1h-indazoles, benzothiazoles, 1,2-benzoisoxazoles, 1,2-benzoisothiazoles and chromones and synthesis and use thereof

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

 

The text descriptions are given in facsimile form.

1. A compound selected from formulas I, II, V, VI, VII and VIII



where X1means SN;
X2-X5denote each independently CH or C, where-C is the place of attachment of the group and where one of X2-X5means;
X7-X10denote each independently CH or CR2;
X18-X21denote each independently CH or CR5;
X22and X23denote each independently CH or CR12where at least one of X22or X23mean CR12;
X24means SN;
In the mean CH2or C=O;
In1means SN;
Y represents oxygen or sulfur;
Z means About;
m means 2;
R means hydrogen;
R2and R5denote each independently (C1-C6)alkyl, (C8-C8)cycloalkyl, halogen, imidazolyl, substituted (C1-C6)alkyl and/or oxo group, or9;
R9means hydrogen, (C1-C6)alkyl, which is unsubstituted or substituted one or more times by fluorine, or (C4-C8)cycloalkenyl,
R12about the means (C 1-C6)alkoxygroup, which is substituted one or more times by fluorine, unsubstituted thiazolyl, thiazolyl, substituted (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyran, tetrahydropyranyl or tetrahydropyranyloxy, and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where the said connection means the connection of formula I.

3. The compound according to claim 1, where the said connection means the connection of the formula II.

4. The compound according to claim 1, where the said connection means the connection formula V.

5. The compound according to claim 1, where the said connection means the connection of the formula VI.

6. The compound according to claim 1, where the said connection means the connection of the formula VII.

7. The compound according to claim 1, where the said connection means the connection of the formula VIII.

8. The compound according to claim 1, where R in formulas I and VI denotes hydrogen.

9. The compound according to claim 1, where the said compound is selected from formulas II and V and at least one of the substituents R2and R5means (C1-C6)alkyl.

10. The compound according to claim 1, where the said compound is selected from formulas II and V and at least one R9means (C1-C6)alkyl.

11. The compound according to claim 1, where the said compound is selected from formulas II and VI, and In means=O.

12. The compound according to claim 1, where the said connection means the connection form is s V and means C=O.

13. The compound according to claim 1, where the said connection means the connection of the formula II and Y represents sulphur.

14. The compound according to claim 1, where the said connection means the connection of the formula VI and R12means oxazolyl, thiazolyl, 4-methylthiazolyl or 5-methylthiazolyl.

15. The compound according to claim 1, where the said connection means the connection of the formula VI and R12represents the formula X means tetrahydropyran or dihydropyran.

16. The compound according to claim 1, where the said connection means the connection of the formula II and R12mean 3-methyl-imidazolidin-2-one or 3-isopropylimidazole-2-it.

17. The compound according to claim 1, where R12means the halogenated alkoxygroup.

18. The compound according to claim 1, where R12means a methoxy group, cryptometer, ethoxypropan, cyclopropylmethoxy or cyclopropyl.

19. The compound according to claim 1, where R5means a methoxy group.

20. The compound according to claim 1 where In the means of CH2.

21. The compound according to claim 1, where the said connection means the connection of the formula II and R means (C1-C6)alkyl.

22. The compound according to claim 1, where the said connection means the connection of the formula II and R2means (C3-C8)cycloalkyl.

23. The compound according to claim 1, where the said connection means the connection of the formula II and R2means halogen.

24. The compound according to claim 1, where mentioned with the Association means a compound of the formula II and R 2means imidazolyl, substituted (C1-C6)alkyl and/or oxo group.

25. The compound according to claim 1, where the said connection means the connection of the formula II and R2means OR9.

26. The compound according to claim 1, where the said connection means the connection of the formula V and R5means (C1-C6)alkyl.

27. The compound according to claim 1, where the said connection means the connection of the formula V and R5means (C3-C8)cycloalkyl.

28. The compound according to claim 1, where the said connection means the connection of the formula V and R5means halogen.

29. The compound according to claim 1, where the said connection means the connection of the formula V and R5means imidazolyl, substituted (C1-C6)alkyl and/or oxo group.

30. The compound according to claim 1, where the said connection means the connection of the formula V and R5means OR9.

31. The connection point 24, where R9means (C1-C6)alkyl, which is unsubstituted or substituted by one or more F.

32. The connection clause 29, where R9means (C1-C6)alkyl, which is unsubstituted or substituted by one or more F.

33. The compound according to claim 1, where the said compound is selected from
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole, 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazol is,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(triptoreline)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo [3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(triptoreline)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole,
4-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazole and their pharmaceutically acceptable salts.

34. The compound according to claim 1, where the said compound is selected from
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-4H-chromen-4-it
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazole;
and their pharmaceutically acceptable salts.

35. The compound according to claim 1, where the said compound is selected from
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazole,
3-(1,4-Diaz is bicyclo[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(triptoreline)-1,2-benzisothiazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazole,
3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chromen-4-it,
3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chromen-4-it,
3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-it,
6-(cyclopropylmethoxy)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
6-cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole and
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole;
and their pharmaceutically acceptable salts.

