Benzimidazole compound and pharmaceutical use thereof

FIELD: chemistry.

SUBSTANCE: described are novel compounds of general formula (I)

, where the value of each symbol is defined in the claim, which are ORL-1 receptor agonists.

EFFECT: improved bioavailability, based on improved metabolic stability, strong and high selectivity and can be used in medicine.

7 cl, 148 ex, 35 tbl

 

The technical field to which the invention relates

The invention relates to the detected compound that is an agonist of the receptor ORL-1, suitable for pharmaceutical use, or its salt, or containing drug.

The level of technology

Receptor ORL-1 (similar opioid receptor 1) (see non-patent document 1, non-patent document 2) is a receptor found in 1994 as the fourth opioid receptor, followed by receptor δ, κ and μ, and its amino acid sequence is approximately 60% homologous to the amino acid sequence of other opioid receptors. However, it is clearly different from other opioid receptors that are not associated with naloxone, which is a nonselective antagonist of opioid receptors (see non-patent document 2). Although the receptor ORL-1 is expressed in peripheral organs such as the intestines, spleen, etc., it is widely distributed mainly in the Central nervous system and, in particular, largely is expressed in the cortex, hippocampus, hypothalamus, an almond-shaped body and the spinal cord (see non-patent document 3, non-patent document 4).

In 1995, endogenous ligands for receptor ORL-1 were consistently identified groups of experiments the residents in France and Switzerland and are called nociception (see non-patent document 5) and organism FQ (see non-patent document 6). It was reported that nociceptin is a peptide of 17 amino acids, which plays an important role in the functions of the Central nervous system, such as learning, memory, fear and stress (see non-patent document 7).

In particular, it was reported that injection of trace amounts nociceptin in the hippocampus of rats makes them upset training in the method of learning in the water maze (see non-patent document 8), and that the mouse-knockout, devoid of receptor nociceptin, faster acquires skills in the method of learning in the water maze compared to a normal mouse (wild-type), and that the mouse-knockout demonstrates increased long-term potentiation (LTP) in the hippocampus, compared with the normal mouse (see non-patent document 9). Thus, it is believed that nociceptin has a suppressive effect on the function of memory and learning. In addition, it was reported that the introduction of nociceptin in the ventricle of the rat brain has anti-fobia action, is virtually equivalent to the action of diazepam in behavioral pharmaceutical tests such as the test of a conflict situation, svetolunova test, test elevated cross maze and the like (see non-patent document 10). In addition, it was reported that mouse-knockout without receptor nociceptin who demonstrates an increased susceptibility to stress and impaired ability to adapt to stress, compared with normal mouse (see non-patent document 11). In other words, it is believed that nociceptin has physiological effects, which exerts a protective effect against fear and stress, and it is believed that the agonist receptor ORL-1 potentially exerts anti-fobia action, which is based on the mechanism that is completely different from the mechanism of action of benzodiazepine compounds.

On the basis of the above, I believe that the compounds having an agonistic activity against receptor ORL-1, suitable for the treatment of mental disorders, neuropathy and physiological disorders, in particular, to improve the condition when the disease is caused by fear and stress, melancholy, traumatic lesions, memory loss due to Alzheimer's or another dementia, symptoms of epilepsy and convulsions, symptoms of acute and/or chronic pain, relief of withdrawal symptoms medicines, including withdrawal symptoms caused by the termination of abuse of drugs, alcohol abuse, control of water balance, excretion of Na+disorders , arterial blood pressure, disorders of nutrition, such as obesity and anorexia, and disorders of circadian rhythm sleep (see patent documents 1 to 9).

Non-patent shall document 1: FEBS Lett. 347: 284-288, 1994

Non-patent document 2: FEBS Lett. 341: 33-38, 1994

Non-patent document 3: Eur. J. Pharmacol. 340: 1-15, 1997

Non-patent document 4: Pharmacol. Rev. 53: 381-415, 2001

Non-patent document 5: Nature 377: 532-535, 1995

Non-patent document 6: Science 270: 792-794, 1995

Non-patent document 7: Br. J. Pharmacol. 129, 1261-1283, 2000

Non-patent document 8: Eur. J. Neurosci. 9, 194-197, 1997

Non-patent document 9: Nature 394: 577-581, 1998

Non-patent document 10: Proc. Natl. Acad. Sci. USA 94, 14854-14858, 1997

Non-patent document 11: Proc. Natl. Acad. Sci. USA 96, 10444-10449, 1999

Patent document 1: JP-A-2000-26466

Patent document 2: JP-A-11-228575

Patent document 3: JP-A-10-212290

Patent document 4: WO 99/36421

Patent document 5: WO 98/54168

Patent document 6: WO 01/39775

Patent document 7: WO 00/06545

Patent document 8: WO 03/082333

Patent document 9: WO 05/028466

Description of the invention

Problems solved by the present invention

It was reported that Ro64-6198, a known agonist of the receptor ORL-1, has a bioavailability (BA), component 4% (Proc. Natl. Acad. Sci. USA 97: 4938-4943, 2000).

The authors of the present invention have conducted intensive studies of compounds with affinity for the receptor ORL-1, in particular, compounds with agonistic action against the receptor ORL-1, and found that the compounds represented by the following formula (I)or their salts have strong agonistics the m action in relation to the receptor ORL-1, have increased metabolic stability and expected to have high bioavailability; thus was accomplished the present invention.

The object of the invention is an agonist of the receptor ORL-1, which has a strong action, shows high selectivity and has a high metabolic stability compared to known compounds.

Part of the solution

Thus, the present invention proposes the following:

[1] a Compound represented by the formula (I)

where cycle And means one of the radicals

m and n are the same or different and each denotes an integer from 1 to 3;

R1means a hydrogen atom,

lower alkyl,

lower alkenyl,

-C(O)-lower alkyl,

-C(O)O-lower alkyl,

-C(O)-phenyl, where phenyl optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy,

lowest alkyl-carboxyl,

lower alkyl-C(O)-phenyl, where phenyl optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy,

lower alkyl-C(O)O-lower alkyl,

lower alkenyl-C(O)O-lower alkyl,

lower alkyl-O-lower alkyl,

lower alkyl-C(O)-NR3R4,

-S(O)2-lower alkyl,

-S(O)2is phenyl, where phenyl optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy,

lower alkyl-S-lower alkyl,

lower alkyl-S(O)-lower alkyl,

lower alkyl-S(O)2-lower alkyl,

lower alkyl-S(O)-NR3R4,

lower alkyl-NR3R4,

lower alkyl-NR5-C(O)-lower alkyl,

phenyl, where phenyl optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy, or

benzyl, where phenyl optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy;

R3and R4the same or different and each means a hydrogen atom, a lower alkyl, which is optionally substituted C3-7cycloalkyl, cycloalkyl or lower alkenyl, or R3and R4together with the neighboring nitrogen atom optionally form a saturated nitrogen-containing heterocycle, which is optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy;

R5means a hydrogen atom, lower alkyl or lower alkenyl;

R2means a hydrogen atom, lower alkyl, halogen atom, lower alkoxy, trifluoromethyl, nitro, amino or cyano;

Ra and Rb are the same or different and each means a hydrogen atom, lower alkyl, halogen atom, lower alkoxy, trifluoromethyl, triptoreline, hydroxyl, who and Jethro, amino, alkanolamine or cyano,

provided that when the loop And means (C), any one of Ra or Rb means a group other than hydrogen atom;

X is O or S;

Y represents CH2C(CH3)2, O, S, SO or SO2; and

Z denotes CH or N,

provided that when the loop And means (b), m is 2, n is 2, Y represents CH2and X is O, R1is a group other than a hydrogen atom, lower alkyl, -C(O)-lower alkyl and-C(O)O-lower alkyl,

or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[2] the Connection on p.[1], where R2means a hydrogen atom, and X is O or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[3] a Connection on p.[1], where R1means lower alkyl-C(O)-NR3R4(one of R3and R4means a hydrogen atom or lower alkyl-C(O)-NR3R4(R3and R4together with the adjacent nitrogen atom form a saturated nitrogen-containing heterocycle, which is optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy),

or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[4] the Connection on p.[1], which is selected from

2-{3-[1-(1,2,3,4-tetrahydro Talin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-(1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

1-(4-fluoro-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

2-{3-(4-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-(3,3-dimethyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(2,3,3A,4,5,6-hexahydrobenzo[de]chromen-6-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

1-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

2-{3-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

2-{3-[1-(3-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(8-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-methoxyisatin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-hydroxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide and

2-{3-[1-(6-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[5] a Drug for the prophylaxis and/or treatment of diseases associated with the receptor ORL-1, which contains the compound (I) under item[1] or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[6] a Drug for the prophylaxis and/or treatment of diseases of the Central nervous system associated with the receptor ORL-1, which contains the compound (I) under item[1] or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[7] a Drug for the prophylaxis and/or treatment of diseases of the Central nervous force the topics which contains the compound (I) p.[1], or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[8] a Drug for the prophylaxis and/or treatment of sleep disorders, which contains the compound (I) under item[1] or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[9] a Drug for the prophylaxis and/or treatment of alcoholism, which contains the compound (I) under item[1] or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[10] a Drug for the prophylaxis and/or treatment of addiction to the excessive use of drugs, which contains the compound (I) under item[1] or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

[11] medicine for the prevention and/or treatment of anxiety or stress disorder, which contains the compound (I) under item[1] or its racemic mixture, or its corresponding enantiomer, or its pharmaceutically acceptable salt.

In the present description pharmaceutically acceptable salt comprises an acid additive salts with inorganic acid or organic acid, and salts with inorganic bases. In addition, the present from reenie also encompasses the racemic mixture of compound (I) and its corresponding enantiomer.

The usefulness of the invention

The compound (I) of the present invention has a higher agonistic action against the receptor ORL-1 and is suitable for the prophylaxis and/or treatment of diseases associated with receptor ORL-1, for example, diseases of the Central nervous system (in particular, fear and stress disorders, melancholy, traumatic injury, Alzheimer's disease, dementia, sleep disorders, addiction to the excessive use of drugs, alcoholism), the symptom acute and/or chronic pain, disorders of the arterial blood pressure or irregularities of diet, such as obesity and anorexia. In particular, since the compound of the present invention has better metabolic stability and, as expected, has a higher bioavailability compared to known from the technical field connections, it can be used as a medicinal substance for the preparation of a medicinal product.

Brief description of drawings

Figure 1 shows agonistic activity against receptor ORL-1 for the compounds of examples 2, 4 and 8.

Figure 2 shows agonistic activity against receptor ORL-1 for the compounds of examples 79 and 80.

Figure 3 shows agonistic activity against receptor ORL-1 with the of dinani examples 104 and 110.

The best option is the implementation of the present invention

The following are the definitions for each character in the formula (I). In this definition applies regardless of whether the term individually or in combination.

“Lower alkyl” means1-6alkyl straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl and the like, preferably1-4alkyl straight or branched chain, more preferably methyl, ethyl, propyl and isopropyl.

“Lower alkenyl” means2-6alkenyl straight or branched chain, such as vinyl, 1-propenyl, 2-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and the like, preferably2-4alkenyl straight or branched chain.

“Halogen” means chlorine, iodine, fluorine or bromine, preferably chlorine, fluorine or bromine, most preferably fluorine.

“Lower alkoxy” means1-6alkoxy with a straight or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary, butoxy, pentyloxy, hexyloxy and the like, preferably1-4alkoxy with a straight or branched chain, most preferably methoxy.

“Alkanolamine” means an amino group containing From2-6and conoil, such as acetylamino, propionamido, bucillamine, pentanediamine and the like, preferably acetylamino.

“Cycloalkyl” means C3-7cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, preferably cyclopropyl.

“Saturated nitrogen-containing heterocycle formed by R3and R4together with the adjacent nitrogen atom” means a 5 - or 6-membered cycle which optionally additionally contains from 1 to 3 heteroatoms selected from nitrogen atom, oxygen and sulfur atom, such as piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, methylpiperazine, thiazolidin, 2,4-dioxothiazolidine and the like, preferably means piperazine, morpholine, pyrrolidine and 2,4-dioxothiazolidine, most preferably pyrrolidin and 2,4-dioxothiazolidine.

“-C(O)-means a carbonyl.

“-NR5-C(O)-”, where a value of R5indicated in the above formula (I), means amide.

“-S(O)-means sulfinil.

“-S(O)2-” means sulfonyl.

“Pharmaceutically acceptable salt” includes acid additive salts with inorganic acids and organic acids such as chloromethane acid, oxalic acid, maleic acid, fumaric acid, etc. and salts with inorganic bases, such as sodium, potassium, calcium, magnesium, etc.

When the as phenyl or a saturated nitrogen-containing heterocycle, formed together with the adjacent nitrogen atom, in the formula (I) is substituted by lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy, the number of substituents is preferably from 1 to 3.

The preferred compound is a compound of formula (I), where R1means a hydrogen atom, -C(O)-lower alkyl, lower alkyl-carboxyl, lower alkyl-O-lower alkyl, lower alkyl-C(O)-NR3R4or lower alkyl-NR3R4;

R3and R4the same or different and each means a hydrogen atom, a lower alkyl, which is optionally substituted C3-7cycloalkyl, or cycloalkyl, or R3and R4together with the neighboring nitrogen atom optionally form a saturated nitrogen-containing heterocycle, which is optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy;

R2means a hydrogen atom or a halogen atom;

Ra and Rb are the same or different and each means a hydrogen atom, lower alkyl, halogen atom, lower alkoxy, hydroxyl, trifluoromethyl, alkanolamine or cyano, provided that when the loop And means (C), any one of Ra or Rb means a group other than hydrogen atom;

Y represents CH2C(CH3)2, O, S or SO2; and the other symbols are defined in the above formula (I), provided that when the loop And means (b), m is avno 2, n is 2, Y represents CH2and X is O, R1is a group other than hydrogen atom and -- C(O)-lower alkyl.

The most preferred compound is the compound of formula (I), where the cycle And means the following formula:

R1means a hydrogen atom, -C(O)-lower alkyl, lower alkyl-carboxyl, lower alkyl-O-lower alkyl, lower alkyl-C(O)-NR3R4or lower alkyl-NR3R4;

R3and R4the same or different and each means a hydrogen atom, lower alkyl or cycloalkyl, or R3and R4together with the neighboring nitrogen atom optionally form a saturated nitrogen-containing heterocycle, which is optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy;

R2means a hydrogen atom or a halogen atom;

Ra and Rb are the same or different and each means a hydrogen atom, lower alkyl, halogen atom, lower alkoxy, hydroxyl, trifluoromethyl, alkanolamine or cyano;

Y represents CH2C(CH3)2, O, S or SO2; and

other symbols are defined in the above formula (I).

For example, you can specify the following connection:

compounds selected from

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2{3-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-(1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

1-(4-fluoro-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-it,

2-{3-(4-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide and

2-{3-(3,3-dimethyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

or their racemic mixtures, or the corresponding enantiomer, or its pharmaceutically acceptable salt.

Another preferred compound is a compound of formula (I), where the cycle And means the following formula (b):

R1means a hydrogen atom, -C(O)-lower alkyl, lower alkyl-C(O)-NR3R4or lower alkyl-NR3R4;

R3and R4the same or different and each means a hydrogen atom, a lower alkyl, which is optionally substituted C3-7cycloalkyl, or cycloalkyl, or R3and R4together with the neighboring nitrogen atom optionally form a saturated nitrogen-containing heterocycle, which is optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy;

R2means a hydrogen atom or a halogen atom;

Ra and Rb are the same or different is s and each means a hydrogen atom, lower alkyl, halogen atom, lower alkoxy or hydroxyl;

X is O;

Y represents CH2or O;

Z denotes CH; and other symbols are defined in the above formula (I), provided that when m is 2, n is 2, and Y represents CH2, R1is a group other than hydrogen atom and -- C(O)-lower alkyl.

For example, you can specify the following connection:

compounds selected from

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

1-[1-(2,3,3A,4,5,6-hexahydrobenzo[de]chromen-6-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

2-{3-[1-(2,3,3A,4,5,6-hexahydrobenzo[de]chromen-6-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

1-[2-(cyclopropylamino)ethyl]-3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it,

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-3-(2-isoprop aminoethyl)-1,3-dihydro-2H-benzimidazole-2-it,

3-{3-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}propyl}thiazolidin-2,4-dione,

1-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she

2-{3-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

or their racemic mixtures, or the corresponding enantiomer, or its pharmaceutically acceptable salt.

Another preferred compound is a compound of formula (I), where the cycle And means the following formula (C):

R1means a hydrogen atom, -C(O)-lower alkyl, or lower alkyl-C(O)-NR4R5(one of R4and R5means a hydrogen atom or lower alkyl-C(O)-NR4R5(R4and R5together with the adjacent nitrogen atom form a saturated nitrogen-containing heterocycle, which is optionally substituted lower alkyl, halogen atom, lower alkoxy, phenoxy or benzyloxy);

R2means a hydrogen atom or a halogen atom;

Ra and Rb are the same or different and each means a hydrogen atom, lower alkyl, halogen atom, lower alkoxy, hydroxyl or cyano, provided that one of Ra and Rb means a group other than hydrogen atom;

X is Oh; and

other symbols are defined in baseprovider the th formula (I).

For example, you can specify the following connection:

compounds selected from

2-{3-[1-(5-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(3-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(8-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-methoxyisatin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

2-{3-[1-(5-hydroxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide and

(R)-2-{3-[1-(6-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,

or their racemic mixtures, or the corresponding enantiomer, or its pharmaceutically acceptable salt.

The compound of formula (I) (unless otherwise specified, includes compounds of formula (I), where the cycle And signifies one of the groups (a), (b) and (C)),

can be obtained, for example, in the following ways :

Method 1

where the value of each symbol defined in the above formula (I), provided that the loop And does not mean the group (a)

Sedimentary (II) is subjected to reductive aminating using the compounds of formula (III) and obtain the connection formula (I). The compounds of formula (II) and formula (III) are known compounds, and the compound of formula (II) can be obtained according to the method described in J. Chem. Soc., Perkin Trans. 1, 1160, 1973, and the compound of formula (III) can be obtained according to the method described in J. Med. Chem., 2001, 44, 3378 or Org. Lett., 2006, 8, 3311.

Reductive amination of catasetinae, such as a compound of the formula (II)with an amine such as a compound of the formula (III)described in J. Org. Chem., 55, 2552-54, 1990. Conducting the reaction at the specified method comprises the interaction of a ketone and an amine in a solvent such as tetrahydrofuran (THF), methanol or ethanol, or a suitable mixture of ethanol and THF in the presence of Ti(IV)-isopropoxide and cyanoborohydride sodium. The reaction temperature is in the range from about minus 78 to 100°C and the reaction time ranges from several tens of minutes up to 2 days.

Method 2

where L denotes a leaving group such as halogen atom, arylsulfonate, alkylsulfonate, arylphosphonate, alkylphosphonate and the like, and other symbols are defined in formula (I).

The compound of formula (I) are obtained by substitution reaction of compounds of formula (III) and compounds of formula (X)obtained from the alcohol represented by the formula (IV), which is obtained by recovery of the ketone represented by the formula (II). The reaction of substitution of the connection is of formula (X) and the compounds of formula (III) is carried out in N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dichloroethane, methanol, ethanol, diethyl ether, etc. or mixtures of these solvents in the presence of inorganic bases such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride and the like, or organic bases such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, etc. may also be present in a catalytic amount or a slight excess of sodium iodide, potassium iodide and the like, the reaction Temperature is from about room temperature to 200°C, and the reaction time is from several minutes to 2 days.

Method 3

where the value of each symbol defined in the formula (I).

The compound of formula (VII) can be obtained according to the method described in WO 03/082333 using the compound (IV) as the starting material, as shown in the diagram above.

The compound of formula (VII) is treated with a phenylenediamine or pyridylamino represented by the formula (VIII), and obtain the connection formula (IX), which cyclizes with the formation of the compounds of formula (I-1), where R1means a hydrogen atom.

Reductive amination of catasetinae form is s (VII) a phenylenediamine or pyridinediamine formula (VIII) is carried out in N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dichloroethane, methanol, ethanol, diethyl ether, etc. or mixtures of these solvents in the presence of a complex metal hydride (in particular, triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride, lithium borohydride, lithium aluminum hydride, etc). The reaction temperature is from about minus 78 to 100°C., and the reaction time ranges from several tens of minutes up to 2 days. Phenylenediamine or pyridinediamine formula (VIII) and catasetinae formula (VII) are known compounds. For example, a phenylenediamine of the formula (VIII) can be obtained according to the method described in J. Org. Chem., 2001, 66, 919 or Org. Synth., 1943, 501, and pyridinediamine can be obtained according to the method described in Org. Synth., 1964, 34. Catasetinae formula (VII) can be obtained according to the method described in Bioorganic & Medicinal Chemistry Letters, 1999, 9, 2343.

