Benzopyrrole derivatives containing hexahydropyridine cycle

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

 

The present invention relates to compounds having the ability to bind to the serotonin 1A receptor, and to its use as a pharmaceutical preparation. More specifically, this invention relates to means for the treatment or prevention of symptoms of the lower urinary tract.

In the peripheral system serotonin affects the relaxation of smooth muscle, platelet aggregation and regulation of the activity of the gastrointestinal tract. On the other hand, in the Central nervous system serotonin acts as a neurotransmitter and is deeply connected with the propulsion system, the perceptual system, the physiological functions such as regulation of body temperature, sleep, feeding behavior, vomiting, sexual behavior, neuroendocrine system, cognition and memory or biorhythm, and pathological conditions such as anxiety, aggression, obsessie, mood disorder, hallucination, schizophrenia, autism or drug dependence (see, for example, non-patent document 1, non-patent document 2).

Serotonin receptors are classified into 7 families in the interval from 5-NT to 5-NT. 5-NT consists of 5 subtypes (5-HT1A, 5-NTV, 5-NTS, 5-1D, 5-NTE and 5-1F).

Receptor 5-HT1A widely distributed in the Central nervous system. In the brain this receptor is distributed with a high density, especially cerebral limbic system, mainly in the hippocampus, septum, amygdala complex and nuclei of the seam. In the spinal cord it is distributed with a high density in the cortex posterior horns, from which depart of primary afferent fibers (layers I and II), the inner part of the anterior horn, where localized motoneurons (layers VIII-IX), and the lateral intermediate nucleus, where preganglionarnah sympathetic cells (layer VII). In the nerve certaninly receptor exists as a presynaptic receptor in the cell bodies of serotonergic nerve (5-HT1A somatodendritic autoreceptor) and as a postsynaptic receptor on the nerve, which innervates the serotonin nerve. Such presynaptic receptor leads to negative regulation with feedback from the release of serotonin.

Step 5-HT1A receptor in a living organism and disease, are involved in receptor explained due to the discovery of agonists and antagonists that are selective in relation to the 5-HT1A receptor.

Examples of such diseases are depression and anxiety. It is believed that presynaptic 5-HT1A receptor is important in the treatment of depression. As the drugs currently used selective inhibitor of serotonin reuptake (SSRI) and selective inhibitor of the reuptake of serotonin/noradrenaline (SNRI). These drugs inhibit the absorption is shown transmitters in the nerve cells, increasing the concentration of transmitter in the synaptic cleft and in defensibility receptor, which is what makes them effective. Recently it became known that (-) pindolol (which shows affinity for adrenaline β and NTA receptor has an antagonistic effect against NTA receptor) promotiom the beginning of the pharmacological effects of an SSRI, thereby increasing the degree of its effectiveness in patients who are prone to depression. This can occur because the blocking presynaptic 5-HT1A receptor increases the secretion of serotonin at nerve endings, resulting in enhanced desensitization of the receptor (see, for example, non-patent document 3).

According to a study by M. Barros et al. using monkeys assumes the possibility of using an antagonist of 5-HT1A receptor for anxiety disorder. Using as a measure of fear and anxiety behavior monkeys at the sight of a stuffed predatory animal, investigated the effect of the antagonist of 5-HT1A receptor on anxiety. The results showed that the tool has an anxiolytic effect (see, for example, non-patent document 4). These results spoke about the possibility of using an antagonist of 5-HT1A receptor as a means for the prevention or treatment of depression or anxiety disorder.

Predpolagalos is also that 5-HT1A receptor is associated with cognitive ability, memory and learning. Antagonist of glutamate receptors of the NMDA type or dissection vault brain disorder cognitive abilities. This disorder cognitive abilities are treated with the use of an antagonist of 5-HT1A receptor (see, for example, non-patent document 5 and non-patent document 6). Yasuno F. et al. was introduced to a man antagonist of 5-HT1A receptor labelled11C ([11C]WAY-100635). After that they checked positron emission tomography correlation between memory and plot attributable to the 5-HT1A receptor (see, for example, non-patent document 7). The result was found negative correlation between improved memory and ability [11C]WAY-100635 contact hippocampal postsynaptic 5-HT1A receptor. In accordance with this result assumes that postsynaptic 5-HT1A receptors distributed in the hippocampus, have a negative effect on memory. These research results suggest the possibility that the antagonist of 5-HT1A receptor effective in disorders of cognitive or memory impairment or a learning disability.

In addition, in recent years has been reported (see, for example, non-patent document 8) about the connection of the 5-HT1A receptor with reflex urination.

Examples of causes of symptoms related to reservoir accumulation of urine may include neurogenic bladder caused by encephalopathy (including cerebrovascular disorder, Parkinson's disease, brain tumor, multiple sclerosis and the like), senile dementia, myelopathy or spinal disease, unstable bladder, benign prostatic hyperplasia, prostate cancer, necrosis urinary bladder, interstitial cystitis of the bladder, irritation of the bladder, caused by chronic cystitis or chronic prostatitis, cystospaz, enuresis (including nocturnal enuresis), nycturia and psychogenic dysuria.

In studies of reflex voiding in rats, the 5-HT1A agonist receptor contributes to reflex urination (see, for example, non-patent document 8), whereas the antagonist of 5-HT1A receptor inhibits the reflex urination when measured with the use of rhythmic compression of the bladder or cystometrogram. In addition, in the case of applying a partial agonist at 5-HT1A receptor the effect of suppression of reflex urination is reduced depending on the degree of agonistic actions specified means (see, for example, non-patent document 9). In light of these results it is expected that the antagonist of 5-HT1A receptor is new,based on a new mechanism of action treatment for symptoms regarding the accumulation of urine (including increased urinary frequency, acute urge to urinate and incontinence of urine and so on) (see, for example, non-patent document 10).

In addition to the above, there is a wide range of diseases, which also involved the 5-HT1A receptor. Examples of such diseases may include neuropsychiatric disorder (e.g., obsessive-compulsive disorder (see, for example, non-patent document 11), borderline personality disorder (see, for example, non-patent document 12), post-traumatic stress disorder (see, for example, non-patent document 13), panic disorder, schizophrenia (see, for example, non-patent document 14), genital insufficiency (see, for example, non-patent document 14), alcohol and/or cocaine dependence (see, for example, non-patent document 15 and non-patent document 16), sleep disorders (see for example, non-patent document 14), pain (see, for example, non-patent document 14), migraine (see, for example, non-patent document 17), a disorder of visual attention (see, for example, non-patent document 18), the temperature instability (see, for example, non-patent document 14), vomiting (see, for example, non-patent document 19), gastrointestinal disorder (see, for example, non-patent document 14), eating disorder (see, for example, non-patent document 14), Hyper is enzio (see, for example, non-patent document 20), neurodegenerative disease (see, for example, non-patent document 21 and non-patent document 22) (for example, cerebral ischemia, Alzheimer's disease etc), dyskinesia caused by Parkinson's disease (see, for example, non-patent document 23), and symptoms associated with withdrawal from the ingestion of nicotine or Smoking (see, for example, non-patent document 24).

Accordingly, it is expected that the antagonist of 5-HT1A receptor will be the agent for the prevention or treatment of this wide range of diseases. Though it has been conducted active research on the creation of such an antagonist at 5-HT1A receptor, such tools on the market yet. Therefore, the creation of a superior antagonist at 5-HT1A receptor was desirable.

Had a lot of messages related compounds with antagonistic effect against 5-HT1A receptor. However, for use as a treatment for symptoms of the lower urinary tract it is known only a few compounds described in patent document 1 and patent document 2.

The compound described in patent document 1, is a compound represented by the following formula, or its pharmacologically acceptable salt:

where R represents a hydrogen atom or the like; R1presented yet a hydrogen atom or the like; R2represents a halogen atom or the like, and represents a monocyclic aryl group, or other Structural feature of this connection is that it contains N-phenyliminomethyl group as piperazinone side chain.

Thus, from the point of view of the chemical structure of the compound described in patent document 1, is completely different from that represented by formula (I) compounds of the present invention, characterized in that it contains unsubstituted or monosubstituted karbamoilnuyu group in the 6 position on the indole skeleton and contains a methoxy group in the aryl group arylalkyl side chain extending from the nitrogen atom in piperidinium cycle orthopaedie relative to the alkyl side chain".

Patent document 2 is the closest to the present invention the prior art. Herein disclosed for the treatment of symptoms of the lower urinary tract, containing the compound represented by the following formula, its salt or its hydrate:

where the cycle Ar1represents a benzene or the like; D represents a nitrogen atom or the like; R3and R4are the same or different and represent hydrogen atoms or the like; R5is tomoderate or the like; R1and R2represent hydrogen atoms or the like, or are linked together to form a cycle containing X; and m represents 0 or an integer from 1 to 6.

The compound described in patent document 2, identical to the one described in patent document 3, the compound represented by formula (I)or the compound described in the examples. The structural feature of this connection is that "it is indole or indolinyl skeleton containing cyclic amine which may be substituted arylalkyl group or the like as a side chain structure".

Among the compounds disclosed in the patent document 3, specific examples of compounds that are close to the compound of the present invention, represented by formula (I)can include compounds represented by the following formula:

where each of R1and R3represents a hydrogen atom; R2represents karbamoilnuyu group; R5represents arylalkyl group which may be substituted; n and m are 0; p is 2; each of T and Z represents a nitrogen atom and Y represents a methine group. The closest connection is the one described in example 337. However, these disclosed compounds Ogre is Iceni compounds "are indole or indolinyl skeleton containing cyclic amine which may be substituted arylalkyl group or the like as a side chain". There are no descriptions with the join clause of the present invention, represented by formula (I), "which contains unsubstituted or monosubstituted karbamoilnuyu group in the 6 position on the indole skeleton and contains a methoxy group in the aryl group arylalkyl side chain extending from the nitrogen atom in piperidinium cycle orthopaedie relative to the alkyl side chain".

Thus, the compound described in patent document 2 is different from the compounds of the present invention, represented by formula (I), from the viewpoint of chemical structure and, therefore, does not have a chemical structure that is characteristic of the compounds of the present invention.

In addition, in patent document 2 describes testing methods for binding with [3H]-8-hydroxydiphenylamine (example 1 test), test antagonist of 5-HT1A receptor (example 2 trials) and trials related to antagonistic effect against induced by agonist of 5-HT1A receptor hypothermia in rats (example 3 tests). However, the document did not revealed no compound, no concrete results (pharmacological effects). Therefore, nebo is possible on the basis of such descriptions to understand the present invention in its entirety.

Among the compounds described in patent document 3 and patent document 2, closest to the connection of the present invention, represented by formula (I)is the compound described in example 337, which is represented by the following formula:

As described later in the results of pharmacological research pharmacological effect of this compound is characterized by the fact that the compound has affinity for 5-HT1A, but its antagonistic activity against receptor weakly.

On the other hand, the compound of the present invention, represented by the following formula (I):

differs in that it contains unsubstituted or monosubstituted karbamoilnuyu group in the 6 position on the indole skeleton and contains a methoxy group in the aryl group arylalkyl side chain extending from the nitrogen atom in piperidinium cycle orthopaedie relative to the alkyl side chain, thanks to which it has increased antagonism to 5-HT1A receptor.

Thus, the connection of the present invention has effects that are quite different from the effects of the compounds described in patent document 3 and patent document 2.

The purpose of this invention is to provide compounds with the affinity of the 5-HT1A receptor and expressing antagonism to the receptor, used for therapeutic purposes.

Non-patent document 1: Peroutka S.J., 5-Hydroxytryptamine receptor subtypes, Annu. Rev. Neurosci. 1988; 11: p.45-60;

non-patent document 2: H.Matsui, and three others, Neurotransmitter Today, 19(2), 1997, p.131-146;

non-patent document 3: Farde L., and four others, PET-Determination of robalzotan (NAD-299) induced 5-HT(1A) receptor occupancy in the monkey brain, Neuropsychopharmacology., 2000 Apr.; 22(4): p.422-9;

non-patent document 4: M. Barros, and seven others, Anxiolytic-like effects of the selective 5-HT1A receptor antagonist WAY 100635 in non-human primates, Eur. J. Pharmacol., 2003 Dec. 15; 482(1-3): p.197-203;

non-patent document 5: Harder JA, Ridley RM. The 5-HT1A antagonist, WAY 100635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys. Neuropharmacology. 2000 Feb. 14; 39(4): p.547-52:

non-patent document 6: Harder JA, and four others, The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive induced by his or her fornix transection in the known as marmoset. Psychopharmacology (Berl.). 1996 Oct.; 127(3): 245-54;

non-patent document 7: Yasuno F., and nine others, Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory, Am. J. Psychiatry. 2003 Feb.; 160(2): p.334-40;

non-patent document 8: A. Lecci, and three others, Involvement of 5-hydroxytryptamine1A receptors in the modulation of micturition reflexes in the anesthetized rat, J. Pharmacol. Exp. Ther., 1992 Jul.; 262(1): p.181-9;

non-patent document 9: Testa R., and nine others, the Effect of several 5-hydroxytryptamine(1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635, J. Pharmacol. Exp. Ther., 1999 Sep.; 290(3): p.1258-69;

non-patent document 10: Andersson KE, R. Pehrson, CNS involvement in overactive bladder: pathophysiology and opportunities for pharmacological intervention, Drugs, 2003; 63(23): p.2595-611;

non-patent document 11: Bourin M., and another, The future of antidepressants, Biomed Pharmacother., 1996; 50(1): p.7-12;

repatent the initial document 12: Hansenne, M., and seven others, 5-HT1A dysfunction in borderline personality disorder, Psychol. Med. 2002 Jul.; 32(5): p.935-41;

non-patent document 13: Wilson MS., and another, Effects of fluoxetine on the 5-HT1A receptor and recovery of cognitive function after traumatic brain injury in rats, Am. J. Phys. Med. Rehabil., 2002 May; 81(5): p.364-72;

non-patent document 14: Fletcher A., and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol. Sci., 1993 Dec.; 14(12): p.441-8;

non-patent document 15: Zhou FC., and three others, Additive reduction of alcohol drinking by 5-HT1A antagonist WAY 100635 and serotonin uptake blocker fluoxetine in alcohol-preferring P rats, Alcohol. Clin. Exp. Res., 1998 Feb.; 22(1): p.266-9;

non-patent document 16: Carey RJ., and two others, a 5-HT1A agonist/antagonist modification of cocaine stimulant effects: implications for cocaine mechanisms. Behav Brain Res., 2002 Apr. 15; 132(1): p.37-46;

non-patent document 17: Boers PM., and three others, Naratriptan has a selective inhibitory effect on trigeminovascular neurones at central 5-HT1A and 5-HT(1B/1D) receptors in the cat: implications for migraine therapy, Cephalalgia., 2004 Feb.; 24(2): p.99-109;

non-patent document 18: Balducci C., and four others, Reversal of visual attention dysfunction after AMPA lesions of the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT1A receptor antagonist WAY 100635, Psychopharmacology (Berl.), 2003 Apr.; 167(1): p.28-36;

non-patent document 19: Gupta YK., and another, Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis in dogs, Indian J. Physiol. Pharmacol., 2002 Oct.; 46(4): p.463-7;

non-patent document 20: Dabire H., Central 5-hydroxytryptamine (5-HT) receptors in blood pressure regulation, Therapie., 1991 Nov.-Dec.; 46(6): p.421-9;

non-patent document 21: H. Kruger, and two others, Effects of ionotropic glutamate receptor blockade and 5-HT1A receptor activation on spreading depression in rat neocortical slices, Neuroreport., 1999 Aug. 20; 10(12): p.2651-6;

non-patent to the side 22: Suchanek b, and two others, The 5-HT1A receptor agonist BAY x 3702 prevents staurosporine-induced apoptosis, Eur. J. Pharmacol., 1998 Aug. 14; 355(1): p.95-101;

non-patent document 23: Bibbiani f, and two others, Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models, Neurology., 2001 Nov. 27; 57(10): p.1829-34;

non-patent document 24: Kurt Rasmussen, and sixteen others, The Novel 5-Hydroxytryptamine1A Antagonist LY426965: Effects on Nicotine Withdrawal and Interactions with Fluoxetine, J. of Pharmacol. Experimental. Therapeutics., 294: 688-700: (2000);

patent document 1: international publication WO99/06384;

patent document 2: JP-A-2002-114684;

patent document 3: international publication WO98/43956.

As stated above, it can be expected that the compounds having the ability to bind to 5-HT1A receptor and also showing an antagonistic effect against the specified receptor, is a tool for the treatment of symptoms of the lower urinary tract, based on a new mechanism of action. However, the compound which has a high ability to bind to 5-HT1A receptor and is antagonism of this receptor and which is able to provide excellent clinical effect in the treatment or prevention of symptoms of the lower urinary tract and, in particular, symptoms related to the accumulation of urine, still not found.

A means for solving problems

Under these circumstances, the authors of the present invention conducted intensive studies. As a result, they have found that the connection is out, described below, which has the ability to bind to 5-HT1A receptor and exerts an antagonistic effect against this receptor, is useful as a means for the treatment or prevention of symptoms of the lower urinary tract and, in particular, increased frequency of urination or urinary incontinence, which ultimately ended by the present invention.

Thus, the present invention is characterized by the following distinctive features 1)-34):

1) a Compound represented by the following formula (I)or its pharmacologically priemlemaya salt:

where R1and R2represent substituents adjacent to each other, and together with the two carbon atoms to each of which they are attached, form:

(1) a 5-7 membered non-aromatic carbocyclic group,

(2) a 5-7 membered non-aromatic heterocyclic group,

(3) a 6-membered aromatic carbocyclic group, or

(4) a 5 - or 6-membered aromatic heterocyclic group,

which may be substituted by 1-4 substituents, selected from the following group of substituents B1;

R3represents a hydrogen atom or methyl group; and

R6is a Deputy selected from the following group A1 deputies,

group A1 mandated the residents: (1) a hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group can be substituted by one or two C1-C6 alkyl groups),

the group V1 of substituents: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) oxoprop, (7) carboxyl group, (8) C3-C8 cycloalkyl group, (9) C2-C6 Alchemilla group, (10) C2-C6 Alchemilla group, (11) C1-C6 allylthiourea, (12) C1-C6 alkoxycarbonyl group, (13) C1-C6 alkylsulfonyl group, (14) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may shall be substituted by halogen atom, a hydroxyl group or C1-C6-alkoxygroup), (15) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (16) amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (17) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), (18) C1-C6 alkoxyimino, (19) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (20) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

2) the compound according to the above item 1) or its pharmacologically acceptable salt, where R1and R2represent substituents adjacent to each other, and together with the two carbon atoms to each of which they are attached, form a group represented by the following formula:

where a hydrogen atom in each cyclic group can be substituted by 1-4 substituents, selected from the following groups B1 Deputy is,

the group V1 of substituents: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) oxoprop, (7) carboxyl group, (8) C3-C8 cycloalkyl group, (9) C2-C6 Alchemilla group, (10) C2-C6 Alchemilla group, (11) C1-C6 allylthiourea, (12) C1-C6 alkoxycarbonyl group, (13) C1-C6 alkylsulfonyl group, (14) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by a halogen atom, a hydroxyl group or C1-C6-alkoxygroup), (15) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (16) amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (17) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), (18) C1-C6 alkoxyimino, (19) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (20) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

3) the connection described above PU is KTU 1) or its pharmacologically acceptable salt, which is represented by formula (I-a-1), formula (I-a-2), formula (I-a-3) or (I-a-4):

where R3represents a hydrogen atom or methyl group; R4aand R5arepresent substituents selected from the following group V1 of substituents; R6is a Deputy selected from the following group A1 substituents; R11arepresents a hydroxyl group, R12arepresents a hydrogen atom or C1-C6 alkyl group, or R11aand R12arepresent a carbonyl group or a group of the formula C=N-OR8c(where R8crepresents a C1-C6 alkyl group), together with the carbon atoms to which are attached R11aand R12a; Xarepresents a methylene group where the hydrogen atom of the above methylene group may be replaced by Deputy, selected from the following group V1 of substituents, or an oxygen atom; and nais an integer from 1 to 3,

group A1 deputies: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl g is the SCP, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups),

the group V1 of substituents: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) oxoprop, (7) carboxyl group, (8) C3-C8 cycloalkyl group, (9) C2-C6 Alchemilla group, (10) C2-C6 Alchemilla group, (11) C1-C6 allylthiourea, (12) C1-C6 alkoxycarbonyl group, (13) C1-C6 alkylsulfonyl group, (14) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by a halogen atom, a hydroxyl group or C1-C6-alkoxygroup), (15) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (16) amino group (where the above amino group may be substituted by the Deputy, you the early group, consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (17) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), (18) C1-C6 alkoxyimino, (19) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (20) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same and the same carbon atom, together with the oxygen atom and the above carbon atom;

4) the compound according to the above item 3) or its pharmacologically acceptable salt, where R11aand R12aform a carbonyl group together with the carbon atoms to which R11aand R12aattached;

5) the compound according to the above item 3) or (4) or its pharmacologically acceptable salt, where R4aand R5arepresent substituents selected from the following group B2 substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 ALK is supplemented flax group,

group B2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 alkoxygroup, (6) C1-C6 alkoxy-C1-C6 alkyl group, (7) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (8) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

6) the compound according to any one of the above paragraphs (3) (-5) or its pharmacologically acceptable salt, where R4aand R5arepresent substituents selected from the following group B5 substituents, and R6is a Deputy selected from the following group A4 deputies,

group A4 deputies: (1) a hydrogen atom, and (2) C1-C6 alkoxygroup,

group B5 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 alkoxy-C1-C6 alkyl group, (4) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (5) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

7) the compound according to any one of you described is e (3)to (6) or its pharmacologically acceptable salt, where Xarepresents an oxygen atom;

8) the compound according to above described paragraph (1) or its pharmacologically acceptable salt, which is represented by formula (I-b-1), formula (I-b-2), formula (I-b-3) or formula (I-b-4):

where R4aand R5arepresent substituents selected from the following group B5 substituents, and R6is a Deputy selected from the following group A4 deputies,

group A4 deputies: (1) a hydrogen atom, and (2) C1-C6 alkoxygroup,

group B5 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 alkoxy-C1-C6 alkyl group, (4) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (5) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

9) the compound according to the above item 3) or its pharmacologically acceptable salt, where R11arepresents a hydroxyl group, and R12arepresents a hydrogen atom or C1-C6 alkyl group;

10) the compound according to the above item 9) or its pharmacologically acceptable salt, where R4aand R5ato depict ablaut a Deputy, selected from the following group B2 substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

group B2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 alkoxygroup, (6) C1-C6 alkoxy-C1-C6 alkyl group, (7) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (8) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

11) the compound according to the above item 9) or 10) or its pharmacologically acceptable salt, where Xarepresents an oxygen atom;

12) the compound according to the above item 3) or its pharmacologically acceptable salt, where R11aand R12atogether form a group of formula =N-OR8c(where R8crepresents a C1-C6 alkyl group);

13) the compound according to the above item 12) or its pharmacologically acceptable salt, where R4a and R5arepresent substituents selected from the following group v3 of substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

the group v3 of substituents: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 alkoxygroup and (6) C1-C6 alkoxy-C1-C6 alkyl group;

14) the compound according to the above item 12) or (13) or its pharmacologically acceptable salt, where Xarepresents an oxygen atom;

15) the compound according to above described paragraph (1) or its pharmacologically acceptable salt, which is represented by formula (I-c-1) or formula (I-c-2):

where R3represents a hydrogen atom or methyl group and R4d, R5dand R6represent substituents selected from the following group A1 deputies,

group A1 deputies: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) 1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy, selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups);

16) the compound according to the above item 15) or its pharmacologically acceptable salt, where R4dand R5drepresent substituents selected from the following group V4 of substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

group B4 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 alcok the group and (4) C1-C6 alkoxy-C1-C6 alkyl group;

17) the compound according to above described paragraph (1) or its pharmacologically acceptable salt, which is represented by formula (I-d-1) or formula (I-d-2):

where R3represents a hydrogen atom or methyl group; R4e andR5erepresent substituents selected from the following group A1 substituents; R6is a Deputy selected from the following group A1 substituents; and each of Xeand Yerepresents (1) an oxygen atom, (2) methylene group, (3) -CONR7e- (where R7erepresents (1) hydrogen atom or (2) C1-C6 alkyl group), (4) -NR7eCO- (where R7eis above a certain value), (5) -NR8e- (where R8erepresents (1) C1-C6 alkyl group, or (2) C1-C6 acyl group), or (6) single bond,

group A1 deputies: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup, (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups);

18) the compound according to the above item 17) or its pharmacologically acceptable salt, where R4eand R5erepresent substituents selected from the following group v3 of substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

the group v3 of substituents: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 alkoxygroup and (6) C1-C6 alkoxy-C1-C6 alkyl group;

19) the compound according to above described paragraph (1) or its pharmacologically acceptable salt, which is represented by formula (I-e-1) or formula (I-e-2):

where R3represents a hydrogen atom or methyl group; R6is a Deputy selected from the following group A1 substituents; R7frepresents (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C3-C8 cycloalkyl group, (4) C2-C6 alkenylphenol group, (5) C2-C6 alkylamino group, or (6) C1-C6 alkoxy-C1-C6 alkyl group; and each of Xfand Yfrepresents (1) a single bond, (2) a methylene group which may have a Deputy, selected from the following group A1 substituents, or (3) a carbonyl group,

group A1 deputies: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl g is uppy, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups);

20) the compound according to the above item 19) or its pharmacologically acceptable salt, where R6is a Deputy selected from the following group A2 substituents; R7fis a Deputy selected from the following group V4 of substituents; and each of XfYfrepresents (1) a single bond, (2) a methylene group which may have a Deputy, selected from the following group V4 of substituents, or (3) a carbonyl group,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

group B4 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-6 alkoxygroup and (4) C1-C6 alkoxy-C1-C6 alkyl group;

21) the compound according to above described paragraph (1) or its pharmacologically acceptable salt, which is represented by formula (I-f-1), formula (I-f-2), formula (I-f-3), formula (I-f-4), formula (I-g-1), formula (I-g-2), formula (I-h-1), formula (I-h-2), formula (I-h-3) or formula (I-h-4):

where R3represents a hydrogen atom or methyl group and R6and R7grepresent substituents selected from the following group A1 substituents (excluding hydroxyl group for R7g),

group A1 deputies: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups);

