N-dihydroalkylsubstituted 2-oxoimidazole derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein R means dihydrosubstituted C2-C6alkyl group, and Cy represents spiro[4.5]dec-6-yl, spiro[2.5]oct-4-yl, spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl or 1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl-group. Said compounds act as nociceptive receptor antagonists, and are applied e.g. as agents improving acceptability of narcotic analgesics, relieving narcotic analgesic dependence or narcomania; as an analgesic intensifier; antiobesity agents or appetite suppressants; agents for treating decreasing cognition and senile dementia /amnesia; agents for treating developing cognition disorder; therapeutic agents in schizophrenia; agents for treating neurodegenerative diseases; antidepressants or therapeutic agents in affective disorder; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents in polyuria; and therapeutic agents in hypotension and similar.

EFFECT: preparation of the compounds acting as nociceptive receptor antagonists.

11 cl, 5 ex, 3 tbl

 

The technical field

This invention relates to substances which are antagonistic to the binding nociceptin with nociceptive the ORL1 receptor (receptor, similar to the opioid receptor type 1).

Compounds that inhibit the binding nociceptin with nociceptin receptor ORL1, applicable as analgetika diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; means improving the portability of narcotic analgesics represented by morphine; means weakening the dependence on narcotic analgetic represented by morphine or against addiction; amplifiers analgesics; anti-obesity or means to suppress appetite; therapeutic or prophylactic agents at lower cognitive abilities and age-related dementia/amnesia, cerebrovascular diseases and Alzheimer's disease; means for developing treatment of disorders of cognitive abilities with attention deficit, hyperfunctional disorders and inferiority assimilation; a remedy for schizophrenia; agents for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressant or therapeutic agents in affective disorder therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents the polyuria; and a remedy for hypotension, and the like.

Description of the prior

Nociceptin (the same substance as orphanin FQ) is a peptide composed of 17 amino acid fragments, and has a structure identical with the structure of opioid peptide. Nociceptin affect reactivity in relation to nociceptive stimulation, has an appetite stimulant activity by reducing the ability of spatial learning, antagonism in relation to the analgesic actions of classical opiate agonists, inhibitory action on the release of dopamine action in relation to water diuresis, vasodilating action and a systemic effect in reducing blood pressure, and, as I believe, he takes part in intracerebral controlling pain, appetite and memory formation through nociceptin receptor ORL1 [seeNature,377, 532 (1995);Society for Neuroscience,22, 455 (1996);NeuroReport,8, 423 (1997);Eur.J.Neuroscience,9, 194 (1997);Neuroscience,75, 1 (1996);ibid., 333 (1996);LifeScience,60, PL15 (1997);ibid., PL141 (1997);Proceeding for National Academy of Sciences,94, 14858 (1997)].

In addition, it is known that the affected mouse, in case of inhibiting the expression of noticeablemoderate reduced tolerance to morphine or memory and the ability to increase absorption [see Nof euroscience Letters,237, 136 (1997);Nature,394, 577 (1998)].

It was also published that nociceptin itself causes symptoms similar to withdrawal symptoms observed in addiction to the excessive use of morphine, and which ones antagonist nociceptive receptor increases tolerance to morphine, dependence and symptoms similar to withdrawal symptoms [seePsychopharmacology,151, 344-350 (2000);Journal of Neuroscience,20, 7640 (2000)].

On the other hand, reported that defective mouse protein predecessor nociceptin demonstrate behavior similar to anxiety, and changes in response to stress [seeProceeding for National Academy of Sciences,96, 10444 (1999)].

Therefore, substances that are particularly inhibit the binding nociceptin with nociceptin receptor ORL1, applicable as analgetika against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; means improving the portability of narcotic analgesics represented by morphine; tools to ease the dependence on narcotic analgetic represented by morphine or against addiction; amplifiers analgesics; anti-obesity or means to suppress appetite; therapeutic or prophylactic agents which when reduced cognitive abilities and age-related dementia/amnesia cerebrovascular diseases and Alzheimer's disease; agents for the treatment of developing disorders cognitive abilities with attention deficit, hyperfunctional disorders and inferiority assimilation; therapeutic agents in schizophrenia; agents for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressant and treatment in affective disorders; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents the polyuria; and remedies for hypotension and the like.

International publication WO98/54168 orJ.Med.Chem. 5061-5063 (1999) disclose compounds exhibiting antagonism to bind nociceptin with nociceptive the ORL1 receptor. In particular, it is disclosed the compound of the following formula (A):

(hereinafter designated as “compound A”) in connection with excellent selective antagonism of binding nociceptin with nociceptive receptor.

International publication WO98/54168.

J.Med.Chem. 5061-5063 (1999).

Disclosure of invention

Applicants investigated compounds with structures similar to the structure of the connection And to create compounds which have antagonistic activity to bind nociceptin is with nociceptin receptor ORL1, to open that data connection with bi - or tricyclic aliphatic carbocyclic group with specific numbers of carbon atoms instead cyclooctyl group and also having dihydroxyethylene the substituents on the nitrogen atom, have a well-balanced activities, which consists not only in the selective inhibition of binding nociceptin with nociceptin receptor ORL1, but also in the manifestation of an excellent metabolic properties in vivo, and can be compounds that are particularly suitable for people. This invention completed based on this discovery.

Thus, the present invention relates to

(1) a derivative of 2-accomidate formula (I):

in which R means dihydroxytoluene1-C6alkyl group, and su means optionally substituted C6-C10-bi - or tricyclic aliphatic carbocyclic group, or their pharmaceutically acceptable salts.

The invention also applies to

(2) a pharmaceutical composition containing a pharmaceutically acceptable adjuvant and the compound described above in (1), or its pharmaceutically acceptable salt; and

(3) method for producing a medicinal product for use as analgetika; means improving the portability of narcoticsondansetron; aid dependence on narcotic analgesics or against addiction; amp analgesics; anti-obesity or means to suppress appetite; treatment for reducing cognitive abilities and age-related dementia/amnesia, cerebrovascular diseases and Alzheimer's disease; means for developing treatment of disorders of cognitive abilities with attention deficit, hyperfunctional disorders and inferiority assimilation; a remedy for schizophrenia; means for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressant or therapeutic agent for affective disorder; a therapeutic or preventive agent for diabetes insipidus; a therapeutic or preventive agent for polyuria; and a remedy for hypotension, which involves mixing the compounds described above in (1), or its pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant.

The best way of carrying out the invention

Below the invention is discussed in detail with reference to specific examples.

In the formula (I) R is C1-C6alkyl group containing two hydroxyl groups, and specific examples include 2-hydroxy-1-(hydroxymethyl)ethyl, 2,3-dihydro shall sapropel, 2,3-dihydroxy-2-methylpropyl, 2,3-dihydroxybutyl, 2,4-dihydroxybutyl, 3,4-dihydroxybutyl, 2,3-dihydroxy-1-methylpropyl, 2-hydroxy-1-(hydroxymethyl)propyl, 3-hydroxy-1-(hydroxymethyl)propyl, 3-hydroxy-2-(hydroxymethyl)propyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 4,5-dihydroxyphenyl, 2,3-dihydroxy-1-methylbutyl, 2,4-dihydroxy-1-methylbutyl, 3,4-dihydroxy-1-methylbutyl, 2-hydroxy-1-(hydroxymethyl)butyl, 3-hydroxy-1-(hydroxymethyl)butyl, 4-hydroxy-1-(hydroxymethyl)butyl, 2,3-dihydroxy-2-methylbutyl, 2,4-dihydroxy-2-methylbutyl, 3,4-dihydroxy-2-methylbutyl, 2-hydroxy-2-(hydroxymethyl)butyl, 3-hydroxy-2-(hydroxymethyl)butyl, 4-hydroxy-2-(hydroxymethyl)butyl, 2,3-dihydroxy-3-methylbutyl, 2,4-dihydroxy-3-methylbutyl, 3,4-dihydroxy-3-methylbutyl, 4-hydroxy-3-(hydroxymethyl)butyl, 2,3-dihydroxy-1,1-dimethylpropyl, 2-hydroxy-1-(hydroxymethyl)-1-methylpropyl, 3-hydroxy-1-(hydroxymethyl)-1-methylpropyl, 1,1-bis(hydroxymethyl)propyl, 2,3-dihydroxy-1,2-dimethylpropyl, 2-hydroxy-1-(hydroxymethyl)-2-methylpropyl, 3-hydroxy-2-(hydroxymethyl)-2-methylpropyl, 2,3-dihydroxy-1-ethylpropyl, 2-hydroxy-1-(2-hydroxyethyl)propyl, 2-hydroxy-1-(1-hydroxyethyl)propyl, 3-hydroxy-1-(2-hydroxyethyl)propyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2.5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-d is hydroxyhexyl, 3,6-dihydroxyphenyl, 4,5-dihydroxybenzyl and 4,6-dihydroxyphenyl. Preferred examples are3-C4alkyl group containing two hydroxyl groups and, in particular, are recommended 2,3-dihydroxypropyl, 2-hydroxy-1-(hydroxymethyl)ethyl and 2,3-dihydroxy-2-methylpropyl group.