The compound of formula (IX)obtained in the reaction, can be carbonyliron or thiocarbanilide in a known manner (see Bioorganic & Medicinal Chemistry Letters, 1996, 6, 1641; Chem. Pharm. Bull., 1989, 37, 962; Bioorganic & Medicinal Chemistry Letters, 1999, 9, 1537, etc. and to obtain the compound of formula (I-1).

Method 4

where the value of each symbol defined in the formula (I).

The compound of formula (I1), where R1means a hydrogen atom, is subjected to alkylation, alkenylamine, generirovanie, basiliani and acylation with the formation of the compounds of formula (I).

The compound of the formula (I-1), where R1means a hydrogen atom, can be subjected to alkylation, alkenylamine, generirovanie, basiliani and acylation in the usual way, for example, in the presence of the corresponding alkylhalogenide, alkenylamine, benzylchloride or acylhomoserine, such as methyliodide, allylbromide, benzylbromide, ethylbromide, acetylchloride, ethylbromoacetate etc. Specified reaction is carried out in the presence of a metal hydride such as sodium hydride, at a temperature of from about minus 78 to 100°C., and the reaction time ranges from several tens of minutes up to 2 days.

The compound of formula (VII) can also be obtained by reduction reaction of compound (XI), which can be obtained by the coupling of compounds of formula (II) with hydroxylamine, as shown in the following diagram.

where a cycle As defined in formula (I).

The compound of formula (XI), which is a starting compound can be obtained in a known manner. For example, you can use the methods described in “The Chemistry of Open-Chain Organic Nitrogen Compounds”, Vol.2, p.1 (1966) and “Organic Functional Group Preparations”, Vol.3, p.322 (1972).

The restoration of the SIMA, having the formula (XI), the amine can be carried out in a known manner by catalytic hydrogenation, by the action of a mixture of Raney alloy - the sodium hydroxide, DIBORANE and bis(2-methoxyethoxy)aluminum hydride, sodium, etc. for Example, you can use the methods described in “Shin Jikken Called Koza (Courses in Experimental Chemistry)”, Vol.14, p.1339 (1978).

Method 5

where R11means lower alkyl-carboxyl, R12means lower alkyl-C(O)NR3R4and the values of R3, R4and other symbols are defined in formula (I).

Carboxylic acid represented by the formula (I-2)or its reactive derivative interacts with the amine to form compounds of formula (I-3). Reactive derivative of the compound of carboxylic acid includes gelegenheid acid, such as acid chloride, acid anhydride, mixed acid anhydride derived from ethylchloride and the like, esters such as methyl ester, ethyl ester and the like, and reactive derivatives obtained from carbodiimide, such as WSC·HCl (water-soluble carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), etc.

The reaction is carried out in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dichloroethane, Tolu is l, etc. The reaction temperature is from about minus 78 to 100°C., and the reaction time ranges from several tens of minutes up to 2 hours. Where necessary, as the absorber acid using an organic base, such as pyridine, triethylamine, diisopropylethylamine etc.

If the compound of formula (I), synthesized as described above is obtained in the form of a racemate, an optically pure compound can be obtained by converting the racemic mixture into its enantiomeric components. You can also select selective steric isomer of the racemic mixture on a suitable intermediate stage.

In addition, the enantiomer of the compounds of formula (I) can be obtained by using optically active starting material (IV)', according to the method described in WO03/082333, as shown in the following diagram.

Method 3'

where the value of each symbol defined in the above formula (I).

Where necessary, the obtained compound of formula (I) is transformed into pharmaceutically acceptable salt. The process of obtaining salts are known and it is done at room temperature are well known ways. Discusses not only salts with inorganic acid, and salts with organic acid, and when the compound has a carboxyl group, discusses the salt with inorganic base and organization the technical base. Examples of such salts are acid additive salts such as the hydrochloride, oxalate, fumarate, maleate and the like, sodium salt, potassium salt, calcium salt, magnesium salt.

The compound of the present invention can be administered orally or parenterally. Dosage form comprises a tablet, capsule, granule, powder, injection, ointment, suppository, etc. you can make by mixing the compound of the present invention with various pharmaceutically acceptable additives, such as excipient, filler, lubricant, binder, baking powder, coating for tablets, film-forming, base, solvent and the like, using conventional methods.

Although the dose can be choose as appropriate in accordance with the symptom, age, dosage form and the like, for oral drug dose is usually from 0.1 to 5000 mg, preferably from 1 to 1000 mg per day, and can be entered in one portion or in several portions.

Examples

Although below presents the results in the form of examples, preparative examples and pharmacological tests, these examples are provided for better understanding of the present invention and do not limit the scope of the present invention.

Example 1

1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

α-Tetra is he (1.0 g) is dissolved in ethanol (20 ml), add sodium borohydride (0.26 g) and the mixture is stirred at room temperature for 30 minutes To terminate the reaction type 1H. the solution chloroethanol acid (10 ml). The ethanol is evaporated and the aqueous solution extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and concentrated. The resulting residue is dissolved in chloroform (10 ml), add thionyl chloride (1.0 ml) and the mixture with stirring, refluxed for 30 minutes Chloroform and thionyl chloride evaporated under reduced pressure and the residue is dissolved in dimethylformamide (10 ml). Add potassium carbonate (2.5 g), 4-(2-keto-1-benzimidazolinyl)piperidine (0.50 g) and potassium iodide (0,69 g), and then the mixture was stirred at 150°C for 2 hours. After cooling to room temperature, water is added and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get listed in the title compound (481 mg) as a solid yellow color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.74 (m, 3H), 1,92-2,05 (m, 3H), 2,27 of-2.32 (m, 2H), 2,60 (m, 1H), 2,73 (m, 4H), 3,01 (m, 1H), 3,92 (m, 1H), 4,36 (m, 1H), 7,06-7,26 (m, 6N), 7,33 (d, J=7.8 Hz, 1H), 7,80 (d, J=7.5 Hz, 1H), of 9.21 (users, 1H).

FAB-MS (M+N)+: 348.

Example 2

2-{3-[1-(1,2,3,4-t is traditonally-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

1-[1-(1,2,3,4-Tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (476 mg) was dissolved in tetrahydrofuran (5 ml), added 60%sodium hydride (66 mg) and the resulting suspension is stirred at 50°C for 30 minutes After cooling to room temperature, add ethylbromoacetate (0,167 ml) and the mixture is stirred for 1 hour. Add 40%solution of methylamine in methanol (5 ml), the mixture is stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (567 mg) in the form of a solid pale yellow color.

1H-NMR (CDCl3) δTMS: 1,67-of 1.74 (m, 3H), 1.93 and-2,04 (m, 3H), 2,27 of-2.32 (m, 2H), 2,60 (m, 1H), 2.71 to 2,86 (m, 7H), to 3.02 (m, 1H), 3,92 (m, 1H), 4,35 (m, 1H), 4,51 (c, 2H), 6,18 (users, 1H), 7,06-7,26 (m, 6H), 7,35 (d, J=7.5 Hz, 1H), for 7.78 (d, J=7,6 Hz, 1H).

FAB-MS (M+N)+: 419.

Example 3

(R)-1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) (S)-(+)-1,2,3,4-Tetrahydro-1-naphthol (1.0 g) and diphenylphosphoryl (2,23 g) dissolved in toluene (10 ml), add databaseconnect (1,23 g) and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with toluene, the organic layers are combined and washed nerastvorim chloroethanol acid and water, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane/ethyl acetate) and receive (R)-1-azido-1,2,3,4-tetrahydronaphthalen (1.20 g) as a colourless oil.

1H-NMR (CDCl3) δTMS: 1,81-of 1.84 (m, 1H), 1.93 and-2,04 (m, 3H), 2.77-to 2,85 (m, 2H), 4,57 (m, 1H), 7,14-7,29 (m, 4H).

(2) (R)-1-Azido-1,2,3,4-tetrahydronaphthalen (1.20 g) was dissolved in a mixed solvent (11 ml) of tetrahydrofuran/water (10:1), add triphenylphosphine (2.35 g) and the mixture with stirring, refluxed for 2 hours. After cooling to room temperature, the solvent evaporated, to the residue add 1H. the solution chloroethanol acids, and waste products are removed by extraction with ethyl acetate. The aqueous phase is alkalinized with potassium carbonate and the mixture extracted with ethyl acetate. The extract is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified on laminirovannom silica gel and receive (R)-1,2,3,4-tetrahydronaphthalen-1-ylamine (759 mg) as a colourless oil.

1H-NMR (CDCl3) δTMS: 1,67-of 1.81 (m, 2H), 1,92-2,05 (m, 2H), 2,34-2,82 (m, 2H), 3,98 (t, J=5.7 Hz, 1H), 7,07-7,19 (m, 3H), 7,41 (d, J=8.7 Hz, 1H).

(3) (R)-1,2,3,4-Tetrahydronaphthalen-1-ylamine (759 mg) was dissolved in ethanol (7.3 ml) and add potassium carbonate (70 mg). Add 1-ethyl-1-methyl-4-oxopiperidine iodide (1,59 g)dissolved in water (4,4) - Rev. l), and the mixture with stirring, refluxed for 1 hour. The reaction mixture was poured into water, the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane/ethyl acetate) and receive (R)-1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-one (910 mg) as an oily substance pale yellow color.

1H-NMR (CDCl3) δTMS: 1,59 was 1.69 (m, 2H), 1,96 is 2.01 (m, 2H), 2,43-2,49 (m, 4H), 2,75-2,82 (m, 4H), 2,86 of 2.92 (m, 2H), 4,00-of 4.05 (m, 1H), 7,07-7,22 (m, 3H), to 7.77 (d, J=6,9 Hz, 1H).

(4) (R)-1-(1,2,3,4-Tetrahydronaphthalen-1-yl)piperidine-4-one (910 mg) was dissolved in tetrahydrofuran (21 ml) and added 1,2-phenylenediamine (859 mg). The solution is cooled in a bath with ice, add triacetoxyborohydride sodium (2,31 g) and acetic acid (0,92 ml), and then the mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into water, the mixture is alkalinized with potassium carbonate and extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and receive (R)-N-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]benzene-1,2-diamine (970 mg) as a solid pale yellow color.

1/sup> H-NMR (CDCl3) δTMS: 1,40 (m, 1H), 1,55-1,75 (m, 3H), 1,96 is 2.01 (m, 3H), 2,10 (m, 1H), 2,24 (m, 1H), 2,61-and 2.83 (m, 5H), 3,20-to 3.35 (m, 3H), 3,83-3,88 (m, 1H), 6,64-to 6.80 (m, 4H), 7,07-7,16 (m, 3H), 7,71 (d, J=6,9 Hz, 1H).

(5) (R)-N-[1-(1,2,3,4-Tetrahydronaphthalen-1-yl)piperidine-4-yl]benzene-1,2-diamine (570 mg) was dissolved in tetrahydrofuran (3 ml), added 1,1'-carbonyldiimidazole (344 mg) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into water and the resulting mixture extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get listed in the title compound (543 mg) as a solid white color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.74 (m, 3H), 1,92-2,05 (m, 3H), 2,27 of-2.32 (m, 2H), 2,60 (m, 1H), 2,73 (m, 4H), 3,01 (m, 1H), 3,92 (m, 1H), 4,36 (m, 1H), 7,06-7,26 (m, 6H), 7,33 (d, J=7.8 Hz, 1H), 7,80 (d, J=7.5 Hz, 1H), of 9.21 (users, 1H).

FAB-MS (M+H)+: 348.

The following compounds can be synthesized in accordance with the above examples.

Example 4

(R)-2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 2 using (R)-1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get specified header soy is inania in a solid white color.

1H-NMR (CDCl3) δTMS: of 1.65 and 1.75 (m, 3H), 1.93 and-2,04 (m, 3H), 2,28 is 2.33 (m, 2H), 2,60 (m, 1H), 2,70-of 2.86 (m, 7H), to 3.02 (m, 1H), 3,92 (m, 1H), 4,35 (m, 1H), 4,51 (c, 2H), 6,15 (users, 1H), 7,06-7,26 (m, 6H), 7,35 (d, J=7.5 Hz, 1H), for 7.78 (d, J=7,6 Hz, 1H).

FAB-MS (M+H)+: 419.

[α]D24=+17.2°C.

Example 5

(S)-1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 3, using (R)-(-)-1,2,3,4-tetrahydro-1-naphthol, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,64-of 1.73 (m, 3H), 1,92-2,05 (m, 3H), 2,29 of-2.32 (m, 2H), 2,61 (m, 1H), 2,73 (m, 4H), 3,01 (m, 1H), 3,92 (m, 1H), 4,36 (m, 1H), 7,06-7,26 (m, 6H), 7,33 (d, J=7.2 Hz, 1H), 7,80 (d, J=7.5 Hz, 1H), 9,45 (users, 1H).

FAB-MS (M+N)+: 348.

Example 6

(S)-2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 2 using (S)-1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,66-1,72 (m, 3H), 1,89-2,03 (m, 3H), 2,28 is 2.33 (m, 2H), 2,60 (m, 1H), 2.71 to 2,86 (m, 7H), to 3.02 (m, 1H), 3,92 (m, 1H), 4,35 (m, 1H), 4,51 (c, 2H), 6,16 (users, 1H), 7,06-7,22 (m, 6H), 7,35 (d, J=7.5 Hz, 1H), 7,79 (d, J=7,6 Hz, 1H).

FAB-MS (M+H)+: 419.

[α]D25=+16,8°.

Example 7

1-[1-(5-methyl-1,2,34-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 5-methyl-tetralone, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.73 (m, 3H), 1,92-of 2.09 (m, 3H), 2.23 to (c, 3H), 2,27 of-2.32 (m, 2H), 2.57 m-2,72 (m, 4H), 2,87 (m, 1H), 3,01 (m, 1H), 3,92 (m, 1H), 4,36 (m, 1H), 7.03 is-7,17 (m, 5H), 7,33 (d, J=8,9 Hz, 1H), 7,72 (d, J=7,7 Hz, 1H), 9,36 (users, 1H).

FAB-MS (M+N)+: 362.

Example 8

2-{3-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.74 (m, 3H), 1,89-of 2.09 (m, 3H), 2.23 to (c, 3H), 2,28 (m, 2H), 2,56-of 2.72 (m, 4H), and 2.79 (d, J=4.5 Hz, 3H), 2,85 (m, 1H), to 3.02 (m, 1H), 3,90 (m, 1H), 4,35 (m, 1H), 4,51 (c, 2H), 6,16 (users, 1H), 7.03 is-7,17 (m, 5H), was 7.36 (d, J=7.5 Hz, 1H), of 7.70 (d, J=7,86 Hz, 1H).

FAB-MS (M+H)+: 433.

Example 9

(R)-1-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) a Solution of 5-methyl-1,2,3,4-tetrahydronaphthalen-1-she (3.2 g), (R)-tert-butylsulfide (2.4 g) and tetraisopropoxide titanium (9.0 g) in tetrahydrofuran (50 ml) is stirred at a temperature of 75°C for 96 hours. The reaction mixture is cooled to minus 50°C and a small portion is added sodium borohydride (3.0 g). The mixture is stirred for 7 hours and allow it to gradually warm to room temperature. The reaction mixture was poured into ice water, the mixture extracted with ethyl acetate and the extract washed with water and saturated saline solution and then dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and receive (RS)-2-methyl-N-((S)-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)propan-2-sulfinamide (2.3 g) as a solid pale brown color.

1H-NMR (CDCl3) δTMS: 1,21 (c, 9H), 1,79-of 1.85 (m, 2H), 1,90-2,02 (m, 2H), of 2.23 (s, 3H), 2,50-2,60 (m, 1H), 2.70 height is 2.80 (m, 1H), 3,20 (s, 1H), 4,58 (m, 1H), 7,08-to 7.15 (m, 2H), 7,29-7,31 (m, 1H).

(2) (RS)-2-Methyl-N-((S)-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)propan-2-sulfinamide (277 mg) under cooling in a bath with ice dissolved in 5-10%solution of hydrogen chloride in methanol (25 ml) and the mixture while cooling with ice, stirred for 2 hours. To the solution was added 1N. an aqueous solution of sodium hydroxide and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on laminirovannom silica gel (hexane/ethyl acetate) and receive (R)-1-amino-5-methyl-1,2,3,4-tetrahydronaphthalen (130 mg) as an oily material brown color.

1N the Mrs (CDCl 3) δTMS: 1,67-of 1.73 (m, 1H), 1,78-of 1.85 (m, 1H), 1,92 is 2.01 (m, 2H), 2,52-a 2.71 (m, 2H), 3,97-4,00 (m, 1H), 7,03 (d, J=7,3 Hz, 1H), 7,13 (t, J=7,3 Hz, 1H), 7,26 (m, 1H).

(3) (R)-1-Amino-5-methyl-1,2,3,4-tetrahydronaphthalen (1,71 g) dissolved in ethanol (20 ml) and add potassium carbonate (1.47 g). Add dissolved in water (5 ml), 1-ethyl-1-methyl-4-oxopiperidine iodide (3,14 g) and the mixture with stirring, refluxed for 5 hours. The reaction mixture was poured into water and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and receive (R)-1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-one (1.84 g) as an oily substance pale yellow color.

1H-NMR (CDCl3) δTMS: 1,50-1,70 (m, 2H), 1,96 of 1.99 (m, 1H), 2,04-of 2.09 (m, 1H), 2,22 (c, 1H), 2,43-of 2.58 (m, 5H), 2,64-by 2.73 (m, 1H), 2,73-2,2,79 (m, 2H), 2,86 of 2.92 (m, 2H), 4,01 is 4.13 (m, 1H),? 7.04 baby mortality (d, J=7,3 Hz, 1H), 7,11 (t, J=7,6 Hz, 1H), 7,68 (d, J=7,6 Hz, 1H).

(4) (R)-1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-one (1.84 g) was dissolved in dichloromethane (55 ml) and added 1,2-phenylenediamine (1.23 g). To the resulting solution add triacetoxyborohydride sodium (3,61 g) and acetic acid (0,97 ml). The mixture is stirred at room temperature for 24 hours, alkalinized with a saturated solution of sodium bicarbonate and extracted with chloroform. xtract washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and receive (R)-N-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]benzene-1,2-diamine (1,83 g) as a solid pale brown color.

1H-NMR (CDCl3) δTMS: 1,40 (m, 1H), 1,55-1,75 (m, 3H), 1,96 is 2.01 (m, 2H), 2,04-of 2.15 (m, 2H), 2,22 (c, 3H), 2,24 (m, 1H), 2,50-2,75 (m, 4H), 2,80-2,90 (m, 1H), 3,20-to 3.35 (m, 3H), 3,83-3,88 (m, 1H), 6,65-to 6.80 (m, 4H), 7,01 (d, J=7.2 Hz, 1H), was 7.08 (t, J=7,6 Hz, 1H), 7.62mm (d, J=7,6 Hz, 1H).

(5) (R)-N-[1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]benzene-1,2-diamine (1,83 g) dissolved in tetrahydrofuran (100 ml), add 1,1'-carbonyldiimidazole (973 mg) and the mixture is stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and crystallized from a mixture of hexane/ethyl acetate, getting mentioned in the title compound (1.2 g) as a solid white color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.74 (m, 3H), 1,89-of 2.15 (m, 3H), 2,22 (c, 3H), 2,27-of 2.36 (m, 2H), 2,50-a 2.71 (m, 4H), 2,88 (m, 1H), to 3.02 (m, 1H), 3,90 (m, 1H), 4,36 (m, 1H), 7,02-7,16 (m, 5H), 7,34 (d, J=7,6 Hz, 1H), 7,71 (d, J=7,6 Hz, 1H), to 9.57 (users, 1H).

FAB-MS (M+H)+: 362.

[α]D29,7 =+38,4 (c=0.5, chloroform).