36. The compound according to claim 1, where the said compound is selected from
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazole,
3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chromen-4-it,
3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-it,
6-bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
1-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-isopropylimidazole-2-it,
1-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-methylimidazolidine-2-it,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-oxazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(deformedarse)-1H-indazole br/> 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(deformedarse)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-Piran-4-yloxy)-1H-indazole,
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazole,
(3E)-3-(1,4-diazabicyclo[3.2.2]non-4-ylmethylene)-6-methoxy-2,3-dihydro-4H-chromen-4-it,
(3E)-3-(1,4-diazabicyclo[3.2.2]non-4-ylmethylene)-5-methoxy-2,3-dihydro-4H-chromen-4-it, and
(3E)-3-(1,4-diazabicyclo[3.2.2]non-4-ylmethylene)-7-methoxy-2,3-dihydro-4H-chromen-4-it;
and their pharmaceutically acceptable salts.

37. Connection p where the above-mentioned compound represented cleaners containing hydrochloride or hydroforming salt.

38. The connection clause 37, where the said compound is selected from
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(triptoreline)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo [3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(trif is ormaetxe)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole,
hydroformed 4-(1,4-diazabicyclo [3.2.2]non-4-ylcarbonyl)-1H-indazole.

39. The connection 34, where the said compound is selected from
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-4H-chromen-4-it
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazole.

40. Connection p where the above-mentioned compound represented cleaners containing hydrochloride or hydroforming salt.

41. Connection p where the above-mentioned compound selected from
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole,
hydrochloride 3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(triptoreline)-1,2-benzisothiazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-Benzino is jasola,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chromen-4-it,
hydroformed 6-(cyclopropylmethoxy)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
hydroformed 6-cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole and
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole.

42. Connection p where the above-mentioned compound represented cleaners containing hydrochloride or hydroforming salt.

43. Connection § 42, where the said compound is selected from
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chromen-4-it,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-it,
hydroformed 6-bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
hydroformed 1-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-isopropylimidazole-2-it,
hydroformed 1-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-methylimidazolidine-2-it,
hydroformed 3-(1,4-diazabicyclo [3.2.2]non-4-ylcarbonyl)-5-(1,3-oxazol-2-yl)-1H-indazole,
hydrochloride 3-(1,4-diazabicyclo [3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(deformedarse)-1H-indazole,
HYDROFORM the ATA 3-(1,4-diazabicyclo [3.2.2]non-4-ylcarbonyl)-6-(deformedarse)-1H-indazole,
hydroformed 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-Piran-4-yloxy)-1H-indazole,
hydrochloride 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazole,
hydroformed (3E)-3-(1,4-diazabicyclo [3.2.2]non-4-ylmethylene)-6-methoxy-2,3-dihydro-4H-chromen-4-it,
hydroformed (3E)-3-(1,4-diazabicyclo [3.2.2]non-4-ylmethylene)-5-methoxy-2,3-dihydro-4H-chromen-4-it, and
hydroformed (3E)-3-(1,4-diazabicyclo[3.2.2]non-4-ylmethylene)-7-methoxy-2,3-dihydro-4-chromen-4-it.

44. The compound according to claim 1, where the said compound is 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazol or its pharmaceutically acceptable salt.

45. The compound according to claim 1, where the said compound is 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol or its pharmaceutically acceptable salt.

46. Pharmaceutical composition for activating/stimulating nicotinic receptor α-7 in a patient, comprising the compound according to any one of claims 1 to 45 and a pharmaceutically acceptable carrier.

47. The use of compounds according to any one of claims 1 to 45 for selective activation/stimulation of nicotinic receptors α-7 patient from whom such activation/stimulation gives a therapeutic effect.

48. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from a psychotic disorder,a neurodegenerative disease, including dysfunction of the cholinergic system, and/or violation of the state memory and/or cognitive abilities.

49. Use p, where said patient is suffering from schizophrenia, fear, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Alzheimer's disease, dementia Taurus Levi, amyotrophic lateral sclerosis, damage to memory, memory loss, lack of cognitive abilities, attention deficit and/or attention deficit and hyperresponsiveness.

50. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from dementia and/or other condition with memory loss.

51. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from memory corruption due to Alzheimer's disease, mild cognitive impairment due to age, schizophrenia, Parkinson's disease, Huntington's disease, a disease of Peak disease of Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral stilnoct, multi-infarct dementia, HIV infection and/or cardiovascular disease.

52. The use of compounds according to any one of claims 1 to 45 for the treatment and/or prevention of dementia in patients with Alzheimer's disease.

53. The use of compounds according to any one of claims 1 to 45 for the treatment of the patient in the holding from alcohol or treatment of the patient with antinociceptive therapy.

54. The use of compounds according to any one of claims 1 to 45 for the treatment of the patient, to ensure neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity.

55. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from the tendency to nicotine, pain, disturbances of circadian rhythm in connection with the flight through several time zones, obesity and/or diabetes.