22) the connection of isonomy above, paragraph 21) or its pharmacologically acceptable salt, where R6is a Deputy selected from the following group A2 substituents, and R7gis a Deputy selected from the following group V7 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

group A3 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, and (5) C1-C6 alkoxy-C1-C6 alkyl group;

23) the compound according to the above item 21) or 22) or its pharmacologically acceptable salt, where R6is a Deputy selected from the following group A4 substituents, and R7gis a Deputy selected from the following group B6 deputies,

group A4 deputies: (1) a hydrogen atom, and (2) C1-C6 alkoxygroup,

group B6 deputies: (1) a hydrogen atom, and (2) C1-C6 alkyl group;

24) the compound according to above described paragraph (1) or its pharmacologically acceptable salt, which is represented by formula (I-i-1) or formula (I-i-2):

where R3represents a hydrogen atom or methyl group and R6, R9hand R10hrepresent substituents selected from the following group is s A1 deputies; and XhYhrepresent (1) a methine group or (2) a nitrogen atom,

group A1 deputies: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups);

25) the compound according to above described paragraph (24) or its pharmacologically acceptable salt, where R9h, R10h, R6represent substituents selected from the following group A2 substituents, and Xhand Yhrepresent (1) a methine group or (2) atom AZ is the one

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) cyano, (5) C1-C6 alkoxygroup, (6) amino group, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group;

26) the compound according to the above paragraphs (8)-25), where R6represents a hydrogen atom;

27) the compound according to the above item 1), selected from the following group, or its pharmacologically acceptable salt:

1) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide,

2) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

3) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

4) 1-{1-[2-(6-methoxy-3-oxonian-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

5) 1-{1-[2-(6-methoxy-2-methylbenzothiazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

6) 1-{1-[2-(6-methoxy-2-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

7) 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

8) 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

9) 1-{1-[2-(5-methoxy-1-oxonian-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide and

10) 1-{1-[2-(7-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carbox the amide;

28) the compound according to the above item 1), selected from the following group, or its pharmacologically acceptable salt:

1) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide,

2) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide and

3) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide;

29) a pharmaceutical composition comprising as an active ingredient the compound represented by the following formula (I)or its pharmacologically acceptable salt:

where R1and R2represent substituents adjacent to each other, and together with the two carbon atoms to each of which they are attached, form:

(1) a 5-7 membered non-aromatic carbocyclic group,

(2) a 5-7 membered non-aromatic heterocyclic group,

(3) a 6-membered aromatic carbocyclic group, or

(4) a 5 - or 6-membered aromatic heterocyclic group,

which may be substituted by 1-4 substituents, selected from the following group V1 of substituents;

R3represents a hydrogen atom or methyl group, and

R6is a Deputy selected from the following group A1 deputies,

group A1 deputies: (1) at the m of hydrogen, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 Alchemilla group, (9) C2-C6 Alchemilla group, (10) C1-C6 allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group) and (16) carnemolla group (where the above carnemolla group can be substituted by one or two C1-C6 alkyl groups),

the group V1 of substituents: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) oxoprop, (7) carboxyl group, (8) C3-C8 cycloalkyl group, (9) C2-C6 Alchemilla group, (10) C2-C6 Alchemilla group, (11) C1-C6 allylthiourea, (12) C1-C6 alkoxycarbonyl group, (13) C1-C6 alkylsulfonyl group, (14) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may shall be substituted by halogen atom, a hydroxyl group or C1-C6-alkoxygroup), (15) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (16) amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (17) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), (18) C1-C6 alkoxyimino, (19) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (20) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom;

30) the pharmaceutical composition according to paragraph 28), characterized in that it is a tool for the treatment or prevention of symptoms of the lower urinary tract;

31) the pharmaceutical composition according to paragraph 30), characterized in that it is a tool for the treatment or prevention of symptoms related to the accumulation of urine;

32) the pharmaceutical composition according to paragraph 30 or 31), characterized in that it is a tool for the treatment or prevention of high frequency m is cheapostay or urinary incontinence;

33) the pharmaceutical composition according to paragraph 29), characterized in that it is a tool for the treatment or prevention of a decrease in cognitive ability associated with Alzheimer's disease or senile dementia, reduced learning ability or memory disorder, or anxiety disorder,

34) the pharmaceutical composition according to paragraph 29), characterized in that it is a tool for the treatment or prevention of schizophrenia, emotional disorders, alcohol and/or cocaine addiction, symptoms associated with withdrawal from the ingestion of nicotine or Smoking, or disorders of visual attention; and

35) the pharmaceutical composition according to paragraph 29), characterized in that it is a tool for the treatment or prevention of sleep disorders, migraine, temperature instability, eating disorders, vomiting, gastrointestinal disorders or genital failure.

The compound of the present invention, represented by formula (I), its pharmacologically acceptable salt and a tool for the treatment or prevention of symptoms of the lower urinary tract, which have the ability to contact the serotonin 1A receptor - all these new inventions, which are not described in any publications.

Below explains the meaning of the symbols or terms used in this description is AI, and provides a detailed description of the present invention.

In addition, it should be noted that for convenience in this specification, the structural formula of the compound indicates the specific isomer. However, the present invention encompasses all geometric isomers found in the structures of the compounds, such as optical isomers based on asymmetric carbons, stereoisomers, tautomers and mixtures of isomers. Thus, the present invention is not limited to the structural formula shown in this description for convenience, but may also include an isomer or mixture of isomers. Consequently, it is possible that the compound has in the molecule asymmetric carbon atom and that there are optically active substance and the racemate. In the present invention has no restrictions on these cases and both cases are included in the scope of the present invention. In addition, the possible case of crystalline polymorphism. This case is also not limited, and can be either a single crystal form or a mixture of crystalline forms, with the addition of the anhydride may be a hydrate.

In this description, the term "symptoms of the lower urinary tract" is used as the generic name symptoms related to the disorder of the mechanism of accumulation of urine and disorder mechanism mosaicus the project.

When used in this description, the term "urinary dysfunction" means different types of disorders/abnormalities"that can impair normal urination, which include (1) the anomaly volume of urine, such as polyuria, oliguria or anuria, (2) the anomaly frequency of urination", such as increased frequency of urination or aigakikoeru, (3) difficulty urinating", (4) "inures", (5) "urinary incontinence", (6) "anomaly condition when urinating", such as enuresis, (7) "anomaly flow of urine, such as decreased flow of urine, decreased force of urination, interruption or double emptying, etc. in Addition, the term "urinary dysfunction" includes diseases that are considered dependent in relation to disorders/abnormalities described in paragraphs (1)to(7), which are considered major. For example, urinary dysfunction, of course, includes the following disorders: neurogenic bladder, neurotic increased frequency of urination, unstable bladder, increased urinary frequency associated with a state of irritation of the bladder, caused by chronic bladder, increased urinary frequency associated with a state of irritation of the bladder, chronic prostatitis, an imperative urge to urinate, poderia is their urine, reflex incontinence, stress incontinence, urinary incontinence, overflow urinary bladder, urinary incontinence, associated with the state of irritation of the bladder, chronic cystitis, urinary incontinence, associated with the state of irritation of the bladder, chronic prostatitis, nycturia, psychogenic dysuria, nocturnal enuresis, etc.

When used in this description, the term "anxiety disorder" means, for example, generalized anxiety disorder, panic disorder, phobic neurosis (e.g., agoraphobia, anthropophobia, simple phobia), obsessive-compulsive disorder or the like Used in the present description the term "emotional disturbance" means a depression (classic depression), manic-depressive psychosis (bipolar disorder), dysthymia (depressive neurosis) or similar

Each of the "5 to 7-membered non-aromatic carbocyclic group", "5-7-membered non-aromatic heterocyclic group", "6-membered aromatic carbocyclic group" and "5 - or 6-membered aromatic heterocyclic group"contained in the tool of the present invention for the treatment or prevention of symptoms of the lower urinary tract represented by the above formula (I), has the following value.

The term "5-chlena non-aromatic carbocyclic group" means a non-aromatic hydrocarbon group, containing 5-7 carbon atoms. Examples of such groups may include cyclopentyloxy group, tsiklogeksilnogo group and cycloheptyl group.

The term "5 to 7-membered non-aromatic heterocyclic group" means a nonaromatic heterocyclic group containing 1-4 heteroatom. Preferred examples of such groups may include pyrrolidinyloxy group, imidazolidinyl group, pyrazolidine group, piperidinyl group, piperazinilnom group, morpholinyl group, tetrahydropyranyloxy group, dioxinlike group, piperidine-2-oxoline group, dihydro-[1,3]oxazin-2-oxoline group, a [1,4]oxazepan-5-oxoline group, dihydro-[1,3]oxazin-2,4-DIOXOLANYL group, 5,6-dihydro-1H-pyridine-2-oxoline group, tetrahydropyran-4-oxoline group, 2,3-dihydropyran-4-oxoline group, tetrahydropyran-4-hydroxyl group, oxepin-4-oxoline group, 1,3-oxazolidin-2-oxoline group, etc.

The term "6-membered aromatic carbocyclic group" means a phenyl group.

A preferred example of the "5 - or 6-membered aromatic heterocyclic group" may be (1) nitrogen-containing heteroaromatic group, such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group; (2) sulfur-containing heteroaromatic the ski group, such as thienyl group; (3) oxygen-containing heteroaromatic group, such as furilla group, oxaspiro[5,4]dekheila group; (4) heteroaromatic groups containing two or more heteroatoms, such as thiazolidine group, isothiazolinone group, oxazoline group, isoxazolyl group, and the two or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom.

In the formula (I) each of the groups A1 deputies, group A2 deputies, group A3 deputies, group A4 deputies, group V1 of substituents, the B2 group substituents, the group v3 of substituents, the groups R4 substituents, B5 group of deputies, group B6 substituents and groups V7 substituents include the following groups.

Group A1 deputies consists of (1) hydrogen atom, (2) halogen atom, (3) ceanography, (4) hydroxyl group, (5) nitro, (6) carboxyl group, (7) C3-C8 cycloalkyl group, (8) C2-C6 alkenylphenol group, (9) C2-C6 alkenylphenol group, (10) C1-C6 of allylthiourea, (11) C1-C6 alkoxycarbonyl group, (12) C1-C6 alkylsulfonyl group, (13) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by 1-3 substituents selected from the group consisting of halogen atom, hydroxyl group and C1-C6 of alkoxygroup), (14) C1-C6 of alkoxygroup (where the above-described C1-C6 alkoxygroup can is to be substituted by 1-3 halogen atoms), (15) an amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (16) carbamoyl group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), and (17) C1-C6 of alkoxyimino.

Group A2 deputies consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography, (5) C1-C6 of alkoxygroup, (6) amino groups, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl groups.

Group A3 deputies consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography and (5) C1-C6 alkoxy-C1-C6 alkyl groups.

Group A4 deputies consists of (1) hydrogen atom or (2) C1-C6 of alkoxygroup.

The group V1 of substituents consists of (1) hydrogen atom, (2) halogen atom, (3) ceanography, (4) hydroxyl group, (5) nitro, (6) carbonyl group, (7) carboxyl group, (8) C3-C8 cycloalkyl group, (9) C2-C6 alkenylphenol group, (10) C2-C6 alkenylphenol group, (11) C1-C6 of allylthiourea, (12) C1-C6 alkoxycarbonyl group, (13) C1-C6 alkylsulfonyl group, (14) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by a halogen atom, a hydroxyl group is Oh or C1-C6-alkoxygroup), (15) C1-C6 of alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (16) amino (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (17) carbamoyl group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), (18) C1-C6 of alkoxyimino, (19) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (20) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom.

When the substituents described in (19) or (20), shown specifically, they are represented, for example, by the following formula:

Group B2 deputies consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 of alkoxygroup, (6) C1-C6 alkoxy-C1-C6 alkyl group, (7) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (8) tetrahydropyranyl group formed by two C1-C3 al the ilen groups, attached to the same carbon atom, together with the oxygen atom and the above carbon atom.

The group v3 of substituents consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 of alkoxygroup and (6) C1-C6 alkoxy-C1-C6 alkyl groups.

Group B4 deputies consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 of alkoxygroup and (4) C1-C6 alkoxy-C1-C6 alkyl groups.

Group B5 deputies consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 alkoxy-C1-C6 alkyl group, (4) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (5) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom.

Group B6 deputies consists of (1) hydrogen atom or (2) C1-C6 alkyl groups.

Group B7 deputies consists of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography and (5) C1-C6 alkoxy-C1-C6 alkyl groups.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom, iodine atom. Preferably it is fluorine atom, chlorine atom or bromine atom.

The term "C1-C6 alkyl group" means an alkyl group containing 1-6 the low carbon atoms. Preferred examples of such groups include unbranched or branched alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, n-pencilina group, isopentyl group, neopentyl group, n-exilda group, 1-methylpropyl group, 1,2-dimethylpropylene group, 2-ethylpropyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group or 3-methylpentyl group.

The term "C2-C6 Alchemilla group" means alkenylphenol group containing 2-6 carbon atoms. Preferred examples of such groups include unbranched or branched alkeneamine groups such as vinyl group, allyl group, 1-protanilla group, Isopropenyl group, 1-butene-1-ilen group, 1-butene-2-ilen group, 1-butene-3-ilen group, 2-butene-1-ilen group or 2-butene-2-ilen group.

The term "C2-C6 Alchemilla group" means alkylamino group containing 2-6 carbon atoms. Preferred examples of such groups include unbranched or did the run alkyline group, such as etinilnoy group, 1-proponila group, 2-proponila group, Butyrina group, puntinella group or hexylamine group.

The term "C3-C8 cycloalkyl group" means a cyclic alkyl group containing 3-8 carbon atoms. Preferred examples of such groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group.

The term "C1-C6 alkoxygroup" means an alkyl group containing 1-6 carbon atoms, where the hydrogen atom is replaced by oxygen atom. Preferred examples of such groups include a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, sec-propoxylate, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, n-pentyloxy, isopentylamine, sec-pentyloxy, tert-pentyloxy, n-hexyloxy, isohexadecane, 1,2-DIMETHYLPROPANE, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1-Dimethylbutane, 2,2-Dimethylbutane, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylpentylamino, 3-methylpentylamino, hexyloxy etc.

The term "C1-C6 allylthiourea" means an alkyl group containing 1-6 of operon the x atoms, where the hydrogen atom is substituted by a sulfur atom. Preferred examples of such groups include metalcorp, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, tert-butylthiourea, n-intelligroup, isopentype, pointertype, n-vexillographer, 1-methylpropyloxy etc.

The term "C1-C6 alkoxycarbonyl group" means a group formed by linking the carbonyl group with the above alkoxygroup. Preferred examples of such groups include methoxycarbonyl group and ethoxycarbonyl group.

The term "C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom" means cyclopentyloxy group or tsiklogeksilnogo group.

The term "C1-C6 alcoolica group (C1-C6 alkylcarboxylic group" means an alkyl group containing 1-6 carbon atoms, where the hydrogen atom is replaced by a carbonyl group. Preferred examples of such groups include acetyl group, propionyl group and butyryloxy group, etc.

The term "C1-C6 alkylsulfonyl group" means an alkyl group containing 1-6 carbon atoms, where the hydrogen atom is substituted sulfonyloxy group. Preferred examples of such groups include methanesulfonyl group, econsultancy the second group and so on

The term "amino group which may be substituted by C1-C6 alkyl group" means an amino group to which is attached alkyl group containing 1-6 carbon atoms. Preferred examples of such groups include an amino group, methylaminopropyl, ethylamino, propylamino etc.

Examples of the "amino group which may be substituted formyl group"include an amino group and formylamino.

The term "amino group which may be substituted by C1-C6 alkanoyloxy group" means an amino group to which is attached alkanoyloxy group containing 1-6 carbon atoms. Preferred examples of such groups include acetylamino, propionamido, bucillamine etc.

The term "amino group which may be substituted by C1-C6 alkylsulfonyl group" means an amino group to which is attached alkylsulfonyl group containing 1-6 carbon atoms. Preferred examples of such groups include an amino group, methanesulfonylaminoethyl, ethanolamines, n-propanesulfonate, n-butanesulfonate, N-methylmethanesulfonamide etc.

The term "carnemolla group which may be substituted by one or two C1-C6 alkyl group" means karbamoilnuyu group, where one or two hydrogen atoms may be mo is about - or disubstituted by C1-C6 alkyl groups. Preferred examples of such groups include N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, N-ethylcarbazole group, N,N-diethylcarbamoyl group, etc.

The term "C1-C6 alkoxyimino" means aminogroup, where the hydrogen atom is substituted by C1-C6-alkoxygroup. Preferred examples of such groups include methoxyimino, toksikologiya etc.

The following describes the connection of the present invention, represented by formula (I).

The compound represented by formula (I)selectively binds to the serotonin 1A receptor and is antagonism of this receptor. It is used for treatment or prevention of diseases, which also involved serotonin A1 receptor, such as symptoms of the lower urinary tract. Preferred examples of such compounds may include the compound represented by formula (I-a-1), the compound represented by formula (I-a-2), the compound represented by formula (I-a-3), the compound represented by formula (I-a-4), the compound represented by formula (I-c-1), the compound represented by formula (I-c-2), the compound represented by formula (I-d-1), the compound represented by formula (I-d-2), the compound represented by formula (I-e-1), the compound represented by formula (I-e-2), the compound represented by formula (I-f-1), the compound represented by Faure who Ulai (I-f-2), the compound represented by formula (I-f-3), the compound represented by formula (I-f-4), the compound represented by formula (I-g-1), the compound represented by formula (I-g-2), the compound represented by formula (I-h-1), the compound represented by formula (I-h-2), the compound represented by formula (I-h-3), the compound represented by formula (I-h-4), the compound represented by the formula (I-i-1)and the compound represented by formula (I-i-2).

Among these compounds as compounds represented by formula (I-a-1), (I-a-2), (I-a-3) or (I-a-4), more preferred is a compound where in each formula

R11aand R12aform a carbonyl group together with the carbon atoms to which R11aand R12aattached

Xarepresents an oxygen atom

R3represents a hydrogen atom or methyl group,

R4aand R5arepresent substituents selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 alkoxy-C1-C6 alkyl group, (4) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (5) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above and the Ohm carbon,

R6is a Deputy selected from the group consisting of (1) hydrogen atom or (2) C1-C6 of alkoxygroup, and

Na is an integer from 1 to 3,

or its pharmacologically acceptable salt.

As compounds represented by formula (I-c-1) or (I-c-2), more preferred is a compound where in each formula

R3represents a hydrogen atom or methyl group,

R4dand R5drepresent substituents selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 of alkoxygroup and (4) C1-C6 alkoxy-C1-C6 alkyl group, and

R6is a Deputy selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography, (5) C1-C6 of alkoxygroup, (6) amino groups, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

or its pharmacologically acceptable salt.

As compounds represented by formula (I-d-1) or (I-d-2), more preferred is a compound where in each formula

R3represents a hydrogen atom or methyl group,

each of Xeand Yerepresents (1) an oxygen atom, (2) methylene group, (3) -CONR7e- (where R7erepresents (1) hydrogen atom or (2) C1-C6 ALK is optimum group), (4) -NR7eCO- (where R7eis above a certain value), (5) -NR8e- (where R8erepresents (1) C1-C6 alkyl group, or (2) C1-C6 acyl group), or (6) single bond,

R4e andR5erepresent substituents selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) hydroxyl group, (5) C1-C6 of alkoxygroup and (6) C1-C6 alkoxy-C1-C6 alkyl group, and

R6is a Deputy selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography, (5) C1-C6 of alkoxygroup, (6) amino groups, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

or its pharmacologically acceptable salt.

As compounds represented by formula (I-e-1) or (I-e-2), more preferred is a compound where in each formula

R3represents a hydrogen atom or methyl group,

R6is a Deputy selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography, (5) C1-C6 of alkoxygroup, (6) amino groups, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group,

R7fis a Deputy, selected from the group SOS is oasa from (1) hydrogen atom, (2) C1-C6 alkyl group and (3) C1-C6 alkoxy-C1-C6 alkyl group, and

each of Xfand Yfrepresents substituents selected from the group consisting of (1) a single bond, (2) a methylene group which may have a Deputy selected from the group consisting of a hydrogen atom, C1-C6 alkyl groups and C1-C6 alkoxy-C1-C6 alkyl group, and (3) a carbonyl group,

or its pharmacologically acceptable salt.

As compounds represented by formula (I-f-1), (I-f-2) (I-f-3), (I-f-4), (I-g-1), (I-g-2), (I-h-1), (I-h-2), (I-h-3) or (I-h-4), more preferred is a compound where in each formula

R3represents a hydrogen atom or methyl group,

R6is a Deputy selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography, (5) C1-C6 of alkoxygroup, (6) amino groups, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group, and

R7gis a Deputy selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography and (5) C1-C6 alkoxy-C1-C6 alkyl group,

or its pharmacologically acceptable salt.

As compounds represented by formula (I-i-1) or (I-i-2), more preferred is a compound where each of the four the OLE

R3represents a hydrogen atom or methyl group,

R9h, R10hand R6represent substituents selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) halogen atom, (4) ceanography, (5) C1-C6 of alkoxygroup, (6) amino groups, where the nitrogen atom may be substituted by C1-C6 alkyl group, and (7) C1-C6 alkoxy-C1-C6 alkyl group, and

each of Xhand Yhrepresents (1) a methine group or (2) a nitrogen atom,

or its pharmacologically acceptable salt.

Among these groups of compounds the most preferred compounds are the following. In the case of compound represented by formula (I-b-1), (I-b-2), (I-b-3) or (I-b-4), most preferred is a compound where in each formula, R3represents a hydrogen atom or methyl group, R4aand R5arepresent substituents selected from the group consisting of (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C1-C6 alkoxy-C1-C6 alkyl group, (4) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (5) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom, and R6 is a Deputy selected from the group consisting of (1) hydrogen atom or (2) C1-C6 of alkoxygroup, or its pharmacologically acceptable salt. In the case of compound represented by formula (I-f-1), (I-f-2), (I-f-3), (I-f-4), (I-g-1), (I-g-2), (I-h-1), (I-h-2), (I-h-3) or (I-h-4), most preferred is a compound where in each formula, R3represents a hydrogen atom or methyl group, R6is a Deputy selected from the group consisting of (1) hydrogen atom or (2) C1-C6 of alkoxygroup, and R7gis a Deputy selected from the group consisting of (1) hydrogen atom or (2) C1-C6 alkyl group, or its pharmacologically acceptable salt.

In particular, preferred are compounds selected from the following group, or a pharmacologically acceptable salt:

1) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide,

2) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

3) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

4) 1-{1-[2-(6-methoxy-3-oxonian-5-yl)ethyl]piperidine-4-yl)-1H-indole-6-carboxamide,

5) 1-{1-[2-(6-methoxy-2-methylbenzothiazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

6) 1-{1-[2-(6-methoxy-2-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carbox the ID,

7) 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

8) 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

9) 1-{1-[2-(5-methoxy-1-oxonian-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide and

10) 1-{1-[2-(7-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide.

Among them, for example,

1) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide,

2) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide, and

3) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide.

These compounds or their pharmacologically acceptable salts have a strong antagonism to 5-HT1A receptor and are useful as remedies for the treatment or prevention of symptoms of the lower urinary tract and, in particular, symptoms related to the accumulation of urine.

Preferred variants of the above compounds represented by formula (I)described above. But the active ingredients of a medicinal product according to the present invention is not limited to the specific compounds described in this description. Can be selected to the extent possible, all options included in the scope of compounds represented by formula (I).

Described below is the procedure for obtaining compounds of the present invention, represented by formula (I).

The connection represented by the General formula (I):

where R1, R2, R3and R6have the same meanings as described above, synthesize, for example, according to the General methods 1-5 obtain, described below. As used below, the term "room temperature" means a temperature from about 15°C to 30°C.

[General procedure 1 retrieve]

where R(1)represents a lower alkyl group such as methyl group or ethyl group, lower aracelio group such as benzyl group, or the like; R(2)represents a hydrogen atom, methyl group or the like; X represents a leaving group including a halogen atom (chlorine atom, bromine atom, iodine atom etc), sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov or the like; R(13)represents a methyl group, ethyl group or the like, which can be either hydrolyzed; P(1)represents a protective group for an amino group which may be removed, such as benzyloxycarbonyl group, tert-butyloxycarbonyl group or the like; and R1, R2, R 3and R6have the same meanings as described above.

The above method [public method 1 receipt] is a method for obtaining compounds of the present invention, represented by formula (I), which is used as a compound (1-1) as the source material and carry out multi-stage process from [stage 1-1] to [stage 1-7].

The compound (1-1) can also be obtained from a commercially available product by methods known to experts in this field. Examples of such known methods may include: Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1), 71-74 (1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15), 1653 (1986), and Sakamoto Takao, Yoshinori Kondo, Hiroshi Yamanaka, Chem. Pharm. Bull., Vol. 34, p. 2362 (1986).

As for the compounds (1-2) and the compound (1-6), can be used directly commercially available products, or these compounds may also be obtained from commercially available products by methods known to experts in this field. The compound (1-9) and the compound (1-10) can be obtained from commercially available products by methods known to experts in this field or can be also obtained by the method described in this description and in the examples received.

[Stage 1-1]

This stage is the stage of obtaining the compound (1-3) vosstanovit the NYM aminating the compound (1-1) and compound (1-2).

The reaction can be carried out under the same conditions, which are usually used for reductive amination of carbonyl compounds and amino compounds. The reaction of recovery at this stage is not particularly limited. Examples of such reactions include the reaction of reductive amination using a reducing agent such as borane or borhydride compound, and the reaction of catalytic reduction using a metal catalyst in a hydrogen atmosphere.

Examples of the reaction of reductive amination using borhydride complex compounds can be the methods described in publications, such as W. S. Emerson, Organic Reactions, 4, 174 (1948), C. F. Lane, Synthesis, 135 (1975), J. C. Ctowell and S. J. Pedegimas, Synthesis, 127 (1974), A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and R. D. Shah, Journal of Organic Chemistry, 61, 3849 (1996).