Example 10

(R)-2-{3-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

(R)-1-[1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (995 mg) dissolved in DMF (10 ml). Add sodium hydride (132 mg, 60%) and the resulting suspension is stirred at room temperature for 40 minutes Add ethylbromoacetate (458 μl) and the mixture is stirred for 4 hours. The reaction mixture was poured into ice water and extracted with a mixture of ethyl acetate. The extract is washed with water and saturated aqueous ammonium chloride, dried over sodium sulfate and concentrated. To the residue add 40%solution of methylamine in methanol (30 ml), stirred at room temperature for 2.5 h and then the reaction mixture was concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (chloroform/methanol), crystallized from ethyl acetate and get listed in the title compound (1.0 g) as crystals pale yellow color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.74 (m, 3H), 1,89-of 2.09 (m, 3H), 2.23 to (c, 3H), 2,28 (m, 2H), 2,56-of 2.72 (m, 4H), and 2.79 (d, J=4.5 Hz, 3H), 2,85 (m, 1H), to 3.02 (m, 1H), 3,90 (m, 1H), 4,35 (m, 1H), 4,51 (c, 2H), 6,16 (users, 1H), 7.03 is-7,17 (m, 5H), was 7.36 (d, J=7.5 Hz, 1H), of 7.70 (d, J=7,86 Hz, 1H).

FAB-MS (M+H)+: 433.

[α]D29,1=+26,8 (c=0.5, chlorofo is m).

Example 11

1-[1-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 5-chloro-1-tetralone, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,62 to 1.76 (m, 3H), 1,92 is 2.10 (m, 3H), 2,28 of-2.32 (m, 2H), 2,58-to 2.67 (m, 3H), 2,87 totaling 3.04 (m, 3H), 3,88 (m, 1H), 4,35 (m, 1H), 7,06-7,25 (m, 5H), 7,31 (d, J=7.5 Hz, 1H), 7,78 (d, J=7.5 Hz, 1H), 9,40 (users, 1H).

FAB-MS (M+H)+: 382.

Example 12

2-{3-[1-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[1-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,62 to 1.76 (m, 3H), 1,89-of 2.09 (m, 3H), to 2.29 (m, 2H), 2,58 of 2.68 (m, 3H), and 2.79 (d, J=4,8 Hz, 3H), 2,89 (m, 2H), 3,01 (m, 1H), 3,90 (m, 1H), 4,32 (m, 1H), 4,51 (c, 2H), 6,17 (users, 1H), 7,06-7,19 (m, 5H), 7,32 (d, J=7.5 Hz, 1H), 7,76 (d, J=7.68 per Hz, 1H).

FAB-MS (M+H)+: 453.

Example 13

1-[1-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 5,7-dimethyl-1-tetralone, get mentioned in the title compound in the form of a solid white color.

1 H-NMR (CDCl3) δTMS: 1,62-1,72 (m, 3H), 1.93 and-a 2.13 (m, 3H), 2,19 (c, 3H), 2,27-of 2.34 (m, 5H), 2,54-2,99 (m, 6H), 3,86 (m, 1H), 4,35 (m, 1H), 6.87 in (c, 1H),? 7.04 baby mortality-7,14 (m, 3H), 7,34 (d, J=6,9 Hz, 1H), 7,51 (c, 1H), 9,62 (users, 1H).

FAB-MS (M+H)+: 376.

Example 14

2-{3-[1-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[1-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,65-1,71 (m, 3H), 1,92-2,07 (m, 3H), 2,19 (c, 3H), 2,25 is 2.33 (m, 5H), 2,61-2,84 (m, 8H), to 3.00 (m, 1H), 3,86 (m, 1H), 4,33 (m, 1H), 4,51 (c, 2H), 6,21 (users, 1H), 6,88 (c, 1H), 7,06-7,17 (m, 3H), 7,35 (d, J=7.5 Hz, 1H), 7,49 (c, 1H).

FAB-MS (M+H)+: 447.

Example 15

1-(1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 1-indanone get mentioned in the title compound in the form of a solid brown color.

1H-NMR (CDCl3) δTMS: 1,78 is 1.86 (m, 2H), 2,09-of 2.16 (m, 2H), 2,39 (m, 2H), has 2.56 (m, 2H), 2,79-to 3.09 (m, 4H), 4,35 (m, 1H), of 4.44 (m, 1H),? 7.04 baby mortality for 7.12 (m, 3H), 7,21-7,26 (m, 3H), 7,35 (m, 1H), 7,43 (m, 1H), for 9.64 (users, 1H).

FAB-MS (M+H)+334.

Example 16

2-{3-(1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method specified in the application is e 2, using 1-(1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid brown color.

1H-NMR (CDCl3) δTMS: 1,76-to 1.86 (m, 2H), 2,08-of 2.16 (m, 2H), 2,39 (m, 2H), by 2.55 (m, 2H), 2,80 (d, J=4.9 Hz, 3H), 2,82-3,10 (m, 4H), 4,35 (m, 1H), of 4.44 (m, 1H), 4,50 (c, 2H), 6,17 (users, 1H), 7,05-7,14 (m, 3H), 7.23 percent-7,26 (m, 3H), of 7.36-the 7.43 (m, 2H).

FAB-MS (M+H)+: 406.

Example 17

1-(4-fluoro-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-she hydrochloride

Similarly to the method shown in example 1, using 4-fluoro-1-indanone, get 1-(4-fluoro-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-it, which is then converted into the hydrochloride using 4h. solution chloroethanol acid in ethyl acetate, getting mentioned in the title compound in the form of a solid brown color.

1H-NMR (DMSO-d6) δTMS: to 1.83 (m, 2H), 2,50 (m, 2H), 2,60 (m, 1H), 2,80 (m, 1H), 2,99 be 3.29 (m, 5H), 3,51 (m, 1H), 4,60 (m, 1H), 5,10 (m, 1H), 6,98 (m, 3H), 7,26 (t, J=9 Hz, 1H), 7,43 (m, 1H), 7,71 (m, 1H), 7,86 (m, J=7.5 Hz,, 1H), 10,9 (users, 1H), 11,6 (users, 1H).

FAB-MS (M+H)+: 352.

Example 18

2-{3-(4-fluoro-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide hydrochloride

Similarly to the method shown in example 2, using 1-(4-fluoro-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he will receive 2-{3-(4-fluoro-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-about the co-benzimidazole-1-yl}-N-methylacetamide, which is then converted into the hydrochloride using 4h. solution chloroethanol acid in ethyl acetate and get listed in the title compound in the form of a solid pale yellow color.

1H-NMR (DMSO-d6) δTMS: to 1.87 (m, 2H), 2,44 (m, 3H), 2,60 (m, 3H), and 2.83 (m, 1H), 3,01-to 3.41 (m, 5H), 3,53 (m, 1H), 4,43 (c, 2H), 4,67 (m, 1H), 5,10 (m, 1H), 7,05 (m, 3H), 7,27 (t, J=9 Hz, 1H), 7,42 (m, 1H), 7,76 (m, 1H), 7,82 (m, J=7.5 Hz, 1H), 8,11 (users, 1H), 11,4 (users, 1H).

FAB-MS (M+H)+: 423.

Example 19

1-(4-methyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 4-methyl-1-indanone get mentioned in the title compound in the form of a solid brown color.

1H-NMR (CDCl3) δTMS: 1,74-of 1.85 (m, 2H), 2,11-of 2.16 (m, 2H), and 2.27 (c, 3H), 2,39 (m, 2H), 2,54 (m, 2H), 2,74-to 2.85 (m, 3H), 3,05 (m, 1H), 4,34 (m, 1H), 4,45 (m, 1H),? 7.04 baby mortality-to 7.18 (m, 5H), 7,26-7,34 (m, 2H), 9,54 (users, 1H).

FAB-MS (M+H)+: 348.

Example 20

2-{3-(4-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide hydrochloride

Similarly to the method shown in example 2, using 1-(4-methyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he will receive 2-{3-(4-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide, which is then converted into the hydrochloride using 4h. solution chloroethanol acid in ethyl acetate and get indicated the data in the title compound in the form of a solid brown color.

1H-NMR (DMSO-d6) δTMS: to 1.86 (m, 2H), 2.26 and (c, 3H), 2,39 (m, 1H), 2,60 (m, 4H), 2,87 (m, 2H), 3.00 and-3,26 (m, 5H), 3,49 (m, 1H), 4,43 (c, 2H), of 4.66 (m, 1H), 5,04 (m, 1H),? 7.04 baby mortality (m, 3H), 7,24 (m, 2H), 7,79 (m, 2H), 8,12 (m, 1H), 11,3 (users, 1H).

FAB-MS (M+H)+: 419.

Example 21

1-(6-methyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 6-methyl-1-indanone get mentioned in the title compound in the form of a solid brown color.

1H-NMR (CDCl3) δTMS: 1,78 is 1.86 (m, 2H), 2,08-of 2.15 (m, 2H), 2,38 (c, 3H), 2,41 (m, 2H), 2,54 (m, 2H), 2,79-2,89 (m, 3H), 3,05 (m, 1H), 4,33 was 4.42 (m, 2H), 7.03 is for 7.12 (m, 5H), 7.23 percent (m, 1H), 7,34 (m, 1H), 9,37 (users, 1H).

FAB-MS (M+H)+: 348.

Example 22

2-{3-(6-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide hydrochloride

Similarly to the method shown in example 2, using 1-(6-methyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he will receive 2-{3-(6-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide, which is then converted into the hydrochloride using 4h. solution chloroethanol acid in ethyl acetate and get listed in the title compound in the form of a solid brown color.

1H-NMR (DMSO-d6) δTMS: to 1.86 (m, 2H), 2,35 (c, 3H), 2,39 (m, 1H), of 2.51 (m, 4H), 2,85 (m, 2H), 3,03-3,26 (m, 5H), 3,49 (m, 1H), 4,43 (c, 2H), of 4.66 (m, 1H), equal to 4.97 (m, 1H),? 7.04 baby mortality (m, 3H), 7,24 (m, 2H), 7,79(m, 2H), 8,13 (m, 1H), 11,3 (users, 1H).

FAB-MS (M+H)+: 419.

Example 23

1-(7-methyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 7-methyl-1-indanone get mentioned in the title compound in the form of a solid brown color.

1H-NMR (CDCl3) δTMS: 1,67 (m, 1H), 1,90 (m, 2H), 2,23 (m, 3H), 2,42 (m, 2H), 2,52 (c, 3H), 2,69 (m, 1H), 2,90 (m, 2H), 3.04 from (m, 1H), 4,35 (m, 1H), 4,46 (m, 1H), 7,00-7,22 (m, 7H), was 9.33 (users, 1H).

FAB-MS (M+H)+: 348.

Example 24

2-{3-(7-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide hydrochloride

Similarly to the method shown in example 2, using 1-(7-methyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-he will receive 2-{3-(7-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide, which is then converted into the hydrochloride using 4h. solution chloroethanol acid in ethyl acetate and get listed in the title compound in the form of a solid brown color.

1H-NMR (DMSO-d6) δTMS: of 1.84 (m, 2H), 2,30 (m, 1H), 2,50 (c, 3H), 2,59 (d, J=4.5 Hz, 3H), 2,68-a 3.01 (m, 4H), 3,23-to 3.64 (m, 5H), 4,42 (c, 2H), of 4.66 (m, 1H), 4,90 (m, 1H), 7,02 (m, 3H), 7,15 (d, J=7,4 Hz, 1H), 7,24 (d, J=7,4 Hz, 1H), 7,33 (t, J=7.5 Hz, 1H), 7,80 (m, 1H), 8,13 (m, 1H), 10,3 (users, 1H).

FAB-MS (M+H)+: 419.

Example 25

1-(3,3-dimethyl-1-indan-1-reparacin-4-yl)-1,3-dihydr what-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 3,3-dimethyl-1-indanone get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,20 (c, 3H), 1.39 in (c, 3H), of 1.80 (m, 1H), was 1.94 (m, 3H), to 2.29 (m, 2H), 2,65 (m, 2H), 2,75 (m, 1H), 3,10 (m, 1H), to 4.38 (m, 1H), 4,54 (m, 1H), 7,05-7,11 (m, 3H), 7,18 (m, 1H), 7.23 percent (m, 2H), 7,34 (m, 2H), for 9.47 (users, 1H).

FAB-MS (M+H)+: 362.

Example 26

2-{3-(3,3-dimethyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-(3,3-dimethyl-1-indan-1-reparacin-4-yl)-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,20 (c, 3H), 1,38 (c, 3H), 1,76 is 1.96 (m, 4H), and 2.27-2.40 a (m, 2H), 2,62 (m, 2H), 2,75 (m, 1H), and 2.79 (d, J=4,7 Hz, 3H), 3,11 (m, 1H), 4,37 (m, 1H), 4,51 (c, 2H), 4,54 (m, 1H), 6.73 x (users, 1H), 7,06-7,19 (m, 4H), 7,25 (m, 2H), 7,38 (m, 2H).

FAB-MS (M+N)+: 433.

Example 27

1-[1-(6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 1-benzocoumarin get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,40 (m, 1H), 1,72 (m, 3H), 1,91-of 2.15 (m, 6H), was 2.34 (m, 1H), 2,49-of 2.58 (m, 3H), of 3.27 (m, 1H), 3,32 (m, 1H)and 3.59 (m, 1H), 4,36 (m, 1H), 7,05-7,14 (m, 7H), from 7.24 (m, 1H), 9,46 (users, 1H).

FAB-MS (M+H)+: 362.

Example 28

2-{3-[1-(6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[1-(6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid pale yellow color.

1H-NMR (CDCl3) δTMS: the 1.44 (m, 1H), 1,68 (m, 3H), 1,87-2,17 (m, 6H), was 2.34 (m, 1H), of 2.51 2.63 in (m, 3H), and 2.79 (d, J=4.9 Hz, 3H), 3,23 (m, 1H), 3,32 (m, 1H), to 3.58 (m, 1H), 4,33 (m, 1H), 4,50 (c, 2H), 6,17 (users, 1H),? 7.04 baby mortality-7,14 (m, 7H), 7,26 (m, 1H).

FAB-MS (M+H)+: 433.

The following compounds in examples 29-45 can be synthesized as in example 1.

Example 29

1-[1-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 5-methoxy-1-tetralone, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,59-of 1.74 (m, 3H), 1,88-to 2.06 (m, 3H), 2.26 and to 2.35 (m, 2H), 2.40 a-a 2.71 (m, 3H), 2.77-to 2,89 (m, 2H), to 3.02 (m, 1H), 3,82 (c, 3H), with 3.89 (m, 1H), 4,35 (m, 1H), 6,72 (d, J=8.0 Hz, 1H), 7,06-7,13 (m, 3H), 7,20 (m, J=8.0 Hz, 1H), 7,33 (d, J=7,4 Hz, 1H), 7,47 (d, J=7.8 Hz, 1H), 8,88 (users, 1H).

FAB-MS (M+H)+: 378.

Example 30

1-[1-(5-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

b> Example 31

1-[1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 32

1-[1-(5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 33

1-[1-(8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 34

1-[1-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 35

1-[1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 7-fluoro-1-tetralone, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,65-to 1.77 (m, 3H), of 1.92 (m, 1H), 2,01-2,05 (m, 2H), 2,31-is 2.37 (m, 2H), 2,56-of 2.72 (m, 4H), 2,89 (m, 1H), 3,01 (m, 1H), a 3.87 (m, 1H), to 4.38 (m, 1H), 6,84 (dt, J=2,7, 8,3 Hz, 1H), 7,00-to 7.15 (m, 4H), 7,34 (d, J=7.7 Hz, 1H), 7,55 (DD, J=2.7, and is 10.7 Hz, 1H), 9.28 are (users, 1H).

FAB-MS (M+H)+: 366.

Example 36

1-[1-(6-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 37

1-[1-(7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 38

1-[1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 39

1-[1-(7-methoxy-1,2,3,4-tetrahed naphthalin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 7-methoxy-1-tetralone, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: of 1.63 to 1.76 (m, 3H), 1,89-2,05 (m, 3H), 2,29-of 2.36 (m, 2H), 2.57 m)-by 2.73 (m, 4H), 2,88 (m, 1H), 3,03 (m, 1H), 3,85 (c, 3H), 3,88 (m, 1H), 4,36 (m, 1H), 6.73 x (DD, J=2,8, 8,3 Hz, 1H), 6,99 (d, J=8,3 Hz), 7,06-7,11 (m, 3H), 7,32 (d, J=7,6 Hz, 1H), 7,42 (d, J=2.7 Hz, 1H), 9,02 (users, 1H).

FAB-MS (M+H)+: 378.

Example 40

1-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 41

1-[(1-chroman-4-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method shown in example 1, using 4-chromanol get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,75-to 1.79 (m, 1H), 1,89-of 1.92 (m, 1H), 1,97-of 2.15 (m, 2H), 2,25-is 2.37 (m, 2H), 2.57 m (m, 1H), was 2.76-to 2.85 (m, 2H), 3,03 (m, 1H), 3,99 (m, 1H), 4,11-4,16 (m, 1H), 4,18-to 4.41 (m, 2H), 6,80 (DD, J=0,9, 8,1 Hz, 1H), 6,94 (dt, J=1,0, 7,4 Hz), 7,06-to 7.15 (m, 4H), 7,30 (d, J=7,1 Hz, 1H), 7,60 (d, J=7,6 Hz, 1H), 8,87 (users, 1H).

FAB-MS (M+H)+: 350.

Example 42

1-[(1-thiochroman-4-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 43

1-[(1,1-dioxide-3,4-dihydro-2H-thiochroman-4-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 44

1-[1-(5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 45

1-[1-(5-acetamido-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Compounds in the following examples 46-74 can be synthesized analogously to the method described in example 2, using the above connection.

Example 46

2-{3-[1-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[1-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,63-of 1.73 (m, 3H), 1,88-2,05 (m, 3H), 2.23 to to 2.35 (m, 2H), 2,46-a 2.71 (m, 3H), 2,78-is 2.88 (m, 5H), to 3.02 (m, 1H), 3,89 (d, J=4.0 Hz, 1H), with 3.89 (m, 1H), 4,34 (m, 1H), 4,50 (d, J=3,7 Hz, 2H), 6,14 (users, 1H), 6,72 (m, 1H),? 7.04 baby mortality-7,21 (m, 4H), of 7.36 (m, 1H), 7,46 (m, 1H).

FAB-MS (M+H)+: 449.

Example 47

2-{3-[1-(5-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 48

2-{3-[1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 49

2-{3-[1-(5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 50

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)Piperi the Jn-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N,N-dimethylacetamide

Example 51

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}ndimethylacetamide

Example 52

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-ethylacetamide

Example 53

2-{3-[1-(5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 54

2-{3-[1-(5-acetylamino-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 55

2-{3-[1-(8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 56

2-{3-[1-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 57

2-{3-[1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using (RS)-1-[1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,64-of 1.78 (m, 3H), 1,89-2,03 (m, 3H), 2,29-of 2.36 (m, 2H), 2.57 m-2,72 (m, 4H), 2,80 (d, J=4.9 Hz, 3H), 2,85-only 2.91 (m, 1H), to 3.02 (m, 1H), a 3.87 (m, 1H), 4,36 (m, 1H), 4,51 (c, 2H), 6,13 (users, 1H), 6,85 (m, 1H), 7,00-was 7.08 (m, 2H) 7,12-7,21 (m, 2H), was 7.36 (d, J=7,4 Hz), 7,54 (DD, J=2,6, a 10.6 Hz, 1H).

FAB-MS (M+H)+: 437.

Example 58

2-{3-[1-(6-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 59

2-{3-[1-(7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 60

2-{3-[1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 61

2-{3-[1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,64 to 1.76 (m, 3H), 1,92 is 2.01 (m, 3H), 2,28-of 2.36 (m, 2H), 2,73 (d, J=7.9 Hz, 3H), 2,78-2,89 (m, 1H), to 3.02 (m, 1H), 3,84 (c, 3H), 3,88 (m, 1H), 4,35 (m, 1H), 4,50 (c, 2H), 6,14 (users, 1H), 6.73 x (m, 1H), 6,99-7,16 (m, 4H), 7,34 (m, 1H), 7,40 (m, 1H).

FAB-MS (M+H)+: 449.

Example 62

2-{3-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 63

1-[2-(methylamino)ethyl]-3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 64

1-[2-(dimethylamino)ethyl]-3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 65

1-(2-methoxyethyl)-3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Example 66

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-cyclopropylacetic

Example 67

2-{3-[1-[(1-chroman-4-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method shown in example 2, using 1-[(1-chroman-4-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 1,75-of 1.78 (m, 1H), 1,89-of 1.92 (m, 1H), 1,97 with 2.14 (m, 2H), 2,24-is 2.37 (m, 2H), 2,55-2,62 (m, 1H), 2,75-of 2.86 (m, 5H), 3,02 was 3.05 (m, 1H), 3,99 (m, 1H), 4,13-4,19 (m, 1H), 4,33 was 4.42 (m, 2H), 4,51 (c, 2H), 6,12 (users, 1H), 6,80 (d, J=8,2 Hz, 1H), 6,94 (dt, J=0,9, 7,4 Hz, 1H), 7,05-to 7.18 (m, 4H), 7,34 (m, 1H), to 7.59 (d, J=7.7 Hz, 1H).

