).

e) 2-[4-(2-t-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl)methyl]phenyl-3-cyano - imidazo(1,2-a)pyridine.

0,22 g of compound of example 41d) react with 0.2 g of NaBH4analogously to example 2A). Obtain 0.2 g of the named compound. MS (DCl): 420 (M+H).

f) 2-[4-[(2-n-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl)methyl]phenyl]-3-(1/3)-t ri - MailScanner-t the house in 5 ml of xylene 36 h at 115aboutWITH (N2). After cooling, is extracted and washed with toluene. Obtain 0.3 g of the named product, which is used further in the quality of the product is raw.

d) 2-[4-[(2-n-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl)methyl]phenyl]-3-(1/3)-t ri - phenylmethyl-tetrazol-5-yl)imidazo(1,2-a) pyridine.

0.3 g of the compound of 41f) interact in 5 ml of CH2Cl2and 1 ml of tetrahydrofuran with 10 equivalents of 10N NaOH. After 5 min is added 0.15 g triphenylmethane. After 24 h stirring at room temperature, water is added, the separated organic mass and thickens. Obtain 0.27 g of the named compound. MS (DCl): 703 (M+H).

h) 2-[4-[(2-n-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl)methyl]phenyl]-3-(Tetra - Zol-4-yl)imidazo(1,2-a)pyridine.

0.27 g of the compound from example 41f) interact in 3 ml of methanol with 1 ml of 5N HCl. After 2 h at room temperature, diluted with methanol and installed using 10N NaOH to pH 13. The methanol is removed in vacuo. The residue is diluted with water and extracted 2 times with toluene. The aqueous phase is neutralized by glacial acetic acid and the product is extracted. Obtain 0.12 g of the named compound. MS (DCl): 461 (M+H).

Examples of formula 1b, are shown in table.3, get the oppo is] phenyl} imidazo(1,2-a)PI-ri Ding-acid ethyl ester.

Get out of 1.2 mmol of 3-methoxymethyl-5-n-butyl pyrazole (known from EP-A-323 842), 1.5 mmol of the compound from example 1C) and 2 mmol of sodium hydride in 40aboutIn F. Processing is the same as that described in example 2d) methods. MS (DCl): 447 (M+H).

b) 2-{ 4-[(3-Methoxymethyl-5-n-butyl-pyrazole-1-yl)methyl] phenyl} imidazo(1,2-a)PI-ri Ding-acid.

Produced from compound of example 53A) shown in example 1E) methods. MS (DCl): 419 (M+H).

P R I m e R 54. 2-{4-[(2-n-Butyl-4-methylthio-5-carboxy-imidazol-1-yl)methyl]Fe - nil}imidazo(1,2-a)pyridine-3-carboxylic acid.

a) ethyl ester of 2-amino-2-cyano-acetic acid.

To 35 g (0,246 mol) 2-cyanophlyctis-acid-ethyl ester-2-oxime in 350 ml of water and 280 ml of saturated solution of hydrogencarbonate sodium at room temperature portions (15 min) is added 119 g dithionite sodium. Directly after heated 1 h at 35aboutC; then saturated with NaCl and extracted 5 times with dichloromethane. After drying with calcium chloride the organic phase is condensed. Get to 11.8 g of the above compound in the form of butter.

Rf (CH2Cl2/CH3OH 9/1)=0,6.

b) Ethyl ester of 2-cyano-2-p-butylcarbamoyl acid.

To 3.6 g (28,09 mmol) up>about
3.39 ml (28,09 mmol) veterinaria in 5 ml of CH2CL2. Immediately after stirred for 1 h at room temperature. The organic phase is then washed 3 times with water and saturated NaCl solution, dried with calcium chloride and thickens. Crystallization of the DIP gives 1.7 g of the named compound.

Rf(CH2Cl2/CH3OH 9/1)=0,35.

Melting point: 87oC.

c) ethyl ester of 3-amino-2-p-BUTYLCARBAMATE-methylthioribose acid.