Su means optionally substituted C6-C10-bi - or tricyclic aliphatic carbocyclic group.

As the “substituent” in the “optionally substituted C6-C10-bi - or tricyclic aliphatic carbocyclic group” includes, for example, halogen, such as fluorine, chlorine and the like, and1-C6alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl and the like. Preferably recommended With1-C4alkyl groups.

“C6-C10-bi - or tricyclic aliphatic carbocyclic group” refers to saturated aliphatic carbocyclic group, which are bi - or tricyclic group. For example, the Spiro[2.5]Oct-4-yl, Spiro[2.5]Oct-5-yl, Spiro[2.5]Oct-6-yl, Spiro[3.5]non-5-yl, Spiro[3.5]non-6-yl, Spiro[3.5]non-7-yl, Spiro[4.5]Dec-6-yl, Spiro[4.5]Dec-7-yl, Spiro[4.5]Dec-8-yl, bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.2]Oct-2-yl, 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl, 1-Spiro(bicycl the[2.2.1]heptane-2,1'-cyclopropane)-5-yl, 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-6-yl and the like.

As specific examples of the substituent of the su can be called Spiro[2.5]Oct-4-yl, Spiro[2.5]Oct-5-yl, Spiro[2.5]Oct-6-yl, Spiro[3.5]non-5-yl, Spiro[3.5]non-6-yl, Spiro[3.5]non-7-yl, Spiro[4.5]Dec-6-yl, Spiro[4.5]Dec-7-yl, Spiro[4.5]Dec-8-yl, bicyclo[2.2.1]hept-2-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl, 3,3-dimethylbicyclo[2.2.1]hept-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-6-yl, bicyclo[2.2.2]Oct-2-yl, 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl, 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-5-yl, 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-6-yl and the like. Preferably recommended Spiro[4.5]Dec-6-yl, Spiro[2.5]Oct-4-yl, Spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl, 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl and the like.

According to the invention derivatives of 2-accomidate having on the nitrogen atom in position 1 dihydroxyethylene group and, in addition, having as Deputy su optionally substituted C6-C10-bi - or tricyclic aliphatic carbocyclic group have a very good balanced physiological activity with high antagonism to nociceptive receptor and high metabolic stability.

As specific examples of compounds of formula (I) can be named the following:

1) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[4.5]Dec-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

2) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

3) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6R)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

4) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(6S)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

5) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(6R)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

6) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[3.5]non-5-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

7) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(5S)-Spiro[3.5]non-5-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

8) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(5R)-Spiro[3.5]non-5-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

9) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(5S)-Spiro[3.5]non-5-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

10) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(5R)-Spiro[3.5]non-5-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

11) 1-(2,3-dihydroxypropyl)-3-{1-[(3,3-dimethylbicyclo[2.2.1]hept-2-yl)methyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

12) 1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1S,2S,4R)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

13) 1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1S,2R,4R)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

14) 1-[(2R)-2,3-dihydrox is propyl]-3-(1-{[(1R,2R,4S)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

15) 1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1R,2S,4S)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

16) 1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1S,2S,4R)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

17) 1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1S,2R,4R)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

18) 1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1R,2R,4S)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

19) 1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1R,2S,4S)-3,3-dimethylbicyclo[2.2.1]hept-2-yl]methyl}piperidine-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

20) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

21) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

22) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4R)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

23) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

24) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(4R)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

25) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

26) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

27) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3R,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

28) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1S,3R,4R)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

29) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1S,3S,4R)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

30) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

31) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1R,3R,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

32) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1S,3R,4R)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

33) 1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1S,3S,4R)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

34) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

35) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(4R)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

36) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

37) 1-[2-hydroxy-1-(guide oxymethyl)ethyl]-3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

38) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

39) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3R,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

40) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1S,3R,4R)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

41) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1S,3S,4R)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

42) 1-(2,3-dihydroxy-2-methylpropyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

43) 1-[(2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

44) 1-[(2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4R)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

45) 1-[(2S)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

46) 1-[(2S)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4R)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it.

Preferably recommended:

1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

1-[(2S 2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it,

1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S or 6R)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it.

Methods for obtaining compounds of formula (I)

These compounds of formula (I) can be obtained by the following methods or by methods described in WO98/54168.

The method of obtaining 1

The method of obtaining 1 uses 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazole-2-it, which is a known compound, and provides the compounds of formula (I) through three or four stages.

The scheme of reactions 1

in which Rpmeans a lower alkyl group having two protected hydroxyl group, L is a group to delete, sumeans optically active group su and su and R have the same values as previously described.

The compound of formula (II) and the compound of formula (III) is subjected to reaction reductive alkylation in an organic solvent in the presence of a reducing agent to obtain a compound of formula (IV).

The amount used of the compounds of formulas (II)and (III), accordingly, they are generally used in equimolar amounts, or either one of them is used in slight molar excess.

As a reducing agent, for example, can be called cyanoborohydride sodium, traceability sodium, biscyanopropyl zinc, biscyanopropyl Nickel and the like.

The amount of reducing agent is from mol to molar excess, preferably 1-5 moles per mole of the compounds of formula (II).

The reaction is usually carried out in an organic solvent. Examples of the solvent include alcohols such as methanol, ethanol and propanol; ethers such as diethyl ether, tetrahydrofuran (THF/”THF) and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; and aprotic polar solvents such as dimethylformamide (DMF/”DMF”), acetonitrile and hexamethylene phosphoric acid, or a mixture of solvents.

Approximate reaction temperature is usually in the range of -20°C-100°C, preferably 0°C.-room temperature, and the duration of reaction is usually from 5 minutes to 7 days, preferably 1-6 hours.

As compounds of the formula (III) can be used, for example, the following connections.

Then the compound of formula (IV) is condensed with the compound of the formula (V) in an organic solvent in the presence of a base to obtain the compounds of formula (VI).

The compound of formula (V) is used in an amount of from mol to molar excess, preferably 1-5 moles per mole of the compounds of formula (IV).

Examples of the base include sodium hydride, potassium hydride, hexamethyldisilazide Li, hexamethyldisilazide sodium, hexamethyldisilazide potassium, potassium carbonate and sodium carbonate. Preferably recommended sodium hydride and potassium hydride.

The amount of base is from mol to molar excess, preferably 1-5 moles per mole of the compounds of formula (V).

To accelerate the reaction in the reaction system may be added to the alkali metal halide such as sodium iodide, potassium iodide or the like. This can be used, for example, 0.1 mol - molar excess of alkali metal halide per mole of the compounds of formula (IV).

As the organic solvent, for example, can be called DMF, THF, hexamethylene phosphoric acid and the like.

Approximate reaction temperature is usually in the range -0°C To 150°C, and it is preferable that the interval of room temperature to 130°C. the Duration of the reaction is usually in the range of 5 cm min to 7 days, preferably from one hour to 12 hours.

In the compound of formula (V) L is a group to delete, which can be, for example, benzosulfimide, p-toluensulfonate, methanesulfonate group, fluorine or bromine.

Specific examples of compounds of the formula (V) include the following compounds:

To obtain optically active compounds of formula (Ia), when necessary connection of the formula (VI) sequentially divided into optical isomers by using an optically active column, and remove the protection of hydroxyl groups of the compounds of formula (Ia) with a compound of formula (I).

Such hydroxyl-protective group is not limited, while they have the required function. For example, you can name groups such as tert-butyl; alkylsilane, for example, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; methoxymethyl; tetrahydropyranyl; trimethylsilylethynyl; aralkyl, for example, benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, trityl; and acyl, for example, formyl and acetyl, among which particularly preferred methoxymethyl, tetrahydropyranyl, trityl, trimethylsilyloxy, tert-butyldimethylsilyl and acetyl.