FAB-MS (M+H)+: 421.

Example 68

2-{3-[1-[(1-thiochroman-4-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 69

2-{3-[1-(1,1-dioxide-3,4-dihydro-2H-thiochroman-4-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 70

2-{3-[1-(5-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

When the EP 71

2-{3-[1-(8-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 72

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-6-fluoro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 73

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}acetic acid

Example 74

2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-thioxo-benzimidazole-1-yl}-N-methylacetamide

Example 75

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) 1,2,2A,3,4,5-hexahydronaphthalen-1-ylamine

To a solution of ethyl (1,2,3,4-tetrahydronaphthalen-1-yl)acetate (31.0 g) in ethanol (100 ml) add a solution of sodium hydroxide (4n., 100 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated to half the original volume under reduced pressure and the residue is washed with ethyl acetate. The aqueous layer acidified with diluted chloroethanol acid and extracted with chloroform. The obtained organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and get (1,2,3,4,-tetrahydronaphthalen-1-yl)acetic acid.

the (1,2,3,4,-tetrahydronaphthalen-1-yl)acetic acid is added polyphosphoric acid (75%, 150 g) and the mixture is stirred at a temperature of 100°C for 1.5 hours. The reaction mixture was poured into ice water and the resulting mixture extracted with ethyl acetate. The organic layers are combined, washed with water and saturated salt solution, dried over magnesium sulfate and filtered, and the solvent is then evaporated under reduced pressure. The residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get 2A,3,4,5-tetrahydro-2H-acenaphthylen-1-he (12.1 g, 37%) as a solid white color.

2A,3,4,5-Tetrahydro-2H-acenaphthylen-1-he (4,85 g) dissolved in methanol (70 ml). To the obtained solution under cooling with ice add sodium borohydride (1.07 g) and the mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into water and the mixture extracted with ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated, obtaining 2A,3,4,5-tetrahydro-2H-acenaphthylen-1-ol.

To a cooled solution (0°C) 2A,3,4,5-tetrahydro-2H-acenaphthylen-1-ol and diphenylphosphinite (9,31 g) in toluene (90 ml) is added DBU (databaseconnect) (5,04 ml) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into water, the mixture extracted with toluene. The organic layers are combined, washed with water, dried over magnesium sulfate and concentrated. Cheese is th product is dissolved in a mixed solvent (77 ml) THF/water (10:1), add triphenylphosphine (being 9.61 g) and the mixture refluxed for 1 hour. After cooling to room temperature, the solvent evaporated, to the residue add 1H. the solution chloroethanol acid (100 ml) and unwanted substances are removed by extraction with ethyl acetate. The aqueous phase is alkalinized with potassium carbonate and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated, obtaining 1,2,2A,3,4,5-hexahydronaphthalen-1-ylamine.

(2) 1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-one

To a mixture of 1,2,2A,3,4,5-hexahydronaphthalen-1-ylamine, potassium carbonate (3,89 g) and ethanol (60 ml) was added 1-ethyl-1-methyl-4-oxopiperidine iodide (at 8.36 g)dissolved in water (15 ml)and the mixture refluxed for 2 hours. The reaction mixture was poured into water and the resulting mixture extracted with ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get 1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-one (1.01 g, 14%) as oil.

(3) 1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

To a cooled solution (0°C) 1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-it (100 g, to 3.92 mmol) and 1,2-phenylenediamine (642 mg) in dichloroethane (30 ml) add triacetoxyborohydride sodium (1,99 g) and acetic acid (0,509 ml) and the resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was poured into water, the mixture is neutralized with potassium carbonate and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and obtain N-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]benzene-1,2-diamine (1,16 g) in the form of oil.

N-[1-(1,2,2A,3,4,5-Hexahydronaphthalen-1-yl)piperidine-4-yl]benzene-1,2-diamine (1,15 g) dissolved in THF (70 ml), add 1,1'-carbonyldiimidazole (0,591 g) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into water and the mixture extracted with ethyl acetate. The extract is washed with water and saturated aqueous ammonium chloride, dried over magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (0,76 g) as a solid white color

1H-NMR (CDCl3) δTMS: 9,10 (c, 1H), 7,30-7,00 (m, 7H), 4,40-4,30 (m, 1H), 4,06 (d, J=7.8 Hz, 1H), 3,20-3,00 (m, 3H), 2,97-2,62 (m, 2H), 2,60-of 2.34 (m, 5H), 2,20-2,00 (m, 2H), 1,90-to 1.60 (m, 6H), 1.18 to 1,00 (m, 2H).

+: 374.

Example 76

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

N-[1-(1,2,2A,3,4,5-Hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (0,30 g) dissolved in DMF (15 ml). Add sodium hydride (35 mg, 60%) and the resulting suspension is stirred at room temperature for 30 minutes Add ethylbromoacetate (0.1 ml) and the mixture is stirred for 1 hour. The reaction mixture was poured into water and extracted with a mixture of ethyl acetate. The extract is washed with water and saturated aqueous ammonium chloride, dried over sodium sulfate and concentrated, obtaining ethyl {3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}acetate. Add 40%solution of methylamine in methanol (20 ml) and stirred at room temperature for 1 hour and then the reaction mixture was concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (333 mg) as white powder.

1H-NMR (DMSO-d6) δTMS: 8,10-of 8.00 (m, 1H), 7,30-of 6.90 (m, 7H), 4,39 (c, 2H), 4,25-of 4.05 (m, 1H), 3,93 (d, J=7.5 Hz, 1H), 3,10-of 2.75 (m, 4H), 2,60-2,52 (m, 3H), 2.40 a-1,50 (m, 6H), 1,10-of 0.90 (m, 2H).

FAB-MS (M+H)+: 445.

Example 77

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)Pipa is one-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (a stereoisomer of example 75)

(1) 1,2,2A,3,4,5-hexahydronaphthalen-1-ylamine (stereoisomer of example 75(1))

To a mixture of 2A,3,4,5-tetrahydro-2H-acenaphthylen-1-it (12.2 g, to 70.9 mmol), hydroxylamine hydrochloride (a 7.85 g) and water (90 ml) slowly with stirring and heated to 75°C. add sodium acetate (14.5 g), methanol (120 ml), THF (30 ml) and water (60 ml) and the resulting mixture is stirred for 2 hours and 40 minutes After cooling to room temperature, the methanol evaporated under reduced pressure, and the resulting precipitates are filtered, washed with water and get the oxime 2A,3,4,5-tetrahydro-2H-acenaphthylen-1-she (13.5 g).

The oxime 2A,3,4,5-tetrahydro-2H-acenaphthylen-1-it (7,00 g) add a solution of (approximately 65%, 50 ml) bis(2-methoxyethoxy)aluminiumhydride sodium in toluene and the mixture heated to 80°C and stirred for 2 hours. After cooling to room temperature the reaction mixture was poured into ice water and the mixture extracted with chloroform. After concentration under reduced pressure, the residue is extracted with 1N. solution chloroethanol acid. The aqueous layer was alkalinized with potassium carbonate and extracted with chloroform. The extract is washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, obtaining mentioned in the title compound (5.34 g, 83%).

(2) 1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,dihydro-2H-benzimidazole-2-he (a stereoisomer of example 75)

By the method similar to that shown in example 75(2) and (3)using 1,2,2A,3,4,5-hexahydronaphthalen-1-ylamine (stereoisomer of example 75(1)), get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: 9,17 (users, 1H), 7,40-to 6.95 (m, 6H), 4,57-4,37 (m, 2H), 3,21-of 3.06 (m, 1H), 2.91 in-1,50 (m, 16H), 1,30-1,15 (m, 1H).

FAB-MS (M+H)+: 374

Example 78

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide (a stereoisomer of example 76)

Similarly to the method described in example 76, using 1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (a stereoisomer of example 75), get mentioned in the title compound in the form of a solid white color.

1H-NMR (DMSO-d6) δTMS: 8,10-with 8.05 (m, 1H), 7,38-6,92 (m, 7H), 4,40 (c, 2H), 4.26 deaths-4,08 (m, 1H), 3,18-2,99 (m, 1H), 2,82-of 2.58 (m, 8H), 2,44-of 1.95 (m, 6H), 1,80-of 1.05 (m, 5H).

FAB-MS (M+H)+445.

Example 79

(1RS, 3aSR)-2-{3-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 76, using (1RS, 3aSR)-1-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (see WO2005/028466, example 1)are specified in the title compound in the form of a solid white color.

Obtained (1RS,3aSR)-2-{3-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide divided into (+)-form and (-)-form optical splitting using HPLC.

The analysis of the conditions of the optical splitting:

column: CHIRALPAK(R)AD-H

size: 0,46 cm internal diameter × 25 cm

mobile phase: hexane/ethanol/diethylamine =70/30/0,1 (vol./about.)

flow rate: 1.0 ml/min

temperature: 40°C

wave length: 283 nm

Isomer 1)1H-NMR (CDCl3) δTMS: 7,60-7,53 (m, 1H), 7,39-7,32 (m, 1H), 7,21-to 6.95 (m, 5H), 6,13 (users, 1H), 4,51 (c, 2H), to 4.41-the 4.29 (m, 1H), a 3.87-of 3.80 (m, 1H), is 3.08-of 2.97 (m, 1H), 2,90-by 2.73 (m, 7H), 2,68-of 2.20 (m, 4H), 2,11-of 1.20 (m, 15H), 0,92-0,82 (m, 2H).

FAB-MS (M+H)+: 459.

[α]D=-36,6° (C=0,24, Meon)

Isomer 2)1H-NMR (CDCl3) δTMS: 7,60-7,53 (m, 1H), 7,39-7,32 (m, 1H), 7,21-to 6.95 (m, 5H), 6,12 (users, 1H), 4,51 (c, 2H), to 4.41-the 4.29 (m, 1H), a 3.87-of 3.80 (m, 1H), is 3.08-of 2.97 (m, 1H), 2,90-by 2.73 (m, 7H), 2,68-of 2.20 (m, 4H), 2,11-of 1.20 (m, 15H), 0,92-0,82 (m, 2H).

FAB-MS (M+H)+: 459.

[α]D=+37,2° c to 0.24, MeOH).

Example 80

(1RS, 3aRS)-2-{3-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 76, using (1RS, 3aRS)-1-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (see WO2005/028466, example 1)are specified in the title compound in the form of a solid white color.

Obtained (1RS, 3aRS)-form is separated into (+)-form and (-)-form optical splitting using HPLC.

The analysis of the conditions of the optical splitting:

column: CHIRALPAK(R)IA

size: 0,46 cm within the indoor diameter × 25 cm

mobile phase: hexane/ethanol/diethylamine = 60/40/0,1 (vol./about.)

flow rate: 1.0 ml/min

temperature: 40°C

wave length: 283 nm

Isomer 1)1H-NMR (CDCl3) δTMS: to 7.67-of 7.48 (m, 1H), 7,40-7,30 (m, 1H), 7,20-to 6.95 (m, 5H), 6,12 (users, 1H), 4,51 (c, 2H), 4,40-the 4.29 (m, 1H), 4,05-3,95 (m, 1H), is 3.08-of 2.97 (m, 1H), 2,87-2,70 (m, 7H), 2,67 is 2.51 (m, 2H), 2,42 was 2.25 (m, 2H), 2,10-1,70 (m, 8H), 1.55V is 1.20 (m, 5H).

FAB-MS (M+H)+: 459.

[α]D=+54,6° (c 0,14, CDCl3).

Isomer 2)1H-NMR (CDCl3) δTMS: to 7.67-of 7.48 (m, 1H), 7,40-7,30 (m, 1H), 7,20-to 6.95 (m, 5H), 6,13 (users, 1H), 4,51 (c, 2H), 4,40-the 4.29 (m, 1H), 4,05-3,95 (m, 1H), is 3.08-of 2.97 (m, 1H), 2,87-2,70 (m, 7H), 2,67 is 2.51 (m, 2H), 2,42 was 2.25 (m, 2H), 2,10-1,70 (m, 8H), 1.55V is 1.20 (m, 5H).

FAB-MS (M+H)+: 459.

[α]D=-58,3° (c of 0.13, MeOH).

Example 81

1-[1-(2,3,3A,4,5,6-hexahydrobenzo[de]chromen-6-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) 3,3A,4,5-tetrahydro-2H-benzo[de]chromen-6-he

To a suspension of lithium aluminum hydride (3,45 g) in THF (400 ml) under ice cooling are added dropwise a solution of ethyl chroman-4-ilaclama (10.0 g) in THF (50 ml) and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture are added water (3,45 ml), 15%aqueous sodium hydroxide solution (3,45 ml) and water (10 ml), the mixture is filtered, washed with ethyl acetate and concentrated under reduced pressure, getting chroman-4-ylmethanol (7,58 g).

To the mixture chroman-4-ylmethanol (15.0 g), methylene chloride (80 ml) and triethylamine (12.9 ml) under cooling to ban the ice added dropwise methanesulfonanilide (6.85 ml) and the resulting mixture was stirred for 2 hours. The reaction mixture was poured into water and the resulting mixture extracted with methylene chloride. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated, obtaining chroman-4-ylmethyl methanesulfonate.

To a solution of chroman-4-ylmethyl methanesulfonate in ethanol (650 ml) is added potassium cyanide (9,23 g) and the mixture with stirring, refluxed for 15 hours. After cooling to room temperature the mixture is concentrated under reduced pressure, to the residue water is added and the mixture extracted with ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated, obtaining 3-chroman-4-ylpropionic.

A mixture of 3-chroman-4-ylpropionic, ethanol (150 ml) and 50%aqueous sodium hydroxide (100 ml) with stirring and refluxed for 26 hours. After cooling to room temperature the mixture was washed with a complex ether, the aqueous layer was acidified with 4n. solution chloroethanol acid and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated, obtaining 3-chroman-4-ylpropionic acid (9,96 g).

3-chroman-4-ylpropionic acid (9.95 g) is added polyphosphoric acid (75%, 150 g) and the mixture is stirred at a temperature of 100°C for 1.5 hours. The MCA is ü poured into ice water and the mixture extracted with ethyl acetate. The obtained organic layer was washed with water and saturated salt solution, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get 3,3A,4,5-tetrahydro-2H-benzo[de]chromen-6-he (a 4.03 g, 44%) as a solid yellow color.

(2) 2,3,3A,4,5,6-hexahydro-2H-benzo[de]chromen-6-ylamine

Similarly to the method described in example 75(1), using 3,3A,4,5-tetrahydro-2H-benzo[de]chromen-6-he get mentioned in the title compound in the form of a solid white color.

(3) 1-[1-(2,3,3A,4,5,6-hexahydrobenzo[de]chromen-6-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method described in example 75(2) and (3)using 2,3,3A,4,5,6-hexahydro-2H-benzo[de]chromen-6-ylamine, get mentioned in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: for 9.47 (s, 1H), 7,35-7,25 (m, 2H), 7,13-7,03 (m, 4H), to 6.67 (d, J=8,1 Hz, 1H), 4,43-4,32 (m, 2H), 4,13 (t, J=10,8 Hz, 1H), 3,88 (d, J=6,9 Hz, 1H), 3,05-of 2.50 (m, 5H), 2.40 a-to 2.15 (m, 3H), 2.05 is is 1.60 (m, 7H), 1.18 to of 1.05 (m, 1H).

FAB-MS (M+H)+: 390.

Example 82

2-{3-[1-(2,3,3A,4,5,6-hexahydro-benzo[de]chromen-6-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 76, using 1-[1-(2,3,3A,4,5,6-hexahydro-benzo[de]chromen-6-yl)piperidine-4-yl]-1,3-dig the DRO-2H-benzimidazole-2-it, get listed in the title compound in the form of a solid white color.

1H-NMR (CDCl3) δTMS: of 7.36-7.23 percent (m, 2H), 7,20-7,00 (m, 4H), to 6.67 (d, J=7.8 Hz, 1H), 6,16 (users, 1H), 4,50 (c, 2H), 4,45-to 4.23 (m, 2H), 4,22-4.09 to (m, 1H), 3,90-a 3.83 (m, 1H), 3,06-of 2.50 (m, 8H), 2.40 a is 1.60 (m, 9H), 1,25-of 1.05 (m, 1H).

FAB-MS (M+H)+: 461.

Example 83

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) 1,2,2A,3,4,5-hexahydronaphthalen-5-ylamine

Similarly to the method described in example 75(1), using ethyl indan-1-ylacetic, get 2,2A,3,4-tetrahydro-1H-acenaphthylen-5-it is in the form of a solid white color.

Similarly to the method described in example 75(1), obtained using 2,2A,3,4-tetrahydro-1H-acenaphthylen-5-it, get mentioned in the title compound in the form of a solid white color.

(2) 1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method described in example 75(2) and (3)using 1,2,2A,3,4,5-hexahydronaphthalen-5-ylamine, get mentioned in the title compound in the form of a solid white color.

Isomer 1)1H-NMR (CDCl3) δTMS: 9,48 (users, 1H), 7,53 was 7.45 (m, 1H), 7,38-7,00 (m, 6H), 4,40-to 4.23 (m, 1H), 3,93 (d, J=7.8 Hz, 1H), 3,03-2,07 (m, 12H), 1,97 of-1.83 (m, 1H), 1,73-of 1.45 (m, 4H), 1,07-0,98 (m, 1H).

FAB-MS (M+H)+: 373.

Isomer 2)1H-NMR (CDCl3) δTMS: 9,29 (users, 1H), 7,50-7,00 (m, 7H), 4,50-430 (m, 1H), 4,17-4,00 (m, 1H), 3,10-2,00 (m, 12H), 1,94 is 1.20 (m, 7H).

FAB-MS (M+H)+: 373.

Example 84

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 76, using 1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of a solid white color.

Isomer 1)1H-NMR (CDCl3) δTMS: 7,50-7,37 (m, 2H), 7,21-7,03 (m, 5H), 6,12 (users, 1H), 4,51 (c, 2H), to 4.41-4,30 (m, 1H), 4,10-4,00 (m, 1H), 3,10-2,77 (m, 9H), 2,67-2,03 (m, 6H), 1.93 and a 1.25 (m, 6H).

FAB-MS (M+H)+: 445.

Isomer 2)1H-NMR (CDCl3) δTMS: EUR 7.57-to 7.50 (m, 1H), 7,46-7,02 (m, 6H), 6,15 (users, 1H), 4,50 (c, 2H), 4,40-of 4.25 (m, 1H), 4,00-3,90 (m, 1H), 3,17-2,10 (m, 15H), 1,95 to 1.47 (m, 5H), 1,17-0,98 (m, 1H).

FAB-MS (M+H)+: 445.

Example 85

1-[2-(cyclopropylamino)ethyl]-3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

1-[1-(1,2,2A,3,4,5-Hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (1,00 g) dissolved in DMF (30 ml), added 60%sodium hydride (140 mg) and the resulting suspension is stirred for 1 hour. Then add N-(2-bromacil)phthalimide (818 mg) and the resulting mixture is stirred at a temperature of 100°C for 1 hour. The reaction mixture is cooled to room temperature, poured into saturated aqueous solution of CHL is reed ammonium and the mixture is extracted with ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get 2-{2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2-oxopentanoate-1-yl}ethyl}isoindole-1,3-dione.

A mixture of 2-{2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2-oxopentanoate-1-yl}ethyl}isoindole-1,3-dione, ethanol (35 ml) and hydrazine (0,42 ml) with stirring and refluxed for 2 hours. After cooling to room temperature, the solvent evaporated and the residue purified column chromatography on silica gel (chloroform/methanol)to give 1-(2-amino-ethyl)-3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2-oxopentanoate-2-he (420 mg, 38%) as oil.

1-(2-amino-ethyl)-3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2-oxopentanoate-2-he (210 mg) was dissolved in dichloroethane (10 ml) and add cyclopropanecarboxaldehyde (41 μl), triacetoxyborohydride sodium (0,248 g) and acetic acid (to 0.032 ml). The mixture is stirred at room temperature for 13 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract is washed with saturated salt solution, dried over anhydrous surfacematerial and concentrate. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (80 mg, 34%) as oil.