56. The use of compounds according to any one of claims 1 to 45 to promote Smoking cessation in a patient.

57. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from weak cognitive damage (MCI), vascular dementia (VaD)associated with age-related decline in cognitive abilities (AACD), amnesia associated with surgical open heart surgery, cardiac and/or General anesthesia, memory deficits from exposure to anesthetics, sleep deprivation, caused by cognitive impairment, chronic fatigue syndrome, narcolepsy associated with AIDS dementia associated with epilepsy, cognitive impairment, down syndrome, associated with alcoholism dementia, memory impairment caused by the use of drugs/substances, Boxing dementia (boxer syndrome), and dementia animals.

58. The use of compounds according to any one of claims 1 to 45 for Les the possible loss of memory.

59. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from memory corruption.

60. Use p where the above-mentioned memory corruption occurs due to reduced activity of nicotinic acetylcholine receptors.

61. The use of compounds according to any one of claims 1 to 45 for the treatment or prevention of a disease or condition resulting from dysfunction of the transmission of nicotinic acetylcholine receptors in a patient.

62. The use of compounds according to any one of claims 1 to 45 for the treatment or prevention of a disease or condition resulting from defective or malfunctioning functioning of nicotinic acetylcholine receptors in a patient.

63. The use of compounds according to any one of claims 1 to 45 for the treatment or prevention of a disease or condition resulting from suppressed transmission nicotinic acetylcholine receptors.

64. The use of compounds according to any one of claims 1 to 45 for the treatment or prevention of a disease or condition resulting from loss of cholinergic synapses in the patient.

65. The use of compounds according to any one of claims 1 to 45 for protecting neurons in a patient from neurotoxicity induced activation of α7nACh receptors.

66. The use of compounds according to any one of claims 1 to 45 for the treatment or prevention of neurodegenerative disorders by John is euromania binding peptides β α7nACh receptors in a patient.

67. The use of compounds according to any one of claims 1 to 45 for the treatment of a patient suffering from an inflammatory disease.

68. Use p, in which the aforementioned inflammatory disease means rheumatoid arthritis, diabetes or sepsis.

69. The use according to any one of paragraphs 44-67, where the said patient is human.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes with general formula: The method involves reacting aliphatic aldehyde (acetic, propionic, butyric, valerianic, caproic) saturated with hydrogen sulphide with 1,2-diaminoethane in molar ratio diamine:aldehyde:hydrogen sulphide equal to 1:3:2, at 0°C for 3 hours. 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes can be used as selective sorbents and extraction agents of precious metals, as antibacterial, antiviral, fungicidal and acaricidal agents.

EFFECT: stereoselective synthesis of one conformationally pure 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3,2,1]octane isomer; the method is also distinguished by simplicity of carrying experiments and availability of initial reagents.

1 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there described are diazabicyclic aryl derivatives of general formula I , their enantiomers or any mixture of those enantiomers, or their pharmaceutically acceptable salts, where radical values A, L, B and n are given in the description, and pharmaceutical composition containing the above diazabicyclic aryl derivatives.

EFFECT: new compounds represent cholinergic ligands of nicotinic receptors of acetylcholine and modulators of receptors and carrying agents of monoamines, and can be used for treatment of diseases and illnesses related to cholinergic system of central nervous system and periphery nervous system, which are related to activity of muscles, endocrine diseases, inflammatory diseases, and neurodegenerative diseases.

12 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to new crystalline form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including 2 moles water to 1 mole (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, the form II content being equal 75% and more; the above form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3,3,1]non-4-yl)benzamide hydrochloride has one or more optional properties, as follows: a) form II infrared spectrum include characteristic peak at 835±1.5 cm-1; b) X-ray pattern obtained on the above form powder is essentially corresponds to image Fig. 21; and c) water content rates 8.3% to 9.8%. The invention relates also to the form II ofhydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride production methods, to the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, and the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride identification method, as well as to pharmaceutical composition and treatment method for gastrointestinal motility impairment related disorders.

EFFECT: composition has improved properties for medical applications.

22 cl, 1 ex, 11 tbl, 22 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely experimental surgery, and can be used as an anaesthesia care in experimental operative interventions. That is ensured by initial narcosis by intramuscular introduction in the same syringe of a combination of preparations, including ketamine in a dose 1.0-1.5 ml per 3-4 kg of an animal's body weight and rometar in a dose 2.0-4.9 ml per 3-4 kg of the animal's body weight. After 4-5 minutes following the initial narcosis, pofol is administered intravenously in a dose 1.0-3.0 ml per 3-4 kg of the animal's body weight; then 1-7 minutes later, intubation follows that includes the second administration of pofol in a dose 0.2-0.3 ml regardless the animal's body weight. The following injections of pofol to maintain anaesthesia are carried out in the beginning of each hour of the operative intervention with considering its duration in a dose 1.0 ml regardless the animal's body weight.

EFFECT: method ensures the optimal conditions to prepare the animal for the noninhalation anaesthesia due to preliminary combined intramuscular introduction of rometar and ketamine, and also maintained adequate anaesthesia with low doses of the administered preparations owing to their potentiation interactions.

4 ex

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