To 2.9 g (13,67 mmol) of compound 2b) and to 0.19 ml (about 1.36 mmol) of triethylamine in 60 ml of absolute ethanol is added at room temperature, 2 ml (27,26 mmol) condensed mercaptan. After 3 days, add another 0.5 ml of methylmercaptan. Over the next 24 h at room temperature is injected again with 0.5 ml of methylmercaptan and to 0.19 ml triethyl, and the following 24 h and stirred at room temperature. Directly after the solvent is removed and the remainder of the DIP crystallizes, thus obtain 2.4 g of the above compound Rf (CH2Cl2/EE 4/1)0,3.

Melting point: 120oC.

d) ethyl ester of 2-n-butyl-4-methylthio-imidazole-5-carboxylic acid.

To 4,17 g (20.0 mmol) of phosphorochloridate in 20 ml of CH2CL2CL2. Allow to reach room temperature and diluted with 30 ml of CH2CL2. After 2 h is added with ice cooling to 300 ml of 1N solution hydrogencarbonate sodium and stirred 1 h. Then the phases are separated, the aqueous phase extracted 3 times with IT and related organic phases are dried with calcium chloride. Chromatography on SiO2c CH2Cl2/EE 9/1. Rf (CH2Cl2/EE 9/1) or= 0.6. MS (DCl): 243 (M++H).

e) ethyl ester 2-{4[(2-n-butyl-4-methylthio-5-etoxycarbonyl-imidazol-1-yl)-methyl]phenyl}imide AOR(benovoy acid.

0.71 g (1.97 mmol) of the compound from example 1C), of 0.48 g (1.97 mmol) of the compound from example 54d) and 0.90 g (6,48 mmol) of potassium carbonate are mixed in 10 ml of abs. DMF 24 h at room temperature. The reaction solution is condensed to dry, the residue is dissolved in IT, ITS solution is washed 3 times with water and 1 time with saturated solution of NaHCO3, dried over Na2SO4and thickens. Chromatography on a silica gel with a heptane 1/1 and 4/1 give 0.51 g of the above compound in the form of oil. Rf(SiO2EE/heptane 4/1)=0,4. MS (FAB): 521 (M+H).

f) 2-{4-[(2-n-butyl-4-methylthio-5-carboxy-imidazol-1-yl)methyl]phenyl}imidazo(1,2-a)pcislot.

0.2 g (0,395 mmol) of the compound from example a) in 5 ml of ethane is SUB>4was set at pH 3 and extracted with HER. Drop down when the concentration of ITS solution precipitate was otshatyvalsya and dried in high vacuum. Received 60 mg of the named compound. So pl. 199oC (decomposition). MS (FAB): 493 (M+H).

P R I m e R 55. 2-{4-[(2-n-Butyl-4-methylsulfinyl-5-carboxy-imidazol-1-yl)me - til]phenyl}imidazo(1,2-a)pyridine-3-Carbo - new acid.

a) Ethyl ester of 2-[4-(2-t-butyl-4-methylsulfinyl-5-etoxycarbonyl-imidazo-1-yl)methyl]imidazo (1,2 new acid.

300 mg (0,577 mmol) of the compound from example e) are mixed in 10 ml of abs. CH2CL2with 0,199 g (0,577 mmol) 3-chloroperoxybenzoic acid (50% solution) for 3 h at room temperature. Was added 10% solution of sodium bisulfite was extracted with ITS associated organic phases were washed with a 10% solution of Na2CO3, dried over Na2SO4and thickened. Chromatography on a silica gel gave 250 mg of the named compound. MS (FAB): 537 (M+H).

b) 2-[4-(2-t-butyl-4-methylsulfinyl-5-carboxy-imidazol-1-yl)methyl]phenyl}them - data(1,2-a)pyridine-3-carboxylic acid.

250 g (0,466 mmol) of the compound from example 55A) react exchange method described in example 54f). Receive 50 mg of the named compound. MS (FAB): 481 (M+H).