1H-NMR (CDCl3) δTMS: 7,42-7,38 (m, 1H), 7,22-to 6.95 (m, 6H), 4,56-4,37 (m, 2H), 4.09 to 3,95 (m, 2H), 3,20-3,10 (m, 1H), 3,01 (t, J=6.9 Hz, 2H), 2,90-1,50 (m, 19H), 1,37 is 1.13 (m, 2H), 1.00 and-0,83 (m, 1H), 0.50 to 0,37 (m, 2H), 0,17 to 0.08 (m, 2H).

FAB-MS (M+H)+: 471.

Example 86

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-3-(2-isopropylaminoethyl)-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method described in example 85, using acetone instead of cyclopropanecarboxaldehyde receive specified in the title compound in the form of oil.

1H-NMR (CDCl3) δTMS: 7,41-7,37 (m, 1H), 7,22-6,91 (m, 5H), 4,50-4,37 (m, 2H), 3,99 (t, J=6.9 Hz, 2H), 3,20-1,50 (m, 21H), of 1.05 (d, J=6.0 Hz, 6H).

FAB-MS (M+H)+: 459.

Example 87

3-{3-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}propyl}thiazolidin-2,4-dione

To a mixture of 1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (500 mg), dimethylacetamide (3 ml) and potassium carbonate (370 mg) is added 3-bromopropane (0,242 ml) and the resulting mixture was stirred at 85°C for 2 hours. The reaction mixture is cooled to room temperature, water is added and the precipitate are filtered, obtaining 1-[1-(1,2,2A,3,4,5-hexahydroazepin the flax-5-yl)piperidine-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazole-2-it.

1-[1-(1,2,2A,3,4,5-Hexahydronaphthalen-5-yl)piperidine-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazole-2-he and 2,4-thiazolidinedione (314 mg) was dissolved in THF (25 ml), add 40%solution (1,22 ml) of triphenylphosphine (702 mg) and diethyl of azodicarboxylate (DEAD) in toluene and the resulting mixture is stirred at 50°C for 2 hours. Concentrate the reaction mixture under reduced pressure and the resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate), obtaining mentioned in the title compound (160 mg).

1H-NMR (CDCl3) δTMS: 12,3 (users, 1H), 9,20 (users, 1H), 7,63-7,42 (m, 2H), 7,38-of 7.23 (m, 2H), 7,20-7,03 (m, 2H), 7,00-6,92 (m, 1H), around 4.85 (d, J=6.3 Hz, 1H), 4,78-4,58 (m, 1H), 4,00-of 3.85 (m, 3H), 3,81 (c, 2H), 3,66 (t, J=6.9 Hz, 2H), 3,30-2,70 (m, 8H), 2,68 and 1.80 (m, 8H), 1.70 to 1,25 (m, 2H) (triptorelin).

FAB-MS (M+H)+: 531.

Example 88

1-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) 6-fluoro-2A,3,4,5-tetrahydro-2H-acenaphthylen-1-he

To a solution of 2-forfeitable alcohol (25,0 g) in triethylamine (37.5 ml) and methylene chloride (250 ml) under ice cooling are added dropwise methanesulfonanilide (16,7 ml) and the mixture is stirred for 30 minutes to Give the reaction mixture to warm to room temperature, washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated, obtaining 2-(2-forfinal)utilmate ulpanat.

To a suspension of 60%sodium hydride (8,24 g) in DMF (200 ml) under ice cooling are added dropwise diethylmalonate (24,9 g) and the resulting suspension is stirred at 50°C for 30 minutes After cooling to room temperature, added dropwise a solution of 2-(2-forfinal)ethylmethanesulfonate in DMF (30 ml) and the mixture is stirred at a temperature of 150°C for 1 hour. After cooling to room temperature the mixture was poured into ice water and extracted with a mixture of ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, obtaining dimethyl 2-[2-(2-forfinal)ethyl]malonate.

Dimethyl 2-[2-(2-forfinal)ethyl]malonate, sodium hydroxide (22,7 g), ethanol (150 ml) and water (100 ml) is refluxed for 1.5 hour. The mixture is concentrated under reduced pressure, and the residue is acidified chloroethanol acid, and then extracted with chloroform. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, obtaining 4-(2-forfinal)butane acid.

To 4-(2-forfinal)butane acid added polyphosphoric acid (75%, 100 g) and the mixture is stirred at a temperature of 150°C for 1.5 hours. The reaction mixture was poured into ice water and extracted with a mixture of ethyl acetate. Received organic the sky layer is washed with water and saturated salt solution, dried over magnesium sulfate and filtered, and the solvent is then evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get 5-fluoro-3,4-dihydro-2H-naphthalene-1-he (10.2 g, 33%) as oil.

To a suspension of 60%sodium hydride (4.12 g) in toluene (200 ml) under ice cooling are added dropwise ethyl diethylphosphonoacetate (20.4 ml) and the resulting mixture was stirred at room temperature for 45 minutes Then added dropwise a solution of 5-fluoro-3,4-dihydro-2H-naphthalene-1-she (15.3 g) in toluene (50 ml) and the mixture is stirred at a temperature of 80°C for 2 hours. After cooling to room temperature the reaction mixture was poured into ice water and extracted with a mixture of toluene. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and obtain ethyl (5-fluoro-3,4-dihydro-2H-naphthalene-1-ilidene)acetate.

A mixture of ethyl (5-fluoro-3,4-dihydro-2H-naphthalene-1-ilidene)acetate, catalyst 10%palladium on coal (3 g) and ethanol (150 ml) is stirred under hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite and concentrated, obtaining ethyl (5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetate.

To a solution of ethyl (5-fluoro-1,2,3,4-tet is Aeronavale-1-yl)acetate in ethanol (30 ml) add a solution of sodium hydroxide (4n., 30 ml) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to ½ of the original volume and the residue is washed with ethyl acetate. The aqueous layer was acidified with diluted chloroethanol acid and extracted with chloroform. The obtained organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and filtered, and the solvent is evaporated under reduced pressure, obtaining (5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid.

To the obtained (5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid is added polyphosphoric acid (75%, 100 g) and the mixture is stirred at a temperature of 120°C for 1 hour. The reaction mixture was poured into ice water and extracted with a mixture of ethyl acetate. The obtained organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and filtered, and the solvent is then evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and get 6-fluoro-2A,3,4,5-tetrahydro-2H-acenaphthylen-1-he (6,70 g, 34%) as a solid orange color.

(2) 6-fluoro-1,2,2A,3,4,5-hexahydro-2H-acenaphthylen-1-ylamine

Similarly to the method described in example 75(1), using 6-fluoro-2A,3,4,5-tetrahydro-2H-acenaphthylen-1-it, get listed is in the title compound in the form of oil.

(3) 1-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Similarly to the method described in example 75(2) and (3)using 6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-ylamine, get mentioned in the title compound in the form of oil.

1H-NMR (CDCl3) δTMS: 9,14 (users, 1H), 7,35-to 6.80 (m, 6H), 4,42-4,27 (m, 1H), 4.00 points (d, J=7.5 Hz, 1H), 3,18-of 2.97 (m, 3H), 2,96 is 2.80 (m, 1H), 2,70-of 2.30 (m, 6H), 2,20-2,03 (m, 2H), 1,87-to 1.63 (m, 4H), of 1.20 to 1.00 (m, 1H).

FAB-MS (M+H)+: 392.

Example 89

2-{3-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Similarly to the method described in example 76, using 1-[1-(6-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it, get mentioned in the title compound in the form of oil.

1H-NMR (DMSO-d6) δTMS: 8,13-with 8.05 (m, 1H), 7,30-7,22 (m, 1H), 7,20-7,13 (m, 1H), 7,07-6,83 (m, 4H), 4,40 (c, 2H), 4,25-4,10 (m, 1H), 3,92 (d, J=7,6 Hz, 2H), 3,50-3,30 (m, 2H), 3,20-of 2.72 (m, 4H), 2,59 (d, J=4,8 Hz, 3H), 2.40 a-2,00 (m, 6H), 1,80-of 1.52 (m, 4H), 1,10-0,93 (m, 1H).

FAB-MS (M+H)+: 463.

As described above in examples 75-89, can be obtained the compounds in the following examples 90-102.

Example 90

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-ethylacetamide

Example 91

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-1-yl)piperidine-4-yl]-2,dihydro-2-oxo-benzimidazole-1-yl}-N-dimethylacetamide

Example 92

2-{3-[1-(8-fluoro-1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 93

2-{3-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-ethylacetamide

Example 94

2-{3-[1-(7-fluoro-2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 95

2-{3-[1-(7-methyl-2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 96

2-{6-fluoro-3-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 97

1-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-3-(2-isopropylaminoethyl)-1,3-dihydro-2H-benzimidazole-2-he

Example 98

1-[1-(2,3,3A,4,5,6-hexahydro-1H-phenalen-1-yl)piperidine-4-yl]-3-(2-cyclopropylamino)-1,3-dihydro-2H-benzimidazole-2-he

Example 99

1-[1-(1,2,2A,3,4,5-hexahydronaphthalen-5-yl)piperidine-4-yl]-3-(2-oxo-2-pyrrolidin-1-retil)-1,3-dihydro-2H-benzimidazole-2-he

Example 100

2-{3-[1-(9-fluoro-2,3,3A,4,5,6-hexahydro-benzo[de]chromen-6-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 101

2-{3-[1-(1,2,3,7,8,9,10,10A-octahydrocyclopenta[de]naphthalene-6-yl)Pieper is DIN-3-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 102

2-{3-[1-(2,6,7,8,9,9a-hexahydrobenzo[cd]azulene-6-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Example 103

(R)-1-[1-(5-percentin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) To 4-fluoro-1-naphthyloxy acid (18 g) is added thionyl chloride (70 ml) and N,N-dimethylformamide (few drops) and the mixture refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in dichloromethane (1200 ml). When cooled in a bath with ice add the aluminum chloride 23,5 g) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The residue is purified column chromatography on silica gel and get a 5-percentin-1-he (9.4 g).

1H-NMR (DMSO-d6) δTMS: 3,79 (c, 2H), 7,24 (DD, 1H), 7,35-7,40 (m, 1H), to 7.77 (t, 1H), 7,78 (d, 1H), 8,24 (d, 1H).

(2) To a cooled (-30°C.) solution of (R)-2-methyl-CBS-oxazaborolidine (3.0 ml, 1M solution in toluene) is added a complex of borane·THF (14 ml, 1M solution in THF) and the mixture is stirred for 45 minutes added dropwise a solution of 5-percentin-1-she (2.5 g) in dichloromethane (30 ml), the mixture is again cooled down to minus 30°C and PE is amerivault at this temperature for 1 hour. Then, while cooling with ice, add methanol (8 ml) and 1N. the solution chloroethanol acid and the mixture extracted with chloroform. The extract is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated, obtaining (S)-5-fluoro-1-acenaphthene (2.55 g).

1H-NMR (CDCl3) δTMS: 2,07 (users, 1H), 3,20 (d, 1H), 3,76 (DD, 1H), 5,70-5,80 (m, 1H), 7,20-7,35 (m, 2H), 7,55-the 7.65 (m, 2H), of 7.90 (DD, 1H).

(3) To a solution of (S)-5-fluoro-1-acenaphthene (2.3 g, 12.2 mmol) and diphenylphosphinite (4.4 g, 16 mol) in toluene (25 ml) is added DBU (2,44 g) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with toluene. The organic layers are combined, washed 1H. solution chloroethanol acid, dried over magnesium sulfate and concentrated. Azide form crude product obtained after purification column chromatography on silica gel, dissolved in a mixed solvent (25 ml), THF/water (10/1). Add triphenylphosphine (2.7 g) and the mixture is stirred at room temperature for 18 hours. The solvent is evaporated, to the residue add 1H. the solution chloroethanol acid (200 ml) and waste matter is removed by extraction with ethyl acetate. The aqueous phase is alkalinized with potassium carbonate and extracted with chloroform. The extract is dried over sodium sulfate and concentrate to obtain the amine is howling form of a crude product. The crude amine (1.35 g) was dissolved in ethanol (15 ml). Add 1-ethyl-1-methyl-4-oxopiperidine iodide (2.35 g), dissolved in a mixture of potassium carbonate (180 mg) in water (5 ml)and the resulting mixture is refluxed for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and receive (R)-1-(5-percentin-1-yl)piperidine-4-one (630 mg).

1H-NMR (CDCl3) δTMS: 2,40-to 2.55 (m, 4H), 2,65 is 2.75 (m, 2H), 2,85-2,95 (m, 2H), of 3.25 to 3.45 (m, 2H), of 5.05-of 5.15 (m, 1H), 7,05-7,20 (m, 2H), 7,50-of 7.60 (m, 2H), a 7.85 (d, 1H).

(4) To a cooled (0°C.) solution of (R)-1-(5-percentin-1-yl)piperidine-4-it (630 mg) and 1,2-phenylenediamine (510 mg) in THF (100 ml) add triacetoxyborohydride sodium (1.35 g) and acetic acid (0.6 ml) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and neutralized mixture with potassium carbonate and then extracted with chloroform. The extract is washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and receive (R)-N-[1-(5-percentin-1-yl)piperidine-4-yl]benzene-1,2-diamine (1.08 g). Obtained dia the new form (1.08 g) was dissolved in THF (10 ml), add carbonyldiimidazole (600 mg) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol), and recrystallized from a mixed solvent of ethyl acetate/diisopropyl ether and receive specified in the title compound (1.1 g) as a solid white color.

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 2H), 2,35-2,60 (m, 4H), of 2,75 2,85 (m, 1H), 2.95 and-3,10 (m, 1H), 3,38 (d, 2H), 4,27-and 4.40 (m, 1H), 5,00-5,08 (m, 1H), 7,00-7,40 (m, 5H), 7,25-7,35 (m, 1H), 7,55-of 7.60 (m, 2H), 7,80-of 7.90 (m, 1H), 9,85 (users, 1H).

FAB-MS (M+H)+: 388.

Example 104

(R)-2-{3-[1-(5-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide·maleate

(R)-1-[1-(5-Percentin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (1.1 g) dissolved in THF (20 ml). Add sodium hydride (150 mg, 60%) and the suspension is stirred at 40°C for 20 min After cooling to room temperature, add ethylbromoacetate (550 mg) and the resulting mixture is stirred at 45°C for 30 minutes Then at room temperature is added methylamine (40%solution in methanol, 27 ml) and the mixture is stirred for 40 minutes On the Les confirm what ester form completely disappeared, the mixture was poured into water and extracted with chloroform. The extract is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated, to give crude product (1,36 g) (R)-2-{3-[1-(5-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide. The resulting crude product is treated with 1.1 equivalents of maleic acid and get listed in the title compound (950 mg).

1H-NMR (DMSO-d6) δTMS: 1,80-2,00 (m, 2H), 2,59 (c, 3H), 2,50-2,70 (m, 1H), 2,80-of 3.80 (m, 7H), 4,42 (c, 2H), 4,45-4,60 (m, 1H), 5,50-the ceiling of 5.60 (m, 1H), 6,07 (c, 2H), 7, 00-7,15 (m, 3H), 7,30-of 7.48 (m, 3H), 7,75-7,80 (m, 1H), 7,88 (users, 1H), to 7.99 (d, 1H), 8,05-of 8.15 (m, 1H).

FAB-MS (M+H)+: 459.

[α]D20=+26,4°.

Example 105

1-[1-(5-percentin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

5-Percentin-1-he (1.9 grams) is dissolved in methanol (40 ml), add sodium borohydride (470 mg) and the resulting mixture was stirred at room temperature for 40 minutes To the reaction mixture is added slowly an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 5-fluoro-1-acenaphthene (1.8 g). The resulting alcoholic form (1.56 g) was dissolved in chloroform (12 ml). When the cooling gap is the situation in a bath with ice, add thionyl chloride (2 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved in N,N-dimethylformamide (20 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (1.4 g), potassium carbonate (3.4 g) and sodium iodide (1.3 g) and the resulting mixture is stirred at a temperature of 145°C for 40 minutes to Give the mixture to cool and extracted the reaction mixture with ethyl acetate, the extract washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel, recrystallized from ethyl acetate and get listed in the title compound (690 mg).

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 2H), 2,35-2,60 (m, 4H), of 2,75 2,85 (m, 1H), 2.95 and-3,10 (m, 1H), 3,38 (d, 2H), 4,27-and 4.40 (m, 1H), 5,00-5,08 (m, 1H), 7,00-7,40 (m, 5H), 7,25-7,35 (m, 1H), 7,55-of 7.60 (m, 2H), 7,80-of 7.90 (m, 1H), 9,85 (users, 1H).

FAB-MS (M+H)+: 388.

Example 106

2-{3-[1-(5-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide·3/2 maleate

The crude product obtained as in example 104, using 1-[1-(5-percentin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (700 mg), treated with 1.5 equivalents of maleic acid and get listed in the title compound (420 mg).

1H-NMR (DMSO-d6) δTMS: 1,80-2,00 (m, 2H), 2,59 (c, 3H), 2,55 is 2.80 (m, 2H), 3.00 and-of 3.60 (m, 5H), 3,70-3,90 (m, 2H), 4,42 (c, 2H), 4,50 with 4.65 (m, 1H), ceiling of 5.60-of 5.68 (m, 1H), 6,12 (c, 3H), 7,00-to 7.15 (m, 3H), 7,0-to 7.35 (d, 1H), 7,37-of 7.48 (m, 1H), 7,78-a 7.85 (m, 1H), 7,83 (d, 1H), of 7.90 (d, 1H), 8,08-of 8.15 (m, 1H).

FAB-MS (M+H)+: 459.

Example 107

1-[1-(3-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) To the mixture (11 g), 2-chloro-1-naphthylacetic acid and 7-chloro-1-naphthylacetic acid added thionyl chloride (50 ml) and N,N-dimethylformamide (few drops)and the mixture is then refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in dichloromethane (500 ml). When cooled in a bath with ice added aluminium chloride (13 g) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The remainder is allocated, purified column chromatography on silica gel and receive a 3-chlorazepate-1-he (600 mg) and 8-chlorazepate-1-he (3.0 g).

3-chlorazepate-1-he:

1H-NMR (CDCl3) δTMS: 3,82 (c, 2H), 7,26 (d, 1H), 7,54 (t, 1H), of 7.70 (d, 1H), 7,98 (d, 1H), 8,07 (d, 1H).

8-chlorazepate-1-he:

1H-NMR (CDCl3) δTMS: 3,84 (c, 2H), 7,25 (d, 1H), 7,49 (d, 1H), 7,55-the 7.65 (m, 2H), 7,80 (d, 1H), 8,08 (d, 1H).

(2) 3-Chlorazepate-1-he (1.0 g) is dissolved in methanol (25 ml), add sodium borohydride (220 mg) and the mixture is stirred at room temperature for 1 hour. the reaction mixture is added slowly an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 3-chloro-1-acenaphthene (1.0 g). Spirit form (1.0 g) dissolved in chloroform (15 ml). When cooled in a bath with ice, add thionyl chloride (2 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved in N,N-dimethylformamide (12 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (900 mg), potassium carbonate (2.2 g) and sodium iodide (800 mg) and the resulting mixture is stirred at a temperature of 145°C for 1 hour. Allow the mixture to cool, and extracted the reaction mixture with ethyl acetate, the extract washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel and recrystallized from ethyl acetate, getting mentioned in the title compound (1.0 g).

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 2H), 2,35-to 2.65 (m, 4H), 2.70 height is 2.80 (m, 1H), 3.00 and-3,10 (m, 1H), 3,35 is-3.45 (m, 2H), 4,30-and 4.40 (m, 1H), 4,90-5,00 (m, 1H), 7,00-to 7.15 (m, 3H), 7,25-7,35 (m, 1H), 7,49 (d, 1H), 7,50-of 7.60 (m, 3H), 7,70 (d, 1H), 9,60 (users, 1H).

FAB-MS (M+H)+: 404.

Example 108

2-{3-[1-(3-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide·1/2 fumarate

The crude product obtained as in example 104, using the-W 1-[1-(3-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (1.3 g), treated with 1.0 equivalent of fumaric acid and get listed in the title compound (277 mg).

1H-NMR (DMSO-d6) δTMS: 1,60-1,80 (m, 2H), 2,25-2,60 (m, 5H), 2,60 (c, 3H), 2,90 was 3.05 (m, 1H), 3,15-3,55 (m, 3H), 4,25-and 4.40 (m, 1H), to 4.41 (c, 2H), 5,00-5,10 (m, 1H), 6,62 (c, 1H), 7,00-to 7.15 (m, 2H), 7,30 (d, 1H), of 7.48 (d, 1H), 7,55-the 7.65 (m, 2H), 7,74 (d, 1H), 7,75-a 7.85 (m, 1H), 8,05-of 8.15 (m, 1H).