In particular, as the protective groups of the 1,2 - or 1,3-diols, for example, can be called mithilanchal, ateledensity, femilet licenseall, 4-methoxyphenylacetonitrile, isopropylidene and benzylideneacetone.

Methods of removal of the protective groups vary depending on the type of protective group and the stability of individual compounds represented by formula [Ia]. For example, the removal is performed by the methods described in the literature [see Protective Groups in Organic Synthesis, by T.W. Greene, John Wiley and Sons Co., (1981)]or methods similar to them, by solvolysis using an acid or base, ie, by the way, for example, in which the acid number is from 0.01 mol to a large molar excess, preferably triperoxonane acid, formic acid, chloride-hydrogen acid or the like; or in which the base amount which is equimolar to a large molar excess, preferably sodium hydroxide, calcium hydroxide or the like, communicates to the target compound; chemical recovery, consume hydrogenated complex of the metal, or by catalytic regeneration, while using the catalyst of palladium-on-coal or catalyst Raney Nickel.

In the case of diol-protective groups, such as ketal, acetal and the like, the removal of protection can be carried out by hydrolysis of compounds of formula (VI) using chloride-hydrogen acid, in a solvent such as THF, dioxane who or the like, at temperatures from room temperature to 100°C.

If necessary, the compound of formula (VI) can be optically split by the methods of chromatography using an optically active column to obtain optically active compounds of formula (Ia).

As the optically active column can be called, for example, CHIRALPAK®AD, CHIRALPAK®AD-H CHIRAL CELL®OD and CHIRAL CELL® OD-H (Daicel C., Ltd.).

As elution solvent-solvent in this case can be called mixed solvents, such as hexane/2-propanol/diethylamine = 1900/100/2 - 800/200/1 by volume, or hexane/ethanol/diethylamine = 1900/100/2 - 800/200/1 volume.

As methods of detecting compounds in this case can be applied, for example, ultraviolet rays in the wavelength range near 280 nm.

The method of obtaining 2

The method of obtaining 2 is a method for producing compounds of formula (I), using the compounds of formula (IV) as the original product.

The scheme of reactions 2

in which Ms means methanesulfonyl group, Thea means triethylamine, and su, su∗, RpL and R have the same meanings defined above.

In the compound of formula (IV) to impose mesyl group by known methods, designed to transform it into a compound of formula (VII), which successfully separated into optical is their isomers according to the method of obtaining 1 with obtaining the compounds of formula (VII). Then mesyl group (methylsulfonyl group in the compound of formula (VII) is removed using fluoride, Tetra-n-butylamine (F) to obtain the compounds of formula (VIIb), which is subjected to interaction with the compound of the formula (V) according to the method of obtaining 1 to obtain the compounds of formula (Ia), which is then converted into a compound of formula (I) by removing the protection.

The compound of formula (I)thus obtained can be isolated and purified by conventional means of separation, for example, by solvent extraction, recrystallization, column chromatography, preparative thin-layer chromatography or the like.

These compounds may be converted into pharmaceutically acceptable salts according to the accepted practice. On the contrary, the salt can be converted into the free compounds commonly used methods.

As salts of the compounds of formula (I) can be called additive salts of acids with piperidinyloxy group.

As examples of such additive salts of the acids can be called inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate and the like; salts of carboxylic acids such as maleate, fumarate, tartrate, citrate, ascorbate, triptorelin and the like; sulfonates such as methanesulfonate, isethionate, bansilalpet, p-colorsort is at and the like.

The effect of the compounds of this invention as antagonists nociceptive receptor shown in the following pharmacological test examples.

Pharmacological test example 1 (a quantitative analysis of inhibition of binding nociceptive receptor)

cDNA, which encodes a gene of the human receptor nociceptin, combined with the expression vector pCR3 (Invitrogen) to prepare pCR3/ORL1. Then pCR3/ORL1 were subjected to transfection in Cho cells, using transfected (Nippongene) to obtain lines with stable expression (SNO/ORL1 cells)having a resistance of 1 mg/ml G418. The membrane fraction was prepared from this line with stable expression to perform a quantitative analysis of the binding of the receptor. Membrane sample component 11 μg, 50 PM [125I] Tyr14-nociceptin (Amersham Pharmacia), 1 mg SPA beads of agglutinin seedlings of wheat (based on PVT; Amersham Pharmacia) and each test compound suspended in NC buffer (50 mm Hepes, 10 mm sodium chloride, 1 mm magnesium chloride, 2.5 mm calcium chloride, 0.1% of BSA, 0.025% of bacitracin, pH 7.4) and incubated at 37°C for 60 minutes, and then radioactivity was determined. The activity of binding to nociceptive receptor was defined as a concentration of 50%inhibition (IC50value) [125I] Tyr14-nociceptive linking each tested connection is possible. The results were as shown in table 1.

Table 1
ConnectionIC50size (nm)
Example 11,6
Example 25,1
Example 38,7
Example 41,9
Example 52,8

Pharmacological test example 2 (antagonism against the activation of G proteins caused by nociception)

Cho cells that stably represented nociceptive the ORL1 receptor, was used to study the actions of each of the tested compounds against the activation of G proteins caused by nociception. A membrane sample prepared from Cho/ORL1 cells, 50 nm nociceptin, 200 PM GTPy[35S] (NEN), 1.5 mg SPA beads of agglutinin wheat germ (Amersham Pharmacia) and each of the test compounds were mixed in GD buffer (20 mm Hepes, 100 mm sodium chloride, 10 mm magnesium chloride, 1 mm EDTA, 5 μm GDP, pH 7.4) and incubated at 25°C for 150 minutes, and then radioactivity was determined. Antagonism against the activation of G proteins, called notice the other, meant a concentration of 50%inhibition (IC50value) for each tested compounds against GTPy[35S] binding. The results were as shown in table 2.

Table 2
ConnectionIC50size (nm)
Example 1a 3.9
Example 28,6
Example 318,0
Example 46,0
Example 54,5

Pharmacological test example 3 (evaluation of metabolic stability)

The metabolic activity of the test compounds were investigated using microsome human liver. Prepared 100 mm potassium phosphate buffer (pH 7.4)containing 10 mm G-6-P, 1.0 mm NADP+(NADP+), 10 units/ml G-6-P DH, 3.0 mm MgCl2and 0.25 mg protein/ml liver microsomes person, each portion of which 392 μl was poured into a variety of vessels and pre-incubated at 37°C for 5 minutes. Then, 8 μl of each 50 μm test compounds (50% solution in acetonitrile) was added to initiated the project for the reaction (final concentration of test compounds: 1 μm). In the period of initiation and 30 min after the reaction, 150 μl of each reaction solution was added to 450 μl of ethanol to the suspension of the reaction, followed by separation by centrifugation (12000 g, 12 min, 4°C). The obtained supernatant was analyzed using LC/MS/MS(LC/MS/MS). Based on the peak areas of the test compounds in each sample in the initial period of the reaction, taken as 100%, was calculated residual ratio of the tested compounds in the sample after 30 minutes of reaction. The results were as shown in table 3.

Residual ratio (%) =

[the area of the peaks (after 30 minutes of reaction)/

the area of the peaks (after 0 min of reaction)] × 100.

Table 3
ConnectionResidual ratio (%)
Example 282
Example 472
Example 565

Pharmaceutical formulation containing the compounds of formula (I)

The compounds of this invention can be administered orally or parenterally, in the form of ready preparative forms suitable for such routes of administration can be and is used as analgetika against diseases, accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; means improving the portability of narcotic analgesics represented by morphine; tools to ease the dependence on narcotic analgesics represented by morphine or against addiction; amplifiers analgesics; anti-obesity or means to suppress appetite; therapeutic or prophylactic agents at lower cognitive abilities and age-related dementia/amnesia, cerebrovascular diseases and Alzheimer's disease; agents for the treatment of developing disorders cognitive abilities with attention deficit, hyperfunctional disorders and inferiority assimilation; remedies in schizophrenia; agents for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressant and treatment in affective disorders; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents the polyuria; and a remedy for hypotension, and the like.