Examples borhydride complex compounds used in this reaction may include sodium borohydride, cyanoborohydride sodium and triacetoxyborohydride sodium.

When the reductant used borhydride compound, the solvent is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Specific examples of the solvent used in this reaction may include methanol, this is ol, tetrahydrofuran, N,N-dimethylformamide, methylene chloride and 1,2-dichloroethane. When this reaction is carried out in the presence of acid, can be obtained preferred results, such as increasing output. The acid is not particularly limited. Preferred examples of such acids may include mineral acids such as chloromethane acid, organic acids such as acetic acid and a Lewis acid such as zinc chloride, a complex of boron TRIFLUORIDE in diethyl ether or tetraisopropoxide titanium(IV).

The compound (1-2) is used in the ratio of 0.8 to 2.5 equivalents, preferably 1-1 .5 equivalents, relative to compound (1-1). Borhydride compound used in respect of 1-3 equivalents, preferably 1-1 .5 equivalents, relative to compound (1-1). The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 12 hours.

The reaction temperature is not particularly limited. It is usually from -78°C to the boiling point of the solvent, preferably from temperature on ice to room temperature.

When carry out the reaction of catalytic reduction in a hydrogen atmosphere, the solvent used is not particularly limited, but he would not slow down the reaction. Examples of the solvent may include methanol, ethanol, tetrahydrofuran is 1,4-dioxane. Examples of the metal catalyst used for this reaction may include palladium, palladium oxide and Raney Nickel. The reaction time is not particularly limited. It is usually from 1 to 48 hours, preferably from 1 to 24 hours.

Reaction conditions are not particularly limited. The reaction can be carried out at a temperature of from room temperature to the boiling point of the solvent at a pressure of from normal up to 150 atmospheres, preferably at a temperature from room temperature to 60°C at a pressure of from normal to 5 atmospheres.

[Stage 1-2]

This stage relates to methods for obtaining compounds (1-4) by cyclization of compounds (1-3) acid.

The reaction can be carried out under the same reaction conditions, which are described, for example, Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1), 71-74 (1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15), 1653 (1986), and Sakamoto Takao, Yoshinori Kondo, Hiroshi Yamanaka, Chem. Pharm. Bull., Vol. 34, p. 2362 (1986).

Solvent used in this reaction are not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Examples of such a solvent include water; a mixed solvent consisting of water and an organic solvent, such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, benzene or toluene; and organic the ski solvents, such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, benzene or toluene. This reaction can be carried out by providing the possibility of action of a suitable acid at a ratio of 1 equivalent to excess amount of the above compound in the specified solvent. Examples of the acid used in this reaction may include acetic acid, hydrogen chloride, chloroethanol acid, Hydrobromic acid, sulfuric acid, nitric acid, triperoxonane acid, p-toluensulfonate acid, pyridinium salt of p-toluensulfonate acid and camphorsulfonic acid.

The reaction time is not particularly limited. It is usually from 1 to 24 hours, preferably from 1 to 4 hours.

The reaction temperature is usually in the range from a temperature on ice to the boiling temperature under reflux of the solvent. It should be noted that [stage 1-1] and [stage 1-2] can be also carried out by conducting the reaction in one pot without isolating the compound (1-3).

[Stage 1-3]

This stage is the stage of obtaining compounds (1-5) alkaline hydrolysis of compounds (1-4).

The reaction can be carried out under the same conditions as are described, for example, Matassa, V. G.; Brown, F. J.; Bernstein, P. R.; Shapiro, H. S.; Maduskuie, T. P. J.; Cronk, L. A.; Vacek, E. P.; Yee, Y. K.; Snyder, D. W.; Krell, R. D.; Lerman, C. L.; Maloney, J. J.; J. Med. Chem., 33 (9), 2621-2629 (1990).

In particular, to the solution containing the compound (1-4)add, for example, a base such as sodium hydroxide. The mixture is then stirred for from several hours to 1 day. Then the mixture is treated with acid, such as citric acid, to obtain the compounds (1-5).

Solvent used in this reaction are not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Examples of such a solvent may include methanol, ethanol, 2-propanol, tetrahydrofuran and 1,4-dioxane. The base used in this reaction are not particularly limited. Preferred examples of such a base may include sodium hydroxide, potassium hydroxide and lithium hydroxide. The amount used is in the range of from 1 equivalent to excess amount, preferably from 1 to 20 equivalents, relative to compound (1-4).

The reaction time is not particularly limited. It is usually from 1 to 24 hours, preferably from 1 to 6 hours.

The reaction temperature is not particularly limited. It is usually in the range from room temperature to the boiling temperature under reflux of the solvent.

When a complex ester is benzyl or allyl ether, carboxylic acid can be obtained under the same conditions, which usually use the Ute when removing the protective group for carboxylic acid derivative (these terms are described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), pp. 248-251).

[Stage 1-4]

This stage is the stage of obtaining the compound (1-7) or compounds (1-5) (1-6) using a condensing agent.

The reaction of condensation of compounds (1-5) and (1-6) condensing agent may be carried out under the same conditions as commonly used conditions are described in the following publications. Such known techniques include Rosowsky, A.; Forsch, R. A.; Moran, R. G.; Freisheim, J. H.; J. Med. Chem., 34 (1), 227-234 (1991), Brzostwska, M.; Brossi, A.; Flippen-Anderson, J. L.; Heterocycles, 32 (10), 1969-1972 (1991), Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P.D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; So, A. G.; Resnick, L.; Tarpley, W. G., Aristoff, P. A.; J. Med. Chem., 37 (7), 999-1014 (1994).

The compound (1-6) can be free form or salt.

Solvent used in this reaction are not particularly limited, but he would not slow down the reaction. Examples of such a solvent may include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, methylene chloride, chloroform, N,N-dimethylformamide, toluene and xylene. Examples of the condensing agent may include CDI (N,N'-carbonyldiimidazole), Bop (hexaphosphate 1H-1,2,3-benzotriazol-1 iloxi(three(dimethylamino))phosphonium), WSC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (N,N-dicyclohexylcarbodiimide) and diethylphosphoramidite Connection (1-6) is used at a ratio of 1 equivalent to excess amount relative to compound (1-5). In addition, if necessary, may be added an organic base, such as triethylamine, at a ratio of 1 equivalent to excess.

The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

The reaction temperature is not particularly limited, and it is different depending on the starting material, the solvent used and the like, Preferably it is in the range from the temperature of the ice to the boiling point of the solvent.

In addition, the compound (1-7) can also be obtained from compound (1-5) (1-6) for the alternative methods described below in (1) and (2).

Alternative method (1)

The compound (1-5) is transformed into a mixed anhydride of the acid. Then the mixed anhydride of the acid is allowed to interact with the compound (1-6) to obtain the compound (1-7). Specified mixed acid anhydride can be synthesized by a method known to specialists in this field of technology. For example, the compound (1-5) is allowed to interact with complex ether of Harborview acid, such as ethylchloride, in the presence of a base such as triethylamine. These ether of Harborview acid and base used in the ratio of 1 to 2 equivalents relative to the compound (1-5). Temperature is the tour of the reaction is in the range from -30° With up to room temperature, preferably from -20°C to room temperature.

Carry out the stage of condensation of the mixed anhydride of the acid and the compound (1-6), for example, providing interoperability mixed acid anhydride with the compound (1-6) in a solvent such as methylene chloride, tetrahydrofuran or N,N-dimethylformamide. The compound (1-6) is used at a ratio of 1 equivalent to excess amount relative to the mixed anhydride of the acid.

The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 12 hours.

The reaction temperature is from -20°C to 50°C, preferably from -20°C to room temperature.

Alternative method (2)

The compound (1-5) is transformed into an activated ester. Then activated complex ether provide interoperability with compound (1-6) to obtain the compound (1-7). The stage of receipt of the activated complex ester may be effected by providing the compound (1-5) interoperability with the reagent for the synthesis of the activated complex ester in a solvent such as 1,4-dioxane, tetrahydrofuran or N,N-dimethylformamide, in the presence of a condensing agent such as DCC. An example of the specified reagent for the synthesis of enabled what about the complex ester is N-hydroxysuccinimide. These reagent for the synthesis of the activated complex ester and condensing agent is used at a ratio from 1 to 1.5 equivalents relative to the compound (1-5). The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

The reaction temperature is from -20°C to 50°C, preferably from -20°C to room temperature.

The stage of condensation of the activated complex ester and compounds (1-6) carry out the provision of ether complex capable of interacting with the compound (1-6) in a solvent such as methylene chloride, tetrahydrofuran or N,N-dimethylformamide. The compound (1-6) is used at a ratio of 1 equivalent to excess amount relative to the activated complex ether.

The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

The reaction temperature is from -20°C to 50°C, preferably from -20°C to room temperature.

[Stage 1-4']

This stage is the stage of obtaining the compound (1-7) condensation of the compound (1-4) (1-6).

This condensation reaction can be carried out under the same conditions, which are usually used for the condensation reaction of the derived complex ester and amino compounds. Known techniques which include Dodd, J. H.; Guan, J.; Schwender, C. F.; Synth. Commun., 23 (7), 1003-1008 (1993), Sim, T. B.; Yoon, N. M.; and Synlett, (10), 827-828 (1994). Used aminosidine (1-6) can be free form or salt.

Solvent used in this reaction are not particularly limited, but he would not slow down the reaction. Examples of such a solvent may include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, toluene, xylene and acetic acid. In addition, the solvent can also be used aminosidine (1-6). The compound (1-6) is used at a ratio of 1 equivalent to excess amount relative to compound (1-4).

The reaction time is not particularly limited. It is usually from 1 to 48 hours, preferably from 1 to 24 hours.

The reaction temperature is not particularly limited, and it is different depending on the starting material, the solvent used and the like, Preferably it is in the range from room temperature to the boiling temperature of the solvent.

Furthermore, in this reaction, the reaction solution may be added acid, such as p-toluensulfonate acid or camphorsulfonic acid, a Lewis acid such as trimethylaluminum, or bases, such as sodium hydride, to obtain good results, such as reducing the reaction time or increasing output. the moreover, can be used properly closed heat-resistant vessel such as an autoclave to heat the reaction mixture to a high temperature from 100°, 250°C with getting good results, such as reducing the reaction time.

[Stage 1-5]

This stage is the stage of obtaining compounds (1-8) removing the protective group for the secondary amino compounds (1-7).

The reaction of removing the protection can be carried out under the same conditions, which is usually used for removal of the protective group for the amino compounds. Such conditions are described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), pp. 309-405. When the amino group of the compound (1-7) protect, for example, benzyloxycarbonyl group, the protective group is removed by hydrogenolysis of the compound (1-7), using palladium-on-carbon as catalyst, in a solvent such as alcohol, to obtain the compound (1-8).

[Stage 1-6]

This stage is the stage of obtaining the compound represented by the General formula (I), by reaction of reductive amination between the compound (1-8) and the compound (1-9).

At this stage use the compound (1-8) and the compound (1-9) as starting materials and method described above in the section relating to the method of obtaining ([stage 1-1]), for the synthesis of compounds, not only the frame of General formula (I). In addition, as the compound (1-9) can be directly used commercially available product, or the specified connection can be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained in accordance with examples of the preparation in this specification, or according to the method described in section [General methods A, B, C, D or E of receipt]. And yet, the connection (1-8) can be free form or salt.

[Stage 1-7]

This stage is the stage of obtaining the compound represented by the General formula (I), the implementation of the nucleophilic substitution reaction between compound (1-8) and the compound (1-10).

This nucleophilic substitution reaction can be carried out under the same conditions, which are usually used for communicating secondary amine with a halogenated compound (for example, under the conditions described by Hirai, Y.; Terada, T.; Okaji, Y.; Yamazaki, T.; Tetrahedron Lett., 31 (33), 4755-4758 (1990), and so on). In addition, as the compound (1-10) can be used directly commercially available product, or the specified connection can be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained with the examples get in this specification, or according to the method, described in section [General procedure E to obtain]. In addition, the connection (1-8) can be free form or salt.

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include methanol, ethanol, propanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, methylene chloride, chloroform, N,N-dimethylformamide and dimethylsulfoxide. The compound (1-10) is used at a ratio between 1 and 10 equivalents, preferably 1 to 5 equivalents, relative to compound (1-8).

The reaction time is not particularly limited. It is usually from 1 to 72 hours, preferably from 1 to 48 hours.

The reaction temperature ranges usually from room temperature to the boiling temperature under reflux of the solvent, preferably from room temperature to 100°C.

In addition, the Foundation can give good results, such as increasing output. Used the base is not particularly limited, if only it didn't slow the reaction. Preferred examples of such a base may include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, databaseconnect, sodium hydride, potassium hydride, sodium methoxide, the methods of the led potassium, tert-piperonyl potassium, triethylamine and diisopropylethylamine.

The connection represented by the General formula (I)can also be obtained according to the method described in the next section [General procedure 1' receipt].

[The General procedure 1' retrieve]

where R(2), R1, R2, R6and P(1)have the same meanings as described above, and X represents a leaving group such as halogen atom (chlorine atom, bromine atom, iodine atom or the like) or sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov.

The above method [Public method 1' receipt] is a method for obtaining compounds of the present invention represented by the General formula (I), which contains many stages [stage 1'-1] to [stage 1'-9].

As compounds (1'-1) can be directly used commercially available product, or the connection can be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, commercially available products can be used directly as compounds (1-2) and the compound (1-6) or pointed to by the e compounds can be obtained from commercially available products by the methods well-known experts in this field.

[Stage 1'-1]

This stage is the stage of synthesis of the compound (1'-2) using the compound (1'-1) and the compound (1-6) as starting materials and method described above in the described method get ([stage 1-4]).

[Stage 1'-2]-[stage 1'-4]

This stage is the stage of obtaining the compound (1'-6) from the compound (1'-2) joint use of various reactions known to specialists in this field of technology.

Examples of such known method may include: Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1), 71-74 (1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15), 1653 (1986), and Sakamoto Takao, Yoshinori Kondo, Hiroshi Yamanaka, Chem. Pharm. Bull., Vol. 34, p. 2362 (1986).

In particular, the compound (1'-6) can be obtained by implementation stages [stage 1'-2] to [stage 1'-4]. Needless to say that the method of obtaining the compound (1'-6) is not limited to these stages. The compound (1'-6) can also be obtained by the methods described in these publications.

[Stage 1'-2]

This stage is the stage of obtaining the compound (1'-4) from the compound (1'-2) and connections (1'-3).

The method of obtaining raminosoa derived compounds (1'-4) from nitrocellulose derived compounds (1'-2) is a method of synthesis known to the skilled in allestimenti. The reaction can be carried out under the same conditions as are described, for example, Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996).

[Stage 1'-3]

This stage is the stage of obtaining the compound (1'-5) from the compound (1'-4).

The method of obtaining acatalog derived compounds (1'-5) from raminosoa derived compounds (1'-4) is a method of synthesis known to specialists in this field of technology. The reaction can be carried out under the same conditions as described in Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996); and so on

[Stage 1'-4]

This stage is the stage of obtaining the compound (1'-6) from the compound (1'-5).

The method of synthesis of aniline derivative of the compound (1'-6) restoration of nitro-derivatives of the compound (1'-5) is a method of synthesis known to specialists in this field of technology. An example of such a method can be restore by catalytic hydrogenation using a catalyst based on a noble metal such as Raney Nickel, palladium, ruthenium or rhodium. In this case, it is preferable to use palladium or palladium hydroxide. In other cases, it is also preferred response and recovery with the use of iron in neutral conditions using ammonium chloride.

[Stage 1'-5]

This stage is when Adia synthesis of compound (1'-7) using the compound (1'-6) and the compound (1-2) as starting materials and method presented in the above method of obtaining ([stage 1-1]).

[Stage 1'-6]

This stage is the stage of synthesis of the compound (1-7) by using the compound (1'-7) as the source material and the method presented in the above method of obtaining ([stage 1-2]).

[Stage 1'-7]

This stage is the stage of synthesis of the compound (1-8) using the compound (1-7) as the source material and the method presented in the above method of obtaining ([stage 1-5]).

[Stage 1'-8]

This stage is the stage of synthesis of the compounds represented by the General formula (I)using the compound (1-8) (1-9) as starting materials and the method presented in the above method of obtaining ([stage 1-6]).

[Stage 1'-9]

This stage is the stage of synthesis of the compounds represented by the General formula (I)using the compound (1-8) and the compound (1-10) as starting materials and the method presented in the above method of obtaining ([stage 1-7]).

[General procedure 2 obtain]

where R(2)has the same meaning as described above, and R(9)represents a C6H(R1)(R2)(R6)(OMe)-(CH2)2-.

The compound (1-1) can be obtained from commercially available about the ukta way well-known specialists in this field of technology. Examples of such method can include Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1), 71-74 (1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15), 1653 (1986), and Sakamoto Takao, Yoshinori Kondo, Hiroshi Yamanaka, Chem. Pharm. Bull., Vol. 34, p. 2362 (1986).

In addition, as the compound (2-1) can be used directly commercially available product, or the specified connection can also be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained by the method described in section [General procedure F to obtain].

[Stage 2-1]

This stage is the stage of synthesis of the compound (2-2) conducting the reaction of reductive amination between the compound (1-1) and compound (2-1) method presented in the above method of obtaining ([stage 1-1]).

[Stage 2-2]

This stage is the stage of synthesis of the compound (2-3) using the compound (2-2) as the source material and the method presented in the above method of obtaining ([stage 1-2]).

[Stage 2-3]

This stage is the stage of synthesis of the compound (2-4) using the compound (2-3) as the source material and the method presented in the above method of obtaining ([stage 1-3].

[Stage 2-4]

This stage is the stage of synthesis of the compounds represented by the General formula (I)using the compound (2-4) as a starting material, and the method presented in the above method of obtaining ([stage 1-4]). As the compounds (1-6) can be directly used commercially available product, or the specified connection can also be obtained from a commercially available product by a method known to specialists in this field of technology.

[Stage 2-5]

This stage is the stage of synthesis of the compounds represented by the General formula (I) using the compound (2-3) as a starting material, and the method presented in the above method of obtaining ([stage 1-4']).

The connection represented by the General formula (I)can also be obtained by the following [General methodology 2' receipt].

[General method 2' retrieve]

where R(2), R(9)and R(13)have the same meanings as described above.

This stage is the stage of obtaining compounds of the present invention represented by the General formula (I), using compound (1'-6) as the starting material and the implementation of the [stage 2'-1] and [stage 2'-2]. The compound (1'-6) can be obtained from the commercially available product --- the Ohm, well-known specialists in this field of technology. The compound (2-1) can be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained by the method described in [shared approach to obtain F], which is described later.

[Stage 2'-1]

This stage is the stage of synthesis of the compound (2'-1) by using the compound (1'-6) and the compound (2-1) as starting materials and the method presented in the above method of obtaining (stage 1-1).

[Stage 2'-2]

This stage is the stage of synthesis of the compounds represented by the General formula (I), using compound (2'-1) as the source material and the method presented in the above method of obtaining ([stage 1-2]).

[General procedure 3 obtain]

where R(2)and R(9)have the same meanings as described above, Z represents OR(1)(where R(1)has the same meaning as described above), or R(2)HN.

[Stage 3-1]

The compound (3-2) can be synthesized by using the compound (3-1) and the compound (2-1) as starting materials and the method presented in the above method of obtaining ([stage 1-1]).

[Stage 3-2]

This stage is the stage I obtain the compound (3-3) by the cyclization of the compound (3-2). The method of synthesis of indole derived by cyclization of acetylene (3-2) well-known specialists in this field of technology. The reaction can be carried out under the same conditions as are described, for example, Fujiwara Junya, Fukutani Yoshimi, Hiromi Sano, Keiji Maruoka, Hisashi Yamamoto, J. Am. Chem. Soc., Vol. 105, P. 7177 (1983); and Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Perez, M.; Garcia-Martin, M. A.; Gonzalez, J. M.; J. Org. Chem., 61 (17), 5804-5812 (1996).

[Stage 3-3]

This stage is the stage of synthesis of the compound (3-4) using the compound (3-3) and the method presented in the above method of obtaining ([stage 2-3]). But in the case where the compound (3-3) already has a suitable Deputy, this stage can be excluded.

[Stage 3-4]

This stage is the stage of synthesis of the compounds represented by the General formula (I)using the compound (3-4) as the source material and the method presented in the above method of obtaining ([stage 1-4]). But in the case where the compound (3-3) already has a suitable Deputy, this stage can be excluded. The compound (3-1)used in the common method of obtaining, can be synthesized by the method described in section [General method G of receipt].

[General procedure 4 obtain]

where R(1), R(2), R(9)and X have the same meanings as described above, and D p is ecstasy a carboxyl group or a group able to be modified at the carboxyl group.

The compound (4-1) can be obtained by a method known to specialists in this field of technology. The connection can be synthesized under the same conditions as are described, for example, Quallich, G. J.; Morrissey, P. M.; Synthesis, (1), 51-53 (1993), Urban, F. J.; Breitenbach, R.; Gonyaw, D.; Synth. Commun., 26 (8), 1629-1638 (1996), Zhu, J.; Beugelmans, R.; Bourdent, S.; Chastanet, J.; Roussi, G.; J. Org. Chem., 60 (20), 6389-6396 (1995).

[Stage 4-1]

This stage is the stage of obtaining the amino compounds (4-2) exposure nitro compounds (4-1) response recovery.

The restoration of the nitrogroup is a reaction, well-known specialists in this field of technology. An example of such a recovery may be catalytic hydrogenation using a catalyst made of noble metal such as Raney Nickel, palladium, palladium hydroxide, ruthenium, rhodium or platinum. Another example may be a method using iron, tin or zinc in a neutral or acidic conditions.

[Stage 4-2]

This stage is the stage of synthesis of the compound (4-3) using the compound (4-2) as the source material and the method presented in the above method of obtaining ([stage 1-1]).

[Stage 4-3]

This stage is the stage of obtaining the compound (4-4) halogenoalkanes connection (4-3).

The reaction can be carried out with such the e conditions, what is described, for example, Chan, F.; Magnus, P.; Mciver, E. G.; Tetrahedron Lett., 41 (6), 835-838 (2000), Owa, T.; Okauchi, T.; Yoshimatsu, K.; Sugi, N.; Ozawa, Y.; Nagasu, T.; Koyanagi, N.; Okabe, T.; Kitoh, K.; Yoshino, H.; Bioorg. Med. Chem. Lett., 10 (11), 1223-1226 (2000), Kubo, A., Nakai, T., Synthesis, 365 (1980).

In particular, for example, a solution containing the compound (4-3), is heated with phosphorus oxychloride or the like to obtain compound (4-4).

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include acetonitrile and toluene. In addition, as a solvent can be used as phosphorus oxychloride. The phosphorus oxychloride is used in a ratio of 1 equivalent to excess amount relative to the source material.

The reaction temperature ranges usually from a temperature on ice to the boiling temperature under reflux of the solvent of the solvent, and more preferably from room temperature to the boiling temperature under reflux of the solvent.

The reaction time is not particularly limited. It is usually from 0.2 to 48 hours, preferably from 0.2 to 24 hours.

Additionally, there may be cases where good results, such as increased output can be obtained by adding the base is. The base used in this reaction is not particularly limited, if only it didn't slow the reaction. Preferred examples of such bases may include triethylamine, pyridine and diisopropylethylamine.

[Stage 4-4]

This stage is the stage of obtaining compound (4-5) the reaction of dehalogenase connection (4-4).

This reaction can be carried out under the same conditions as are used for known reactions dehalogenase aromatic cycle. The reaction can be carried out under the same conditions as are described, for example, Candiani, I.; Debernardinis, S.; Cabri, W.; Marchi, M.; Bedeschi, A.; Penco, S.; Synlett, (4), 269-270 (1993), Tanaka, A.; Ito, K.; Nishino, S.; Motoyama, Y.; Takasugi, H.; Chem. Pharm. Bull., 42 (3), 560-569 (1994).

In particular, the compound (4-5) can be obtained by hydrogenation of a solution containing the compound (4-4) in the presence of a metal catalyst.

The solvent used in the reaction of catalytic reduction in a hydrogen atmosphere is not particularly limited, but he would not slow down the reaction. Examples of such a solvent may include methanol, ethanol, tetrahydrofuran and 1,4-dioxane. The examples used in this reaction the metal catalyst may include palladium, platinum oxide and Raney Nickel. Reaction conditions are not particularly limited. The reaction can be carried out at a temperature from room temperatureto boiling point under reflux of the solvent at a pressure of from normal up to 150 atmospheres, preferably at a temperature from room temperature to 60°C at a pressure of from normal to 5 atmospheres. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

[Stage 4-5]

This stage is the stage of obtaining the compound represented by the General formula (I), the conversion of the substituent D in the compound (4-5).

Conversion of compound (4-5) in the compound represented by the General formula (I)may be carried out according to the General methods known to experts in this field of technology. When Deputy D is, for example, alkoxycarbonyl group, the compound represented by the General formula (I)can be synthesized by the method presented in the description of the [stage 1-3] and [stage 1-4] or [stage 1-4'].

[General procedure 5 obtain]

where R(2)and R(9)have the same meanings as described above, and R'(2)and R'(9)represent respectively R(2)and R(9), appropriately modified.

[General procedure 5 obtain] is a method of obtaining a compound represented by the General formula (I)', of the compounds represented by the General formula (I)as starting material. (Compound represented by the General formula (I)', included in the compound represented by the General formula (I).)

[Stage 5-1]

This stage is the stage of obtaining the compound represented by the General formula (I)', a modification of R(2)or R(9)in the compound represented by the General formula (I).

Modification of R(2)and R(9)can be carried out by carrying out various reactions known to specialists in this field of technology, or the joint use of different reactions. In addition, the compound represented by the General formula (I)', can also be obtained by methods described in the examples to obtain in this description.

Next described is a method of obtaining basic compounds used in the invention described in this application. First described compound (1-9)used in [common procedures 1 get] and [General methodology 1' receipt]. Connection [1-9] can be obtained by [General methodology And obtain]-[General method E get] and [General methodology N receipt]. The final compounds obtained by these methods can sometimes be represented by different formulas in the description of each stage. But all these connections correspond to the compound (1-9).