FAB-MS (M+H)+: 475.

Example 109

1-[1-(5-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) Acenaphthen-1-he (11 g) was dissolved in N,N-dimethylformamide (80 ml), add N-chlorosuccinimide (9.0 g) and the mixture is stirred at room temperature for 2 days. The reaction mixture was extracted with ethyl acetate and the extract washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel and recrystallized from ethanol, to give crude crystals (3.5 g) 5-chlorazepate-1-it.

(2) 5-Chlorazepate-1-he (1.9 grams) is dissolved in methanol (35 ml), add sodium borohydride (430 mg) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added slowly an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the floor is th 5-chloro-1-acenaphthene (1.9 grams).

1H-NMR (CDCl3) δTMS: 1,80-2,30 (users, 1H), 3,20 (d, 1H), of 3.77 (DD, 1H), 5,70-of 5.75 (m, 1H), 7,21 (d, 1H), 7,52 (d, 1H), 7,55-of 7.60 (m, 1H), 7,66 (DD, 1H), to 7.99 (d, 1H).

(3) Alcohol form (1.9 grams) dissolved in chloroform (20 ml). When cooled in a bath with ice, add thionyl chloride (3 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved in N,N-dimethylformamide (20 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (1.7 g), potassium carbonate (4,14 g) and sodium iodide (1.5 g) and the resulting mixture is stirred at a temperature of 140°C for 1 hour. Allow the mixture to cool and extracted the reaction mixture with ethyl acetate, the extract washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel, getting mentioned in the title compound (1.1 g).

1H-NMR (DMSO6) δTMS: 1,50-1,70 (m, 2H), 2,25-2,60 (m, 5H), 2,90-3,00 (m, 1H), 3,30 is 3.40 (m, 2H), 4,05-4,20 (m, 1H), 4.95 points-of 5.00 (m, 1H), 6.90 to-7,00 (m, 3H), of 7.23 (d, 1H), 7,33 (d, 1H), 7.62mm (m, 2H), 7,73 (DD, 1H), 7,86 (d, 1H), 10,82 (users, 1H).

FAB-MS (M+H)+: 404.

Example 110

2-{3-[1-(5-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(5-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazo the l-2-she (1.3 g), washed by suspension in acetone and receive specified in the title compound (237 mg).

1H-NMR (DMSO-d6) δTMS: 1,60-1,75 m, 2H), 2,25-to 2.65 (m, 5H), 2,59 (c, 3H), 2,90-3,00 (m, 1H), 3,30 is 3.40 (m, 2H), 4,10-4,20 (m, 1H), to 4.41 (c, 2H), 4.95 points-of 5.05 (m, 1H), 7,00-7,10 (m, 3H), 7,25-7,35 (m, 2H), 7,55-the 7.65 (m, 2H), 7,70-7,80 (DD, 1H), 7,80-of 7.90 (d, 1H), 8,05-8,15 (users, 1H).

FAB-MS (M+H)+: 475.

Example 111

1-[1-(8-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he·hydrochloride

(1) 8-Chlorazepate-1-he (2.0 g, 9,87 mmol) dissolved in methanol (40 ml), add sodium borohydride (400 mg) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added slowly an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 8-chloro-1-acenaphthene (2.0 g).

1H-NMR (CDCl3) δTMS: 1,50-1,60 (users, 1H), 3,30 (d, 1H), 3,79 (DD, 1H), 5,70-5,80 (m, 1H), 7,34 (d, 1H), 7,42 (d, 1H), of 7.48 (DD, 1H), 7,63 (d, 1H), 7,69 (d, 1H).

(2) Alcohol form (2.0 g) dissolved in chloroform (18 ml). When cooled in a bath with ice, add thionyl chloride (2 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved in N,N-dimethylformamide (20 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (1.7 g), potassium carbonate (4.4 g) and sodium iodide (1.5 g) and the resulting mixture is stirred at a temperature of 140°C for 1 hour. Allow the mixture to cool and extracted the reaction mixture with ethyl acetate, the extract washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel, obtaining crude crystals (2.1 g) (RS)-1-[1-(8-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it. The crude crystals treated with 4n. solution chloroethanol acid in ethyl acetate and recrystallized from acetone, getting mentioned in the title compound (305 mg).

1H-NMR (DMSO-d6) δTMS: of 1.65 and 1.75 (m, 1H), 1,90-2,00 (m, 1H), 2,60-of 2.75 (m, 1H), 2,80 is 3.15 (m, 3H), 3,60 of 3.75 (m, 1H), 3,80-3,90 (m, 2H), 4,05-4,20 (m, 1H), 3,50-the 3.65 (m, 1H), 5,55-5,70 (m, 1H), 6.90 to-7,00 (m, 3H), 7,50-of 7.60 (m, 1H), 7,60 to 7.75 (m, 3H), to 7.84 (d, 1H), with 8.05 (d, 1H), 10,92 (users, 1H), 11,67 (users, 1H).

FAB-MS (M+H)+: 404.

Example 112

2-{3-[1-(8-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide·oxalate

The crude product obtained as in example 104, using 1-[1-(8-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (1.2 g), treated with 1.1 equivalents of oxalic acid and get listed in the title compound (473 mg).

1H-NMR (DMSO-d6) δTMS: 1,55-1,65 (m, 1H), 1,70-1,80 (m, 1H), 2,60 (c, 3H), 2,25-2,70 (m, 5H), 3,05 is 3.15 (m, 1H), 3,35 is-3.45 (m, 1H), 3,55-the 3.65 (m, 1H), 4,20-4,30 (m, 1H), 4,40 (c, 2H), 5,15-5,25 (m, 1H), 7,00-7,10 (m, H), 7,26 (d, 1H), 7,43 (d, 1H), 7,50-of 7.60 (m, 2H), 7,73 (d, 1H), a 7.85 (d, 1H), 8,10 (users, 1H).

FAB-MS (M+H)+: 475.

Example 113

1-[1-(5-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) Acenaphthen-1-he (25 g) dissolved in N,N-dimethylformamide (200 ml), add N-bromosuccinimide (27 g) and the mixture is stirred at room temperature for 2 days. The precipitated crystals are filtered, recrystallized from ethanol and receive 5-bromazepam-1-he (16 g).

1H-NMR (CDCl3) δTMS: 3,79 (c, 2H), 7,33 (d, 1H), 7,80-of 7.90 (m, 2H), 8,01 (d, 1H), 8,28 (d, 1H).

(2) 5-Bromazepam-1-he (5,3 g) dissolved in methanol (80 ml), add sodium borohydride (1.0 g) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added slowly an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 5-bromo-1-acenaphthene (4.4 g).

1H-NMR (CDCl3) δTMS: 1,60-1,80 (users, 1H), 3,19 (d, 1H), 3,76 (DD, 1H), 5,74 (d, 1H), 7,17 (d, 1H), 7,60 (d, 1H), to 7.67 (DD, 1H), 7,72 (d, 1H), 7,94 (d, 1H).

(3) Alcohol form (4.4 g) was dissolved in chloroform (40 ml). When cooled in a bath with ice, add thionyl chloride (5 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved is in N,N-dimethylformamide (40 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (3.2 g), potassium carbonate (7.0 g) and sodium iodide (2.65 g) and the resulting mixture is stirred at a temperature of 140°C for 1 hour. Allow the mixture to cool and extracted the reaction mixture with ethyl acetate, the extract washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel, obtaining crude crystals (8.0 g). The crude crystals (300 mg) is washed by suspension in acetone and receive specified in the title compound (121 mg).

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 2H), 2,35-2,60 (m, 4H), 2.70 height is 2.80 (m, 1H), 3.00 and-3,10 (m, 1H), 3,35 is 3.40 (m, 2H), 4,25-and 4.40 (m, 1H), 4.95 points-of 5.05 (m, 1H), 7,00-7,10 (m, 3H), 7,17 (d, 1H), 7,25-7,35 (m, 1H), to 7.59 (d, 1H), 7,60-7,70 (m, 2H), 7,89 (d, 1H), 8,78 (users, 1H).

FAB-MS (M+H)+: 450.

Example 114

2-{3-[1-(5-bromazepam-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(5-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (1.2 g), washed by suspension in acetone and receive specified in the title compound (597 mg).

1H-NMR (DMSO-d6) δTMS: 1,50-1,75 (m, 2H), 2,20-2,60 (m, 5H), 2,59 (c, 3H), 2,90-3,00 (m, 1H), 3,30 is-3.45 (m, 1H), 4,00-and 4.40 (m, 2H), 4,42 (c, 2H), 4.95 points-of 5.05 (m, 1H), 6,85-7,10 (m, 3H), 7,25-7,35 (m, 2H), 7,63 (d, 1H), 7,70-a 7.85 (m, 3H), 8,19 (m, H).

FAB-MS (M+H)+: 521.

Example 115

1-[1-(3-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) To a mixture of (43 g), 2-bromo-1-naphthylacetic acid and 7-bromo-1-naphthylacetic acid added thionyl chloride (100 ml) and N,N-dimethylformamide (few drops)and the mixture is then refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in dichloromethane (1000 ml). When cooled in a bath with ice added aluminium chloride (43 g) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The residue is isolated and purified column chromatography on silica gel, and get 3-bromazepam-1-he (1.5 g) and 8-bromazepam-1-he (6.8 g).

3-bromazepam-1-he:

1H-NMR (CDCl3) δTMS: of 3.77 (c, 2H), 7,66 (d, 1H), 7,70 to 7.75 (m, 2H), of 7.97 (d, 1H), of 8.06 (d, 1H).

8-bromazepam-1-he:

1H-NMR (CDCl3) δTMS: 3,85 (c, 2H), 7,49 (d, 1H), to 7.61 (DD, 1H), 7,74-7,80 (m, 2H), 7,89 (d, 1H).

(2) 3-Bromazepam-1-he (1.5 g, 6,07 mmol) dissolved in methanol (30 ml), add sodium borohydride (280 mg) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added slowly an aqueous solution of lorida ammonium and extracted with a mixture of ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 3-bromo-1-acenaphthene (1.6 g). Spirit form (1.6 g) dissolved in chloroform (18 ml). When cooled in a bath with ice, add thionyl chloride (2 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved in N,N-dimethylformamide (13 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (1.5 g, of 5.26 mmol), potassium carbonate (2.7 g) and sodium iodide (970 mg) and the resulting mixture is stirred at a temperature of 140°C for 1 hour. Allow the mixture to cool and extracted the reaction mixture with ethyl acetate, the extract washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel and recrystallized from acetone, getting mentioned in the title compound (1.8 g).

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 2H), 2,40-2,60 (m, 4H), 2.70 height is 2.80 (m, 1H), 3.00 and-3,10 (m, 1H), 3,35 is-3.45 (m, 2H), 4,30-and 4.40 (m, 1H), 4,90-5,00 (m, 1H), 7,00-to 7.15 (m, 3H), 7,25-7,35 (m, 1H), 7,50-of 7.60 (m, 4H), 7,60-of 7.70 (m, 1H), 9,85 (users, 1H).

FAB-MS (M+H)+: 450.

Example 116

2-{3-[1-(3-bromazepam-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(3-b is masenate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (700 mg), recrystallized from acetone and receive specified in the title compound (125 mg).

1H-NMR (CDCl3) δTMS: 1,60-1,75 m, 2H), 2,25-to 2.65 (m, 7H), 2,59 (c, 3H), 2,90-3,00 (m, 1H), 3,30 is 3.40 (m, 1H), 4,15-of 4.25 (m, 1H), to 4.41 (c, 2H), 5,01 (users, 1H), 6,95-7,10 (m, 3H), 7,31 (d, 1H), 7,55-of 7.70 (m, 3H), 7,79 (d, 1H), 8,05-8,15 (m, 1H).

FAB-MS (M+H)+: 521.

Example 117

1-[1-(8-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) 8-Bromazepam-1-he (2.4 g) is dissolved in methanol (45 ml), add sodium borohydride (450 mg) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added slowly an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under eigendom pressure receiving 8-bromo-1-acenaphthene (2.2 g) as a crude product.

(2) the Crude product is alcohol form (2.2 g) dissolved in chloroform (18 ml). When cooled in a bath with ice, add thionyl chloride (2.5 ml) and the mixture refluxed for 1 hour. The solvent is evaporated and the resulting residue is dissolved in N,N-dimethylformamide (18 ml). Add 4-(2-keto-1-benzimidazolinyl)piperidine (2.0 g), potassium carbonate (3.7 g) and sodium iodide (1.35 g) and the resulting mixture is stirred at a temperature of 140°C for 1 hour. Allow the mixture to cool and extracted the reaction with the ect with ethyl acetate, the extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel and recrystallized from ethyl acetate, getting mentioned in the title compound (1.1 g).

1H-NMR (CDCl3) δTMS: 1,60-1,70 (m, 1H), 1,80-1,90 (m, 1H), 2,25-2,50 (m, 3H), 2,50-2,70 (m, 2H), 3,15-3,30 (m, 2H), 3,45-3,55 (m, 1H), 4,30-and 4.40 (m, 1H), 4,90-5,00 (m, 1H), 7,00-to 7.15 (m, 3H), 7,25-7,40 (m, 2H), of 7.48 (DD, 1H), 7,50-the 7.65 (m, 3H), 9,48 (users, 1H).

FAB-MS (M+H)+: 450.

Example 118

2-{3-[1-(8-bromazepam-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(8-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (500 mg)is recrystallized from ethyl acetate and get listed in the title compound (285 mg).

1H-NMR (CDCl3) δTMS: 1,60-1,70 (m, 1H), 1,80-1,90 (m, 1H), 2,20-of 2.30 (m, 1H), 2,30-to 2.40 (m, 2H), 2,50-2,75 (m, 2H), 2,78 (d, 3H), 3,15-3,30 (m, 2H), 3,45-3,55 (m, 1H), 4,30-and 4.40 (m, 1H), 4,49 (c, 2H), 4.95 points-of 5.00 (m, 1H), 6,15 (users, 1H), 7,00-7,10 (m, 1H), 7,10-7,20 (m, 2H), 7,30-7,40 (m, 2H), of 7.48 (DD, 1H), 7,75-the 7.65 (m, 3H).

FAB-MS (M+H)+: 521.

Example 119

1-[1-(3-cyanoacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

1-[1-(3-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (1,25 g) dissolved in N,N-dimethylformamide (16 ml), add cyanide zinc is (380 mg) and tetranitropentaerithrite (1.6 g) and the resulting mixture was stirred at 110°C for 1 hour. Allow the mixture to cool, to the reaction mixture poured water and ethyl acetate and the mixture filtered through celite. The filtrate is extracted with ethyl acetate, wash the extract with saturated salt solution and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified column chromatography on silica gel and recrystallized from acetone, getting mentioned in the title compound (1.0 g).

1H-NMR (CDCl3) δTMS: 1,60-1,80 (m, 2H), 2.40 a-to 2.65 (m, 4H), 2.70 height is 2.80 (m, 1H), 3.00 and-3,10 (m, 1H), 3,55-the 3.65 (m, 2H), 4,25-and 4.40 (m, 1H), 5,00-5,10 (m, 1H), 7,00-to 7.15 (m, 3H), 7,20-7,30 (m, 1H), 7,35 is 7.50 (m, 1H), EUR 7.57 (d, 1H), 7,60-7,80 (m, 3H), of 9.55 (users, 1H).

FAB-MS (M+H)+: 395.

Example 120

2-{3-[1-(3-cyanoacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(3-cyanoacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (800 mg)is recrystallized from a solvent mixture of acetone/ethyl acetate and get listed in the title compound (450 mg).

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 3H), 2.40 a-to 2.65 (m, 3H), 2.70 height is 2.80 (m, 1H), 2,78 (d, 3H), 3,00-3,20 (m, 1H), 3,55-of 3.60 (m, 2H), 4,25-and 4.40 (m, 1H), 4,49 (c, 2H), 5,03-of 5.06 (m, 1H), 6,18 (users, 1H), 7,00-7,20 (m, 3H), 7,33 (d, 1H), EUR 7.57 (d, 1H), 7,65-7,80 (m, 4H).

FAB-MS (M+H)+: 466.

Example 121

1-[1-(5-cyanoacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

The crude product, which received the same as in example 119, using 1-[1-(5-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (2.5 g), recrystallized from acetone and receive specified in the title compound (850 mg).

1H-NMR (DMSO6) δTMS: 1,55-1,70 (m, 2H), 2,25-2,60 (m, 5H), 2,90-3,00 (m, 1H), 3.45 points-to 3.50 (m, 2H), 4,10-4,20 (m, 1H), 5,00-5,10 (m, 1H), 6.90 to-7,00 (m, 3H), 7,22 (d, 1H), 7,51 (d, 1H),7,72 (d, 1H), 7,80-of 7.90 (m, 2H), 8,11 (d, 1H), 10,83 (users, 1H).

FAB-MS (M+H)+: 395.

Example 122

2-{3-[1-(5-cyanoacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide·oxalate

The crude product obtained as in example 104, using 1-[1-(5-cyanoacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (550 mg), treated with 1.1 equivalents of oxalic acid and get listed in the title compound (481 mg).

1H-NMR (DMSO6) δTMS: 1,70-of 1.85 (m, 2H), 2,45-2,70 (m, 2H), 2,60 (c, 3H), was 2.76-2.95 and (m, 3H), 3,20-3,30 (m, 1H), 3,60-of 3.80 (m, 2H), 4,35-4,50 (m, 1H), to 4.41 (c, 2H), and 5.30-of 5.40 (m, 1H), 7,00-7,10 (m, 3H), 7,30-7,40 (m, 1H), 7,58 (d, 1H), a 7.85-of 8.00 (m, 3H), 8,05-of 8.15 (m, 1H), 8,17 (d, 1H).

FAB-MS (M+H)+: 466.

Example 123

1-[1-(8-cyanoacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

The crude product obtained as in example 119, using 1-[1-(8-bromazepam-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (1.0 g), recrystallized from a solvent mixture of acetone/ethyl acetate and get specified the OE in the title compound (1.4 g).

1H-NMR (CDCl3) δTMS: of 1.65 and 1.75 (m, 1H), 1.85 to 1,95 (m, 1H), 2,30-2,60 (m, 3H), 2,65 is 2.80 (m, 2H), 3.25 to 3.40 in (m, 2H), 3,50-3,60 (m, 1H), 4,40-4,55 (m, 1H), 5,10-5,20 (m, 1H), 7,00-to 7.15 (m, 3H), 7,40-to 7.50 (m, 2H), 7,60-of 7.70 (m, 3H), of 7.75 (d, 1H), 9,63 (users, 1H).

FAB-MS (M+H)+: 395.

Example 124

2-{3-[1-(8-cyanoacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(8-cyanoacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (1.3 g), double-purified column chromatography on silica gel and get listed in the title compound (122 mg).

1H-NMR (CDCl3) δTMS: 1,70-of 1.95 (m, 2H), 2,30-2,60 (m, 3H), 2,60 is 2.80 (m, 2H), 2,78 (d, 2H), of 3.25 to 3.35 (m, 2H), 3,50-3,60 (m, 1H), 4,40-of 4.45 (m, 1H), 4,50 (c, 2H), 5,10-5,20 (m, 1H), 6,20 (users, 1H),? 7.04 baby mortality (d, 2H), 7,11 (DD, 1H), 7,17 (DD, 1H), 7,40-to 7.50 (m, 1H), 7,51 (d, 1H), 7,60-of 7.70 (m, 3H), 7,68 (d, 1H).

FAB-MS (M+H)+: 466.

Example 125

1-[1-(5-methoxyisatin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

(1) 5-Bromo-1-acenaphthene (6.4 g) and tert-butyldimethylsilyl (4.6 g) was dissolved in N,N-dimethylformamide (20 ml), under stirring at room temperature add imidazole (4.1 g) and the resulting mixture is stirred at 40°C for 30 minutes after the reaction mixture is extracted with ethyl acetate, wash the extract with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated p. and reduced pressure and the residue purified column chromatography on silica gel, receiving 5-bromo-1-(tert-butoxydiglycol)acenaphthene (8,3 g).

1H-NMR (CDCl3) δTMS: 0,10 (c, 6H), 0,86 (c, 9H), was 3.05 (DD, 1H), of 3.56 (DD, 1H), ceiling of 5.60-5,70 (m, 1H), 6,99 (d, 1H), 7,35 (d, 1H), 7,45-of 7.60 (m, 2H), to 7.77 (d, 1H).