In fact, when applying the compounds of this invention they can be cooked in a different formulation, suitable for individual routes of administration, with formats whitesky acceptable adjuvants. As adjuvants can be used various additives commonly used in the field of medical drugs, examples of which include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hypromellose, carboxymethylcellulose, corn starch, crystalline wax, white petrolatum, magnesium aluminate of metasilicate, anhydrous calcium phosphate, citric acid, trinacria citrate, hydroxypropylcellulose, sorbitol ester sorbitan and carboxylic acid, Polysorbate, ester of sucrose and a carboxylic acid, polyoxyethylene, utverjdenie castor oil, polyvinylpyrrolidone, magnesium stearate, silicon dioxide, talc, vegetable oil, benzyl alcohol, Arabian gum, propylene glycol, polyalkyleneglycol, cyclodextrin or hydroxypropylcellulose and the like.

As a preparative forms, prepared in the form of pharmaceutical compositions, using data adjuvants, can be called a solid formulation such as tablets, capsules, powders and suppositories; preparative liquid forms such as syrups, elexir and preparations for injection. Data formulation can be prepared by conventional methods used in the field of pharmacy. Liquid preparations can be a form that restoratio suspended in water or another suitable medium immediately before use. In particular, preparations for injection can be in the form of a solution or suspension in physiological saline or glucose solution, to which may be added a buffering agent, preservative and the like.

Data formulation may contain a compound or compounds of this invention in proportions of 1-100 wt.%, preferably 1-60 wt.% calculated on the total pharmaceutical preparative form. Data formulation may contain other therapeutically active compounds.

In those cases where the compounds of this invention are used as analgetika against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; means improving the portability of narcotic analgesics represented by morphine; tools to ease the dependence on narcotic analgetic represented by morphine or against addiction; amp analgesics; anti-obesity or means to suppress appetite; therapeutic or prophylactic agents at lower cognitive abilities and age-related dementia/amnesia, cerebrovascular diseases and Alzheimer's disease; agents for treatment of developing disorders cognitive abilities with attention deficit, guy is refunctioning disorders and inferiority assimilation; a remedy for schizophrenia; agents for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressants and treatment in affective disorders; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents the polyuria; or a remedy for hypotension; dose of their introduction or frequency may vary depending on sex, age, body weight, severity of symptoms of individual patients and the type and extent of the alleged therapeutic effect. In General, the dose may be in the range from 0.001 to 50 mg per day per kilogram of body weight, which can be entered one or more times. Preferably the dose is in the range from about 0.01 to about 25 mg/kg per day, in particular from about 0.05 to about 10 mg/kg per day.

Examples

Below the invention is described in more specifically with reference to working examples, it means that the invention is not limited to these working examples. Unless otherwise noted, these various reagents used in the working examples, represented reagents available on the market, and the value H-NMR spectrum was measured using tetramethylsilane was as the reference product, using AL-400-2(400 MHz, JEOL Co.). Also mass spectra measured by the instrument MicromassZQ (Waters Co.) ionization of elektrorazpredelenie (ESI) or chemical ionization at atmospheric pressure (APCI).

Example obtain 1

Getting Spiro[4.5]decane-6-carbaldehyde

1) Spiro[4.5]decane-6-he

Cyclohexanone (3.0 ml) was dissolved in toluene (60 ml) and cooled to 0°C. in a nitrogen atmosphere. Tert-piperonyl potassium (6,86 g) was added to the reaction liquid at 0°C and the mixture was stirred for 30 minutes. To the resulting suspension was added 1,4-dibromethane (3,65 ml), and then the reaction liquid was stirred at 150°C for 6 hours. Cooling the reaction liquid to room temperature, thereto was added water, then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 50/1)to give 690,0 mg specified in the title compounds as a colorless oily substance.

2) Spiro[4.5]decane-6-carbaldehyde

A solution of diethyl(isocyanatomethyl)phosphonate (410 μl) in diethyl ether (5 ml) was cooled to -78°C. in a nitrogen atmosphere. After adding 1.54 M solution of n-utility in hexane (1.7 ml) to the reaction liquid at -78°C. the temperature was raised to 0°C and the mixture was stirred for 15 minutes. To the resulting solution were added at 0°C Spiro[4.5]decane-6-he (300 mg), and the temperature was raised to room temperature with stirring. After an hour of concentrated chloride-ogorodnoy acid (5 ml) was added to the reaction liquid at room temperature, then the mixture was stirred for another 10 hours. The resulting solution was diluted with water and was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, from which drove the solvent, obtaining mentioned in the title compound in crude crude form in the form of a colorless oily substance.

Example of getting 2

Getting Spiro[3.5]nonan-5-carbaldehyde

1) Ethyl 1,4-dioxaspiro[4.5]decane-6-carboxylate

Ethyl 2-oxocyclohexanecarboxylate (11.3 g) and ethylene glycol (11 ml) was dissolved in toluene (100 ml). To the reaction liquid were added camphorsulfonic acid (1,03 g) and the mixture is boiled under reflux for 8 hours with the unit Dean-stark. The reaction liquid was cooled to room temperature, diluted with diethyl ether and washed with saturated aqueous solution of sodium bicarbonate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, from which drove the solvent, obtaining the crude product is specified in the connection header.

2) 1,4-Dioxaspiro[4.5]Dec-6-ylmethanol

The compound obtained in 1)was dissolved in tetrahydrofuran (120 ml) and cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid was added sociallyengaged (a 3.06 g) at 0°C, and then the temperature was raised to room tempera is URS, followed by stirring overnight. The reaction liquid was again cooled to 0°C., to which was added decahydrate sodium sulfate, and the mixture was stirred for one hour with subsequent drying by adding anhydrous sodium sulfate and filtration of the insoluble matter. Drove from the filtrate the solvent was received 9.80 g of crude product specified in the connection header.

3) 6-[(Benzyloxy)methyl]-1,4-dioxaspiro[4.5]Decan

Connection (9.80 g)obtained in 2)was dissolved in tetrahydrofuran (100 ml) and cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid at 0°C was added 60-72% sodium hydride (in the form of a dispersion in oil) (3,34 g), followed by stirring for 30 minutes. To the resulting reaction liquid was added at 0°C benzylbromide (8,4 ml), the temperature was raised to room temperature and the system was stirred for 3 hours. The reaction liquid was diluted with diethyl ether and washed first with water and successively with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent is kept off and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 19/1), receiving of 7.24 g specified in the connection header.

4) 2-[(Benzyloxy)methyl]cyclohexanone

Connection (3,37 g)obtained in 3)was dissolved in tetrahydrofuran (30 ml), to the solution was added 10% chloride-vodorodny the Yu acid (10 ml) at room temperature, followed by stirring for 3 hours. The reaction liquid was diluted with diethyl ether and washed first with water, successively with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent drove and got to 2.94 g of crude product specified in the connection header.

5) 2-[(Benzyloxy)methyl]-1-[1-(phenylthio)cyclopropyl]-cyclohexanol

The solution cyclopropylalanine (2,33 ml) in tetrahydrofuran (50 ml) was cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid at 0°C was added a 1.0 M hexane solution of n-utility (16 ml) with subsequent hour stirring. The reaction liquid was cooled to -78°C and to it was added tertrahydrofuran ring solution (10 ml) of the compound (2,94 g)obtained in 4), followed by stirring at -78°C for 30 minutes and then at 0°C for one hour. Water was added to the reaction liquid which then was extracted with diethyl ether. The extract was washed first with water and then saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 19/1)to give 3.04 from g specified in the connection header.

6) 5-[(Benzyloxy)methyl]Spiro[3.5]nonan-1-he

The compound (3.04 from g)obtained in 5), rest rely in toluene (40 ml), to the solution was added monohydrate p-toluensulfonate acid (1.60 g) and water (0.15 ml) and the mixture was stirred at 90°C for 5 hours. The reaction liquid was diluted with diethyl ether and washed with water, 10% aqueous sodium hydroxide solution and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 19/1)to give 670 mg specified in the connection header.

7) 5-[(Benzyloxy)methyl]Spiro[3.5]nonan

The compound (670 mg)obtained in 6), was dissolved in diethylene glycol (3 ml), to the solution was added hydrazine monohydrate (1.5 ml) and potassium carbonate (838 mg), followed by stirring under heating at 150°C for 3 hours and at 200°C for 5 hours. The reaction liquid was cooled to room temperature, diluted with diethyl ether and then washed with 10% chlorine-hydrogen acid and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation, getting 224 mg of crude specified in the connection header.