Vaya acid.

a) Ethyl ester of 2-{4-[(2-n-butyl-4-methylsulphonyl-5-carboxyamide-1-yl)- methyl]phenyl}imidazo(1,2-a)pyridine-3 - carboxylic acid.

200 mg (0,385 mmol) of the compound from example e) boil in a reverse flow in 10 ml of abs. CH2Cl2with 0,266 g (0.77 mmol) of 3-chloroperoxybenzoic acid (50 ) 15 hours the Reaction solution is connected with a 10% solution of sodium bisulfite, is extracted with ITS associated organic phases are washed with a 10% solution of Na2CO3, dried over Na2SO4and gathering. Chromatography on silicon gel with HER/heptane (4: 1) to give 130 g of the above solution. MS (FAB): 553 (M+H).

b) 2-{ 4-[(2-n-butyl-4-methylsulphonyl-5-carboxy-imidazol-1-yl)methyl] phenyl}them - data(1,2-a)pyridine-3-carboxylic acid.

The named compound was obtained from the compound from example 56a) according to the method described in example 54f). MS (FAB): 497 (M+H).

P R I m e R 57. 2-{4-[(2-n-Butyl-4-methylthio-5-carboxy-imidazol-1-yl)methyl]Fe - Neil}-3-(1H-5-tetrazolyl)-imidazo(1,2-a)PI - ridin.

and) 2-{ 4-[(2-n-Butyl-4-methylthio-5-etoxycarbonyl-imidazol-1-yl)-methyl] phenyl}-3-p iano

1,09 g (3.5 mmol) of the compound from example 41p), 0,85 g (3.5 mmol) of the compound from example 54d) and 1.45 g (10.5 mmol) of K2CO3interact similarly to the method specified is C. MS (FAB): 474 (M+H).

b) 2-{4-[(2-n-Butyl-4-methylthio-5-etoxycarbonyl-imidazol-1-yl)methyl]phenyl}-3- (1H-tetrazol-5-yl)imidazo(1,2-a)pyridine.

473 mg (1 mmol) of the compound from example 57a) are heated with 310 mg (1.5 mmol) trimethyllysine in 3 ml of toluene 3E) in the reverse flow. The reaction solution is diluted with 2 ml of diethyl ether, 20 ml of saturated KF solution and 0.2 ml F4solution (50%) is stirred 16 h at room temperature. It was diluted HER, separated HER-phase and dried over Na2SO4. Thickening HER-phase and chromatography on a silica gel with a methanol (3:1) gave 34,0 mg of the named compound. So pl. 180-215oC. MS (FAB): 517 (M+H).

c) 2-{4-[(2-n-Butyl-4-methylthio-5-carboxy-imidazol-1-yl)methyl]-phenyl}-3-(1H-tet razol-5-yl)imidazo-(1,2-a) pyridine.

180 mg (0.35 mmol) of the compound from example 57b) was entered into the exchange reaction according to the method described in example 54f). Through 5d reaction time was obtained 55 mg of the named compound. So pl. 160oC. MS (FAB): 489 (M+H). The compounds of formula 1C are obtained analogously to examples 54-57, presented in table

1. Substituted azoles of the General formula

< / BR>
where Z N;

X and Y cR2;

R1C2C7-alkyl, C3C7alkenyl;

R2hydrogen, halogen is,

R8hydrogen, C1WITH4-alkyl;

Imidazopyridine or imidazopyrimidines, radicals which can be substituted by the radical R14where R14cyano, CO2R3, tetrazolyl;

L CH2-;

R26and R27hydrogen;

f 0;

n is 0 or 2, or their physiologically compatible salts.

2. The method of obtaining substituted azoles, characterized in that compounds of General formula

< / BR>
where R1C2C7-alkyl, C3C7-quinil;

Z N; X and Y CR2where R2hydrogen, halogen, COOR8CH2OH, S (O)nC1C4-alkyl, SON,

R8hydrogen, C1WITH4-alkyl,

n=0 or 2

alkylate compounds of General formula

< / BR>
L CH2-;

f 0;

Imidazopyridine or imidazopyrimidines, radicals which can be substituted by the radical R14where R14is cyano, CO2R3; tetrazolyl, R3hydrogen, C1C4-alkyl;

R26and R27hydrogen is tsepliaeva group

with the removal of the protective groups and the selection of target products in free form or in the form of physiologically compatible salts.