(2) 5-Bromo-1-(tert-butoxydiglycol)acenaphthene (3.0 g) dissolved in tetrahydrofuran (40 ml)dropwise in a stream of nitrogen and while cooling the mixture to minus 78°C. add a solution of n-utility in hexane (1.6 mol/l, 5.5 ml). Stirred at minus 78°C for 1 hour, added dropwise a solution of N,N-dimethylformamide (640 mg) in tetrahydrofuran and stirred the mixture for 15 minutes At the end of the reaction type 1H. the solution chloroethanol acid and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and obtained as a crude product (RS)-5-formyl-1-(tert-butoxydiglycol)acenaphthen. The crude product formyl form dissolved in dichloromethane (60 ml), while cooling in a bath with ice add m-chlormadinone acid (65%, 3.8 g) and the mixture is stirred at room temperature for 15 hours. Upon termination of the reaction mixture is extracted with chloroform, wash the extract with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified by lodochnoy chromatography on silica gel, receiving 5-hydroxy-1-(tert-butoxydiglycol)acenaphthene (2.1 g).

1H-NMR (CDCl3) δTMS: 0,10 (c, 6H), 0,86 (c, 9H), to 3.09 (DD, 1H), 3,60 (DD, 1H), 5,65-5,70 (m, 1H), 7,10-to 7.15 (m, 2H), was 7.36 (d, 1H), 7,47 (DD, 1H), 7,56 (d, 1H), at 8.36 (c, 1H).

(3) To a solution of 5-hydroxy-1-(tert-butoxydiglycol)acenaphthene (8.5 g) in N,N-dimethylformamide (70 ml) is added potassium carbonate (6.0 g)to the mixture dropwise with stirring at room temperature add methyliodide (5.0 g), and then the mixture is stirred for 9 hours. Upon termination of the reaction mixture is extracted with ethyl acetate, wash the extract with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified column chromatography on silica gel, receiving (RS)-5-methoxy-1-(tert-butoxydiglycol)acenaphthene (7.7 g).

1H-NMR (CDCl3) δTMS: 0,10 (c, 6H), 0,86 (c, 9H), 3.04 from (DD, 1H), 3,55 (DD, 1H), 3,86 (c, 3H), 5,65-5,70 (m, 1H), 6,66 (d, 1H), 7,02 (d, 1H), 7,32 (d, 1H), 7,40 (DD, 1H), 7,82 (d, 1H).

(4) 5-Methoxy-1-(tert-butoxydiglycol)acenaphthene (7,7 g) dissolved in tetrahydrofuran (100 ml)while cooling in a bath with ice added dropwise a solution (120 ml) tetrabutylammonium (1.0 mol) in tetrahydrofuran and the mixture is stirred at room temperature for 1 hour. Upon completion of the reaction, add saturated aqueous solution of ammonium chloride and extracted with a mixture ethylacetate is. The extract is washed with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified column chromatography on silica gel, receiving 5-methoxy-1-acenaphthene (4.0 g). The crude product obtained as in example 103(3), using the obtained alcohol forms (4.0 g), recrystallized from acetone and receive specified in the title compound (1.6 g).

1H-NMR (CDCl3) δTMS: 1,70-1,90 (m, 2H), 2,35-to 2.65 (m, 4H), of 2,75 2,85 (m, 1H), 2.95 and was 3.05 (m, 1H), 3,30 is 3.40 (m, 2H), 3,98 (c, 3H), 4,25-and 4.40 (m, 1H), 4,90-5,00 (m, 1H), 6,78 (d, 1H), 7,00-to 7.15 (m, 3H), 7,15-7,20 (d, 1H), 7,25-7,35 (m, 1H), 7,50-of 7.60 (m, 2H), 7,94 (d, 1H), becomes 9.97 (users, 1H).

FAB-MS (M+H)+: 400.

Example 126

2-{3-[1-(5-methoxyisatin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

The crude product obtained as in example 104, using 1-[1-(5-methoxyisatin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-she (400 mg)is recrystallized from ethyl acetate and get listed in the title compound (450 mg).

1H-NMR (CDCl3) δTMS: 1,70-of 1.85 (m, 3H), 2,35-2,60 (m, 4H), 2,78 (d, 3H), 3.00 and was 3.05 (m, 1H), 3,30 is 3.40 (m, 2H), 3,99 (c, 3H),4,25-and 4.40 (m, 1H), 4,49 (c, 2H), 4.95 points-of 5.00 (m, 1H), 6,14 (users, 1H), 6,79 (d, 1H), 7,00-7,20 (m, 4H), 7,30-7,40 (m, 1H), 7,45-of 7.60 (m, 2H), of 7.90-of 8.00 (m, 1H).

FAB-MS (M+H)+: 471.

Example 127

1-[1-(5-hydroxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

is shown in the header of the connection get method shown in example 128, using 1-[1-(5-methoxyisatin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 128

2-{3-[1-(5-hydroxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

2-{3-[1-(5-Methoxyisatin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide (780 mg) was dissolved in dichloromethane (50 ml)in a stream of nitrogen while cooling to minus 50°C is added dropwise a solution (8.0 ml) tribromide boron (1,0 mol) in dichloromethane and the mixture is slowly allowed to warm for 1 hour. Upon completion of the reaction, the reaction mixture in small portions poured into aqueous potassium carbonate solution, unnecessary substances dissolved in acetone, the mixture is then extracted with chloroform and the extract is dried over sodium sulfate. The solvent is evaporated under reduced pressure, the residue is purified column chromatography on laminirovannom silica gel and get the crude product is specified in the connection header.

1H-NMR (DMSO-d6) δTMS: 1.55V and 1.80 (m, 2H), 2,45-2,60 (m, 5H), 2,60 (c, 3H), 2,90-3,00 (m, 1H), 3,15-to 3.35 (m, 3H), 4,10-of 4.25 (m, 1H), to 4.41 (c, 2H), 4,90-5,00 (m, 1H), PC 6.82 (d, 1H), 7,00-to 7.15 (m, 3H), 7,30 (d, 1H), 7,40-to 7.50 (m, 2H), 7,75-a 7.85 (m, 1H), 8,08-of 8.15 (m, 1H), 9,78 (users, 1H).

FAB-MS (M+H)+: 457.

Example 129

1-[1-(3-methoxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Specified in the header connection receive met the dick, example 125 using 3-bromo-1-acenaphthene.

Example 130

2-{3-[1-(3-methoxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Specified in the header connection receive according to the method described in example 104, using 1-[1-(3-methoxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 131

1-[1-(3-hydroxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Specified in the header connection receive according to the method described in example 128, using 1-[1-(3-methoxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 132

2-{3-[1-(3-hydroxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Specified in the header connection receive according to the method described in example 104, using 1-[1-(3-hydroxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 133

1-[1-(8-methoxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Well-known compound, 8-hydroxyacetate-1-he (7.0 g) (J. Chem. Soc., 1954, p.4299), dissolved in N,N-dimethylformamide (70 ml), add potassium carbonate (7.9 g) and methyliodide (6.8 g) and the mixture is stirred at room temperature for 5 hours. Upon termination of the reaction mixture is extracted with ethyl acetate, the extract washed with saturated R is the target salt and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified column chromatography on silica gel, receiving 8-methoxyacetate-1-he (5.7 g). Received methoxy form dissolved in methanol (25 ml), add sodium borohydride (220 mg) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added slowly an aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 8-methoxy-1-acenaphthene (5.6 g). Specified in the title compound (2.28 g) are obtained according to the method described in example 125 using the resulting alcoholic form.

1H-NMR (CDCl3) δTMS: 1,65-of 1.95 (m, 2H), 2,10-of 2.20 (m, 1H), 2,30-of 2.50 (m, 2H), 2,65-2,90 (m, 3H), 3,30 is 3.40 (m, 1H), 3.45 points-of 3.60 (m, 1H), 4,07 (c, 3H), 4,20-and 4.40 (m, 1H), 5,00-5,10 (m, 1H), 7,00-to 7.15 (m, 3H), 7,20-7,35 (m, 4H), 7,56 (d, 1H), 7,71 (d, 1H), 9,80-10,10 (users, 1H).

FAB-MS (M+H)+: 400.

Example 134

2-{3-[1-(8-methoxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Specified in the title compound (1.4 g) are obtained according to the method described in example 104, using 1-[1-(8-methoxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he (1,58 g).

1H-NMR (CDCl3) δTMS: 1,65-of 1.85 (m, 2H), 2,10-of 2.20 (m, 1H), 2,35-of 2.50 (m, 2H), 2,78 (d, 3H), 2,65-2,95 (m, 3H), 3,30-3,40 (who, 1H), 3,45-3,55 (m, 1H), 4,07 (c, 3H), 4,20 is 4.35 (m, 1H), 4,48 (c, 2H), 5,00-of 5.05 (m, 1H), 6,14 (users, 1H), 7,00-to 7.15 (m, 3H), 7,20-7,40 (m, 4H), EUR 7.57 (d, 1H), 7,72 (d, 1H).

FAB-MS (M+H)+: 471.

Example 135

1-[1-(8-hydroxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Specified in the header connection receive according to the method described in example 128, using 1-[1-(8-methoxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 136

2-{3-[1-(8-hydroxyacetate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Specified in the header connection receive according to the method described in example 104, using 1-[1-(8-hydroxyacetate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 137

(R)-1-[1-(6-percentin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

To a suspension of 60%sodium hydride (5,00 g) in toluene (250 ml) under cooling in a bath with ice added dropwise ethyl diethylphosphonoacetate (23.9 ml) and the mixture is stirred at room temperature for 1 hour. Then added dropwise a solution of 5-fluoro-3,4-dihydro-2H-naphthalene-1-it (18.0 g) in toluene (50 ml) and the mixture is stirred at a temperature of 80°C for 3 hours. After cooling to room temperature the reaction mixture was poured into ice water and extracted with a mixture of toluene. The extract is washed with water and saturated salt solution, drying is over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and obtain ethyl (5-fluoro-3,4-dihydronaphthalene-1-yl)acetate (17,4 g).

To a solution of ethyl (5-fluoro-3,4-dihydronaphthalene-1-yl)acetate (16.4 g) in benzene (500 ml) was added DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) (21,5 g) and the mixture when heated, stirred for 3 hours. After cooling, the precipitated precipitated solid is dissolved 1H. the sodium hydroxide solution and extracted with a mixture of toluene. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography on silica gel (hexane/ethyl acetate) and obtain ethyl (5-fornatale-1-yl)acetate (5,66 g).

To a solution of ethyl (5-fornatale-1-yl)acetate (5,96 g) in ethanol (50 ml) is added 1N. the sodium hydroxide solution (50 ml) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was poured into water and the mixture is washed with ethyl acetate. The aqueous layer was acidified with 1N. solution chloroethanol acid and extracted with chloroform, washing the extract with water and saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, obtaining (5-fornatale-1-yl)acetic acid (4,34 g). Specified in the header Conn is get out the method shown in example 103, using (5-fornatale-1-yl)acetic acid.

1H-NMR (DMSO-d6) δTMS: 1,56 by 1.68 (m, 2H), 2,27 at 2.59 (m, 5H), 2.95 and (d, 1H), 3,39 is-3.45 (m, 2H), 4,11-4,13 (m, 1H), 4,91-4,94 (m, 1H), 6,92-7,00 (m, 4H), 7,22-of 7.48 (m, 4H), to 7.59 (t, 1H), 7,72 (d, 1H).

FAB-MS (M+H)+: 388.

Example 138

(R)-2-{3-[1-(6-percentin-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Specified in the header connection receive according to the method described in example 104, using (R)-1-[1-(6-percentin-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

1H-NMR (DMSO-d6) δTMS: 1,62-1,72 (m, 2H), 2,29-2,62 (m, 9H), 2.95 and (d, 2H), 3,30 is 3.40 (m, 1H), 3,40-3,55 (m, 2H), 4,10-4,30 (m, 1H), to 4.41 (c, 2H), 4.92 in-of 4.95 (m, 1H), 7,01-7,06 (m, 4H), 7,29-of 7.48 (m, 4H), to 7.61-7,56 (m, 1H), 7,72 (d, 1H), 8.07-a 8,08 (m, 1H).

FAB-MS (M+H)+: 458.

[α]D20=+32,2°.

Example 139

(R)-1-[1-(6-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-he

Specified in the header connection receive according to the method described in example 103, using 6-chloro-1-acenaphthene.

Example 140

(R)-2-{3-[1-(6-chlorazepate-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide

Specified in the header connection receive according to the method described in example 104, using (R)-1-[1-(6-chlorazepate-1-yl)piperidine-4-yl]-1,3-dihydro-2H-benzimidazole-2-it.

Example 141

(R)-1-[1-acenaphthen-1-yl)piperidine-4-and the]-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he

(1) (R)-1-(1-Acenaphthen-1-yl)piperidine-4-one (2.5 g) dissolved in ethanol (20 ml) and added 2,3-diaminopyridine (1.1 g). The solution is cooled in a bath with ice and add tetraisopropyl orthotitanate (3.5 g). The mixture is stirred at room temperature for 3 hours, cool the reaction mixture in a bath with ice and add sodium borohydride (0.6 g). The mixture is stirred at room temperature for 3 hours, then the reaction mixture was poured into ice water, and the insoluble matter is separated by filtration. The filtrate is extracted with chloroform and washed extract with a saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and receive (R)-N3-[1-(1-acenaphthen-1-yl)piperidine-4-yl]pyridine-2,3-diamine (1.4 g) in powder form red-yellow color.

1H-NMR (CDCl3) δTMS: 1,45-of 1.56 (m, 2H), 1,94 is 2.01 (m, 2H), and 2.26 (m, 1H), 2.49 USD (m, 1H), 2,66 (m, 1H), 2,85 (m, 1H), 3,07-3,20 (m, 2H), 3,39 (m, 2H), 4.26 deaths (users, 1H), 4,91 (t, J=5 Hz, 1H), 6,63 (DD, J=5 Hz and 7.6 Hz, 1H), 6,74 (d, J=7,6 Hz, 1H), 7,27 (d, J=6,9 Hz, 1H), 7,43-7,52 (m, 3H), 7,56 (d, J=5 Hz, 1H), to 7.61 (d, J=8,2 Hz, 1H), 7,68 (d, J=7.7 Hz, 1H).

(2) (R)-N3-[1-(1-Acenaphthen-1-yl)piperidine-4-yl]-pyridine-2,3-diamine (1.4 g) dissolved in tetrahydrofuran (10 ml), add 1,1'-carbonyldiimidazole (0.8 g) and the mixture is stirred at room temperature for 5 hours. The reaction mixture was howling is up in water and extracted with a mixture of ethyl acetate. The extract was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (1.3 g) as a solid yellow color.

1H-NMR (CDCl3) δTMS: 1,78-of 1.85 (m, 2H), 2.26 and is 2.46 (m, 3H), 2,54-2,60 (m, 1H), 2,81 (m, 1H), to 3.02 (m, 1H), 3.43 points (m, 2H), to 4.38 (m, 1H), 4,99 (t, J=5.5 Hz, 1H), 6,99 (DD, J=5.3 Hz, 7.8 Hz, 1H), 7,30 (d, J=6,8 Hz, 1H), 7,45-of 7.55 (m, 4H), 7,63 (d, J=8,2 Hz, 1H), 7,71 (m, 1H), 8,04 (d, J=5.3 Hz, 1H), 10,34 (users, 1H).

FAB-MS (M+H)+: 371.

[α]D24=+48,44° (c 1.0, chloroform).

Example 142

(R)-2-{1-[1-(acenaphthen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-imidazo[4,5-b]pyridine-3-yl}-N-methylacetamide

(R)-1-[1-(Acenaphthen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he (1 g) dissolved in DMF (30 ml). Add sodium hydride (120 mg, 60%) and the resulting suspension is stirred at room temperature for 20 minutes Add ethylbromoacetate (500 mg) and the resulting mixture is stirred for 2 hours. The reaction mixture was poured into ice water and extracted with a mixture of ethyl acetate. The extract is washed with water and saturated aqueous ammonium chloride, dried over magnesium sulfate and concentrated, obtaining the ethyl (R)-2-{1-[1-acenaphthen-1-yl)piperidine-4-yl]-1,2-dihydro-2-oxo-imidazo[4,5-b]pyridine-3-yl}acetate. Add 40%is actor of methylamine in methanol (20 ml) and the mixture is stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (0,86 g) as white powder.

1H-NMR (CDCl3) δTMS: 1,78 is 1.86 (m, 2H), 2,24 is 2.44 (m, 3H), of 2.54 (m, 1H), 2,78 (m, 1H), 2,80 (d, J=4,7 Hz, 3H), to 3.02 (m, 1H), 3,42 (d, J=5.4 Hz, 2H), to 4.38 (m, 1H), 4,62 (c, 2H), to 4.98 (t, J=5.4 Hz, 1H), 6,24 (users, 1H), 7,02 (DD, J=5,2 Hz, 7.8 Hz, 1H), 7,30 (d, J=6,9 Hz, 1H), 7,45-of 7.55 (m, 4H), 7,63 (d, J=8,2 Hz, 1H), 7,71 (m, 1H), 8,03 (DD, J=1.2 Hz, 5.2 Hz, 1H).

FAB-MS (M+H)+: 442.

[α]D24=+42,16° (C 1.0, chloroform).

Example 143

(R)-1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he

Specified in the title compound obtained as a solid substance of white color according to the method described in example 141 using (R)-1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-one and 2,3-diaminopyridine.

1H-NMR (CDCl3) δTMS: 1,60-1,80 (m, 3H), 1.85 to 2,10 (m, 3H), 2,15 was 2.25 (m, 2H), 2,45 (m, 1H), 2,70-2,90 (m, 4H), 3,05 (m, 1H), 3,92 (m, 1H), 4,37 (m, 1H), 7,00 for 7.12 (m, 2H), 7,14 (DD, J=7,7, and 7.8 Hz, 1H), 7,19 (DD, J=7,7, and 7.8 Hz, 1H), 7,51 (d, J=7.8 Hz, 1H), to 7.77 (d, J=7.7 Hz, 1H), of 8.06 (d, J=5.4 Hz, 1H), 10,00 (users, 1H).

FAB-MS (M+H)+: 349.

[α]D24=+46,0° (0.5, chloroform).

Example 144

(R)-2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-imidazo[4,5-b]pyridine-1-yl}-N-methylacetamide·fumarate

Specify the second header connection receive in the form of a white powder, preparing a solution in acetone of the amorphous material obtained as described in example 142, using (R)-1-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-it, and treating the solution in acetone of 1.1 equivalents of fumaric acid.

1H-NMR (DMSO-d6) δTMS: 1,60-1,75 m, 3H), equal to 1.82 (m, 1H), 1.85 to 2,00 (m, 2H), 2,10-of 2.30 (m, 2H), 2,35 is 2.55 (m, 2H), 2.57 m (c, 3H), 2,60-2,90 (m, 3H), to 3.02 (m, 1H), 3,90 (m, 1H), 4,33 (m, 1H), to 4.41 (c, 2H), 6,62 (c, 2H), 7,02-7,25 (m, 4H), of 7.65 to 7.75 (m, 2H), 7,94 (d, J=5,2 Hz, 1H), 8,08 (m, 1H).

FAB-MS (M+H)+: 420.

[α]D24=+13,65° (c 0.25, methanol).

Example 145

(R)-1-[1-(acenaphthen-1-yl)piperidine-4-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he

(R)-1-[1-(Acenaphthen-1-yl)piperidine-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he (0,78 g) dissolved in DMF (20 ml), added 60% sodium hydride (90 mg) and the resulting suspension is stirred for 20 minutes Then add methyliodide (340 mg) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The extract is washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (chloroform/methanol) and get listed in the title compound (0,58 g) as yellow powder.

1H-NMR (CDCl 3) δTMS: 1,76-of 1.84 (m, 2H), 2,24 at 2.45 (m, 3H), 2,53 at 2.59 (m, 1H), 2,78 (m, 1H), 3,01 (m, 1H), 3.43 points (m, 2H), 3,49 (c, 3H), 4,39 (m, 1H), to 4.98 (t, J=5.5 Hz, 1H), 6,98 (DD, J=5.3 Hz, 7.8 Hz, 1H), 7,30 (d, J=6,8 Hz, 1H), 7,45-of 7.55 (m, 4H), 7,63 (d, J=8,2 Hz, 1H), 7,72 (m, 1H), 8,04 (d, J=5.3 Hz, 1H).

FAB-MS (M+H)+: 385.