[General procedure a receipt] (Method of synthesis of compounds (1-9))

where cycle And represents (1) a bicyclic group formed by condensation of benzene cycle and a 5-7 membered non-aromatic carbocyclic group, (2) a bicyclic group formed by condensation of benzene cycle and a 5-7 membered non-aromatic heterocyclic group, (3) a bicyclic group formed by condensation of benzene cycle and 6-membered aromatic carbocyclic group, (4) a bicyclic group formed by condensation of benzene cycle and 5 - or 6-membered aromatic heterocyclic group, or benzene, can be converted into (1)-(4); each of R(4), R(5)and R(6)is a Deputy, is required for synthetic modifications, when necessary, such as C1-C6 alcoolica group, hydroxymethylene group which may be protected with TBDMS group, or the like, or C1-C6 alkoxygroup, which may be substituted by C1-C6 alkoxycarbonyl group, and the Deputy, selected from the following group V1 of substituents, and R'(4), R(4), R'(5), R(5), R'(6), R(6)represent substituents formed by a suitable modification of R(4), R(5)and R(6)where each of R(4), R(5)/sub> , R(6), R'(4), R'(5), R'(6), R(4), R(5)and R(6)is a Deputy, in A cycle; and L(1)means a leaving group and represents a halogen atom (chlorine atom, bromine atom or iodine atom) or sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov,

the group V1 of substituents: (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxyl group, (5) the nitro-group, (6) oxoprop, (7) carboxyl group, (8) C3-C8 cycloalkyl group, (9) C2-C6 Alchemilla group, (10) C2-C6 Alchemilla group, (11) C1-C6 allylthiourea, (12) C1-C6 alkoxycarbonyl group, (13) C1-C6 alkylsulfonyl group, (14) C1-C6 alkyl group (where the above-described C1-C6 alkyl group may be substituted by a halogen atom, a hydroxyl group or C1-C6-alkoxygroup), (15) C1-C6 alkoxygroup (where the above-described C1-C6 alkoxygroup may be substituted by 1 to 3 halogen atoms), (16) amino group (where the above amino group may be substituted by the Deputy selected from the group consisting of C1-C6 alkyl group, formyl group, C1-C6 alkanoyloxy group and C1-C6 alkylsulfonyl group), (17) carnemolla group (where the above carnemolla group may be substituted by one or two C1-C6 alkyl groups), (18) C1-C6 alcox aminogroup, (19) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (20) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom.

As compounds (a-1) can be directly used commercially available product or the above compound can also be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained by methods described in the examples to obtain in this description.

[Stage-1]

This stage is the stage of obtaining the compound (a-3) the reaction of Allilueva between the compound (a-1) and compound (a-2).

This reaction can be carried out under the same conditions as used in the reaction of Allilueva between allergologicum and derivatives of phenol (including heterocyclic cycle) (these conditions are described, for example, Nichols, D. E.; Snyder, S. E.; Oberlender, R.; Johnson, M. P.; Huang, X.; J. Med. Chem., 34 (1), 276-281 (1991), Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Aoki, B.; Koga, H.; Chem. Pharm. Bull., 39 (7), 1760-1772 (1991)).

In particular, provide interoperability with a solution containing the compound (a-1), obtaining peroxide, which then give moznosti to interact with the compound (a-2) obtaining the compound (a-3).

This reaction can be carried out by ensuring interoperability of a suitable base with the above compound at a ratio of 1 equivalent to excess amount relative to the compound in an organic solvent, such as acetone, 2-butanone, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, benzene, or toluene or a mixed solvent. The examples used in this reaction, the base may include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, databaseconnect, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide and tert-piperonyl potassium. The compound (a-2) used in the ratio of 1 to 3 equivalents, preferably from 1 to 1.7 equivalents, relative to compound (a-1).

The reaction time is not particularly limited. It is usually from 1 to 48 hours, preferably from 1 to 24 hours.

The reaction temperature is usually in the range from a temperature on ice to the boiling temperature under reflux of the solvent.

There may be times when can be obtained preferred results, such as an increase or decrease in response time due to the presence of ammonium salts such as Tetra-n-butylammonium, Tetra-n-butylammonium or Tetra-n-butylammonium.

[Stage A-2]

This stage is the fast stage of obtaining compound (a-4) the exposure of the compound (a-3) rearrangement reaction of Clausena.

This reaction can be carried out under the same conditions as are described, for example, Nichols, D. E.; Snyder, S. E.; Oberlender, R.; Johnson, M. P.; Huang, X.; J. Med. Chem., 34 (1), 276-281 (1991), Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Aoki, B.; Koga, H.; Chem. Pharm. Bull., 39 (7), 1760-1772 (1991).

In particular, for example, a solution containing the compound (a-3), is heated with obtaining the compound (a-4).

This reaction can be carried out in the absence of solvent or in a solvent such as N,N-dimethylaniline, N,N-diethylaniline, N is an organic or dichlorobenzene.

The reaction temperature is usually from 100°C to the boiling temperature under reflux of the solvent, and more preferably from 160°210°C.

This reaction is preferably carried out in an atmosphere of nitrogen or argon. There may be times when can be obtained preferred outcomes such as a reduction of the reaction time or increase the yield, by carrying out this reaction using microwave reactor.

In addition, there may be instances synthesis in this reaction isomer provisions (klaisen rearrangement), but this depends on the type of source material. When in position 1 is alliancegroup, compounds, formed by the transfer of the allyl group in position 2, 4 or 6, also included in the scope of the present invention.

[Stage A-3]

This stage is the stage recip is of the compound (a-6) implementation of the methylation reaction between the compound (a-4) and compound (a-5).

This reaction can be carried out under the same conditions as used in the reaction of alkylation (methylation) between the derivatives of phenol (including heterocyclic ring) and methylglucamide or dimethylsulfate (these conditions are described, for example, Chilin, A.; Rodighiero, P.; Pastorini, G.; Guitto, A.; J. Org. Chem., 56 (3), 980-983 (1991), Dike, S. Y.; Merchant, J. R.; Sapre, N. Y.; Tetrahedron, 47 (26), 4775-4786 (1991)).

In particular, provide interoperability with a solution containing the compound (a-4), obtaining peroxide, which then allow you to interact with the compound (a-5) to obtain compound (a-6).

This reaction can be carried out by providing a suitable basis interoperability with the above compound at a ratio of 1 equivalent to excess amount relative to the compound in an organic solvent, such as acetone, 2-butanone, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, benzene, or toluene or a mixed solvent. The examples used in this reaction, the base may include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, databaseconnect, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide and tert-piperonyl potassium.

Examples meteorologi reagent may include methyliodide, methyl bromide, methyl chloride and dimate the sulfate.

The compound (a-5) used in a ratio of from 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (a-4). The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

The reaction temperature is usually in the range from a temperature on ice to the boiling temperature under reflux of the solvent.

There may be times when can be obtained preferred results, such as an increase or decrease in response time due to the presence of ammonium salts such as Tetra-n-butylammonium, Tetra-n-butylammonium or Tetra-n-butylammonium.

In addition, compound (a-6) can be obtained from compound (a-4) as an alternative method.

An alternative way

For example, to the solution containing the compound (a-4)add diazomethane, trimethylsilyldiazomethane or the like, at a ratio of 1 equivalent to excess amount for the implementation of the reaction of obtaining compound (a-6). Examples of the solvent for this reaction may include ether and methanol. The reaction temperature is usually in the range from a temperature on ice to room temperature. This method is known to specialists in this field of technology. The reaction can be carried out under the same conditions, what is written, for example, White, J. D.; Butlin, R. J.; Hahn, H.-G.; Johnson, A. T.; J. Am. Chem. Soc., 112 (23), 8595-8596 (1990).

[Stage A-4]

This stage is the stage of obtaining compounds (1-9) oxidative cleavage of the olefin in parts of allyl compounds (a-6).

The reaction can be carried out under the same conditions, which are usually used in the reaction of oxidative cleavage with obtaining aldehyde of the olefin. Oxidative cleavage used in this reaction are not particularly limited. An example of a specified reaction oxidative cleavage may be the reaction of the oxidative cleavage, including ozone oxidation, the use of osmium tetroxide (which can be used oxidizer in combination), using the K2OsO4(where can be used oxidizer in combination), the use of chromic acid or electrode oxidation.

The oxidant used in the ratio of catalytic amount (0.01 equivalent to excess amount relative to compound (a-6). The oxidant used in combination, is used in a ratio of 1 equivalent to excess amount relative to the above oxidizing agent.

Examples of the reaction of oxidative cleavage, including ozone oxidation may include the methods described, for example, Jagadeesh, S. G.; Krupadanam, G. L. D.; Srimannarayana, G.; Synth. Commun., 31 (10), 1547-1557 (2001), annon, J. G.; Roufos, I.; J. Heterocycl. Chem., 27 (7), 2093-2095 (1990).

In particular, in the reaction of oxidative cleavage, including ozone oxidation of the olefin to the solution containing the compound (a-6), for example, down the stream of oxygen containing some percentage of ozone (obtained using an ozone generator), and then formed ozonid (hydroperoxide, when the solvent used methanol) without allocation is treated with reducing agent to obtain the compound (1-9).

Solvent used in this reaction are not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples may include methylene chloride, ethyl acetate and methanol. The reaction temperature is usually from -100°C to room temperature, and more preferably from -78°C to room temperature. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

When processing a reducing agent can be used, the reducing agent used in the reaction conditions commonly used in the aforesaid reaction of oxidative cleavage. Specific examples of such a reducing agent may include zinc-acetic acid, triphenylphosphine, triethylphosphite, catalytic hydrogenation and dimethyl sulphide.

Furthermore, the method described in Li, G.; Anderson, W. K.; Tetrahedron Lett., 34 (43), 6849-6852 (1993), is an example of the reaction of oxidative cleavage using osmium tetroxide (which can be used oxidizer in combination), K2OsO4(where can be used oxidizer in combination), AD-mix-α(β) or similar

The reaction of the oxidative cleavage of olefins using osmium tetroxide or the like can be carried out under the same conditions as commonly used reaction conditions (for example, the conditions described in the above publications).

The oxidant used in combination is not particularly limited. An example of this oxidant can be periodate sodium.

Used in this reaction the solvent may be a mixed solvent consisting of water and an organic solvent, such as ether, tetrahydrofuran, 1,4-dioxane or acetone. The reaction temperature is usually in the range from a temperature on ice to room temperature.

The reaction of the oxidative cleavage using osmium tetroxide can be also realized by performing a two-stage process in which olefins are oxidized with osmium tetroxide (which can be used together with the oxidant) in 1,2-diol and then from 1,2-diol receive the aldehyde, using an oxidant, such as leads to compounds, which lead or periodate sodium.

The decree is fair two-stage reaction may be carried out under the same conditions, as commonly used, the reaction conditions (for example, the conditions described in Masquelin, T.; Hengartner, U.; Streith, J.; Synthesis, 7, 780-786 (1995), Banfield, S. C.; England, D. B.; Kerr, M. A.; Org. lett., 3 (21), 3325-3327 (2001)).

Examples of the oxidizing agent used in the conversion of olefins to 1,2-diol may include N-oxide N-methylmorpholine and K3Fe(CN)6. Used in this reaction the solvent is a mixed solvent consisting of water and an organic solvent, such as acetonitrile, acetone, tert-butanol or tetrahydrofuran. The reaction temperature is usually in the range from a temperature on ice to room temperature. The reaction time is not particularly limited. It is usually from 0.2 to 48 hours, preferably from 0.2 to 24 hours.

In addition, examples of the oxidizing agent used in the conversion of 1,2-diol in the aldehyde may include leads to compounds, which lead and periodate sodium. Examples of the solvent used in this reaction may include organic solvents, such as benzene, toluene, methylene chloride, simple ether, tetrahydrofuran, 1,4-dioxane or acetone, and mixed solvents consisting of water and these organic solvents. The reaction temperature is usually in the range from a temperature on ice to room temperature. The reaction time is not particularly limited. It is usually from 5 minutes to 48 hours, preferred is compulsory from 5 minutes to 24 hours.

[Stage A-5]

This stage is the stage of synthesis of the compound (a-3) using the compound (a-1) as the starting material and method presented in the above method of obtaining ([stage-1]).

[Stage A-6]

This stage is the stage of synthesis of the compound (a-4) using compound (a-3) as the starting material and method presented in the above method of obtaining ([phase A-2]).

[Stage A-7]

This stage is the stage of obtaining the compound (a-7) appropriate modification (transformation) of the cyclic compound (a-4). Modification (transformation) of the cyclic compound (a-4) according to the present invention can be carried out by carrying out various reactions known to specialists in this field of technology, or the joint use of different reactions. The above compound can also be obtained by the method described in this description and in the examples received. The term "modification (transformation) of A cycle includes the modification (transformation) of the substituent (R(4), R(5)or R(6)).

Specific examples of the various reactions, known to experts in the art, may include oxidation transforming alcohol carbonyl compound such as aldehyde or ketone; oxidation converted aldehyde in carbonophobia; restore a shifting of ester, carboxylic acid or nitrile to the aldehyde or alcohol; the reaction of nitration of aromatic cycle; halogenoalkane aromatic cycle; recovery from the nitro group to the amino group; the recovery of carbon-carbon double bond or triple bond, due to hydrogenation in the presence of a catalyst of a transition metal; the esterification of carboxylic acid; hydrolysis of ester to carboxylic acid; synthesis of aldehyde by hydrolysis of simple enol ether; conversion gidrolizuyushchie nitrile into amide compound or carboxylic acid; restoration of amide compounds to amino compounds; hydroporinae; oxymorphine carbonyl compound such as aldehyde or ketone; nitrilimines oxime group transformation of N alkylation using reductive amination; the method of synthesis of amides using acylation of the amino group; sulfenamidovy amino group; amidation condensation of carboxylic acids and amino compounds; amidation condensation of ester and amino compounds; amidation condensation of carboxylic acids and amino compounds; condensation between the amino group and hydroxyl group using N,N'-carbonyldiimidazole, phosgene or triphosgene; condensation between Amida and hydrox the school group using N,N'-carbonyldiimidazole, phosgene or triphosgene; the reaction conversion of the hydroxyl group in the fluorine using DAST reagent (TRIFLUORIDE dimethylaminostyryl) or the like; O-alkylation of the alcohol or phenol; N-alkylation of amide groups; N-alkylation urethane compounds; alkylation of carbonyl group in α-position by engagement with alkylhalogenide after processing carbonyl compounds base, such as LDA (diisopropylamide lithium); demethylation derived from anisole to phenol derivation; the reaction conversion of the hydroxyl group into a leaving group, such as metilirovanie or bromination hydroxyl group; nucleophilic substitution reaction between a compound containing a leaving group, such as bromine, and aminoguanidinium; the nucleophilic substitution reaction between a compound containing a leaving group such as bromine, and sodium cyanide; nucleophilic interaction of the carbonyl group with a Grignard reagent or alkyl - or phenyllithium; Wittig reaction, Horner reaction of Ammonia; the reaction Mitsunobu; the Beckmann rearrangement, the synthesis of benzoxazole the Beckmann rearrangement, rearrangement of kurzius; reaction Bayer-Villiger; condensation of Dickman; the reaction mix using a transition metal (for example, the reaction mix according to Suzuki, the reaction mix for the Ullmann reaction is sonogashira), the reaction mix by S. L. Buchwald et al. between aminoguanidinium and halogenated aryl compounds, the reaction mix at the Steele etc.); the fusion reaction isoxazol 1,3-dipole accession; the reaction of oxazole using aldehyde and TOSMIC reagent (toiletrieschoice); metallation, due to metal-halogen exchange; formirovanie or amidation, due to the reaction between metilirovaniem (litrownik) connection (litrovaya etc) and familyroom agent such as N,N-dimethylformamide, or lidiruyushchim agent such as dimethylcarbamoyl; the reaction of transformation of compounds in pyridine Quaternary connection with use of or under the conditions of benzylbromide; response recovery Quaternary pyridine to piperidine due to hydrogenation in the presence of a catalyst of a transition metal; a method for the synthesis of ketone compounds by decarboxylation complex of 1,3-keeeper; and protection and exemption from the protection of different functional groups described in the publications, T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991). However, examples are not limited to these reactions.

[Stage A-8]

This stage is the stage of synthesis of the compound (1-9) using compound (a-7) as the starting material and the above-described methods, the floor is ing ([stage A-4]).

[Stage A-9]

This stage is the stage of synthesis of the compound (a-9) using compound (a-1) and compound (a-8) as starting materials and the above-described method ([stage-1]), based on the methods described in publications such as Molina, P., Alajarin, M.; Vidal, A.; Fenau-Dupomt, J.; Declerq, J. P.; J. Org. Chem., 56 (12), 4008-4016 (1991), Mann, A.; Muller, C.; Tyrrell, E.; J. Chem. Soc., Perkin Trans. I, (8), 1427-1438 (1998).

[Stage A-10]

This stage is the stage of synthesis of the compound (a-10) using compound (a-9) as source material and the above-described method ([phase A-2]).

This method of obtaining can give preferred results when kazanowska the rearrangement of 3-methyl-2-bouteilles groups meet at the para-position selectively to 3-methyl-2-butenyloxy.

[Stage A-11]

This stage is the stage of synthesis of the compound (a-11) with suitable modification of the cycle And using compound (a-10) as the starting material and the above-described method ([stage A-7]).

[Stage A-12]

This stage is the stage of synthesis of the compound (1-9) using compound (a-11) as the starting material and the above-described method ([stage A-4]).

[Stage A-13]

This stage is the stage of synthesis of the compound (a-3) using the compound (a-1) as a starting material and OPI is Anna method get ([stage-1]).

[Stage A-14]

This stage is the stage of synthesis of the compound (a-12) a suitable modification of the cycle And using compound (a-3) as the starting material and the above-described method ([stage A-7]).

[Stage A-15]

This stage is the stage of synthesis of the compound (a-13) by using the compound (a-12) as the starting material and the above-described method ([phase A-2]).

[Stage A-16]

This stage is the stage of synthesis of the compound (a-14) a suitable modification of the cycle And using compound (a-13) as the starting material and the above-described method ([stage A-7]).

[Stage A-17]

This stage is the stage of synthesis of the compound (1-9) using compound (a-14) as starting material and the above-described method ([stage A-4]).

[Stage A-18]

This stage is the stage of synthesis of the compound (a-15) by using the compound (a-13) as the starting material and the above-described method ([stage A-3]).

[Stage A-19]

This stage is the stage of synthesis of the compound (1-9) using compound (a-15) as the starting material and the above-described method ([stage A-4]).

[A General method To obtain] (method of synthesis of compounds (1-9))

with each cycle A, R(4), R(5), R(6), R'(4), R'(5), R'(6), R(4), R(5)and R(6)has the same meaning as described above; P(2)means a protective group for hydroxyl group, a represents-CH(Me)2or the like, formed methyl group, ethyl group, or P(2)attached to adjacent to the carbon atom; L(2)means a leaving group, which represents a halogen atom (chlorine atom, bromine atom, iodine atom), or sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov.

As compounds (a-1) can be used directly commercially available product, or the specified connection can also be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained by methods described in the examples to obtain in this description.

As compounds (b-2) can be used directly commercially available product, or the specified connection can also be obtained from a commercially available product by a method known to specialists in this field of technology.

[Stage B-1]

This stage is stadie the synthesis of compound (b-3) using the compound (a-1) as the starting material and the above-described method ([stage-1]).

[Stage B-2]

This stage is the stage of synthesis of the compound (b-4) using the compound (b-3) as the starting material and the above-described method ([phase A-2]).

[Stage B-3]

This stage is the stage of synthesis of the compound (b-5) using the compound (b-4) as the starting material and the above-described method ([stage A-3]).

[Stage B-3-1-1]

This stage is the stage of synthesis of the compound (b-6) appropriate modification of the loop And using the compounds (b-5) as the starting material and the above-described method ([stage A-7]).

[Stage B-3-1-2]

This stage is the stage of synthesis of the compound (b-7) by using the compound (b-6) as starting material and the above-described method ([stage A-4]).

[Stage B-3-1-3]

This stage is the stage of obtaining compound (b-8) protected 1,2-diol (b-7).

The reaction can be carried out under the same conditions, which is usually used for protecting 1,2-diol (for example, conditions described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), pp. 118-142).

For example, the protective group (acetonide) may be entered in 1,2-diol under conditions that allow you to interact 2,2-dimethoxypropane, p-toluensulfonate in catalytic pyridinium number is the number, etc. with the above compound in acetone solvent.

[Stage B-3-1-4]

This stage is the stage of obtaining compounds (1-9) using the compound (b-8) as the starting material and the above-described method ([stage A-7]). According to this method, the cycle appropriately modify (transform), removing the protective group of the 1,2-diol and carry out the reaction of the oxidative cleavage with obtaining interest connection.

The reaction can be carried out under the same conditions, which is usually used when removing the protection of 1,2-diol (for example, conditions described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), pp. 118-142).

For example, 1,2-diol can be obtained by removing the protective group (acetonide) of 1,2-diol under conditions in which 4 N. an ethyl acetate solution of hydrogen chloride allow to act on the connection specified in an ethyl acetate solvent.

Oxidative cleavage can be carried out using the method presented in the above method of obtaining ([stage A-4]).

[Stage B-3-2-1]

This stage is the stage of synthesis of the compound (1-9) using the compound (b-6) as starting material and the above-described method ([stage A-4]).

[Stage B-3-3-1]

This stage t is aetsa stage of synthesis of the compound (1-9) using the compound (b-5) as the starting material and the above-described method ([stage A-4]).

[Stage B-3-4-1]

This stage is the stage of synthesis of the compound (b-9) with compound (b-5) as the starting material and the above-described method ([stage A-4]).

[Stage B-3-4-2]

This stage is the stage of synthesis of the compound (b-10) using the compound (b-9) as source material and the above-described method ([stage B-3-1-3]).

[Stage B-3-4-3]

This stage is the stage of synthesis of the compound (b-11) with suitable modification of the loop And using the compounds (b-10) as the starting material and the above-described method ([stage A-7]).

[Stage B-3-4-4]

This stage is the stage of synthesis of the compound (b-12) with compound (b-11) as the starting material and the above-described method ([stage B-3-1-4]).

[Stage B-3-4-5]

This stage is the stage of synthesis of the compound (1-9) using the compound (b-12) as the starting material and the above-described method ([stage A-4]).

[A General method To obtain] (method of synthesis of compounds (1-9))

with each cycle A, R(4), R(5), R(6), R'(4), R'(5)and R'(6)has the same meaning as described above.

As the compound (c-1) can be used directly commercially available is the product or the above compound can also be obtained from a commercially available product by the way well-known specialists in this field of technology. In addition, it can also be obtained by methods described in the examples to obtain in this description, or by the method described in [General method C' receive] or similar

[Stage C-1]

This stage is the stage of obtaining the compound (c-2)containing one more carbon atom, the reaction of the Wittig.

The reaction can be carried out under the same conditions as are normally used for aldehyde and Wittig reagent (Wittig reaction) (ethoxymethylenemalononitrile) (for example, conditions described in Gibson, S. E.; Guillo, N.; Middleton, R. J; Thuilliez, A.; Tozer, M. J.; J. Chem. Soc., Perkin Trans. I, 4, 447-455 (1997)).

In particular, for example, the Wittig reagent (ethoxymethylenemalononitrile) allow you to interact with the substrate and then with the compound (c-1) to obtain the compound (c-2).

This reaction can be carried out by the action of bases on the Wittig reagent at a ratio of from 0.8 to 1 equivalent relative to the reagent in an organic solvent, such as a simple ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene or toluene. The examples used in this reaction, the base may include sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, tert-piperonyl potassium, n-utility and LDA (diisopropylamide lithium).

The reaction time is not particularly limited. the but is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours.

The reaction temperature is usually from -78°C to room temperature, and more preferably is in the range from a temperature on ice to room temperature.

[Stage C-2]

This stage is the stage of obtaining compounds (1-9) providing the compound (c-2) opportunities to interact with acid.

The reaction can be carried out under the same conditions as are described, for example, Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J.; J. Chem. Soc., Perkin Trans. I, 4, 447-455 (1997).

In particular, for example, the compound (c-2) dissolved in 5 BC chloroethanol acid or the like and then heated for obtaining compounds (1-9).

The reaction can be carried out by the interaction of the acid with the specified connection at a ratio of 1 equivalent to excess amount relative to the compound in a mixed solvent consisting of water and an organic solvent, such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane, or in an organic solvent, such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, methylene chloride or acetonitrile. Preferred examples of the acid used in this reaction may include hydrogen chloride, chloroethanol acid, Hydrobromic acid, sulfuric acid, nitric acid, triperoxonane acid and formic Ki the lot. In addition, it is also possible the transformation of the compound to the aldehyde by trimethylsilylimidazole (which may be formed in the reaction sistee from trimethylsilylpropyne and sodium iodide).

The reaction time is not particularly limited. It is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

The reaction temperature is usually in the range from a temperature on ice to the boiling temperature under reflux of the solvent.

[Stage C-3]

This stage is the stage of synthesis of the compound (c-3) a suitable modification of the loop And using the compound (c-2) as the starting material and the above-described method ([stage A-7]).

[Stage C-4]

This stage is the stage of synthesis of the compound (1-9) using the compound (c-3) as the starting material and the above-described method ([stage C-2]).

The compound (c-1) can also be obtained, for example, [General method C' receive] or [the General method C" receipt].

[General method C' receipt] (method of synthesis of compound (c-1))

with each cycle A, R(1), R(4), R(5)and R(6)has the same meaning as described above; X represents a halogen atom such as chlorine atom or bromine atom, triftormetilfullerenov or the like, and M represents atomically, such as lithium or magnesium.

As the compound (c'-1), compounds (c'-2) or compound (c'-3) can be used directly commercially available product. These compounds can also be obtained from commercially available products by methods known to experts in this field. In addition, they can also be obtained by methods described in the examples to obtain in this description.