8) Spiro[3.5]non-5-ylmethanol

The compound (224 mg)obtained in 7), was dissolved in methanol (5 ml), to the solution was added a catalytic amount of palladium hydroxide, Besenova on activated carbon, and the system was stirred at room temperature for 4 hours in hydrogen atmosphere at a pressure of one atmosphere. Filtering the insoluble substance through celite(Celite®), the filtrate was agglomerated, getting 151 mg of crude specified in the connection header.

9) Spiro[3.5]nonan-5-carbaldehyde

The compound (151 mg)obtained in 8), was dissolved in dimethyl sulfoxide (5 ml) and to the solution was added triethylamine (2 ml) and anhydrous complex sulfurylase acid-pyridine (1,17 g) with subsequent hour stirring at room temperature. The reaction liquid was diluted with diethyl ether and then washed with water, 10% chloride-hydrogen acid, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and drove solvent, receiving 120 mg of crude specified in the connection header.

Example of getting 3

Getting Spiro[2.5]Octan-4-carbaldehyde

1) Ethyl 1,4-dioxaspiro[4.5]Dec-6-ylacetic

Ethyl (2-oxocyclohexyl)acetate (50,05 g) and ethylene glycol (45,5 ml) was dissolved in toluene (200 ml). Monohydrate p-toluensulfonate acid (of 7.75 g) was added to the reaction liquid, which is then boiled under reflux for 5 hours, using the apparatus of the Dean-stark. The reaction liquid was cooled to on the th temperature and thereto was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was removed by distillation, obtaining 76,54 g wet specified in the connection header in the form of light yellowish-brown oily substance.

2) 2-(1,4-Dioxaspiro[4.5]Dec-6-yl)ethanol

Connection (76,54 g)obtained in 1)was dissolved in tetrahydrofuran (350 ml) and cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid was added sociallyengaged (10,36 g) at 0°C, followed by stirring for 3 hours. To the resulting reaction liquid was added decahydrate sodium sulfate (51,85 g) and the mixture was stirred at room temperature overnight. Insoluble in the solution of the substance was filtered through celite(Celite®)and the filtrate was agglomerated give crude specified in the header connection (63,77 g) as a light yellow oily substance.

3) 2-(2-Chloroethyl)cyclohexanone

Connection (63,77 g)obtained in 2)was dissolved in acetonitrile (40 ml) and added to a concentrated chloride-hydrogen acid (250 ml)which was cooled to 0°C. the Temperature of the reaction liquid was raised to room temperature followed by 1.5-hour heated at the boil under reflux. The reaction liquid was cooled to room temperature, diluted with water and extracted with hexane. Extra is t then washed with water and then saturated aqueous sodium hydrogen carbonate, was dried over anhydrous sodium sulfate and solvent was removed by distillation, give crude specified in the header connection (46,15 g) as a light yellow oily substance.

4) Spiro[2.5]Octan-4-one

Connection (46,15 g)obtained in 3)was dissolved in ethanol (100 ml) and cooled to 0°C. To the reaction liquid was added powdered potassium hydroxide (19,97 g) at 0°C and the temperature was raised to room temperature, followed by stirring for 3 hours. The precipitated potassium chloride was filtered, and the filtrate was used in the subsequent reaction in the form of an ethanol solution specified in the connection header.

5) Spiro[2.5]Octan-4-carbonitril

Tert-piperonyl potassium (158,0 g) suspended in dimethyl sulfoxide (370 ml), and to the suspension was added n-toluensulfonate (60,60 g) under ice cooling, followed 15 minutes stirring at 0°C. To the resulting reaction liquid brown was added at 0°C. the ethanol solution of Spiro[2.5]Octan-4-it is obtained in 4), the mixture was heated to room temperature and was stirred for 3 hours. To the reaction liquid were added water (300 ml) and hexane (300 ml) followed by addition of 10% chlorine-hydrogen acid (400 ml). The reaction liquid was extracted with hexane, and the extract was washed with water and saturated aqueous bicarbonate is the atrium. The organic layer was dried over anhydrous sodium sulfate, from which drove the solvent, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 3/1)to give 39,95 g specified in the title compound as a yellowish brown oily substance.

6) Spiro[2.5]Octan-4-carbaldehyde

Connection (39,95 g)obtained in 5), was dissolved in hexane (250 ml) and cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid was added dropwise a 0.95 M solution of diisobutylaluminium in hexane (400 ml) at 0°C. After the drip adding the reaction liquid was heated to room temperature and was stirred for 3 hours. The resulting reaction liquid was again cooled to 0°C. and to it was added dropwise 10% chloride-hydrogen acid (300 ml) with subsequent hour stirring at room temperature. The reaction liquid was extracted with hexane, and the hexane extract was first added to water (1.5 l) and then hydrosulfite sodium (500 g), followed by strong stirring at room temperature for extraction is specified in the header connection in the form of his hydrosulfite adduct in aqueous layer. The water layer with proektirovanii product was separated and to it was added tert-butyl ether (1 l) followed by the addition of sodium hydroxide (280 g) and the ilen by stirring at room temperature. Separating the ether layer, the aqueous layer was again extracted with methyl tert-butyl ether. Received the ether layers were combined and dried over anhydrous magnesium sulfate, of which drove away the solvent, getting 20,04 g specified in the title compounds as a light yellow oily substance.

Example 4

Getting Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-carbaldehyde

1) Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-one

Zinc powder (15,10 g) suspended in diethyl ether (70 ml) and to it was added copper chloride(I) (2,29 g) at room temperature, followed by boiling under reflux for 30 minutes in nitrogen atmosphere. The suspension was cooled to 0°C. and to it was added 3-methyltricyclo[2.2.1]heptane-2-he (7.0 ml) at 0°C. To the reaction liquid slowly dropwise added metandienone (7.0 ml) at 0°C. and after adding dropwise, the reaction liquid was heated under reflux for 30 minutes in nitrogen atmosphere. Cooling the reaction liquid to room temperature, was filtered through celite(Celite®) insoluble matter and the filtrate was washed twice with 5% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel, colonos the Oh chromatography (hexane/ethyl acetate = 100/1 - 7/1), receiving 4,89 g specified in the title compounds as a colorless oily substance.

2) Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-carbaldehyde

Chloride methoxybutyrophenone (6,41 g) suspended in tetrahydrofuran (80 ml) and cooled to 0°C. in a nitrogen atmosphere. After addition of 1.56 M solution of n-utility in hexane (36.2 ml) at 0°C. the reaction liquid was stirred for one hour. In the resulting solution was dark red was added dropwise a solution of Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-one (6,41 g) in tetrahydrofuran (10 ml) at 0°C, and then the temperature was raised to room temperature, followed by stirring overnight. In the reaction liquid at room temperature was added 5 M chloride-hydrogen acid (50 ml) and the mixture was stirred for another 3 hours. The reaction liquid was diluted with water and was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 99/1 - 97/3), receiving 5,04 g specified in the title compounds as a colorless oily substance.

Example of getting 5

Obtain 2,2-dimethyl-1,3-dioxolane-5-yl of methansulfonate

1) 2,2-Dimethyl-,3-dioxolane-5-ol

A solution of 2,2-dimethyl-1,3-dioxolane-5-it (930 mg) in tetrahydrofuran (10 ml) was cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid was added sociallyengaged (293 mg) at 0°C with a subsequent 30-minute stirring. After adding to the reaction mixture of decahydrate sodium sulfate (3 g) at 0°C. the temperature was raised to room temperature followed by additional stirring for 2 hours. The insoluble substance was filtered, and the filtrate was agglomerated. The resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 3/2)to give 743 mg specified in the title compounds as a colorless oily substance.

2) 2,2-Dimethyl-1,3-dioxolane-5-yl methanesulfonate

A solution of 2,2-dimethyl-1,3-dioxolane-5-ol (743 mg) in tetrahydrofuran (10 ml) was cooled to 0°C. in a nitrogen atmosphere. To the reaction liquid was sequentially added triethylamine (1,87 ml) and methanesulfonamide (520 μl) at 0°C with a subsequent 30-minute stirring. After adding a saturated aqueous solution of ammonium chloride, the reaction liquid was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was removed by distillation, getting 837 mg of crude specified in the title compound as a colourless solid.