 

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Ror R$ where R1- aryl which may be substituted by one or more substituents such as lower alkyl, halogen, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyl, hydroxy, lower alkylsulfonate, nitro, amino, lower alkylamino, acylamino or lower alkyl (acyl)amino, or 4-pyridyl,

R2is hydrogen, methyl, substituted amino, lower alkylamino, halogen or acyloxy, acyl, acylamino, cyano, lower alkylthio, lower alkylsulfonyl or tetrazolyl,

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The invention relates to new derivatives of intellipedia General formula

where R1phenyl substituted by substituents selected from the group consisting of lower alkyl, hydroxyl, protected hydroxyl, halogen or lower alkoxy,

And lower alkylen,

In the lower albaniles, or their pharmaceutically acceptable salts which exhibit anti-allergic effect

The invention relates to new chemical compounds with biological activity, particularly to derivatives of dibenzazepine-6,7-dihydro-5H-dibenz [c, e] azepin-7-it is a General formula

R(I)where R is F, Cl, which have garmentindustry activity against microsomal cytochrome P-450-dependent monooxygenase system, liver, metabolizing foreign compounds - xenobiotics

The invention relates to medicine, namely to Pediatrics, and can be used for the treatment of musculoskeletal disorders in children

FIELD: medicine, neurology.

SUBSTANCE: the present innovation describes arylalkylamines that specifically affect certain types of receptor-operated Ca2+-canals, their application and pharmaceutical compositions for treating neurological disorders or diseases.

EFFECT: higher efficiency.

55 cl, 29 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: method involves rectally introducing mixture produced on base of 5% Novocain solution containing isoniazid, rifamycin, ethambutol in therapeutic doses daily during 21 days. The mixture is pretreated in ultrasonic field during 5 min at 2 MHz frequency.

EFFECT: improved bacteriostatic blood and prostate secret activity.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.

EFFECT: enhanced effectiveness of treatment.

18 cl, 3 tbl

FIELD: medicine, phthisiology.

SUBSTANCE: method involves firstly the achievement of lymphotropicity of three chemopreparations by addition of 5% glucose and aloe to solutions of these chemopreparations. Then the conduction paravertebral anesthesia is carried out at the level and at side of administration of preparations. Then three chemopreparations are administrated separately in different intercostals sites, 1-3 times per a week, course of 4-12 injections by subcutaneous paravertebral route, parasternal route in I-X intercostals - in projection of regional lymphatic collectors. Method allows reducing the duration of intensive phase in tuberculosis treatment up to 1-3-6 months, to prevent the development of drug-resistant tuberculosis and adverse effects of chemopreparations and to relieve the residual changes of tuberculosis. Invention can be used in treatment of infiltrative, destructive and drug-resistant pulmonary tuberculosis.

EFFECT: improved and enhanced method of treatment.

2 ex

FIELD: medicine; physiotherapy.

SUBSTANCE: two to here days after surgical operation, vibration massage is made by means of vibration apparatus on thorax area of root of lung being opposite to that one which was subject to operation. Vibration massage is made daily at frequency of 90-100 Hz and amplitude of 0,4-0,5 mm during 3-5 minutes for 13-14 days. Starting from the fourth f the fifth day after operation, when both drainages are removed from post-resection pleural cavity, electric-vibration acupressure is made in parallel on skin covers all around total area of thorax by means of massaging device. Vibration-acupressure is made daily at the second part of day after I-II row chemical preparations are given to patient. Frequency of procedure is 35-40 Hz and amplitude 0,5-0,6 mm. Duration of influence is increased gradually from 3 to 13-14 minutes during 11-12 days.

EFFECT: reduced number of pleural-pulmonary complications; uniform ventilation of all parts of segments of lung subjected to operation.

2 ex, 3 tbl

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