[Stage C' 1-1]

This stage is the stage of obtaining cyanocobalamine (c'-4) providing the compound (c'-1) opportunity to interact with a metal cyanide in the presence or in the absence of an ORGANOMETALLIC catalyst.

The substitution reaction of cyanide metal halogenated aryl (including heterocyclic ring compound is a way known to specialists in this field of technology. This reaction is carried out under the same conditions as are described, for example, Bouyssou, P.; Legoff, C.; Chenault, J.; J. Heterocycl. Chem.; 29 (4), 895-898 (1992), Agarwal, A.; Jalluri, R. K.; Blanton, C. D. J.; Taylor, E. W.; Synth. Commun., 23 (8), 1101-1110 (1993), Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.; King, S.; Verhoeven, T. R.; Synth. Commun. 24 (6), 887-890 (1994), Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-H.; Frey, L.; Karady, S.; Shi, Y, Y.-J.; Verhoeven, T. R.; J. Org. Chem., 60 (14), 4324-4330 (1995).

[Stage C' 1-2]

This stage is the stage of obtaining the compound (c'-5) providing the compound (c'-1) opportunities to interact metalloorganicheskie compound in the presence of an ORGANOMETALLIC catalyst.

This reaction can be carried out under the same conditions, which are usually used in the reaction of a combination of halogenated aryl (including heterocyclic ring) connection or the like with the ORGANOMETALLIC compound in the presence of an ORGANOMETALLIC catalyst. For example, the reaction with the use of tin-containing reagent, such as an ORGANOMETALLIC compound, are described in publications such as Martorell, G.; Garcia-Raso, A.; Saa, J. M.; Tetrahedron Lett., 31 (16), 2357-2360 (1990), Kiely, J. S.; Laborde, E.; Lesheski, L. E.; Bucsh, R. A.; J. Heterocycl. Chem., 28 (6), 1581-1585 (1991). The reaction using boron-containing compounds such as ORGANOMETALLIC compound, are described in publications such as Kerins, F.; O' Shea, D. F.; J. Org. Chem., 67 (14), 4968-4971 (2002). The reaction using magnesium-containing reagent, such as an ORGANOMETALLIC compound, are described in publications such as Park, M.; Buck, J. R.; Rizzo, C. J.; Tetrahedron, 54 (42), 12707-12714 (1998). The reaction using zinc-containing compounds such as ORGANOMETALLIC compound, are described in publications such as Mohanakrishnan, A. K.; Cushman, M.; Synlett, 7, 1097-1099 (1999).

ORGANOMETALLIC catalyst used in this reaction are not particularly limited. Preferred examples of such ORGANOMETALLIC catalyst may include tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II)bis(tert-butil spin)palladium(0), dichloride, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II)acetate, palladium(II) and (1,3-bis(diphenylphosphino)propane)Nickel(II). Such ORGANOMETALLIC catalyst is used at a ratio of from about 0.001 to 0.1 equivalents relative to the starting material.

ORGANOMETALLIC compound is not particularly limited. Preferred examples of such ORGANOMETALLIC compounds may include ORGANOTIN reagents, such as vinyltris-n-botillo, and boron compounds such as 2,4,6-trivinylcyclohexane. This ORGANOMETALLIC compound is used in a ratio of from 1 to 5 equivalents relative to the starting material.

Solvent used in this reaction are not particularly limited, but he would not slow down the reaction. Preferred examples of such a solvent may include benzene, toluene, xylene, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited. It is in the range usually from a temperature on ice to the boiling temperature under reflux of the solvent, preferably from room temperature to the boiling temperature under reflux of the solvent. The reaction time is not particularly limited. It is usually from 1 to 48 hours, preferably from 1 to 24 hours.

the possible cases, when good results, such as increased output can be obtained by implementation of this reaction in the presence of a base. Such a base is not particularly limited. Preferred examples of the base may include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and trimethylethylene.

[Stage C' 1-3]

This stage is the stage of obtaining metalearning compounds (c'-6) implementation of the metal-halogen exchange of halogenated aryl compounds including heterocyclic compound).

The specified metal-halogen exchange can be carried out in a manner known to specialists in this field of technology. In particular, for example, the compound (c'-1) is subjected to metal-halogen exchange using commercially available ORGANOMETALLIC reagent, preferably, alkyllithium reagent, such as n-, sec - or tert-utility, and the Grignard reagent, such as isopropylacrylamide, or magnesium metal, to obtain the corresponding literalnode (including heterocyclic compound) reagent or minyailova (including heterocyclic compound) reagent.

Solvent used at this stage varies depending on the starting material or reagent. Such solvent is not particularly limited, but he would not slowed the reaction is s, to a certain extent dissolved starting material and was always inactive during the reaction. Preferred examples of such a solvent may include diethyl ether, tetrahydrofuran, benzene and toluene. The reaction time is not particularly limited. It is usually from 0.1 to 48 hours, preferably from 0.1 to 2 hours. The reaction temperature varies depending on the starting material or reagent. To reduce the formation of by-products to a minimum, preferably have a low temperature, such as -78°C.

In addition, there may be cases where good results, such as increasing or decreasing the reaction time can be obtained by addition of TMEDA (tetramethylethylenediamine), HMPA (hexamethylphosphoramide) or the like as an additive.

[Stage C' 1-4]

This stage is the stage of obtaining metalearning compounds (c'-6) implementation of the metallation reaction of aryl (including heterocyclic compound) compound (c'-2).

The metallation reaction of aryl compounds including heterocyclic compound) can be carried out in a manner known to specialists in this field of technology. In particular, for example, commercially available ORGANOMETALLIC reagent, preferably, alkyllithium reagent, such as n-, sec - or tert-utility is, allow to act on the compound (c'-2), to obtain the corresponding literalnode (including heterocyclic compound) reagent (c'-6).

This reaction can be carried out under the same conditions as are described, for example, Jacob, P. III; Shulgin, A. T.; Synth. Commun., 11 (12), 957 (1981) or other

The solvent used at this stage varies depending on the starting material or reagent. Such solvent is not particularly limited, but he would not slow down the reaction, to a certain extent dissolved starting material and was always inactive during the reaction. Preferred examples of such a solvent may include diethyl ether, tetrahydrofuran, benzene and toluene. The reaction temperature varies depending on the starting material or reagent. To reduce the formation of by-products to a minimum, preferably have a low temperature, such as -78°C. the reaction Time is not particularly limited. It is usually from 0.1 to 48 hours, preferably from 0.1 to 24 hours.

In addition, there may be cases where good results, such as increasing or decreasing the reaction time can be obtained by addition of TMEDA (tetramethylethylenediamine), HMPA (hexamethylphosphoramide) or the like as an additive.

[Stage C' 1-5]

This stage is the fast stage of receipt of ester or carboxylic acids (c'-7) by the introduction of carbon monoxide in halogenated aryl (including heterocyclic compound) or artribute connection (including heterocyclic connection) (C'-1).

When carrying out the reaction the introduction of carbon monoxide using a catalyst of a transition metal is preferably a commercially available palladium complex such as palladium(II)acetate, in the presence of alcohol, such as preferably methanol, ethanol or tert-butanol, under normal conditions, known to experts in the art, the halogen atom can be converted into the desired carboxylate group. Then carry out the alkaline hydrolysis or acid hydrolysis under normal conditions, known to experts in the art, to obtain the corresponding carboxylic acid.

[Stage C' 1-6]

This stage is the stage of synthesis of the compound (c'-7) using the compound (c'-3) as the source material and the method presented in the above method of obtaining ([stage A-3]).

[Stage C' 2-1]

This stage is the stage of obtaining the compound (c-1) reaction reconnection (c'-4).

As a redox reaction conversion ceanography in formyl group, specialists in the art known reaction of recovery using a metal hydride, such as diisobutylaluminum, in an inactive solvent such as tetrahydrofuran. In addition, the above compound can also be is obtained by reduction using Raney Nickel, as described in T. Sohda et al. (Chem. Pharm. Bull., 39 (6), 1440-1445 (1991)) or O. G. Backeberg et al. (J. Chem. Soc., 3961-3963 (1962)) (which consists in heating the compound in a mixed solvent aravina acid-water or in the provision of connection opportunities to interact with hypophosphite sodium in a mixed solvent of pyridine-acetic acid-water at a temperature in the range from room temperature up to 40°C). The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

[Stage C' 2-2]

This stage is the stage of synthesis of the compound (c-1) using the compound (c'-5) as the starting material and the above-described method ([stage A-4]).

[Stage C' 2-3]

This stage is the stage of obtaining the aldehyde (c-1) of metalearning compounds (c'-6)obtained in the above [stage C' 1-3] or [stage C' 1-4].

Metallosalen the compound (c'-6)obtained in the above [stage C' 1-3] or [stage C' 1-4], provide an opportunity to interact with commercially available familyroom agent, preferably with a reagent such as N,N-dimethylformamide, N-formylmorpholine or ethyl formate, to obtain the corresponding aldehyde (c-1). This reaction formirovaniya well-known specialists in this field of technology.

[Stage C' 2-4]

This stage is to study the th receipt of ester or carboxylic acids (c'-7) from metalearning compounds (c'-6), obtained in the above [stage C' 1-3] or [stage C' 1-4].

Metallosalen the compound (c'-6)obtained in the above [stage C' 1-3] or [stage C' 1-4], provide an opportunity to interact with commercially available etherification agent, preferably with a reagent, such as diethylmalonate or carbon dioxide to convert the compounds into the corresponding (ester or carboxylic acid) compound (c'-7). The reaction of converting the compound into an ester or carboxylic acid, known to specialists in this field of technology.

[Stage C' 2-5]

This stage is the stage of obtaining the compound (c-1) reaction reconnection (c'-7). The reaction can be carried out under the same conditions, which is usually used in the recovery of ester to aldehyde (for example, conditions described in E. Winterfeldt; Synthesis, 617 (1975)).

Preferred reducing agents used in this reaction include diisobutylamine, bis(2-methoxyethoxy)alumoweld sodium bis(N-methylpiperazine)alumoweld.

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include tetrahydrofuran, toluene, and methylene is lore.

The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

The reaction temperature is not particularly limited. It is usually from -78°C to room temperature, preferably from -78°With up to temperature on ice.

[Stage C' 2-6]

This stage is the stage of obtaining alcohol (c'-8) response recovery ester compound (c'-7).

The alcohol (c'-8) can be obtained from compound (complex ester or carboxylic acid) (c'-7) method, well-known specialists in this field of technology.

In the case of ester examples of the reducing agent used in this reaction may include sociallyengaged, lithium borohydride and diisobutylaluminum. The reaction temperature is not particularly limited. It is usually from -78°C to the boiling temperature under reflux of the solvent, preferably from -78°C to room temperature. The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include tetrahydrofuran, simple ether, toluene and methylene chloride.

In the case of carboxylic acids, examples of the reducing agent used in this reaction may include sociallyengaged, Bo is an-tertrahydrofuran ring complex and borane-dimethylsulfide complex. The reaction temperature is not particularly limited. It is usually from -78°C to the boiling temperature under reflux of the solvent, preferably in the range of temperature on ice to the boiling temperature under reflux of the solvent. The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include tetrahydrofuran and ether. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

[Stage C' 2-7]

This stage is the stage of obtaining the aldehyde (c-1) the oxidation reaction of the alcohol (c'-8). The aldehyde can be obtained from alcohol by a method known to specialists in this field of technology.

Examples of known oxidation method used in this reaction may include oxidation in Turn, the oxidation Corey-Kim oxidation on Mofette, PCC oxidation, PDC oxidation, oxidation by Dess-Martin oxidation using a mixture of SO3the pyridine and oxidation using manganese dioxide.

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of t is one solvent may include dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride and chloroform.

The reaction temperature is not particularly limited. It is usually from -78°C to the boiling temperature under reflux of the solvent, preferably from -78°C to room temperature. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

[General method C" retrieve] (method of synthesis of compound (c-1))

with each cycle A, R(4), R(5)and R(6)has the same meaning as described above, and L(1)represents a halogen atom such as chlorine atom or bromine atom.

As the compound (c ' -1) can be used directly commercially available product, or the specified connection can also be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained by methods described in the examples to obtain in this description.

[Stage C" 1-1]

This stage is the stage of obtaining compound (c"-2) serial processing, in which the metal-halogen exchange of the compound (c ' -1) and the obtained compound of the metal is treated with trialkylborane, such as trimethylboron, derivatization Bronevoy acid, cat the PoE process oxidant, such as peracetic acid or N-oxide N-methylmorpholine, to obtain the compound (c"-2).

These responses through Bronevoy acid is a method of synthesis known to specialists in this field of technology. The reaction can be carried out under the same conditions as are described, for example, Gotteland, J.-P.; Halazy, S.; Synlett, 9, 931-932 (1995).

[Stage C" 1-2]

This stage is the stage of synthesis of the compound (c ' -3) using the compound (c"-2) as the starting material and the above-described method ([stage A-3]).

[Stage C" 1-3]

This stage is the stage of obtaining the compound (c ' -4) the reaction of halogenation of the compound (c ' -3).

This halogenation reaction is a method of synthesis known to specialists in this field of technology. The reaction can be carried out under the same conditions as are described, for example, Gray, M. A.; Konopski, L.; Langlois, Y.; Synth. Commun., 24 (10), 1367-1379 (1994).

[Stage C 1-4]

This stage is the stage of obtaining the compound (c-1) from compound (c ' -4).

The method of obtaining the compound (c-1) is a method of synthesis known to specialists in this field of technology. The reaction can be carried out under the same conditions as are described, for example, Valenti, P.; Chiarini, A.; Gasperi, F.; Budriesi, R.; Arzneim.-Forsch., 40 (2), 122-125 (1990); Ventelon, L.; Moreaux, L.; Mertz, J.; Blanchard-Desce, M.; Chem. Commun. (Cambridge), 20, 2055-2056 (1999).

[General met the dick D get] (method of synthesis of compounds (1-9))

with each cycle A, R(4), R(5), R(6), R'(4), R'(5), R'(6), X and M have the same significance as described above; R(7)represents a hydrogen atom or a lower alkyl group such as methyl group or ethyl group; and R(8)represents a lower alkyl group such as methyl group or ethyl group.

As compound (d-1), compound (d-2) and compound (d-5) can be directly used commercially available products. Or these compounds may be obtained from commercially available products by methods known to experts in this field. In addition, these compounds can be also obtained by the methods described in the examples to obtain in this description.

[Stage D-1]

This stage is the stage of obtaining compound (d-3) providing the compound (d-1) possibilities to interact with the ORGANOMETALLIC compound (d-2) in the presence of an ORGANOMETALLIC catalyst.

This reaction can be carried out under the same conditions, which are usually used in the reaction of a combination of halogenated heteroaryl compound or the like with the ORGANOMETALLIC compound in the presence of an ORGANOMETALLIC catalyst.

ORGANOMETALLIC catalyst used in this reaction are not particularly limited. Preferred examples of such ORGANOMETALLIC catalyst may include tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II)dichloride (1,1'-bis(diphenylphosphino)ferrocene)palladium(II), bis(tert-butylphosphine)palladium(0), palladium acetate(II) and (1,3-bis(diphenylphosphino)propane)Nickel(II). Such ORGANOMETALLIC catalyst is used at a ratio of from about 0.001 to 0.1 equivalents relative to the starting material.

ORGANOMETALLIC compound is not particularly limited. Preferred examples of such ORGANOMETALLIC compounds may include ORGANOTIN reagents, such as aritri-n-botillo or tributyl(3-methyl-2-butenyl)tin, and Bioorganicheskaya reagents, such as arylboronic acid or 2-aryl-4,4,5,5-tetramethyl-1,3-dioxaborolan. Such ORGANOMETALLIC compound used with the compared from 1 to 5 equivalents relative to the starting material.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of such a solvent may include benzene, toluene, xylene, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited. It is in the range usually from a temperature on ice to the boiling temperature under reflux of the solvent, preferably from room temperature to the boiling temperature under reflux of the solvent. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

There may be times when good results, such as increased output can be obtained by implementation of this reaction in the presence of a base. Such a base is not particularly limited. Preferred examples of the base may include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and triethylamine.

[Stage D-2]

This stage is the stage of synthesis of the compound (d-4) appropriate modification of the cycle And using compound (d-3) as the starting material and the above-described method ([stage A-7]).

[Stage D-3]

This stage is the stage of synthesis of the compound (1-9) using the compound (d-4) image quality is as the starting material and the above-described method ([stage A-4]).

[Stage D-4]

This stage is the stage of obtaining compound (d-6) providing the compound (d-1) opportunities to interact with compound (d-5) in the presence of an ORGANOMETALLIC catalyst.

This reaction can be carried out under the same conditions, which are commonly used in reactions of a combination of halogenated heteroaryl compound or the like with a simple vinyl ether or the like in the presence of an ORGANOMETALLIC catalyst.

For example, the reaction can be carried out under the same conditions as are described, for example, Andersson, C.-M.; Larsson, J.; Hallberg, A.; J. Org. Chem., 55 (22), 5257-5761 (1990).

ORGANOMETALLIC catalyst used in this reaction are not particularly limited. Preferred examples of such ORGANOMETALLIC catalyst may include tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II)dichloride (1,1'-bis(diphenylphosphino)ferrocene)palladium(II)acetate, palladium(II) and (1,3-bis(diphenylphosphino)propane)Nickel(II). Such ORGANOMETALLIC catalyst is used at a ratio of from about 0.001 to 0.1 equivalents relative to the starting material.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of such a solvent may include benzene, toluene, xylene, N,N-dimethylformamide, 1-m is Teal-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited. It is in the range usually from a temperature on ice to the boiling temperature under reflux of the solvent, preferably from room temperature to the boiling temperature under reflux of the solvent. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

There may be times when good results, such as increased output can be obtained by implementation of this reaction in the presence of a base. Such a base is not particularly limited. Preferred examples of the base may include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and triethylamine.

There may also be cases when the preferred results, such as increased output can be obtained by implementation of this reaction in the presence of ammonium salt such as Tetra-n-butylammonium, Tetra-n-butylammonium or Tetra-n-butylammonium.

[Stage D-5]

This stage is the stage of synthesis of the compound (d-7) appropriate modification of the cycle And using compound (d-6) as starting material and the above-described method ([stage A-7]).

[Stage D-6]

This stage is the stage of synthesis of the compounds the Oia (1-9) using the compound (d-7) as the starting material and the above-described method ([stage C-2]).

[Stage D-7]

This stage is the stage of synthesis of the compound (1-9) using the compound (d-6) as starting material and the above-described method ([stage C-2]).

[General method E get] (method of synthesis of compounds (1-9) (1-10))

with each cycle A, R(4), R(5), R(6), X and M have the same meanings as described above, X' is a leaving group, which represents, for example, halogen atom (chlorine atom, bromine atom, iodine atom etc) or sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov.

As the compound (c'-1) and the compound (c'-2) can be directly used commercially available products. These compounds can also be obtained from commercially available products by methods known to experts in this field. In addition, these compounds can be also obtained by the methods described in the examples to obtain in this description.

[Stage E1-1]

This stage is the stage of synthesis of the compound (c'-5) using the compound (c'-1) as the starting material and the above-described method ([stage C'1-2]).

[Stage E1-2]

This stage is the stage of synthesis of the compound (c'-6) use the cation of the compound (c'-1) as the starting material and the above-described method ([stage C'1-3]).

[Stage E1-3]

This stage is the stage of synthesis of the compound (c'-6) using the compound (c'-2) as the starting material and the above-described method ([stage C'1-4]).

[Stage E2-1]

This stage is the stage of obtaining the compound (e-3) gidroborudovaniya compounds (c'-5).

Hydroporinae olefins are carried out by General methods known to experts in the art of obtaining alcohol.

[Stage E2-2]

This stage is the stage of obtaining the compound (e-3) software metallizovannogo aryl compound (including a heterocyclic ring) (C'-6) opportunities to interact with ethylene oxide.

Metallizovannogo aryl compound (including a heterocyclic ring) provide an opportunity to interact with ethylene oxide according to the General methods known to experts in the art of obtaining alcohol.

[Stage E3-1]

This stage is the stage of obtaining compounds (1-10) converting the hydroxyl group of compound (e-3) in the stretching group.

Examples of leaving groups may include halogen atoms (chlorine atom, bromine atom, iodine atom etc) and sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov.

This reaction can be carried out with the Aceh same conditions, what is usually used in the reaction conversion of the hydroxyl group in the aforementioned leaving group (the conditions described, for example, in R. K. Crossland and K. L. Servis, J. Org. Chem.,35, 3195 (1970)).

When specified the leaving group is, for example, halogen atom, the compound (1-10) can be obtained by providing the compound (e-3) opportunities to interact with thionyl chloride, tierbroker, tribromide phosphorus, tetrachloroethylthio or other Solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include benzene, toluene, xylene, methylene chloride and chloroform.

The reaction temperature is usually from -78°C to the boiling temperature under reflux of the solvent, preferably in the range of temperature on ice to the boiling temperature under reflux of the solvent.

The reaction time is not particularly limited. It is usually from 5 minutes to 48 hours, preferably from 5 minutes to 12 hours.

When specified the leaving group is, for example, sulfonyloxy, the compound (1-10) can be obtained by providing the compound (e-3) opportunities to interact with methanesulfonamido, p-toluensulfonate, three is timetosleep anhydride or the like

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include tetrahydrofuran, toluene, xylene, methylene chloride, chloroform, and N,N-dimethylformamide.

The reaction temperature is usually from -78°C to the boiling temperature under reflux of the solvent, preferably from -78°C to room temperature. There may be times when good results, such as increased output can be obtained by adding a base. The base used in this reaction is not particularly limited, if only it didn't slow the reaction. Preferred examples of such a base may include sodium carbonate, potassium carbonate, triethylamine, pyridine and diisopropylethylamine.

[Stage E3-2]

This stage is the stage of obtaining compounds (1-9) by the oxidation reaction of compound (e-3). The aldehyde can be obtained from the alcohol method, well-known specialists in this field of technology.

Examples of known oxidation method used in this reaction may include oxidation in Turn, the oxidation Corey-Kim oxidation on Mofette, PCC oxidation, PDC oxidation, oxidation by Dess-Martin oxidation using a mixture of SO3the pyridine and TEMPO oxidation.

Races shall foretell, used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Examples of such a solvent may include dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride and chloroform.

The reaction temperature is not particularly limited. It is usually from -78°C to the boiling temperature under reflux of the solvent, preferably from -78°C to room temperature. The reaction time is not particularly limited. It is usually from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

[General procedure F to obtain] (method of synthesis of the compound (2-1))

[General methods obtain F] is a method of obtaining compound (2-1)used in [General methodology 2' receipt].

where R(9) has the same meaning as described above, and R(14) represents a lower alkyl group such as methyl group or ethyl group, or aracelio group such as benzyl group.

[Stage F-1]

This stage is the stage of obtaining the compounds (2-1) providing the compound (f-1) possibilities to interact with the primary amine (f-10).

This reaction is known specialist of the meters in the art. It can be carried out under the same conditions as are described, for example, Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-H.; Frey, L.; Karady, S.; Shi, Y.-J.; Verhoeven, T. R.; J. Org. Chem., 60 (14), 4324-4330 (1995).

[Stage F-2]

This stage is the stage of synthesis of the compound (f-4) using the compound (f-3) as the starting material and the above-described method ([stage 1-6]) or ([stage 1-7]).

[Stage F-3]

This stage is the stage of obtaining the compounds (2-1) by hydrolysis of compound (f-4). This reaction can be carried out under the same conditions, which are usually used in the hydrolysis catalogo connection (for example, conditions described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), pp. 175-223).

The reaction is carried out in the presence of acid. Examples of the acid used in this reaction may include chloroethanol acid, p-toluensulfonate acid, triptoreline acid and camphorsulfonic acid. The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of the solvent used in this reaction may include solvents such as methanol, ethanol, acetone or tetrahydrofuran or a mixed solvent composed of water and methane is a, ethanol, acetone, tetrahydrofuran or the like

[Stage F-4]

This stage is the stage of synthesis of the compound (f-6) using the compound (f-5) as the starting material and the above-described method ([stage 1-6]) or ([stage 1-7]).

[Stage F-5]

This stage is the stage of synthesis of the compound (2-1) using the compound (f-6) as starting material and the above-described method ([E3 stage-2]).

[Stage F-6]

This stage is the stage of synthesis of the compound (2-1) using the compound (f-7) as the starting material and the above-described method ([stage 1-6]) or ([stage 1-7]).

[General method G get] (method of synthesis of compound (3-1))

where X' and Z have the same meanings as described above, and Y represents a nitro-group or amino group.

As the compounds (g-1) can be used directly commercially available product, or the specified connection can also be obtained from a commercially available product by a method known to specialists in this field of technology. In addition, it can also be obtained by methods described in the examples to obtain in this description.

[Stage G-1]

This stage is the stage of obtaining the compound (g-3) the reaction Sonogashira between which the compound (g-1) and trimethylsilylacetamide (g-2). The reaction Sonogashira is a method of synthesis known to specialists in this field of technology. It can be carried out under the same conditions as are described, for example, Erdelyi, M.; Gogoll, A.; J. Org. Chem., 66 (12), 4165-4169 (2001), Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Perez, M.; Garcia-Martin, M. A.; Gonzalez, J. M.; J. Org. Chem., 61 (17), 5804-5812 (1996).

[Stage G-2]

This stage is the stage of obtaining the compounds (3-1) reaction reconnection (g-3).

The restoration of the nitrogroup is a reaction, well-known specialists in this field of technology. In response to the restoration carried out in the presence of acetylene is preferred recovery method of the nitro group to an amino group using tin or zinc in acidic conditions. In addition, can also be used restoration hardware using ameriglide in neutral conditions. The reaction can be carried out under the same conditions as are described, for example, Izumi, T.; Yokota, T.; J. Heterocycl. Chem., 29 (5), 1085-1090 (1992), Hartman, W. W.; Dickey, J. B.; Stampfli, J. G.; Org. Synth., II, 175 (1943) (where Y represents an amino group, this stage is not necessary to perform).

[Regarding the receipt of the compounds (g-1)]

where Z has the same meaning as described above.