Prima is getting 6

Getting [(4R or 4S)-2,2,4-trimethyl-1,3-dioxolane-4-yl]methyl-4-methylbenzenesulfonate

Two kinds of optical isomers (2,2,4-trimethyl-1,3-dioxolane-4-yl)methyl-4-methylbenzenesulfonate (976 mg), which is a pure form of known substance, identified when using CHIRALPAK® AD (Daicel Co., Ltd., 2 ϕ × 25 cm); hexane/ethanol = 9/1), receiving in the first eluate 478 mg (4S or 4R) basis specified in the title compounds as the second eluate 477 mg (4S or 4R) basis specified in the connection header.

Example 1

Obtaining 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S or 6R)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it

1) 3-[1-(Spiro[4.5]Dec-6-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

To a solution of 1-piperidine-4-yl-1,3-dihydro-2H-benzimidazole-2-she (360 mg) in dichloromethane (15 ml) was added at room temperature compound (250 mg)obtained in example a 1, followed by the addition of triacetoxyborohydride sodium (380 mg) at room temperature. The resulting solution was stirred at room temperature for 3 hours, thereto was added 1 M aqueous sodium hydroxide solution and the reaction liquid was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and receive the config residue was purified on silica gel column chromatography (chloroform/methanol = 50/1 - 30/1), receiving 179,5 mg specified in the title compound as a colourless solid.

2) 1-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-3-[1-(Spiro[4.5]Dec-6-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Compound (90 mg)obtained in 1)was dissolved in dimethylformamide (3 ml), and to the solution was added 60-72% sodium hydride (dispersion in oil) (20 mg) at room temperature followed by a 30 minute mixing. After adding [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-4-methylbenzenesulfonate (140 mg) and potassium iodide, the reaction liquid was stirred at 60°C for 14 hours. The reaction liquid was cooled to room temperature, thereto was added 1 M aqueous sodium hydroxide solution followed by extraction with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 5/1 - 2/1)to give 100,2 mg specified in the title compounds as a light yellow oily substance.

3) 1-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-3-{1-[(6S or 6R)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

Two species of diastereoisomers of the compound (100,2 mg)obtained in 2), were isolated when using CHIRALPAK® AD (Daicel Co., Ltd., 2 ϕ × 25 cm); hexane/2-propane is/diethylamine = 6/1/0,007), receiving in the first eluate to 44.1 mg (6S or 6R) basis specified in the connection header.

4) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S or 6R)-Spiro[4.5]Dec-6-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

Compound (44 mg)obtained in 3)was dissolved in tetrahydrofuran (2 ml), to the solution was added 5 M chloride-hydrogen acid (2 ml) at room temperature and was stirred for one hour. The resulting reaction solution was cooled to 0°C, neutralized 1 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified on silica gel thin-layer chromatography (chloroform/methanol = 20/1)to give 28,8 mg specified in the title compounds as a colorless oily substance.

1H-NMR (CDCl3)δ= 1,14-1,85 (19H, m), 1,88 of 1.99 (1H, m), 2,14 is 2.55 (5H, m), 2,90-2,99 (1H, m), 3,05-3,14 (1H, m), 3,55-3,62 (2H, m), 3.96 points-4,10 (3H, m), 4.26 deaths-and 4.40 (1H, m), 7,07-to 7.15 (3H, m), 7,28-7,34 (1H, m).

ESI-MS (+20eV) m/z 442,2

Example 2

Obtaining 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it

1) 3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

To a solution of 1-piperidine-4-yl-1,3-dihydro-2H-benzimidazole-2-it (of 4.00 g) in tetrahydrofuran is e (150 ml) was added at room temperature connection (3,02 g), received in the sample receiving 3, and then triacetoxyborohydride sodium (4.68 g) at room temperature. Mixed solution was stirred at room temperature for 2 hours followed by the addition of 1.5 M aqueous sodium hydroxide solution and extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was removed by distillation, getting to 4.98 g of crude specified in the title compound as a light tan solid.

2) 1-(Methylsulphonyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Connection (4,98g)obtained in 1)was dissolved in chloroform (150 ml). To the solution was added triethylamine (7 ml) and methanesulfonamide (1,94 ml) at room temperature with subsequent 2-hour stirring at room temperature. The reaction liquid was diluted with chloroform and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (chloroform/methanol = 100/1 - 15/1), receiving 5,47 g specified in the title compounds as a light yellow oily substance.

3) 1-(Methylsulphonyl)-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

Two views of the diastereomers of the compound (5,47 g), obtained in 2), were isolated when using CHIRALPAK® AD (Daicel Co., Ltd.; 2 ϕ × 25 cm); hexane/ethanol/diethylamine = 4/1/0,005), receiving in the first eluate of 2.15 g of (4S) basis specified in the connection header.

4) 3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

The compound (2.15 g)obtained in 3)was dissolved in tetrahydrofuran (70 ml), to the solution was added 1 M solution of fluoride, Tetra-n-butylamine in tetrahydrofuran (9.5 ml) at room temperature, and the mixture was stirred for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction liquid which then was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified on N basic silica gel column chromatography (hexane/ethyl acetate = 1/1 - 1/2)to give 1.56 g specified in the title compound as a colourless solid.

5) 1-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he (2,94 g) was dissolved in dimethylformamide (60 ml), and to the solution was added 60-72% sodium hydride (dispersion in oil) (706,6 mg) at room temperature and was stirred for 30 minutes. Reaktsionnoi fluid was added [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-4-methylbenzenesulfonate (7,25 g) and the mixture was stirred at 80°C for 7 hours. After cooling the reaction liquid to room temperature, added with water, followed by extraction with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1 - 1/2), receiving 3,43 g specified in the title compounds as a light yellow oily substance.

6) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he hydrochloride

Connection (2,71 g)obtained in 5), was dissolved in methanol (15 ml), to the solution was added 10% solution of hydrogen chloride in methanol (65 ml) and stirred at room temperature overnight. The reaction liquid was agglomerated, and the obtained solid was washed with ethanol, obtaining 1.6 g specified in the title compound as a colourless solid.

1H-NMR (CDCl3)δ= 0,31 at 0.42 (2H, m), 0,42 is 0.58 (2H, m), 0.76 to 0,86 (1H, m), 1,40 is 1.75 (4H, m), 1,75 is 2.10 (4H, m), 2,72-of 3.00 (4H, m), 3,22-of 3.42 (3H, m), 3,52-of 3.64 (3H, m), 3,65-of 3.78 (2H, m), 4,00-4,08 (3H, m), 4,65-4,80 (1H, m,), 7,10-7,20 (3H, m), 8,02-8,08 (1H, m), 12,60 (1H, USS).

ESI-MS (+20eV) m/z 414,4

Example 3

Obtaining 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it

1) 3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

To a solution of 1-piperidine-4-yl-1,3-dihydro-2H-benzimidazole-2-she (1.5 g) in tetrahydrofuran (15 ml) was added at room temperature compound (1.2 g)obtained in example 4, and sequentially added triacetoxyborohydride sodium (2.0 g) and was stirred for 2 days at room temperature. To the reaction liquid was added 1 M aqueous sodium hydroxide solution followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, then the solvent is kept off and the resulting residue was purified on silica gel column chromatography (chloroform/methanol = 100/1 - 10/1)to give 1,53 g specified in the title compound as a pale orange solid.

2) 1-(Methylsulphonyl)-3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Connection (1,g)obtained in 1)was dissolved in chloroform (15 ml) and cooled to 0°C. the first solution was added triethylamine (1.2 ml) and then methanesulfonanilide (512 μl) at 0°C with subsequent hour stirring at 0°C. the Reaction liquid was diluted with ethyl acetate and washed with 1 M aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate and removed Rast is oritel distillation. The resulting residue was purified on silica gel column chromatography (chloroform/methanol = 200/1 - 20/1)to give 1.90 g specified in the title compounds as a light yellow oily substance.

3) 1-(Methylsulphonyl)-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]-heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

Four types of optical isomers of compound (1.90 g)obtained in 2), were isolated when using CHIRALPAK® AD (Daicel Co., Ltd.; 2 ϕ × 25 cm); hexane/ethanol/diethylamine = 9/1/0,01), receiving in the form of a third eluate 420 mg of (1R,3S,4S) basis specified in the connection header.

4) 3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

The third eluate (420 mg)obtained in 3)was dissolved in tetrahydrofuran (5 ml), and to the solution was added 1 M solution of fluoride, Tetra-n-butylamine in tetrahydrofuran (1.5 ml) at room temperature and the mixture was stirred over night. After removal of the solvent from the reaction liquid obtained residue was purified by silica gel column chromatography (chloroform/methanol = 100/1 - 10/1)to give 294 mg specified in the title compound as a colourless solid.