[α]D24=+45,29° (C 0.6, chloroform).

Example 146

(R)-1-[1-(acenaphthen-1-yl)piperidine-4-yl]-3-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he·2 hydrochloride

The crude product obtained as described in example 145, using ethylbromide (250 mg), treated with 4n. solution chloroethanol acid in ethyl acetate and get listed in the title compound (150 mg) as yellow powder.

1H-NMR (DMSO-d6) δTMS: 1,25 (t, J=7.2 Hz, 3H)and 1.83 (m, 1H), 1,96 (m, 1H), 2,82 (m, 1H), equal to 2.94 (m, 1H), 3,10 (m, 1H), 3,30 (m, 2H), of 3.56 (m, 1H), 3,68 of 3.75 (m, 1H), 3,90 (kV, J=7.2 Hz, 2H), 4,79 (m, 1H), 5,65 (m, 1H), 7,08 (m, 1H), 7,47 (m, 1H), to 7.59 (m, 1H), 7,68 (m, 1H), 7,78 (m, 1H), to 7.93 (m, 1H), 8,01 (m, 1H), 8,25-8,30 (m, 2H), 12,41 (users, 1H).

FAB-MS (M+H)+: 399.

[α]D24=+46,76° (C 0.6, methanol).

Example 147

(R)-1-[1-(acenaphthen-1-yl)piperidine-4-yl]-3-(2-methoxyethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he

Specified in the title compound (670 mg) are obtained in the form of a yellow powder by the method described in example 145, using 2-bromatology ester (320 mg).

1H-NMR (CDCl3) δTMS: 1,77-of 1.85 (m, 2H), 2.26 and is 2.44 (m, 3H), 2,53 at 2.59 (m, 1H), 2,78 (m, 1H), 3,01 (m, 1H), 3,35 (c, 3H), 3,42 (m, 2H), 376 (t, J=5.7 Hz, 2H), 4,18 (t, J=5.7 Hz, 2H), 4,39 (m, 1H), to 4.98 (t, J=5.5 Hz, 1H), 6,97 (DD, J=5.3 Hz, 7.8 Hz, 1H), 7,30 (d, J=6,8 Hz, 1H), 7,45-of 7.55 (m, 4H), 7,63 (d, J=8,2 Hz, 1H), 7,71 (m, 1H), 8,04 (d, J=at 5.3 Hz, 1H).

FAB-MS (M+H)+: 429.

[α]D24=+40,22° (C 1.0, chloroform).

Example 148

(R)-1-[1-(acenaphthen-1-yl)piperidine-4-yl]-3-cyclopropylmethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-he·2 hydrochloride

Specified in the title compound (270 mg) obtained as yellow powder by treating the crude product, obtained as in example 145, using 1-(methyl bromide)cyclopropane (310 mg), 4n. solution chloroethanol acid in ethyl acetate.

1H-NMR (DMSO-d6) δTMS: 0,38 of 0.47 (m, 4H), 1,24 (m, 1H)and 1.83 (m, 1H), 1,97 (m, 1H), 2,85 (m, 1H), 2.95 and (m, 1H), 3,13 (m, 1H), 3,32 (m, 2H), only 3.57 (m, 1H), 3,69 of 3.75 (m, 3H), of 3.96 (m, 1H), 4,78 (m, 1H), to 5.66 (m, 1H), was 7.08 (m, 1H), 7,47 (m, 1H), to 7.59 (m, 1H), 7,68 (m, 1H), 7,78 (m, 1H), to 7.93 (m, 1H), 8,01 (m, 1H), 8,25-8,30 (m, 2H), 12,42 (users, 1H).

FAB-MS (M+H)+: 425.

[α]D24=+38,58° c to 0.7, methanol).

Structural formulas of the compounds according to examples of the present invention is shown in the following tables:

Pharmacological action of the compounds according to the present invention is illustrated below with the help of experimental examples.

Used to compare the control link given below.

Connection AND (WO2005/028466, CIS - or TRANS-stereoisomer of compound 1)

Connection (WO2005/028466, the other stereoisomer of the compound (A)

Experimental example 1: test for the binding of receptor ORL-1

Experimental method and measurement

Using the drug membrane receptor is, obtained from cells NECK, forcibly expressing the receptor ORL-1 person, conduct the test on the binding of [3H]-nociceptin. Namely, the solution of the test compound (50 μl) with different concentrations, the solution of the receptor (900 μl) containing radioactive label the ligand [3H]-nociceptin (50 µl) was successively added in a polypropylene test tube and allow them to react at 25°C for 60 minutes, the Reaction mixture is filtered by suction in the harvester cells using a glass filter Whatman GF/b Filter is washed 3 times with ice 50 mmol/l HEPES buffer and place the filtrate in measuring ampoule. Add liquid scintillation cocktail for ACS-II (Amersham) (2 ml) and the radiation dose is measured liquid scintillation counter (LSC-5100, Aloka). The level of non-specific binding determine using does not contain a label, a ligand naltrexone. The level of inhibition of binding (%) and the inhibition constant (Ki value) calculated in accordance with the following calculation formula:

The level of inhibition of binding (%)={1-(B-N)/(T-N)}×100

N: the level of nonspecific binding, T: the overall level of binding B: the level of binding in the presence of test compounds

The inhibition constant (Ki value)=IC50/(1+L/Kd)

IC50: 50%inhibitory concentration, L: concentration of mecheng the ligand, Kd: dissociation constant of labeled ligand

Experimental example 2: test for receptor binding μ

Method of testing and measurement

Using the drug membrane receptor, obtained from cells SNO, forcibly expressing the receptor μ person conducting the test on the binding of [3H]-DAMGO. Namely, the solution of the test compound (50 μl) with different concentrations, the solution of the receptor (900 μl) containing radioactive label the ligand [3H]-DAMGO (50 µl) was successively added in a polypropylene test tube and allow them to react at 25°C for 60 minutes, the Reaction mixture is filtered by suction in the harvester cells using a glass filter Whatman GF/b Filter is washed 3 times with ice 50 mmol/l buffer Tris/HCl and place the filtrate in measuring ampoule. Add liquid scintillation cocktail for ACS-II (Amersham) (2 ml) and the radiation dose is measured liquid scintillation counter (LSC-5100, Aloka). The level of non-specific binding determine using as ligand does not contain the label of the test compound A. the Level of inhibition of binding (%) and the inhibition constant (Ki value) calculated in accordance with the following calculation formula:

The level of inhibition of binding (%)={1-(B-N)/(T-N)}×100

N: the level of nonspecific binding, T: the overall level of light is ivania, B: the level of binding in the presence of test compounds

The inhibition constant (Ki value)=IC50/(1+L/Kd)

IC50: 50%inhibitory concentration, L: concentration of labeled ligand, Kd: dissociation constant of labeled ligand

Results and discussion

The results are shown in table 35. Affinity values (Ki) for inhibition in the above experiments is marked as “+++” for concentration of not more than 10 nm, as “++” for concentrations of 10-30 nm, as “+” for concentrations of 30-100 nm, as “-” for the concentration of not less than 100 nm, and ND indicates no data.

Table 35
Test connectionAffinity Ki (nm)
ORL-1μ
Connection+++++
Connection+++++
Example 2+++ND
Example 4+++ND
Example 8 +++ND
Example 16+++ND
Example 79++++
Example 80+++-
Example 103+++ND
Example 104+++ND
Example 108+++ND
Example 110+++ND

As indicated in the above table, the compounds of examples 2, 4, 8, 16, 79, 80, 103, 104, 108 and 110 show a high affinity to the receptor ORL-1, as evidenced by the Ki value of 10 nm or less.

Moreover, it was shown that the compounds of examples 79 and 80 have a weak affinity for the μ receptor and exert a selective action on the receptor ORL-1.

Experimental example 3: agonistic action

Experimental method and measurement

Using the drug membrane receptor, obtained from cells NECK, force expressyou the th receptor ORL-1 person, test is done on linking GTPγ35S. namely, the buffer for the reaction or a solution of the test compound (50 μl) with different concentrations of the buffer for the reaction (for total binding) or GTPγS solution (for nonspecific binding, final concentration: 10 umol/l) (50 μl), the membrane solution (850 ml) and the solution GTPγ35S (Amersham Pharmacia Biotech) (final concentration: 100 pmol/l) (50 µl) was successively added in a polypropylene test tube and allow them to react at 30°C for 60 minutes, the Reaction mixture is filtered by suction in the harvester cells using a glass filter Whatman GF/b Filter is washed 3 times with ice 50 mmol/l buffer Tris/HCl (pH 7.4) and place the filtrate in measuring ampoule. Add liquid scintillation cocktail for ACS-II (Amersham) (2 ml) and the radiation dose is measured liquid scintillation counter (LSC-5100, Aloka). Expressing the level of nonspecific binding with the addition of GTPγS as N, the level of binding with the addition of a buffer for the reaction instead of the tested compounds as Well, and the level of binding in the presence of test compounds as In, agonistic activity, namely associated GTPγ35S (%), determined using the following formulas:

Associated GTPγ35S (%)={(B-N)/(A-N)}×100

Results and discussion

As shown in Fig.1-3, is connected to the I in examples 2, 4, 8, 79, 80, 104, and 110 increase the proportion associated GTPγ35S depending on the concentration. Thus, it was shown that the compounds according to examples 2, 4, 8, 79, 80, 104 and 110 act as agonists in relation to the receptor ORL-1.

Experimental example 4: enhancing food consumption effect on rats

Experimental method and measurement

It was reported that the introduction of nociceptin, which is an endogenous agonist of the receptor ORL-1 in the ventricle of rat brain temporarily increases the consumption of food (NeuroReport 8: 369-371, 1996). Thus, it is possible to measure in vivo agonistic activity against receptor ORL-1, using as an indicator of increased food intake by rats. When the rat contain in terms of 12-hour cycle of day and night, the rat consumes the largest amount of food in a dark period of the day. Therefore, the experiment is carried out in the light period of the day when the rat is rarely receives food. Namely, the test compound orally administered in 3-4 hours after the beginning of the light period, and a lot of food determined after 1, 2, 4 and 6 hours after injection. The difference between the weight of food immediately after the introduction and the weight of the food after the introduction of the take for the amount of food consumed, which is recalculated per 1 kg of body weight of the rat.

Results and discussion

Compounds according to examples 2, 4, 8, 79 and 80 cause significant is seleniu food intake by rats. Thus, in vivo it was shown that these compounds act as agonists of the receptor ORL-1.

Example composition 1: tablet

The connection according to the present invention10 mg
Crystalline cellulose180 mg
Corn starch300 mg
Lactose600 mg
Magnesium stearate15 mg

The above components are mixed in the usual way and tabletirujut using a conventional device.

Example composition 2: pill

The connection according to the present invention10 mg
Lactose50 mg
Corn starch20 mg
Crystalline cellulose29,7 mg
Polyvinylpyrrolidone K5.0 mg
Talc5.0 mg
Magnesium stearate0.3 mg
120,0 mg

The compound of the present invention, lactose, corn starch and crystalline cellulose are mixed and molded using pasta polyvinylpyrrolidone K, and the mixture is then sieved through 20 mesh and receive granules. After drying at 50°C for 2 hours granules are sieved through a sieve of 24 mesh, mixed with talc and magnesium stearate and prepare the tablet that weighs 120 mg, with a pestle and mortar with a diameter of 7 mm

Industrial application

The compound (I) of the present invention has better metabolic stability and strong agonistic action against the receptor ORL-1 and can be used for the prevention and/or treatment of diseases associated with the receptor ORL-1, such as diseases of the Central nervous system (in particular, fear and stress disorder, depression, traumatic injury, Alzheimer's disease, dementia, sleep disorder, addiction to the excessive use of drugs, alcohol), the symptom acute and/or chronic pain disorder arterial blood pressure or disorders of nutrition, such as obesity and anorexia.

This application is based on patent request is Oh No. 2007-051842, 2007-059260, 2007-078845 and 2007-093846, subjects in Japan, the contents of which are entirely included in the present description by reference. In addition, in the present invention by reference to the extent that they are disclosed in the present description, also includes all of the above in the present description of the patent documents and non-patent documents.

1. The compound represented by formula (I)

wheremeans the following formula (a)

n means an integer from 1 to 3;
R1means1-6alkyl-C(O)-NR3R4;
one of R3and R4means a hydrogen atom and the other denotes a hydrogen atom, a C1-6alkyl or C3-7cycloalkyl, or R3and R4together with the adjacent nitrogen atom form a saturated nitrogen-containing 5 - or 6-membered ring, optionally additionally containing 1-3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and which may be substituted With1-6the alkyl, a halogen atom, a C1-6alkoxy, phenoxy or benzyloxy;
R2means a hydrogen atom;
Ra and Rb are the same or different and each means a hydrogen atom, a C1-6alkyl, halogen atom or With1-6alkoxy;
X is O;
Y represents CH2C(CH3)2or About; and
Z denotes CH,
or headlamp is asepticheski acceptable salt.

2. The compound according to claim 1, which is selected from
2-{3-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,
2-{3-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,
2-{3-[1-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,
2-{3-(1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,
2-{3-(4-methyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,
2-{3-(3,3-dimethyl-1-indan-1-reparacin-4-yl)-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide,
or its pharmaceutically acceptable salt.

3. The compound according to claim 1, which is a
(R)-2-{3-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-yl]-2,3-dihydro-2-oxo-benzimidazole-1-yl}-N-methylacetamide or its pharmaceutically acceptable salt.

4. Pharmaceutical composition for prevention or treatment of sleep disorders, which contains the compound (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

5. Pharmaceutical composition for prevention or treatment of alcoholism, which contains the compound (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

6. Pharmaceutical composition for prevention or treatment of addiction to h is username use of medicines, which contains the compound (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

7. Pharmaceutical composition for prevention or treatment of anxiety or stress disorder, which contains the compound (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (1) in free form or in form of a salt. In formula (1): X1 and X2 all independently denote halogen; A denotes a radical of formula where (R1)1-2 denotes 1-2 identical or different substitutes selected from a group comprising C1-C4-alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, R2R3N-C1-C4-alkyl, halogen, hydroxy group, C1-C4-alkoxy group, halogen-C1-C4-alkoxy group, C1-C4-alkylthio group, C1-C4-alkanoyl, C1-C4-alkanoylamino group, C1-C4-alkylsulphonylamino group, C1-C4-alkylsulphonyl, C1-C4-alkylthionyl, NR2R3 and morpholinyl; or A denotes a radical of formula where ring (a) denotes a 5-member heterocyclic ring containing 1 or 2 heteroatoms selected from a group comprising O and N, which can further be substituted with C1-C4-alkyl, and which is annelated in positions 3 and 4; and R2 and R3 all independently denote hydrogen or C1-C4-alkyl. The invention also relates to a parasite control composition containing said compounds, a parasite control method on warm-blooded animals and use of compounds of formula (1) to prepare a parasite control composition.

EFFECT: high efficiency of using said compounds.

11 cl, 7 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula , wherein: R1 means phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms and wherein said phenyl, 6-member heteroaryl is optionally substituted by one R7; R2 means phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms and wherein each of said phenyl or 6-member heteroaryl is optionally substituted by one R7; R3 means halogen R7 independently means halogen, OR8, phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms wherein any phenyl or heteroaryl can be optionally substituted by one R14; R14 means halogen, OR8; R8 independently means C1-6alkyl; m is equal to 1; in the form of a free base or its pharmaceutically acceptable salt, and to their pharmaceutically acceptable salt.

EFFECT: compounds possess BACE inhibitory activity.

8 cl, 6 tbl, 136 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of an improved method for synthesis of 5-(methyl-1H-imidazol-1-yl)-3-(trifluoromethyl) benzamide of formula (I), for example compound (1a). The obtained compounds can be used to treat neoplastic diseases such as leukaemia. The method involves reaction of a compound of formula (II)

,

with 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine of formula (IVa):

, .

R1 denotes 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl; R2 denotes hydrogen; R4 denotes hydrogen, lower alkyl or halogen; and R3 denotes lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl. The reaction takes place in an organic solvent in the presence of a base as a catalyst, selected from a group comprising a metal hydride, (volumetric) alkyllithium, metal alkoxide, metal bis-(trimethylsilyl)amide and lithium dialkylamide.

EFFECT: method simplifies synthesis of desired products by excluding expensive compounds and obtaining products with stable high output.

5 cl, 4 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a method of producing a compound of formula

through reaction of a compound of formula 2, where R1 denotes H, C1-C4 alkyl, cyclopropyl, cyclopropylmethyl or methylcyclopropyl, R2 denotes CH3 or Cl, and X denotes Cl or Br, with R1-NH2 in the presence of a carboxylic acid in an essentially anhydrous reaction medium containing a suitable organic solvent, as well as a method of producing a compound of formula

,

where R2 denotes CH3 or Cl, and X denotes O or Br, involving reaction of a compound of formula

,

where R3 denotes C1-C6 alkyl or C3-C6 alkenyl, each optionally substituted with not more than 3 halogen atoms and not more than 1 phenyl, with phosphorus tribromide. Also disclosed is a compound 4, where R2 denotes CH3 or Cl; R3 denotes C1-C6 alkyl or C3-C6 alkenyl, each optionally substituted with not more than 3 halogen atoms and not more than 1 phenyl; and X denotes Cl or Br; provided that when each of R2 and X denotes Cl, R3 is not CH3.

EFFECT: improved method of obtaining the compounds.

12 cl, 6 ex, 4 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to narcology, and can be used for rehabilitation of patients with alcoholism in abstinence syndrome. For this purpose, pharmacotherapy is added with administration of Galodif 100 mg 3 times a day by the therapeutic course 21 days.

EFFECT: method allows ensuring a stable therapeutic effect expressed in lower intensity of morbid attraction to alcohol in the presence of a various degree of intensity of affective disorders due to normothymoleptic, analgesic and vegetostabilising effects.

2 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to food industry, particularly to biologically active food additives. The composition of biologically active substances based on betulin with regulated rate of releasing components for reducing degree of alcohol intoxication, preventing and relieving alcohol intoxication and alcohol withdrawal syndrome contains betulin encapsulated in edible fats or wax or mxiture thereof, amber acid - 50%, ascorbic acid - 50%, glutamic acid - 50% and/or sodium glutamate and food additives, with the following ratio of components in wt %: betulin 1-10, microcapsulated amber acid 50% 1-40, microcapsulated ascorbic acid 50% 1-40, microcapsulated glutamic acid 50% and/or sodium glutamate 50% 2-75 and food additives 1-95.

EFFECT: invention enables to obtain a novel composition, having complex prolonged effect for protecting the body upon consumption of alcohol, for preventing and relieving alcohol intoxication and alcohol withdrawal syndrome, which reduces development of pathological phenomena of alcohol withdrawal syndrome, as well as alcohol tolerance before, during and after consumption.

5 cl, 1 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: in order to stop alcohol abstinence introduction of naloxon in strict sequence after fixed 45 minutes is performed, initially medication is introduced intravenously in dose 0.8 mg slowly during 1-2 minutes, and then only intramuscularly in dose 1.2 mg if weight is lower or equals 75 kg, or in dose 1.6 mg if weight is over 75 kg. In case of necessity intramuscular injections are continued after patient's awakening from drug-induced sleep to repeated sleep and complete stop of abstinence effects.

EFFECT: fast and efficient stop of main symptoms of alcohol abstinence with absence of side effects due to elaborated methods of naloxon introduction.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: for correction of metabolic and morphological disorders in chronic alcoholisation, hypovitaminosis diet is applied in rats. 15 % ethanol is used as a drink. Tykveol 1 ml per 1 kg of animal's body weight pre-mixed with food is introduced.

EFFECT: method provides effective normalisation of free radical oxidation indicators, reduction of hypoxia manifestation and improvement of a morphological pattern of liver, myocardium and pancreas in rats with no side effects.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns an agent for prevention and treatment of alcoholic dependence.

EFFECT: invention provides the efficacy of the offered agent and the presence of a considerable delay and slow release effect of an active principle after introduced.

6 cl, 4 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and its application for prevention and treatment of abuse with psychoactive substances and dependence on psychoactive substances, which contains compound of formula (R)-2-{3-[1-(acenaphthene-1-yl)pyperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl} -N-methyl acetamide or its pharmaceutically acceptable salt as active ingredient.

EFFECT: compound, which is agonist and has highly selective affinity to ORL-1 receptors, possesses effects of reduction of intensity of alcohol abstinence symptoms and suppression of surplus intake of alcohol and other psychoactive substances.

18 cl, 1 tbl, 8 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

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