As described above, as the compounds (g-1) can be directly used in commercial buildings, the sky is the product available or the specified connection can also be obtained from a commercially available product by the way well-known specialists in this field of technology. In particular, various ester compound or amide compound as the compound (g-1) can be synthesized from 4-bromo-3-nitrobenzoic acid according to the General methods known to experts in this field.

[General methods obtain H] (method of synthesis of compounds (1-9))

This technique is a method of synthesis of compounds (1-9), different from the General method E. receipt.

with each cycle A, R(1), R(4), R(5), R(6), R'(4), R'(5)and R'(6)has the same meaning as described above; R(14)represents a hydrogen atom, a lower alkyl group such as methyl group or ethyl group, or a lower aracelio group such as benzyl group; X(1)represents a halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom; P(2)represents a protective group for the alcoholic hydroxyl group, such as acyl group or benzoline group; and P(3)represents a protective group for a phenolic hydroxyl group, such as methoxymethyl group, 1-amoxicilina group or tetrahydropyranyl group.

[Stage H-1]

As the compounds (h-1) can be used directly commercial is available the product or the specified connection can also be obtained from a commercially available product according to the method well-known specialists in the field of technology, such as the technique described in the publication J. Velkov; Mincheva z; J. Bary; G. Boireau; C. Fujier; Synthetic Communications, 27 (3), 375-378 (1997).

This stage is the stage of obtaining compounds (h-2) restoration, protection alcoholic hydroxyl group and then removing the protective group of a phenolic hydroxyl group of compound (h-1).

The reduction of the ester group can be carried out under the same conditions as commonly used in the conditions described, for example, in the 4th edition of theJikken Called Koza26, S. 159-266.

Examples of the reducing agent used in this reaction may include sociallyengaged, lithium borohydride, diisobutylaluminum and bis(2-methoxyethoxy)alumoweld sodium. The reaction temperature is not particularly limited. It is usually from -78°C to the boiling temperature under reflux of the solvent, preferably from -78°C to room temperature. The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Preferred examples of such a solvent may include tetrahydrofuran, simple ether, dimethoxyethane, cyclopentylmethyl simple ether, toluene and methylene chloride.

The specified reducing agent is used in a ratio of from 1 to 3 equivalent is having preferably from 1 to 1.5 equivalents, relative to compound (h-1).

The introduction of a protective group in the alcoholic hydroxyl group can be carried out under the same conditions as commonly used conditions are described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons, Inc.

In this reaction, when the alcoholic hydroxyl group is protected, for example, bentilee group, provide the opportunity vzaimodeystviya of benzoyl chloride with the above alcohol form in the presence of a base, such as triethylamine, in a solvent such as toluene, xylene, ethyl acetate or ether solvent, such as dimethoxyethane or cyclopentylmethyl ether, to obtain the product of interest. The benzoyl chloride can be used at a ratio of 1 equivalent to excess amount relative to the specified alcohol forms of connection. Can be used triethylamine in a ratio of 1 equivalent to excess amount relative to the alcohol form of connection. There may be cases obtain in the present invention the preferred results, such as increasing or decreasing the reaction time, by using N,N,N,N-tetramethylethylenediamine, diisopropylethylamine, N,N-dimethylaniline or the like

The reaction time is not particularly ogranichivaut is usually from 0.5 to 48 hours, preferably from 0.5 to 4 hours. The reaction temperature is from 0°to 100°C, preferably from 0°C to room temperature.

The removal of the protective group for the phenolic hydroxyl group can be carried out under the same conditions as described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons, Inc.

In this reaction, when the phenolic hydroxyl group protects methoxymethyl group, 1-ethoxyethylene group or the like, the hydroxyl group may be given the opportunity to interact with chloroethanol acid in a mixed solvent consisting of toluene, dimethoxyethane and tetrahydrofuran, to obtain the compounds (h-2). The number chloroethanol acid is from 1 equivalent to excess amount relative to the original substances. The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 1 to 4 hours. The reaction temperature is from 0°to 100°C, preferably from 0°C to room temperature.

[Stage H-2]

This stage is the stage of obtaining compound (h-4) software phenolic connection opportunities to interact with 3,3-dimethylacrylamide acid or derivative 3,3-dimethylacrylamide acid such as 3,3-dimethylacrylate.

The reaction of m which can be carried out under the same conditions, as described in publications such as T. Timar et al., "Synthesis of 2,2-Dimethyl-4-Chromanones", J. Heterocyclic Chem., 37, 1389 (2000), J. C. Jaszberenyi et al., "On the Synthesis of Substituted 2,2-Dimethyl-4-Chromanones and Related Compound" Tetrahedron Letters, 30 (20), 2791-2794 (1992), J. C. Jaszberenyi et al., Heterocycles, 38 (9), 2099 (1994). In addition to these methods, the compound (h-4) can also be obtained by providing the compound (h-2) opportunities to interact with 3,3-dimethylacrylamide acid in the presence methanesulfonic acid. 3,3-Dimethylacrylamide acid is used at a ratio of 1 equivalent to excess amount relative to compound (h-2). The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 1 to 4 hours.

The reaction temperature ranges from room temperature to 100°C, preferably from 40°C to 60°C.

[Stage H-3]

This stage is the stage of obtaining compounds (1-9) by removing protection from alcoholic hydroxyl group of compound (h-4) and then by oxidation of the resulting alcohol.

The reaction can be carried out under the same conditions, which is usually used for removal of the protective group for the alcoholic hydroxyl group, are described in publications such as T. W. Green and P. G. M. Wuts, "Protective groups in Organic Chemistry, Second Edition", John Wiley & Sons, Inc. For example, alcoholic hydroxyl group, protected benzoate ester group or the like, with which the Association (h-4) provide the opportunity to interact with 2 N. NaOH solution or the like in an organic solvent such as tetrahydrofuran, methanol or ethanol, or in mixtures thereof with obtaining interest product. 2n. the NaOH solution is used at a ratio of 1 equivalent to excess amount relative to compound (h-4). The reaction time is not particularly limited. It is usually from 0.5 to 48 hours, preferably from 1 to 5 hours.

The reaction temperature is from 0°to 100°C, preferably from room temperature to 50°C.

The following reaction includes a step of obtaining compound (1-9) by oxidation, obtained as described above, compounds containing alcoholic hydroxyl group.

The aldehyde can be obtained from the alcohol method, well-known specialists in this field of technology.

Examples of known oxidation method used in this reaction may include oxidation in Turn, the oxidation Corey-Kim oxidation on Mofette, PCC oxidation, PDC oxidation, oxidation by Dess-Martin oxidation using a mixture of SO3the pyridine and TEMPO oxidation.

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Examples of such a solvent may include dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, this is latitat, water and their mixture.

The oxidizing agent is used at a ratio in the range of from a catalytic amount to excess relative to the alcohol form.

The reaction temperature is not particularly limited. It is usually from -78°C to the boiling temperature under reflux of the solvent, preferably from -5°C to room temperature. The reaction time is not particularly limited. It is usually from 3 to 10 hours, preferably from 3 to 5 hours.

If, for example, TEMPO oxidation, it can be made according to the method described inJikken Called Koza 23, Yuki Gosei V, Sanka HannoMaruzen Co., Ltd., pp. 485-513.

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Examples of such a solvent may include dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate, water and their mixture.

An oxidizer, such as sodium hypochlorite contained in an aqueous solution of sodium bicarbonate, used in a ratio in the range of from a catalytic amount to excess relative to the alcohol form in the presence of a mixture of 2,2,6,6-tetramethylpiperidinyloxy sodium.

The reaction temperature is not particularly limited. It is usually from -20°C to room temperature, preferred is entrusted -5° With up to room temperature. The reaction time is not particularly limited. It is usually from 3 to 10 hours, preferably from 3 to 5 hours.

If, for example, oxidation in Turn, it can be made according to the method described inJikken Called Koza 23, Yuki Gosei V, Sanka Hanno, Maruzen Co., Ltd., pp. 369-403.

The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and to a certain extent dissolved starting material. Examples of such a solvent may include dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate and a mixture thereof.

As oxidizing agent, acting as activator of dimethyl sulfoxide, use oxalicacid, triperoxonane anhydride, acetic anhydride, cycloheximide, pentoxide Diaspora or the like, at a ratio in the range from twice the molar amount up to the excess amount relative to the alcohol form.

As the base used triethylamine, N,N-diisopropylethylamine, pyridine or the like at a ratio in the range from twice the molar amount up to the excess amount relative to the alcohol form.

The reaction temperature is not particularly limited. It is usually from -70°C to room temperature. The reaction time is usually from 3 to 10 hours, preferably from 3 to 5 hours.

The aldehyde (1-9) which can be simply purified by converting it into the adduct of sodium bisulfite according to the method described in D. P. Kjell et al., "A Novel Nonaqueous Method for Regeneration of Aldehydes from Bisulfite Adducts" J. Organic. Chemistry. 64, 5722-5724 (1999). In addition, the aldehyde can also be easily regenerated. The adduct of sodium bisulfite can be obtained by providing the aldehyde form (1-9) opportunities to interact, for example, with an aqueous solution of sodium bisulfite in an organic solvent, such as ethanol, ethyl acetate, or methanol, or a mixture. The specified sodium bisulfite is used in a ratio of 1 equivalent to excess amount relative to compound (1-9). The reaction temperature is not particularly limited. It is usually from 10°C to 40°C, preferably room temperature. The reaction time is usually from 1 to 48 hours, preferably 12 to 24 hours.

Obtained in the manner described above adduct of sodium bisulfite treated with a base such as potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, in an organic solvent, such as ethanol, ethyl acetate, or methanol, or a mixture with obtaining aldehyde form (1-9). The base used in the ratio of 1 equivalent to excess amount relative to the adduct of sodium bisulfite. The reaction temperature is not particularly limited. It is usually from 10°C to 40°C, preferably room temperature. The reaction time is usually, the composition of AET from 1 to 24 hours, preferably from 1 to 2 hours.

The compound (1-9) can be used to obtain compounds represented by formula (I), with clearing or without it.

The effects of the invention

To demonstrate the usefulness of the compounds of the present invention represented by the General formula (I), the authors of the present invention conducted the following tests.

The following examples of test and reference examples are given only for illustrative purposes. Therefore, the tool of the present invention for the treatment or prevention of symptoms of the lower urinary tract is not limited to these examples in any case. Specialists in this field can implement the present invention as much as possible, not only using examples of test and reference examples described below, but also making various changes and additions in the scope defined by the claims in the description to this application. Such changes and additions included in the scope defined by the claims in the description to this application.

Example 1 test[Test concerning the affinity for serotonin 1A receptor]

(1) the Affinity of the test substance relative to the 5-HT1A receptor was investigated by carrying out an experiment on inhibition, which examined the inhibitory effect of the test substance on the binding of [32. On the contrary, he comes to the condition of nesvyazannie G-protein by adding guanosinmonofosfat (Gpp(NH)p). As you know, the agonist of the G-protein receptor usually shows a strong affinity to the receptor, which is able to bind to G-protein, depending on its internal activity. Why were obtained as the affinity of the test substance to the receptor, which is in the state of nesvyazannie with G-protein and the affinity of the test substance to the receptor, which is in the state of binding to G-protein. Then the obtained values were compared with each other to assess the level of internal activity of the test substance. Theoretically, when the value (L/H)obtained by dividing the affinity of the test substance to the receptor in a state of low activity (IC50 value), the affinity of the test substance to the receptor in a state of high activity (IC50 value), equal to 1 or less, the internal activity of the test substance is equal to zero. More than the specified value, the higher the internal activity, which can be obtained. Action is sustained fashion, it is proved that the test substance has no internal activity, when it has a value of L/H, equal to 1 or less, and that the test substance has an inner activity, when it has a value of L/H equal to 2 or greater.

The hippocampus pigs homogenized in 50 mm Tris-HCl buffer (pH 7.4; hereinafter referred to as buffer A), which had already been chilled on ice. The suspension was centrifuged at 40000 × g for 15 minutes. The precipitate suspended in the buffer solution and the resulting solution is then centrifuged at 40,000 × g for 15 minutes. Such operation is repeated 2 or 3 times. Finally the precipitate after centrifugation suspended in buffer solution And in the amount equal to 10 times the wet weight of pig hippocampus, obtaining the membrane fraction. The obtained membrane fraction was stored at -80°before it is applied.

Used for incubation mixture (0.5 ml) contained the appropriate amount of membrane fractions, the test substance with the required concentration, MgCl2(final concentration: 10 mm) or Gpp(NH)p (final concentration: 1 mm), [3H]MPPF (final concentration: 0.5 nm), dimethyl sulfoxide (final concentration: 1% (vol./about.)) and 50 mm Tris-HCl buffer (pH 7,4). The reaction was initiated by addition of the membrane fraction and the mixture is incubated at 37°C for 30 minutes. On on the onanii incubation, the mixture was subjected to vacuum filtration through a glass filter, using the collector cells. The filter was washed chilled on ice with buffer A. Then measured the radioactivity caused by binding with the receptor, using a liquid scintillation counter. Nonspecific binding was defined as binding, detektirovanie in the presence of 10 μm WAY-100635. In the following table 1 shows the results related to the affinity, which presents the IC50 values obtained from the inhibition curve.

(2)Results

The compound of the present invention, its salt or its hydrate showed excellent activity against the receptor binding. It should be noted that the connection And the connection means described in example 337 in WO98/43956.

5
Table 1
The test substance, compound No.Low affinity, IC50 (nm)High affinity, IC50 (nm)The ratio L/H
Connection0,50,13,7
10,260,161,6
20,350,271,3
30,340,460,7
40,150,170,9
0,450,570,8
60,20,21
70,30,410,7
80,230,221
90,130,170,8
150,610,720,8
190,691,10,6
200,160,20,8
220,10,130,8
240,170,220,8
250,160,180,9
260,20,161,3
270,260,231,1
280,190,141,4
300,190,21

td align="center"> 0,24
Table 2
The test substance, compound No.Low affinity, IC50 (nm)High affinity, IC50 (nm)The ratio L/H
Connection 0,50,13,7
310,150,160,9
320,250,261
330,120,170,7
340,20,260,8
350,230,270,9
360,140,260,5
370,390,550,7
380,130,20,7
440,470,41,2
450,690,581,2
460,330,241,4
470,230,231
481,11,20,9
490,270,221,2
510,170,180,9
520,20,220,9
530,460,311,5
540,130,180,7
570,181,3
580,390,331,2
590,120,190,6
600,240,280,9

Table 3
The test substance, compound No.Low affinity, IC50 (nm)High affinity, IC50 (nm)The ratio L/H
Connection0,50,13,7
110,10,220,4
120,160,170,9
130,220,320,7
140,340,460,7
160,170,180,9
290,30,340,9
390,090,130,7
400,170,180,9
410,140,20,7
430,150,220,7
500,21 0,211
560,040,070,5

Example 2 test[Antagonistic effect on hypothermia in mice, caused by the agonist serotonin 1A receptor]

(1) thermistor probe was inserted in the rectum CD-1 (ICR) mice-males (25-45 g) to a depth of approximately 2 cm to measure the body temperature of mice. After subcutaneous administration of the agonist (8-hydroxydiphenylamine) serotonin 1A receptor with a dose of 0.5 mg/kg body temperature decreases. As the antagonist of the serotonin 1A receptor inhibits this action, the antagonistic effect of the test compound relative to the serotonin 1A receptor was evaluated using the effect of inhibition of hypothermia as an indicator. The test results are presented in below table 4. The test substance was administered 15 minutes before injection of the agonist serotonin 1A receptor. Partial agonist at the serotonin 1A receptor itself reduces the temperature of the body in relation to its agonistic action. In addition, he has a weak antagonistic effect on hypothermia in mice, caused by the 8-hydroxydiphenylamine.

(2)Results

The compound of the present invention, its salt or its hydrate showed excellent pharmacological is to function effectively.

Table 4
The test substance, compound No.ED50 (mg/kg)
Connection A>1
10,3
20,4
30,18
40,1
50,24
60,35
70,38
80,07
90,3
200,03
220,1
240,3
250,1
260,25
270,42
280,02
300,62
310,04
320,04
330,12
340,37
350,2
360,2
380,19
440,41
450,26
460,3
470,21
480,06
49 0,28
510,66
520,5
530,3
540,84
570,1
580,53
590,3
600,52

Example 3 test[Inhibitory effect on increased reflex micturition in rats due to the destruction of the top of the mound]

(1) this test used female rats line Sprague-Dawley (200-350 g). Rats did median incision under anesthesia. Then in front of the bladder did a small diameter hole into which was inserted a catheter used to measure intravesical pressure. In the femoral vein catheter was placed, used for introduction of the test substance. These catheters were fixed in the occipital area through the subcutaneous layer. A day later measured the urinary reflex in rats, using cystometrogram. After this, the rats were fixed on the apparatus for stereotaxis brain under anesthesia and then did a scalp incision along the line of symmetry. Then using a dental drill did the hole in the skull in the upper part of the upper mound in accordance with the coordinate charts brain. Then through the hole at back the s was inserted in the upper mound microelectrode (diameter: 0.7 mm; length 1.5 mm) "legion" of the generator. After this, the applied electric current (65°C, 4 minutes) for damage of brain tissue. After the operation, when the rat came out from the state of anaesthesia, again did cystometrogram to confirm amplification of the urinary reflex. Through a catheter inserted in the femoral vein were administered the test substance and evaluated the effect of the test substance in the urinary reflex. In addition, we compared the effects of several of the tested substances, using the maximum response (Emax). The results are shown in table 5.

(2)Results

The compound of the present invention, its salt or its hydrate showed excellent pharmacological effects.

Table 5
The test substance No.Dose (mg/kg, intravenously)The capacity of the bladder Emax (%)
Soedinenie A0,01-36
30,0362
40,03107
200,394

Example 4 testing[The effect of regulation of memory impairment induced by 8-OH-DPAT, in rats]

(1) Rats male line Sprague-Dawley (130-200 g) was nurtured in otdeleniye and used in this test. To stimulate appetite, body weight of rats was reduced by starvation to approximately 80% of the original mass. After that, the increase in body mass is continuously suppressed by limited supply. To test the maze used cascade 8-beam radial maze (diagonal length of the Central platforms: 34 cm, beam length: 60 cm, width of the beam 12 cm). To give the rats the ability to remember the location of baits placed in the rays, the rats were left on the platform of the maze, where baits were placed at the ends of 4 set of rays. Thereafter, rats were kept in the maze for some period of time or until until they ate all the bait. Specified training was performed 1-3 times a day. Rats, sufficiently trained, were subjected to the following experiment. Rats were injected subcutaneously solvent or the test substance. Twenty minutes later they were injected subcutaneously with 0.5 mg/kg 8-OH-DPAT. Then, 20 minutes later, were tested in the maze, the same as during training. The standard error of the memory is defined as an action, which consists in joining the rays, which were not placed bait, and a working memory error was defined as an action, which consists in entering again into the beams, where the bait was previously. While the actions of the rats were recorded. Recorded the time it took for the rat to Nachod is of all four baits. After rats are not found all four bait for a certain period of time, the test was stopped and taken the time was defined as the elapsed time. (Reference: Yoshihiro Hiraga, "Effects of scopolamine upon delayed radial-arm maze performance in rats" Folia pharmacol. Japon. 97, 351-359 (1991)). The results are presented in table 6.

(2)Results

The compound of the present invention, its salt or its hydrate showed excellent pharmacological effect.

Table 6
The number of working memory errorsThe number of standard errors of memoryElapsed time (seconds)N
The solvent (1 ml/kg, subcutaneously)7,13±1,012,63±0,63371±44,88
The test compound No. 20 (0.3 mg/kg, subcutaneously)0,25±0,161,50±0,5752±9,98
Average ± root mean square error

Example 5 testing[Evaluation of anti-anxiety effect test mouse light-dark box]

(1) was modified methodology for Belzung C., Misslin R., and Vogel, E. (Reference: Behavioural effects of the benzodiazepine receptor partial agonist RO16-6028 in mice, Psychopharmacology, 97, 388-391, 1989). This test mouse light is on-dark Boxing conducted in accordance with this modified technique. As the device used for this test used a fitted cap black acrylic box (dark Boxing, 15 × 10 × 20 cm)connected with white acrylic box without a lid (light box, 15 × 20 × 20 cm) using black acrylic tunnel (10 × 7 h 4.5 cm), which produced a light-dark box, in which the mouse can move freely between the dark and light boxes. In this device for testing, to see the behavior of the mouse, the front wall (20 × 20 cm) and rear wall (20 × 20 cm) made of transparent acrylic. Installed lighting that provides illumination of 150 Lux on the floor light box. Then each of the mice male C57BL (20-35 g) were placed in a dark box and started the test. In this experience the test substance was administered to the animal subcutaneously 30 minutes before testing begins.

For mouse behavior was observed within 5 minutes after beginning of test. The state when the 4 legs of the mouse were in contact with the floor light box, defined as being in a bright place and measured the time the mouse in a bright place. The reference time is used as an indicator of anti-anxiety action. The results are presented in table 7.

(2)Results

The compound of the present invention, its salt or its hydrate showed excellent pharmacological efficiency is.

Table 7
The test substance, compound No. 20 (mg/kg)Stay in a bright place (seconds)N
Solvent39±5,57
0,0346±9,47
0,167±197

From the above results it is seen that the compound of the present invention, represented by formula (I), is a new compound shows excellent activity and effects as a drug and is useful as a new tool for the treatment or prevention of symptoms of lower urinary tract disorders, learning or memory, or anxiety disorder. I.e. for the treatment or prevention of symptoms of lower urinary tract disorders, learning or memory, or anxiety disorders according to the present invention is a medicinal product which contains as active component a compound that selectively with affinity to 5-HT1A receptor and with an antagonistic effect with respect to the above receptors in the Central nervous system, its salt or its hydrate. Especially noticeable effects is but has in the treatment or prevention of symptoms, regarding the accumulation of urine, such as frequent urination, imperative urge to urinate or urinary incontinence.

Used in this description, the term "salt" means a pharmacologically acceptable salt. Such salt is not particularly limited, if only she was pharmacologically acceptable salt of the compound represented by the General formula (I)contained in therapeutic or prophylactic agent for symptoms of the lower urinary tract. Preferred examples of such salts may include salts of halogen acids (for example, hydroptere, hydrochloride, hydrobromide and hydroiodide), inorganic salts (e.g. sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate), organic carboxylates (e.g. acetate, oxalate, maleate, tartrate, fumarate and citrate), organic sulfonates (for example, methanesulfonate, triftorbyenzola, aconsultant, bansilalpet, toluensulfonate and camphorsulfonate), salt, amino acids (for example, aspartate and glutamate), salt, Quaternary amines, alkali metal salts (e.g. sodium salt and potassium salt), and salts of alkaline earth metals (such as magnesium salt and calcium salt).

For the treatment or prevention of symptoms of the lower urinary tract of the present invention can be manufactured in the form of dosage forms on icname ways. Preferred dosage forms include tablet, powder, parvula, granule, tablet coating, capsule, syrup, trosha, inhalant, suppository, solution for injection, ointment, eye drops, eye ointments, nasal drops, ear drops, poultices and lotion. For the manufacture of dosage forms can be used commonly used additives. Examples of such additives may include a filler, binder, lubricant substance, dye, corrigent, and, when necessary, a stabilizer, emulsifier, power adsorption, surfactant, a pH regulator, an antiseptic and antioxidant. The above material can be made by mixing the components, usually used as raw materials for pharmaceutical preparations, in the usual way. Examples of such components may include animal or vegetable oils such as soybean oil, solid animal fat or synthetic glycerides; hydrocarbons such as liquid paraffin, squalane or solid paraffin; ester oils such as octyldodecyl or isopropylmyristate; higher alcohols, such as cetosteatil alcohol or beganovic alcohol; silicone resins; silicone oils, surfactants, such as polyoxyethylene esters of fatty acids, sorbitane EPE is s fatty acids, glycerol esters of fatty acids, polyoxyethylenesorbitan esters of fatty acids, polyoxyethylene hydrogenated castor oil, or a block copolymer of polyoxyethylene and polyoxypropylene; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone or methyl cellulose; lower alcohols, such as ethanol or isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol or sorbitol; sugars such as glucose or sucrose; inorganic powders such as silicic acid anhydride, aluminum silicate magnesium or aluminum silicate; and distilled water. Examples of the filler may include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide. Examples of the binder may include polyvinyl alcohol, simple, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, block-copolymer polypropylenglycol and polyoxyethylene and meglumin. Examples of baking powder may include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, actin and calcium-carboximetilzellulozu. Examples of the lubricant may include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil. As a coloring substance use products that are permitted to add to medicines. Examples of corrigenda used in the present invention, can include cocoa powder, menthol, aromatic powder, peppermint oil, borneol and cinnamon powder.

If, for example, oral drug compound as an active ingredient, its salt or its hydrate is mixed with filler. In addition, if necessary, add a binder, baking powder, grease, dye, corrigent or the like, then the resulting mixture by conventional methods produce powder, fine granules, granules, tablets, coated tablets, capsules or the like In the case of tablets or granules these drugs if necessary, suitably coated with sugar or other substances. In the case of liquor or drugs for injection add a pH regulator, a solvent, isotherwise substance and, when necessary, a solubilizer, a stabilizer, etc. Then the resulting mixture is made by conventional methods required dosage forms. In the case of an external preparation method of its manufacture is not restricted and the outdoor pre the Arat can be produced by conventional methods. As materials for the base in this case can be used in a variety of materials commonly used for medicinal quasilegal, cosmetics or the like, Examples of such materials may include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, Ginuwine minerals and distilled water. In addition, if necessary, can also be added pH regulator, antioxidant, chelating agent, antiseptic and antifungal agents, coloring matter, perfume or the like May also be added, when necessary, the components having the calling differentiation effect, such as a means of facilitating the flow of the blood, antibacterial, anti-inflammatory agent, an activator of cells, vitamins, amino acid, humidifier or keratolytic drug. The dosage of therapeutic or prophylactic agent of the present invention varies depending on the severity of symptoms, age, sex, body weight, dosage form, type of salts, the specific type of illness or the like, Usually pharmaceutical drug is administered orally at one time and is divided into several intakes per day dose for adults from about 30 μg to 10 g, preferably from 100 μg to 5 g, and more preferably from 100 μg to 100 mg intravenous drug it is administered once or divided into several injections per day dose for adults from about 30 μg to 1 g, preferably 100 μg to 500 mg and more preferably from 100 μg to 30 mg

The best way of carrying out the invention

Further, the present invention is described in more detail in reference examples and examples. Examples are given for illustrative purposes only and are not intended to limit the scope of the invention. The tool of the present invention for the treatment or prevention of symptoms of the lower urinary tract is a medicine that contains as an active ingredient a compound which has a selective affinity to 5-HT1A receptor, as well as exhibiting antagonistic effect in relation to a specific receptor in the Central nervous system, its salt or its hydrate. Specialists in this area to the maximum extent possible to implement the present invention, not only using reference examples and examples described below, but also introducing various changes and additions in the scope defined by the claims in the description to this application. Such changes and additions included in the scope of the claims in the description to this is awke.