5) 1-(2,2-Dimethyl-1,3-dioxolane-5-yl)-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

The compound (294 m is), obtained above in 4), was dissolved in dimethylformamide (5 ml), and to the solution was added 60-72% sodium hydride (dispersion in oil) (100 mg) at room temperature and was stirred for 30 minutes. To the resulting reaction liquid was added the compound (353 mg)obtained in example getting 5, and the mixture was stirred at 120°C for 2 hours. After 60-72% sodium hydride (dispersion in oil) (100 mg) and the compound (353 mg)obtained in example receiving 5, was added to the reaction liquid twice with a time interval. The reaction liquid was cooled to room temperature, thereto was added 1 M aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (chloroform/methanol = 400/1 - 20/1)to give 132 mg specified in the title compounds as a light yellow oily substance.

6) 1-[2-Hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it. hydrochloride

Compound (132 mg)obtained in 5), was dissolved in methanol (5 ml), to the solution was added 6 M chloride-hydrogen acid (100 μl) at room temperature and was stirred for 3 hours is. Fending off the solvent from the reaction liquid, the resulting solid was washed with ethyl acetate, getting 128 mg specified in the title compound as a colourless solid.

1H-NMR (CD3OD)δ= 0.29 to 0.39 (2H, m), 0,46 is 0.55 (1H, m), 0,66-0,74 (1H, m), 1,46-1,68 (6N, m), 1,79 is 1.86 (1H, m), 2.00 in a 2.12 (2H, m), 2,28-is 2.37 (1H, m), 2,53 at 2.59 (1H, m), 2,74-3,26 (5H, m), 3,49-3,62 (1H, m), 3,71-is 3.82 (2H, m)of 3.94 (2H, DD, J=5,3, and 11.6 Hz), 4,08 (2H, DD, J=8,1, the 11.6 Hz), 4,45 with 4.65 (2H, m), 7,06-7,14 (2H, m), 7,28-7,41 (2H, m)

ESI-MS (+20eV) m/z to 426.2

Example 4

Getting salt of 1-[(2S or 2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-she (2R,3R)-3-carboxy-2,3-dihydroxypropane acid

1) 1-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-3-{[(4S or 4R)-2,2,4-trimethyl-1,3-dioxolane-4-yl]methyl}-1,3-dihydro-2H-benzimidazole-2-he

3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he (753 mg)obtained in (4) of example 2, and potassium iodide (372 mg) was dissolved in dimethylformamide (100 ml), and to the solution at room temperature was added 60-72% sodium hydride (dispersion in oil) (428 mg) and the mixture was stirred for 30 minutes. To the resulting reaction liquid at room temperature was added a solution of [(4R or 4S)-2,2,4-trimethyl-1,3-dioxolane-4-yl]methyl-4-methylbenzenesulfonate (1,99 g)obtained in example getting 6 as the second eluate, in dimethylformamide (30 is l) and the mixture was stirred at 120°C in a continuation of the night. To the reaction liquid was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate = 10/1 - 5/1)to give 1.27 g specified in the title compounds as a light yellow oily substance.

2) salt of 1-[(2S or 2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-Spiro[2.5]Oct-4-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he (2R,3R)-3-carboxy-2,3-dihydroxypropane acid

The compound (1.27 g)obtained in 1)was dissolved in tetrahydrofuran (20 ml), and to the solution was added 1 M chloride-hydrogen acid (20 ml) at room temperature and was stirred overnight. The resulting reaction liquid was cooled to 0°C., and thereto was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (chloroform/methanol = 30/1 - 4/1), receiving 1,09 g free amine bases specified in the connection header. The free amine base (33,2 mg) and (2R,3R)-tartaric acid (11.6 mg) RA is tarali in methanol (3 ml), and the solvent drove away. The obtained solid was washed with ethyl acetate, getting to 44.8 mg specified in the title compound as a colourless solid.

1H-NMR (CD3OD)δ= 0,35 (2H, USS), of 0.45 (2H, USS), 0,84 (1H, m), 1.14 in (1H, d, J=6.2 Hz), 1,20 (3H, s), 1.41 to to 1.82 (8H, m), a 2.01 (2H, m), 2,78-of 3.25 (5H, m), 3,30-3,51 (2H, m), of 3.69 (2H, m)to 3.92 (2H, s), 4,43 (2H, s), 4,60 (1H, m), 7,12 (2H, m), of 7.36 (2H, m).

ESI-MS (+20eV) m/z 428,3

Example 5

Obtain hydrochloride of 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it

1) 1-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he

3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-he (1.47 g)obtained in (4) of example 3, was dissolved in dimethylformamide (25 ml), and to the solution at room temperature was added 60-72% sodium hydride (dispersion in oil) (418 mg) and the mixture was stirred for 15 minutes. To the resulting reaction liquid at room temperature was added a solution of [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-4-methylbenzenesulfonate (2,39 g) in dimethylformamide (5 ml) and the mixture was stirred at 80°C for 5 hours. The reaction liquid was cooled to room temperature, thereto was added fo Paty buffer (pH 6.5), followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 9/1 - 1/1)to give 1.80 g specified in the title compounds as a colorless oily substance.

2) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-it. hydrochloride

The compound (1.75 g)obtained in 1)was dissolved in tetrahydrofuran (57 ml), to the solution was added 1 M chloride-hydrogen acid (19 ml) at room temperature and was stirred for 30 hours. The reaction liquid was neutralized by adding saturated aqueous solution of sodium bicarbonate at 0°C, then was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (chloroform/methanol = 1/0 - 95/5)to give 1.42 g of the free amine compound specified in the header. The amine was dissolved in diethyl ether to the solution at room temperature was added a 4 M solution of hydrogen chloride in dioxane (0,92 ml). Fending off the solvent from the resulting suspension, the remaining solid was washed with a mixture of ethanol/ethyl is Etat (1/1), getting 1.06 g specified in the title compound as a colourless solid.

1H-NMR (CD3OD)δ= 0,27 is 0.38 (2H, m), 0,43-0,57 (1H, m), 0,63-to 0.73 (1H, m), 1,40 was 1.69 (6N, m), 1,78-to 1.87 (1H, m), 1,96-of 2.09 (2H, m), 2,27-is 2.37 (1H, m), 2,52-2,60 (1H, m), 2,70-3,27 (6N, m), 3,51-of 3.60 (2H, m), 3,65-of 3.80 (2H, m)a 3.87-a 4.03 (3H, m), to 4.52-of 4.67 (1H, m), 7,08-7,16 (2H, m), 7,22-7,29 (1H, m), 7,32-7,41 (1H, m).

ESI-MS (+20eV) m/z to 426.2

Industrial applicability

Compounds of the present invention have an effect on the inhibition of binding nociceptin with nociceptin receptor ORL1 and applicable as analgetika against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; means improving the portability of narcotic analgesics represented by morphine; tools to ease the dependence on narcotic analgetic represented by morphine; amplifiers analgesics; anti-obesity or means to suppress appetite; therapeutic or prophylactic agents at lower cognitive abilities and age-related dementia/amnesia, cerebrovascular diseases and Alzheimer's disease; agents for treatment of developing disorders cognitive abilities with attention deficit, hyperfunctional disorders and inferiority assimilation; a therapeutic agent for sysopen and; means for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressant and treatment in affective disorders; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents the polyuria; and a remedy for hypotension, and the like.

1. The compound of formula (I):

in which R means dihydroxytoluene2-C6alkyl group, and su is a Spiro[4.5]Dec-6-yl, Spiro[2.5]Oct-4-yl, Spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl or 1-Spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl group, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R represents dihydroxytoluene3-C4alkyl group.

3. The compound according to claim 2, in which R represents a 2,3-dihydroxypropyl, 2-hydroxy-1-(hydroxymethyl)ethyl or 2,3-dihydroxy-2-methylpropyl.

4. The compound according to claim 1 in which the compound of formula (I)selected from the group consisting of
1) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[4.5]Dec-6-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,
2) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,
3) 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl)Pieper is DIN-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,
4) 1-(2,3-dihydroxy-2-methylpropyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it
5) 1-(2,3-dihydroxypropyl)-3-[1-(Spiro[bicyclo[2.2.1]-heptane-2,1'-cyclopropane]-3-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, or its pharmaceutically acceptable salt.