EXAMPLES

Example 1 obtaining

Synthesis of 1-(piperidine-4-yl)-1H-indole-6-carboxamide

(1)Synthesis of methyl 1-(1-benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxylate

by 44.3 g of Methyl 3-amino-4-(2,2-dimethoxymethyl)benzoate synthesized in accordance with a publication (Tetrahedron Letters, Vol. 37, No. 34, pp. 6045-6048), and 64,9 g of benzyl 4-oxo-1-piperidinecarboxylate was dissolved in 485 ml of acetic acid, followed by stirring at room temperature. Approximately 20 minutes to the reaction solution was added to 58.9 g of triacetoxyborohydride sodium. Then the reaction solution was still stirred for 2 hours. Then to the reaction solution was added 485 ml of water and the resulting mixture was heated to a temperature of from 100°With up to 115°C. after About 3 hours the reaction solution was cooled and then concentrated under reduced pressure. Then to the residue was added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed saturated aqueous sodium bicarbonate and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and the residue was then purified by chromatography on a column with NH silica gel (hexane/ethyl is Etat). The obtained solid is suspended in a mixed solvent consisting of hexane and tert-butyl methyl ether, after which the solution was filtered to obtain a 64.6 g of the desired compound.

1H-NMR (CDCl3) δ 1,80-2,05 (m, 2H), 2.05 is-of 2.23 (m, 2H), 2,92 is 3.15 (m, 2H), 3.96 points (s, 3H), 4,30-4,60 (m, 3H), by 5.18 (s, 2H), return of 6.58 (DD, J=0,4, 2.8 Hz, 1H), 7,30 was 7.45 (m, 6H), to 7.64 (DD, J=0,4, and 8.4 Hz, 1H), 7,80 (DD, J=1,6, and 8.4 Hz, 1H), 8,14 (s, 1H).

(2)Synthesis of 1-(1-benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxylic acid

90.0 g of Methyl 1-(1-benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxylate was dissolved in a mixed solution consisting of 760 ml of methanol and 200 ml of tetrahydrofuran. Then to the reaction solution was added 92 ml of 5 N. aqueous sodium hydroxide solution and the mixture is then heated to a temperature of from 60°C to 70°C. Upon completion of the reaction, the reaction solution was cooled and added to it 65.0 g of ameriglide, followed by concentration under reduced pressure. To the residue was added a 5% aqueous solution of KHSO4to bring the pH to 5-6, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. After drying, the residue was collected from mixed dissolve the I, consisting of hexane and tert-butyl methyl ether, filtration with receipt of 75.6 g of the desired compound.

1H-NMR (CDCl3) δ 1,80-2,04 (m, 2H), 2.06 to of 2.21 (m, 2H), 2,94-and 3.16 (m, 2H), 4,30-4,58 (m, 3H), 5,19 (s, 2H), 6,60 (DD, J=0,8, 3.6 Hz, 1H), 7,30-7,44 (m, 6H), to 7.68 (DD, J=0,8, and 8.4 Hz, 1H), 7,88 (DD, J=1,6, and 8.4 Hz, 1H), they were 8.22 (s, 1H).

(3)Synthesis of benzyl 4-(6-carbarnoyl-1H-indol-1-yl)piperidine-1-carboxylate

of 75.0 g of 1-(1-Benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxylic acid was dissolved in 620 ml of tetrahydrofuran. Then to the solution were added and 38.6 g of 1,1'-carbonylbis-1H-imidazole. The reaction solution was stirred at room temperature for 1.5 hours and was added thereto 134 ml of 28% aqueous ammonia solution. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure and then extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and saturated aqueous ammonium chloride. To separate the organic layer was added tetrahydrofuran and the resulting mixture was dissolved partially hardened to the desired compound, followed by drying over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. Hardened to the desired compound was collected by filtration. Picked this connection required suspended in tet is hydrofuran and the mixture was heated with subsequent filtering. Picked this connection required then suspended in a mixed solvent consisting of tetrahydrofuran and methanol, and the resulting mixture was heated, followed by filtration. The resulting filtrates were combined and concentrated, and, as described above, received the requested connection. The total number of the desired compounds were 64.8,

1H-NMR (CDCl3) δ 1,93 (users, 2H), 2,04-to 2.18 (m, 2H), 3,02 (users, 2H), 4.26 deaths-4,60 (m, 3H), by 5.18 (s, 2H), return of 6.58 (DD, J=0,8, a 3.2 Hz, 1H), 7,28-7,44 (m, 7H), the 7.65 (DD, J=0,4, and 8.4 Hz, 1H), 8,10 (s, 1H).

(4)Synthesis of 1-(piperidine-4-yl)-1H-indole-6-carboxamide

43 g of Benzyl 4-(6-carbarnoyl-1H-indol-1-yl)piperidine-1-carboxylate suspended in a mixed solution consisting of 400 ml of methanol and 600 ml of tetrahydrofuran. Then, to the suspension was added to 3.3 g of 10% palladium-on-carbon. The above suspension was replaced with hydrogen, followed by stirring at room temperature. Upon completion of the reaction, 10% palladium-on-carbon was filtered from the reaction solution, after which the reaction solution was concentrated under reduced pressure. To the residue was added tetrahydrofuran and the resulting mixture was again concentrated under reduced pressure. To the resulting residue were added tetrahydrofuran, followed by stirring for curing the desired connection. Then to the mixture was added tetrahydro the uranium and simple ether followed by cooling on ice. Hardened to the desired compound was collected by filtration. The obtained filtrate was concentrated, and, as described above, received the requested connection. The total number of required connections was 25,2,

1H-NMR (CDCl3) δ 1,88-2,02 (m, 2H), 2.06 to of 2.16 (m, 2H), 2,80 of 2.92 (m, 2H), 3,22-of 3.32 (m, 2H), 4,46 (TT, J=4,0, 12.0 Hz, 1H), return of 6.58 (DD, J=0,8, a 3.2 Hz, 1H), was 7.36-7,44 (m, 2H), 7,65 (d, J=8,4 Hz, 1H), 8,11 (s, 1H).

Example 2 obtaining

Synthesis of N-methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide

(1)Synthesis of N-methyl-1-(1-benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxamide

a 2.00 g of 1-(1-Benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxylic acid was dissolved in 20 ml of tetrahydrofuran and then to the solution was added to 1.03 g of 1,1'-carbonylbis-1H-imidazole. The resulting mixture was stirred at room temperature for 1.5 hours and added to it 4,11 ml of 40% aqueous solution of methylamine. Upon completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and a saturated solution of sodium chloride. After that, the organic layer was dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and the residue was then purified chromatog what afia on a column with NH silica gel (ethyl acetate) and chromatography on a column of silica gel (hexane/ethyl acetate) to give 1.77 g of the desired compound.

1H-NMR (CDCl3) δ 1,80-2,00 (m, 2H), 2,03-2,17 (m, 2H), 2,90-3,10 (m, 2H), 3,06 (d, J=4,8 Hz, 3H), 4,30-4,58 (m, 3H), 5,16 (s, 2H), 6,21 (users, 1H), 6,55 (DD, J=0,8, a 3.2 Hz, 1H), 7,27 (d, J=3.6 Hz, 1H), 7,28-7,40 (m, 6H), to 7.61 (DD, J=0,8, 8.0 Hz, 1H), 8,03 (s, 1H).

(2)Synthesis of N-methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide

1.77 g of N-methyl-1-(1-benzyloxycarbonylamino-4-yl)-1H-indole-6-carboxamide was dissolved in 30 ml of methanol. Then to the resulting solution were added 200 mg of 10% palladium-on-carbon. The atmosphere in the reaction vessel was replaced with hydrogen, followed by stirring the reaction mixture at room temperature. Upon completion of the reaction, 10% palladium-on-carbon was filtered from the reaction solution, after which the reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (ethyl acetate/methanol), followed by curing of the mixed solution consisting of ethyl acetate, tert-butyl methyl ether and methanol, obtaining 973 mg of the desired compound.

1H-NMR (CDCl3) δ 1,86 of 1.99 (m, 2H), 2.06 to and 2.14 (m, 2H), 2,84 (dt, J=2,4, and 12.4 Hz, 2H), 3,06 (d, J=4,8 Hz, 3H), 3,22-3,30 (m, 2H), of 4.44 (TT, J=4,0, 12.0 Hz, 1H), 6,24 (users, 1H), is 6.54 (DD, J=0,8, a 3.2 Hz, 1H), 7,32 and 7.36 (m, 2H,), to 7.61 (DD, J=0,4, and 8.4 Hz, 1H), 8,04 (s, 1H).

Example 3 obtaining

Synthesis of 3-amino-4-(2,2-dimethoxymethyl)benzamide

(1)Synthesis of 3-nitro-4-methylbenzamide

to 20.0 g of 3-Nitro-4-what ethylbenzoic acid was dissolved in 400 ml of tetrahydrofuran. Then to the solution was added to 21.5 g of 1,1'-carbonyldiimidazole and 0.1 ml of dimethylformamide. The resulting mixture was stirred for 45 minutes. After this was added thereto 20 ml of 28% aqueous ammonia solution, followed by stirring at room temperature for 24 hours. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure and the residue was divided between 600 ml of ethyl acetate and 200 ml of water. The organic layer was separated and then washed with 200 ml of 2 N. chloroethanol acid, 100 ml water, 100 ml saturated aqueous sodium bicarbonate solution and 100 ml of saturated solution of sodium chloride. Then it was dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration, the filtrate was concentrated under reduced pressure to obtain 19.5 g of the desired compound.

1H-NMR (CDCl3) δ to 2.67 (s, 3H), 7,47 (d, J=7,6 Hz, 1H), 7,98 (DD, J=2.0 Hz, 1H), 8,40 (d, J=2.0 Hz, 1H).

(2)Synthesis of 3-amino-4-(2,2-dimethoxymethyl)benzamide

19.5 g of 3-Nitro-4-methylbenzamide and 30 g of dimethyl acetal of dimethylformamide was dissolved in 200 ml of dimethylformamide. The resulting mixture was stirred at 140°C for 20 hours. The mixture is then concentrated under reduced pressure. Then to the residue was added 360 ml of methanol and 25 g of chlorotrimethylsilane. The resulting solution was boiled under reflux for 16 hours. The reaction of the races is the thief was cooled and then concentrated under reduced pressure. To the residue were added water and ethyl acetate to separate an organic layer. The organic layer was separated and then washed with a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride. Then it was dried over anhydrous magnesium sulfate. The mixture was filtered through 100 g of a layer of silica gel and then washed with ethyl acetate. Thereafter, the filtrate was concentrated under reduced pressure. Added 0.9 g of 10% palladium-on-carbon to 150 ml of a methanol solution containing the crude product and the mixture was intensively stirred in hydrogen atmosphere. Upon completion of the reaction the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column with NH silica gel (hexane/ethyl acetate) to give 11.5 g of the desired compound.

1H-NMR (CDCl3) δ 2,90 (d, J=5,2 Hz, 2H), 3,38 (s, 6H), 4,16-4,24 (user., 2H), 4,99 (t, J=5,2 Hz, 3H), 5,52-5,67 (user., 1H), 5,93-6,10 (user., 1H), 7,07 (DD, J=1,6 and 7.6 Hz, 1H), 7,10 (d, J=7,6 Hz, 1H), 7,18 (d, J=1.6 Hz, 1H).

Example 1

Synthesis of 1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)2'-Allyloxy-4'-methoxyacetophenone

to 5.00 g of 2'-Hydroxy-4'-methoxyacetophenone was dissolved in 40 ml of N,N-dimethylformamide at room temperature. Then to the reaction solution p is therefore added to 4.16 g of potassium carbonate and 2,80 ml allylbromide. After confirming the disappearance of the materials to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give the ceiling of 5.60 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,61 (s, 3H), of 3.84 (s, 3H), 4,60 with 4.65 (m, 2H), 5,30 lower than the 5.37 (m, 1H), 5,41-5,49 (m, 1H), 6,01-6,18 (m, 1H), 6,44 (d, J=2.4 Hz, 1H), 6,53 (DD, J=2,4, 8,8 Hz, 1H), to 7.84 (d, J=8,8 Hz, 1H).

(2)3'-Allyl-2'-hydroxy-4'-methoxyacetophenone and 5'-allyl-2'-hydroxy-4'-methoxyacetophenone

the ceiling of 5.60 g of 2'-Allyloxy-4'-methoxyacetophenone was dissolved in 10 ml of N,N-diethylaniline. The reaction solution was heated at boiling under reflux in a nitrogen atmosphere. After about 6 hours the reaction solution was set to cool and then to the residue were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed 5 N. chloroethanol acid and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 3,37 g of 3'-allyl-2'-hydroxy-4'-methoxyacetophenone and 1.07 g of 5'-allyl-2'-hydroxy-4'-methoxyacetophenone.

3'-Allyl-2'-hydroxy-4'-methoxyacetophenone

1H-NMR (CDCl3) δ (ppm): 2.57 m (s, 3H), 3,35-to 3.50 (m, 2H), with 3.89 (s, 3H), 4,90-of 5.05 (m, 2H), 5,85-6,05 (m, 1H), 6.48 in (d, J=8,8 Hz, 1H), to 7.64 (d, J=8,8 Hz, 1H), 12,8 (s, 1H).

5'-Allyl-2'-hydroxy-4'-methoxyacetophenone

1H-NMR (CDCl3) δ (ppm): to 2.55 (s, 3H), 3,24-of 3.32 (m, 2H), 3,86 (s, 3H), 5,01-5,10 (m, 2H), 5,90-6,04 (m, 1H), 6,41 (s, 1H), 7,42 (s, 1H), 12.7mm (s, 1H).

(3)7-Allyl-6-methoxy-3-methylbenzo[d]isoxazol

3,37 g of 3'-Allyl-2'-hydroxy-4'-methoxyacetophenone was dissolved in 55 ml of ethanol. Then to the reaction solution was sequentially added 2,61 g hydroxylaminopurine, 3,21 g of sodium acetate and 13 ml of water. The reaction solution was heated at the boil under reflux for about 3.5 hours. After that, 1.30 grams of hydroxylaminopurine and 1.6 g of sodium acetate was dissolved in 6 ml of water and the resulting solution was added to the reaction solution. Resulting reaction solution was still heated by boiling under reflux. After confirming the disappearance of the materials, to the residue were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to get 3,48 g neocide the aqueous-derived oxime. Derived derived oxime and of 6.95 g of triphenylphosphine was dissolved in 150 ml of tetrahydrofuran (THF) and the resulting solution was cooled on ice. Then to the solution was added dropwise 5,22 ml of diisopropylcarbodiimide dissolved in 75 ml of THF. Upon completion of the dripping, the reaction solution was heated to room temperature, then was stirred for approximately 15 hours. The reaction solution was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 1.30 grams of the desired connection.

1H-NMR (CDCl3) δ (ppm): 2,53 (s, 3H), 3,62-3,68 (m, 2H), 3,93 (s, 3H), equal to 4.97-5,13 (m, 2H), of 5.92-6,10 (m, 1H), 6,95 (d, J=8,8 Hz, 1H), 7,42 (d, J=8,8 Hz, 1H).

(4)1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

to 1.00 g of AD-mix-α (hereinafter the manufacturer Aldrich) was dissolved in 5 ml of tert-butanol and 5 ml of water. Then to the solution was added 180 mg of 7-allyl-6-methoxy-3-methylbenzo[d]isoxazol dissolved in 2 ml of tert-butanol. The reaction solution was stirred at room temperature. After confirming the disappearance of the materials to the reaction solution was added 1.20 g of sodium sulfite and the mixture was stirred for approximately 3 hours. To the reaction solution were added water and ethyl acetate to separate an organic layer. The resulting EOS is anceschi layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 176 mg of the crude diol derived. 176 mg derived diol was dissolved in 9 ml of tetrahydrofuran and 3 ml of water and then to the resulting solution was added 261 mg metaperiodate sodium. The resulting mixture was vigorously stirred. After confirming the disappearance of the materials to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 121 mg of the crude derived aldehyde.

121 mg) obtained above derived aldehyde, dissolved in 2 ml of dichloromethane and 57 μl of acetic acid was sequentially added to 4 ml of dichloromethane containing 122 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide. The reaction solution was then stirred for 5 minutes. Then to the reaction solution was added 159 mg triacetoxyborohydride sodium and the mixture is then stirred at room temperature for 8 hours. Then to the reaction solution was added 5 N. HaOH, a saturated aqueous solution of sodium chloride and chloroform to separate the content of inorganic fillers layer. The obtained organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and the residue was purified by chromatography on a column with NH silica gel (ethyl acetate) to obtain 100 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2.06 to of 2.16 (m, 4H), 2,28-2,39 (m, 2H), 2,54 (s, 3H), 2,70-2,78 (m, 2H), 3,11-3,19 (m, 2H), 3,23-of 3.31 (m, 2H), 3,95 (s, 3H), 4,34-to 4.46 (m, 1H), 6,56 (d, J=3.2 Hz, 1H), 6,95 (d, J=8,4 Hz, 1H), 7,38 was 7.45 (m, 3H), of 7.64 (d, J=8,4 Hz, 1H), of 8.09 (s, 1H).

Example 2

Synthesis of 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized using 5'-allyl-2'-hydroxy-4'-methoxyacetophenone as source material, the methods described in example 1, (3)-(4).

1H-NMR (CDCl3) δ (ppm): 2,08-to 2.18 (m, 4H), 2.26 and-a 2.36 (m, 2H), 2,54 (s, 3H), 2,62-2,70 (m, 2H), 2,90-to 2.99 (m, 2H), 3,18 of 3.28 (m, 2H), 3,93 (s, 3H), 4,36-4,48 (m, 1H), return of 6.58 (d, J=3.2 Hz, 1H), 6,97 (s, 1H), 7,35 (s, 1H), 7,38-7,44 (m, 2H), 7,65 (d, J=8,4 Hz, 1H), 8,13 (s, 1H).

Example 3

Synthesis of 1-{1-[2-(6-methoxy-2-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)2 Allyloxy-4-methoxyethanol

1.88 g of 5-Methoxy-2-NITROPHENOL was dissolved in 20 ml of N,N-dimethylformamide. Then to the PE klonoa the solution was sequentially added 1,53 g of potassium carbonate and 1.03 ml of allylbromide. After confirming the disappearance of the materials to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 2,09 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): a 3.87 (s, 3H), 4,62-4,70 (m, 2H), 5,30 is 5.38 (m, 1H), 5,50-to 5.58 (m, 1H), 6,00-6,12 (m, 1H), 6.48 in-6,56 (m, 2H), 8,00 (d, J=9.6 Hz, 1H).

(2)2 Allyloxy-4-methoxyaniline

of 2.09 g of 2-Allyloxy-4-methoxyethanol was dissolved in 20 ml of ethanol, 5 ml of THF and 4 ml of water. Then to the reaction solution was added 4,27 g ameriglide and of 2.23 g of iron and the resulting mixture was stirred under heating at 80°C for 4 hours. Then to the reaction solution was added 2 g of ameriglide, 1 g of iron and 0.25 ml of 5 N. HCl and the resulting mixture was still stirred while heating for about 2 hours. The reaction solution was set to cool and then filtered through celite. Was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of chloride NAT the Oia and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column with NH silica gel (hexane/ethyl acetate) to obtain the 1,09 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3,74 (s, 3H), to 4.52-4,58 (m, 2H), 5.25-in, 5,32 (m, 1H), lower than the 5.37-5,46 (m, 1H), 6,01-6,12 (m, 1H), 6,36 (DD, J=2,4, and 8.4 Hz, 1H), 6,46 (d, J=2.4 Hz, 1H), 6,66 (d, J=8,4 Hz, 1H).

(3)2'-Allyloxy-4'-methoxyacetanilide

3 mg of 4-(Dimethylamino)pyridine and 1 ml of acetic anhydride was sequentially added to 2 ml of pyridine containing 1,09 g 2 allyloxy-4-methoxyaniline, and the reaction solution is then stirred at room temperature. After confirming the disappearance of the starting material, the reaction solution was added 5 N. HCl and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was then utverjdali from a mixture of tert-butyl methyl ether-hexane to obtain 1.04 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): to 2.18 (s, 3H), of 3.78 (s, 3H), 4,54-to 4.62 (m, 2H), and 5.30-of 5.45 (m, 2H), 6,00-6,12 (m, 1H), 6,45-of 6.52 (m, 2H), 7,54 (userd, 1H), they were 8.22 (d, J=9.6 Hz, 1H).

(4)7-Allyl-6-methoxy-2-methylbenzothiazol

1.04 g of 2'-allyloxy-4'-methoxyacetone the ID was dissolved in 20 ml of 1-methyl-2-pyrrolidone. The reaction solution is then stirred under heating at 190°C in nitrogen atmosphere. After eight hours, the reaction solution was set to cool. Then to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain the product (1.01 g). The obtained product was dissolved in 20 ml of acetic acid without purification and the resulting solution was stirred under heating at 135°C. Upon completion of the reaction, the reaction solution was set to cool. After that, the solvent was concentrated under reduced pressure. To the residue was added 5 N. NaOH and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 371 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,60 (s, 3H), 3,55-the 3.65 (m, 2H), 3,88 (s, 3H), 4,95-5,10 (m, 2H), 5,95-6,10 (m, 1H), 6.89 in (d, J=8,8 Hz, 1H), 7,43 (d, J=8,8 Hz, 1H).

(5)-{1-[2-(6-methoxy-2-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was obtained from 7-allyl-6-methoxy-2-methylbenzoxazolium of example 3, (4), by the method described in example 1 (4).

1H-NMR (CDCl3) δ (ppm): 2.06 to to 2.18 (m, 4H), 2,28-to 2.40 (m, 2H), 2,62 (s, 3H), 2,68-2,77 (m, 2H), 3,06-and 3.16 (m, 2H), 3,22-of 3.32 (m, 2H), 3,90 (s, 3H), 4,34-4,47 (m, 1H), return of 6.58 (DD, J=0,6, 3.2 Hz, 1H), to 6.88 (d, J=8,4 Hz, 1H), 7,38-7,46 (m, 3H), to 7.67 (d, J=8,4 Hz, 1H), 8,12 (s, 1H).

Example 4

Synthesis of 1-{1-[2-(6-methoxy-2-methylbenzothiazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)4'-Methoxy-2'-(3-methyl-2-butenyl)oxoacetate

20.7 g of potassium Carbonate and 23.2 ml of 1-bromo-3-methyl-2-butene was sequentially added to 300 ml of acetone containing 25 g of 2'-hydroxy-4'-methoxyacetophenone. The reaction solution was then heated at the boil under reflux. Approximately 6 hours to the solution is added to 4.14 g of potassium carbonate and 4.63 ml of 1-bromo-3-methyl-2-butene and the resulting mixture was heated at the boil under reflux. Approximately 34 hours the reaction solution was set to cool and then filtered through celite. The filtrate was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the desired connection. Another reaction was performed using 2'-hydroxy-4'-methoxyacetophenone (25 g × 2 RA is (a) under the above conditions. The total number of required connections was 98,7,

1H-NMR (CDCl3) δ (ppm): 1,76 (d, J=0.8 Hz, 3H), of 1.81 (d, J=0.8 Hz, 3H), 2,58 (s, 3H), 3,85 (s, 3H), 4,59 (d, J=6,8 Hz, 2H), 5,47-of 5.55 (m, 1H), 6,45 (d, J=2.4 Hz, 1H), 6,51 (DD, J=2,4, 8,8 Hz, 1H), to 7.84 (d, J=8,8 Hz, 1H).

(2)2'-Hydroxy-4'-methoxy-5'-(3-methyl-2-butenyl)acetophenone

and 49.2 g of 4'-Methoxy-2'-(3-methyl-2-butenyl)oxazolidinone was dissolved in 100 ml of N,N-diethylaniline. The reaction solution was boiled under reflux in a nitrogen atmosphere. After 3 hours the reaction solution was set to cool and then add to it 5 N. chloroethanol acid (300 ml) and tert-butyl methyl ether (1000 ml)to separate an organic layer. The obtained organic layer was washed 5 N. chloroethanol acid (300 ml × 2) and a saturated solution of sodium chloride (500 ml) and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the desired connection. Another reaction was performed using 4'-methoxy-2'-(3-methyl-2-butenyl)oxazolidinone (49,0 g) under the above conditions. The total number of the desired compounds were $ 74.1,

1H-NMR (CDCl3) δ (ppm): 1,71 (d, J=0.8 Hz, 3H), of 1.76 (d, J=1.2 Hz, 3H), of 2.54 (s, 3H), up 3.22 (DD, J=0,4, 7.2 Hz, 2H), 3,86 (s, 3H), to 5.21-of 5.29 (m, 1H), 6,9 (s, 1H), 7,40 (d, J=0.8 Hz, 1H), 12.7mm (s, 1H).