5. The compound according to claim 1, where the compound of formula (I), representing
1-(2,3-dihydroxypropyl)-3-[1-(Spiro[4.5]Dec-6-ylmethyl)-piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he or
its pharmaceutically acceptable salt.

6. The compound according to claim 1, where the compound of formula (I), representing
1-(2,3-dihydroxypropyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he or
its pharmaceutically acceptable salt.

7. The compound according to claim 1, where the compound of formula (I), representing
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-[1-(Spiro[bicyclo-[2.2.1]heptane-2,1'-cyclopropane]-3-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he
or
its pharmaceutically acceptable salt.

8. The compound according to claim 1, where the compound of formula (I), representing
1-(2,3-dihydroxy-2-methylpropyl)-3-[1-(Spiro[2.5]Oct-4-ylmethyl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he or
its pharmaceutically acceptable salt.

9. The compound according to claim 1, where the compound of formula (I), representing
1-(2,3-dihydroxypropyl)-3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-elmet the l)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he or
its pharmaceutically acceptable salt.

10. The pharmaceutical composition inhibiting the binding nociceptin with nociceptive receptor containing pharmaceutically acceptable adjuvant and the connection according to claims 1-9, or its pharmaceutically acceptable salt.

11. A method of obtaining a medicinal product for use as analgetika; means improving tolerance to narcotic analgesics; aid dependence on narcotic analgesics or against addiction; amp analgesics; anti-obesity or means to suppress appetite; treatment for reducing cognitive abilities and age-related dementia/amnesia, cerebrovascular diseases and Alzheimer's disease; means for developing treatment of disorders of cognitive abilities with attention deficit, hyperfunctional disorders and inferiority assimilation; drugs in schizophrenia; means for treating neurodegenerative diseases represented by parkinsonism and chorea; antidepressant or therapeutic agents in affective disorder; therapeutic or preventive agent for diabetes insipidus; a therapeutic or preventive agent for polyuria; and a remedy for hypotension, which involves mixing of compounds in any the claims 1-9, or its pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: described is an improved method for synthesis of 3(5)-pyridyl-substituted 5(3)-amino-1,2,4-triazoles of general formula (I)

, where R denotes 2-pyridyl, 3-pyridyl or 4-pyridyl, involving reaction of pyridine carboxylic acid of general formula (II)

, where R assumes said values, with an aminoguanidine hydrocarbonate in the presence of hydrochloric acid in molar ratio acid (II): aminoguanidine hydrocarbonate: hydrochloric acid = 1.0:1.0:1.3-1.5, while boiling the reaction mixture with gradual distillation of water at atmospheric pressure until temperature of the reaction mixture equals 165-180°C and then holding the reaction mixture at this temperature for 3-5 hours and then adding an alkali solution in water, boiling alkaline solution and extraction of the end product by filtering after neutralisation of the reaction mixture and cooling.

EFFECT: method enables to obtain said compounds from cheaper material, increases output of end products and shortens duration of the synthesis process.

1 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula 1a, where X denotes a halogen or C1-C4halogenalkyl; Z denotes N or CR9; each R5 independently denotes halogen or C1-C4halogenalkyl; R9 denotes H, halogen or C1-C4halogenalkyl; R10 denotes H or C1-C4alkyl; and n is an integer from 0 to 3, involving bringing 2-pyrazoline of formula 2a, where X, Z, R5, R9, R10 and n assume values given above, into contact with bromine in a medium of a suitable inert organic solvent at temperature 80-180°C.

EFFECT: obtaining pyrazoles of formula 1a with high output and purity.

7 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing candesartan or a protected form of candesartan, candesartan salt or candesartan ester using a catalyst or several catalysts preferably containing one or more transition metals, and one or more of the following solvents: tetrahydrofuran (THF), THF/NMP (N-methylpyrrolidone), Et2O, DME (dimethoxy ethane), benzene, toluene, involving the following steps: (a) supply and reaction of a compound of formula (I), where R denotes hydrogen, unsubstituted or substituted alkyl or aryl radical, preferably methyl or (cyclohexyloxycarbonyloxy)ethyl, Y1 denotes a group capable of a coupling reaction into which Y2 comes in to form a C-C bond, with a compound of formula (II), having group Y2, where R1 is selected from a group comprising hydrogen, tert. Butyl and triphenylmethyl, preferably triphenylmethyl, to form candesartan, a protected form of candesartan or candesartan ester or candesartan cilexetil or some other candesartan ester, where (i) Y1 denotes B(OR4)2, where each of the radicals R4 independently denotes hydrogen, alkyl, aryl or alkylaryl, preferably hydrogen, and Y2 denotes a halogen, preferably bromine, or (and) Y denotes a halogen, preferably bromine,and Y2 denotes B(OR4)2, where each of radicals R4 independently denotes hydrogen, alkyl, aryl or alkylaryl, preferably hydrogen, and if necessary, (b) conversion to candesartan, candesartan cilexetil or salt.

.

EFFECT: novel method for producing candesartan with high output.

24 cl, 3 dwg, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or its pharmaceutically acceptable salts that possess properties of CB2 receptors agonist and can be used in preparing drugs exerting analgesic effect, in particular, for pain treatment. In compound of the formula (I) R1 is chosen from group consisting of (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C2-C6)-alkenyl, R42N-(C1-C6)-alkyl, R42NC(=O)-(C1-C6)-alkyl, R4O-(C1-C6)-alkyl, R4OC(=O)-(C1-C6)-alkyl, R4C(=O)-(C1-C6)-alkyl, R4C(=O)-NR4-(C1-C6)-alkyl, R42NSO2-(C1-C6)-alkyl, R42NC(=O)-NR4-(C1-C6)-alkyl, radicals phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocycloalkyl-(C1-C6)-alkyl, bicyclic heteroaryl-(C1-C6)-alkyl; Ar represents phenyl or pyridyl; R2 represents (C1-C6)-alkyl that is unsubstituted or substituted at 1-6 carbon atoms with one or more fluorine atom substitute or (C3-C6)-cycloalkyl; R3 is chosen from the following group consisting of: (a) , (b) , (c) , (d) , (e) , (f) , (g) , (h) , (i) , (j) and (k) ; R4 represents group chosen independently from group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl; groups R5 are chosen independently from group consisting of H, (C2-C6)-alkenyl; groups R6 are chosen independently from group consisting of H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, heterocyclyl, radical (C1-C3)-alkyl, phenyl, radical phenyl-(C1-C3)-alkyl, heteroaryl, radicals heteroaryl-(C1-C3)-alkyl, bicyclic heteroaryl and bicyclic heteroaryl-(C1-C3)-alkyl; R5 and R6 can be combined to form 5-7-membered heterocycle; X is chosen from group consisting of -C(R5)2-, -NR5-, C(=O)-, -CH2-CH2-, CH=CH- and -C(R)(R') wherein R and R' represent (C1-C6)-alkyl, -OR'' or H and R'' represents H; Y represents -CH or nitrogen atom and wherein heterocyclyl or heterocycloalkyl represent 5-6-membered ring comprising from 1 to 2 heteroatoms chosen from nitrogen (N) and oxygen (O) atoms that is unsubstituted or substituted with (C1-C6)-alkyl; heteroaryl represents heteroaromatic 5-6-membered ring comprising from 1 to 2 heteroatoms chosen from N, S and sulfur atom (S) that is unsubstituted or substituted with group chosen from group consisting of (C1-C6)-alkyl, nitro-group, halogen atom and acetoxymethyl; bicyclic heteroaryl represents 5-6-membered nitrogen-containing ring condensed with benzene ring. Also, invention relates to a pharmaceutical composition and a method for paintreatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 15 sch, 3 tbl, 130 ex

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or the same As the ode;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to an agent exhibiting antihypertensive activity which represents 1-alkyl-2-alkylcarbamoylglycerins of general formula I . In formula I R means hydrocarbon radical -(CH2)nCH3 (n=10-18), R1 means methyl or ethyl. Also, the invention refers to a method for preparing the compounds of formula I. The method consists in the fact that parent 1-alkylglycerins of general formula II react with trimethylchlorosilane with using triethylamine in toluene medium at temperature -20°C to 0°C, then the reaction mass is added with appropriate alkylisocyanate and processed with ammonium bifluoride in methanol medium at room temperature.

EFFECT: preparation of the agent exhibiting antihypertensive activity.

2 cl, 7 ex

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