(3)6-Methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazol

74,1 g 2'-Hydroxy-4'-methoxy-5'-(3-methyl-2-butenyl)acetophenone was dissolved in 900 ml of ethanol. Then to the solution was added of 56.4 g of hydroxylaminopurine and 69.2 g of sodium acetate dissolved in 315 ml of water. The reaction solution was heated at the boil under reflux for 4 hours. After that, the reaction solution was set to cool and then concentrated under reduced pressure. To the residue was added a saturated solution of sodium chloride (500 ml) and tert-butyl methyl ether (1000 ml)to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride (500 ml × 4) and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to get to 77.4 g of the crude derived oxime. 77,4 g the derived oxime was dissolved in a mixed solvent consisting of 225 ml of acetonitrile and 75 ml of N,N-dimethylacetamide. Then to the solution was added dropwise to 31.6 ml of phosphorus oxychloride for about 15 minutes while cooling on ice. After adding the reaction solution was stirred for 5 minutes under cooling on ice and then warmed to room temperature. Reaction the second solution is then stirred at room temperature for about 50 minutes. After this reaction solution was added dropwise to the stirred mixed solution consisting of 1500 ml tert-butyl methyl ether and 1500 ml of ice water in which was dissolved 56 g of sodium acetate. The obtained organic layer was washed two times with a mixed solution consisting of 120 ml of 2 n sodium hydroxide solution and 250 ml of saturated solution of sodium chloride, and then washed with a saturated solution of sodium chloride (500 ml × 4 times). After that, the obtained product was dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column with NH silica gel (hexane/ethyl acetate). The resulting product was further purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain of 56.2 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,71 (s, 3H), of 1.75 (d, J=1.2 Hz, 3H), 2,58 (s, 3H), 3,36 (DD, J=0,8, 7.2 Hz, 2H), a 3.87 (s, 3H), 5,28 and 5.36 (m, 1H), of 6.96 (s, 1H), 7,38 (s, 1H).

(4)1-{1-[2-(6-methoxy-2-methylbenzothiazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

with 37.2 g of the desired compound was obtained from the above-described 6-methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazole (44,7 g total in 4 downloads) in the manner described in example 1 (4) (but when the diol product was added 1 equivalent of methanesulfonamide is).

37,2 g above the desired compound was recrystallized from 360 ml of methanol with getting to 34.1 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,00-2,24 (m, 4H), 2,24-to 2.40 (m, 2H), 2,60 (s, 3H), 2,62 was 2.76 (m, 2H), 2,86-to 3.02 (m, 2H), 3,14-of 3.32 (m, 2H), with 3.89 (s, 3H), 4,34-to 4.46 (m, 1H), to 6.57 (DD, J=0,8, 2.8 Hz, 1H), 6,99 (s, 1H), was 7.36-7,47 (m, 3H), of 7.65 (DD, J=0,4, and 8.4 Hz, 1H), 8,12 (s, 1H).

Example 5

Synthesis of 1-{1-[2-(2-ethyl-6-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)2'-Hydroxy-4'-methoxypropiophenone

6,00 g of 2',4'-Dihydroxybenzophenone was dissolved in 70 ml of acetone. Then to the reaction solution was sequentially added to 7.09 g of potassium carbonate and 3,03 ml under the conditions. The reaction solution was then heated at the boil under reflux. After about 3 hours the reaction solution was set to cool and then filtered. The filtrate was concentrated under reduced pressure. To the residue was added a saturated solution of sodium chloride and ethyl acetate to separate an organic layer. The obtained organic layer was washed 2 N. chloroethanol acid and a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was utverjdali from a mixture of hexane-ethyl acetate to obtain 5.4 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): of 1.23 (t, J=7.2 Hz, 3H), 2.95 and (sq, J=7.2 Hz, 2H), 3,83 (s, 3H), 6,40-of 6.45 (m, 2H), 7,65 (DD, J=1.6 Hz, 8.0 Hz, 1H), 12,8 (s, 1H).

(2)1-{1-[2-(2-Ethyl-6-methoxybenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized using as starting material 2'-hydroxy-4'-methoxypropiophenone obtained in example 5 (1), by the methods described in example 4, (1)-(4) (but instead of 1-bromo-3-methyl-2-butene used allylbromide and two kinds of isomers obtained subsequent rearrangement of Clausena (3'-allyl-2'-hydroxy-4'-methoxypropiophenone and 5'-allyl-2'-hydroxy-4'-methoxypropiophenone), were introduced respectively in the compound in example 5 and the compound in example 6, described below).

1H-NMR (CDCl3) δ (ppm): 1,45 (t, J=7,6 Hz, 3H), 2,07-of 2.16 (m, 4H), 2,28-is 2.37 (m, 2H), 2,68 was 2.76 (m, 2H), 2,94 (sq, J=7,6 Hz, 2H), 3,06-3,14 (m, 2H), 3,22-of 3.31 (m, 2H), with 3.89 (s, 3H), 4,35-to 4.46 (m, 1H), to 6.57 (d, J=2,8 Hz, 1H), 6.87 in (d, J=8,4 Hz, 1H), 7,37-7,42 (m, 2H), 7,44 (d, J=8,8 Hz, 1H), 7,63 (d, J=8,4 Hz, 1H), 8,10 (s, 1H).

Example 6

Synthesis of 1-{1-[2-(2-ethyl-6-methoxybenzothiazole-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized using the above 5'-allyl-2'-hydroxy-4'-methoxypropiophenone as source material by the method of synthesis described in example 4, (3)-(4) (see methods of synthesis example 5).

1H-NMR (CDCl3) &x003B4; (ppm): USD 1.43 (t, J=7,6 Hz, 3H), 2,07-of 2.16 (m, 4H), 2,24-of 2.34 (m, 2H), 2,62-2,69 (m, 2H), 2,88-2,96 (m, 4H), 3,17-3,26 (m, 2H), 3,88 (s, 3H), 4,32-to 4.46 (m, 1H), 6,56 (DD, J=0,8, a 3.2 Hz, 1H), 6,99 (s, 1H), 7,37-7,42 (m, 2H), 7,44 (s, 1H), 7,63 (d, J=8,4 Hz, 1H), of 8.09 (s, 1H).

Example 7

Synthesis of 1-{1-[2-(5-methoxy-2-methylbenzothiazol-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)5-Allyloxy-2-methylbenzothiazol

2.58 g of 5-Hydroxy-2-methylbenzoate (publication: Synthesis, 1982, 68-69) was dissolved in 15 ml of N,N-dimethylformamide and 15 ml of acetonitrile. Then to the reaction solution was sequentially added 2,39 g of potassium carbonate and 1.61 ml allylbromide. Approximately 6 hours to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 2,78 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,61 (s, 3H), 4.53-in-4,58 (m, 2H), 5,26-5,32 (m, 1H), 5,39-5,46 (m, 1H), 6,01-6,12 (m, 1H), 6.90 to (DD, J=2,4, 8,8 Hz, 1H), 7,14 (d, J=2.4 Hz, 1H), 7,33 (DD, J=0,4, 8,8 Hz, 1H).

(2)4-Allyl-5-hydroxy-2-methylbenzothiazol

2,78 g 5-Allyloxy-2-methylbenzoxazolium was stirred under load, the processes at a temperature of from 185° With up to 190°C in nitrogen atmosphere. After about 5 hours the reaction solution was set to cool. Then to the reaction solution was added to the curing of acetonitrile to obtain 1.44 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,61 (s, 3H), 3.72 points-with 3.79 (m, 2H), is 5.06 (s, 1H), 5,14-5,22 (m, 2H), 6,01-6,14 (m, 1H), for 6.81 (d, J=8,8 Hz, 1H), 7,21 (d, J=8,8 Hz, 1H).

(3)4-Allyl-5-methoxy-2-methylbenzothiazol

1.44 g of 4-Allyl-5-hydroxy-2-methylbenzoxazolium was dissolved in 5 ml of N,N-dimethylformamide and 5 ml of acetonitrile. Then to the reaction solution was sequentially added to 1.05 g of potassium carbonate and 0.55 ml under the conditions. After approximately 16 hours to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 1.26 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,61 (s, 3H), 3,69-to 3.73 (m, 2H), 3,86 (s, 3H), 4,96-of 5.05 (m, 2H), 6,02-6,14 (m, 1H), 6,86 (d, J=8,8 Hz, 1H), 7,24 (d, J=8,8 Hz, 1H).

(4)1-{1-[2-(5-methoxy-2-methylbenzothiazol-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was obtained from a description of the nogo above 4-allyl-5-methoxy-2-methylbenzoxazolium way described in example 1 (4).

1H-NMR (CDCl3) δ (ppm): 2,05-of 2.20 (m, 4H), 2,28-to 2.40 (m, 2H), 2,62 (s, 3H), 2,68 is 2.80 (m, 2H), 3,16-to 3.33 (m, 4H), 3,88 (s, 3H), 4,32 is 4.45 (m, 1H), 6,56 (d, J=3.2 Hz, 1H), 6,86 (d, J=8,8 Hz, 1H), 7,22-7,44 (m, 3H), 7,63 (d, J=8,8 Hz, 1H), of 8.09 (s, 1H).

Example 8

Synthesis of 1-{1-[2-(5-methoxy-2-methylbenzothiazol-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)2-Amino-4-methoxyphenol

10 g of 4-Methoxy-2-NITROPHENOL was dissolved in 120 ml of methanol and 80 ml of ethyl acetate. Then to the reaction solution was added 800 mg of 10% palladium-on-carbon followed by the reduction reaction of hydrogen atmospheres. Upon completion of the reaction the catalyst was removed by filtration and the residue was then concentrated under reduced pressure. The resulting solid is suspended in a mixture of hexane-tert-butyl methyl ether and the suspension is then filtered with getting to 7.77 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3.72 points users, 5H), 4,33 (users, 1H), 6,12-6,24 (m, 1H), 6,33 (users, 1H), 6,58-6,70 (m, 1H).

(2)2-ndimethylacetamide-4-methoxyphenylacetate

2.50 g of 2-Amino-4-methoxyphenol and 12.5 ml of triethylamine were dissolved in 50 ml of tetrahydrofuran. The reaction solution was cooled on ice and then added to it dropwise 3,84 ml acetylchloride. After that, the reaction solution was stirred at room temperature. Upon completion of the reaction to the reaction is th solution was added a saturated solution of sodium bicarbonate and ethyl acetate, to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was utverjdali from a mixture of tert-butyl methyl ether-ethyl acetate to obtain 2.30 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): to 2.18 (s, 3H), of 2.35 (s, 3H), of 3.80 (s, 3H), only 6.64 (DD, J=2,4 Hz and 8.8 Hz, 1H), 7,01 (d, J=8,8 Hz, 1H), 7,08-7,16 (users, 1H), to 7.84 (d, J=2.4 Hz, 1H).

(3)2-ndimethylacetamide-5-bromo-4-methoxyphenylacetic

2.30 g of 2-Ndimethylacetamide-4-methoxyphenylacetate was dissolved in 20 ml of N,N-dimethylformamide. The reaction solution was cooled on ice and then added to it to 1.83 g of N-bromosuccinimide dissolved in 10 ml of N,N-dimethylformamide. After that, the temperature of the reaction solution was raised to room temperature and then the reaction solution was stirred for 12 hours. Then to the reaction solution was added a saturated solution of sodium chloride and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was led from a mixture of hexane-ethyl acetate with recip is of 2.70 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,19 (s, 3H), of 2.36 (s, 3H), with 3.89 (s, 3H), 7,14 (users, 1H), 7,32 (s, 1H), to 7.99 (s, 1H).

(4)6-bromo-5-methoxy-2-methylbenzothiazol

2.70 g of 2-Ndimethylacetamide-5-bromo-4-methoxyphenylacetate was dissolved in 60 ml of methanol and 40 ml of tetrahydrofuran. Then to the reaction solution was added 6,18 g of potassium carbonate and the resulting mixture was then stirred at room temperature. Upon completion of the reaction, the reaction solution was brought to pH 2-3 by adding 5 N. chloroethanol acid. Then to the reaction solution were added ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 2.14 g of the crude 4'-bromo-2'-hydroxy-5'-methoxyacetanilide. 2.14 g obtained as described above, the crude 4'-bromo-2'-hydroxy-5'-methoxyacetanilide was dissolved in 40 ml of acetic acid, after which the reaction solution was stirred under heating at 140°C. after About 20 hours the reaction solution was set to cool and then concentrated under reduced pressure. Then to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate to separate organicheskikh. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue is suspended in methanol tert-butyl methyl ether, after which the suspension was filtered with getting 787 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,61 (s, 3H), 3,93 (s, 3H), 7,16 (s, 1H), to 7.67 (s, 1H).

(5)6-Allyl-5-methoxy-2-methylbenzothiazol

400 mg 6-bromo-5-methoxy-2-methylbenzoxazolium was dissolved in 5 ml of toluene. Then to the reaction solution was sequentially added 769 ál allyltrimethylsilane and 57 mg of tetrakis(triphenylphosphine)palladium. Then the reaction solution was heated at boiling under reflux in a nitrogen atmosphere. After approximately 14 hours, the reaction solution was set to cool and then filtered through celite, followed by concentration under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 202 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): at 2.59 (s, 3H), of 3.45 (d, J=6,4 Hz, 2H), 3,86 (s, 3H), 5,02-5,10 (m, 2H), 5,94-the 6.06 (m, 1H), was 7.08 (s, 1H), 7.23 percent (s, 1H).

(6)1-{1-[2-(5-methoxy-2-methylbenzothiazol-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was obtained as described is use 6-allyl-5-methoxy-2-methylbenzoxazolium way described in example 1 (4).

1H-NMR (CDCl3) δ (ppm): 2.06 to of 2.16 (m, 4H), 2,24-of 2.36 (m, 2H), 2,61 (s, 3H), 2.63 in-a 2.71 (m, 2H), 2,90 are 2.98 (m, 2H), 3,17-3,26 (m, 2H), 3,88 (s, 3H), 4,34-to 4.46 (m, 1H), to 6.57 (DD, J=0.8 Hz, 3.2 Hz, 1H), 7,10 (s, 1H), 7,28 (s, 1H), 7,37-7,42 (m, 2H), 7,63 (DD, J=0.8 Hz, and 8.4 Hz, 1H), 8,10 (s, 1H).

Example 9

Synthesis of 1-{1-[2-(8-methoxy-4-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepan-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)Methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate

The desired compound was obtained from methyl 2-hydroxy-4-methoxybenzoate the methods described in example 4, (1)-(2).

1H-NMR (CDCl3) δ (ppm): 1,70 (s, 3H), 1,74 (d, J=1.2 Hz, 3H), 3,20 (DD, J=0,8, 7.2 Hz, 2H), of 3.84 (s, 3H), 3,90 (s, 3H), 5,20 is 5.28 (m, 1H), 6,41 (s, 1H), 7,51 (t, J=0.8 Hz, 1H), up 10.9 (s, 1H).

(2)8-Methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepine-5-he

a 2.00 g of Methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate, 1.29 g of N-(tert-butoxycarbonyl)-2-aminoethanol and 2,31 g of triphenylphosphine was dissolved in 50 ml of tetrahydrofuran. The mixture was cooled on ice. Then to the reaction solution was added 1.73 ml of diisopropylcarbodiimide at the same temperature and then the temperature was raised to room temperature. Upon completion of the reaction, the reaction solution was concentrated. The residue was purified by chromatography on a column with NH silica gel (hexane/ethyl acetate) to obtain 1.4 g of methyl 2-(2-tert-butoxycarbonylamino)-4-methoxy-5-(3-methyl-2-butenyl)benzoate. The obtained product was dissolved in 15 ml of methanol and the resulting mixture was cooled on ice. Then to the reaction solution was added 10 ml of 4 n solution chloromethane acid-ethyl acetate. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and the resulting mixture was brought to about pH 11 by adding 5 N. aqueous sodium hydroxide solution and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. 1.06 g of the obtained residue was dissolved in 20 ml of toluene and the resulting solution was heated at the boil under reflux. Upon completion of the reaction, the reaction solution was concentrated. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain 601 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,70 (s, 3H), 1,72 (d, J=1.2 Hz, 3H), 3,26 (d, J=7.2 Hz, 2H), 3,48-3,55 (m, 2H), of 3.84 (s, 3H), 4,35-to 4.41 (m, 2H), 5.25-in, 5,32 (m, 1H), 6,44 (s, 1H), 6,47 (users, 1H), 7,80 (s, 1H).

(3)8-Methoxy-4-methyl-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepine-5-he

601 mg 8-methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepine-5-it was dissolved in 15 ml of N,N-dimethylformamide. Then to the reaction solution was added 120 mg hydride NAT the Oia. Ten minutes to the reaction solution was added 215 μl under the conditions and the resulting mixture was then stirred at room temperature. Upon completion of the reaction, to the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate to separate an organic layer. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 513 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1.69 in (s, 3H), 1,72 (d, J=1.2 Hz, 3H), 3,19 (s, 3H), 3,26 (d, J=7,6 Hz, 2H), 3,50-3,60 (m, 2H), 3,82 (s, 3H), 4,32-4,43 (m, 2H), 5,24-5,33 (m, 1H), gold 6.43 (s, 1H), 7,63 (s, 1H).

(4)1-{1-[2-(8-Methoxy-4-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepan-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was obtained from 8-methoxy-4-methyl-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepine-5-it is the method described in example 4 (4).

1H-NMR (CDCl3) δ (ppm): 2.06 to to 2.35 (m, 6H), 2,60-2,70 (m, 2H), 2,78-is 2.88 (m, 2H), 3,15-3,26 (m, 2H), 3,20 (s, 3H), 3,53-to 3.58 (m, 2H), 3,83 (s, 3H), 4,32-of 4.44 (m, 3H), 6,44 (s, 1H), 6,56 (DD, J=0.4 Hz, 3.2 Hz, 1H), of 7.36-7,46 (m, 2H), 7,63 (DD, J=0.4 Hz, 8.0 Hz, 1H), 7,69 (s, 1H), of 8.09 (s, 1H).

Example 10

Synthesis of 1-{1-[2-(8-methoxy-4-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]ox who sepin-7-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

The desired compound was synthesized from N-methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide by the method described in example 9.

1H-NMR (CDCl3) δ (ppm): 2,03-is 2.37 (m, 6H), 2,55-to 2.74 (m, 2H), was 2.76-2,90 (m, 2H), 3,06 (d, J=4,80 Hz, 3H), 3,12-3,26 (m, 2H), 3,20 (s, 3H), 3,50-3,60 (m, 2H), of 3.84 (s, 3H), 4,30-4,43 (m, 3H), 6,28 (users, 1H), 6,44 (s, 1H), is 6.54 (d, J=3.2 Hz, 1H), 7,30-7,42 (m, 2H), to 7.61 (d, J=8.0 Hz, 1H), 7,69 (s, 1H), 8,03 (users, 1H).

Example 11

Synthesis of 1-{1-[2-(5,7-dimethoxy-1-methoxyimino-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)O-methyloxime 4-bromo-5,7-dimethoxyindole-1-it

845 mg of 5,7-Dimethoxyindole-1-it was dissolved in 40 ml of dichloromethane. Then to the reaction solution was added 822 mg of N-bromosuccinimide. Upon completion of the reaction, to the reaction solution was added chloroform. The organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue is suspended in acetone and the suspension was filtered with the receipt of 1.03 g of 4-bromo-5,7-dimethoxyindole-1-it. The resulting product is suspended in a mixed solution consisting of 30 ml of methanol, 10 ml of tetrahydrofuran and 20 ml of chloroform. Then to the reaction solution was added 952 mg methoxyamphetamine and 93 mg of sodium acetate and the resulting mixture was stirred at room temperature. After approximately 4 hours to the reaction solution added 952 mg methoxyamphetamine and 935 mg of sodium acetate. Upon completion of the reaction, the reaction solution was concentrated. To the obtained product was added saturated aqueous sodium bicarbonate solution and ethyl acetate to separate an organic layer. The organic layer was washed saturated aqueous sodium bicarbonate and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue is suspended in tert-butylmethylether ether and the suspension was filtered with getting 896 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,90-3,00 (m, 4H), of 3.95 (s, 3H), of 3.96 (s, 3H), of 4.00 (s, 3H), 6,38 (s, 1H).

(2)1-{1-[2-(5,7-Dimethoxy-1-methoxyimino-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was obtained from O-methyloxime 4-bromo-5,7-dimethoxyindole-1-it is the methods described in example 8, (5)-(6).

1H-NMR (CDCl3) δ (ppm): 2.13 in (users, 4H), 2.21 are a 2.36 (m, 2H), 2,46-of 2.58 (m, 2H), 2,72-2,84 (m, 2H), 2,96 (users, 4H), 3,16 to be 3.29 (m, 2H), with 3.89 (s, 3H), of 3.96 (s, 3H), 4,01 (s, 3H), 4,34-to 4.46 (m, 1H), 6,37 (s, 1H), return of 6.58 (d, J=2.4 Hz, 1H), was 7.36-7,46 (m, 2H), 7,65 (d, J=8,4 Hz, 1H), 8,12 (users, 1H).

Example 12

Synthesis of 1-{1-[2-(8-methoxy-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-ka is oxamide

(1)Methyl 2-(3-ethoxycarbonylmethoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate

3.00 g of methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate was dissolved in 30 ml of N,N-dimethylformamide. Then to the reaction solution was added 2.16 g of potassium carbonate and of 2.23 ml ethyl 4-bromobutyrate and the resulting mixture was then stirred under heating at 80°C. in the Midst of the response to the mixture was added 829 mg of potassium carbonate and 0,86 ml ethyl 4-bromobutyrate. Upon completion of the reaction was added to the reaction solution in ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 2,88 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,25 (t, J=7.2 Hz, 3H), of 1.70 (s, 3H), 1,73 (d, J=1.2 Hz, 3H), 2,10-of 2.20 (m, 2H), 2,61 (t, J=7.2 Hz, 2H), 3,23 (d, J=7.2 Hz, 2H), 3,85 (s, 3H), a 3.87 (s, 3H), 4.09 to (t, J=6.0 Hz, 2H), 4,13 (sq, J=7.2 Hz, 2H), 5,20-and 5.30 (m, 1H), gold 6.43 (s, 1H), to 7.64 (s, 1H).

(2)8-Methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benzo[b]oxepin-5-he

80 ml of tertrahydrofuran ring solution containing a 18.6 mmol of lithium bis(trimethylsilyl)amide, was cooled to -75°C. Dissolved 3,23 g is ethyl 2-(3-ethoxycarbonylmethoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate in 8 ml of tetrahydrofuran and the resulting solution was added dropwise to the above solution. Upon completion of the dripping, the reaction solution was heated to 0°C. Upon completion of the reaction, to the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate to separate an organic layer. The obtained organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain 969 mg of ethyl 8-methoxy-7-(3-methyl-2-butenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-4-carboxylate. After that, 751 mg of the obtained compound was dissolved in 15 ml of tetrahydrofuran. While the reaction solution was stirred under heating at 70°C, was added 4 ml of 5 N. aqueous sodium hydroxide solution 3 portions. After about 2 hours of tetrahydrofuran as the reaction solution was concentrated under reduced pressure and then added to it 10 ml of ethanol. Then, to the obtained ethanol solution was added 5 ml of 5 N. chloroethanol acid and the mixture was again heated at the boil under reflux. Upon completion of the reaction, to the reaction solution were added ethyl acetate and the resulting organic layer was washed with a saturated aqueous solution of sodium chloride. The organic is the second layer then was dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 422 mg of the desired compound.

1H-NMR (CDCl3) δ 1,69 (d, J=0.4 Hz, 3H), 1,72 (d, J=1.2 Hz, 3H), of 2.18 (quintet, J=6.8 Hz, 2H), 2,85 (t, J=6,8 Hz, 2H), 3,24 (d, J=6,8 Hz, 2H), 3,85 (s, 3H), 4,22 (t, J=6,8 Hz, 2H), 5,22-and 5.30 (m, 1H), 6,51 (s, 1H), 7,58 (s, 1H).

(3)1-{1-[2-(8-methoxy-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was obtained from 8-methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benzo[b]oxepin-5-it is the method described in example 4 (4).

1H-NMR (CDCl3) δ (ppm): 2,12 (users, 4H), of 2.20 (quintet, J=6.8 Hz, 2H), 2,29 (users, 2H), 2.63 in (users, 2H), 2,74-of 2.93 (m, 2H), 2,88 (t, J=6,8 Hz, 2H), 3,10-3,30 (m, 2H), a 3.87 (s, 3H), 4,24 (t, J=6,8 Hz, 2H), 4,32-to 4.46 (m, 1H), is 6.54 (s, 1H), to 6.57 (DD, J=0,8, a 3.2 Hz, 1H), was 7.36-of 7.48 (m, 2H), 7,62-to 7.68 (m, 2H), 8,11 (users, 1H).

Example 13

Synthesis of 1-{1-[2-(8-methoxy-5-methoxyimino-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

97 mg of 1-(1-(2-(8-Methoxy-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide was dissolved in a mixed solution consisting of 4 ml of methanol, 2 ml of tetrahydrofuran and 2 ml of chloroform. Then to the reaction solution was added 105 mg methoxyamphetamine and 103 mg of sodium acetate and the resulting mixture was then stirred at room temperature. In the midst of the reaction was added to the reaction solution of 1 g of methoxyamphetamine and 1 g of sodium acetate. Upon completion of the reaction, to the reaction solution was added 1 N. vodni the sodium hydroxide solution, saturated aqueous sodium bicarbonate solution and chloroform to separate the organic layer. The obtained organic layer was washed saturated aqueous sodium bicarbonate and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was utverjdali from a mixture of tert-butyl methyl ether-ethyl acetate to obtain 70 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,95-2,05 (m, 2H), 2.05 is-is 2.40 (m, 6H), 2,55-by 2.73 (m, 2H), 2,75-2,90 (m, 2H), 2,86 (t, J=6,8 Hz, 2H), 3,15-3,30 (m, 2H), 3,82 (s, 3H), 3,98 (s, 3H), 4,17 (t, J=6.0 Hz, 2H), 4,32-to 4.46 (m, 1H), of 6.50 (s, 1H), to 6.57 (d, J=3.2 Hz, 1H), 7,35 (s, 1H), 7,38-7,46 (m, 2H), 7,65 (d, J=8,4 Hz, 1H), 8,11 (users, 1H).

Example 14

Synthesis of 1-{1-[2-(5-methoxy-2,2-dimethyl-1-oxonian-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)5-hydroxy-2,2-dimethylethanol

7.78 g of Tert-butoxide potassium was dissolved in 66,3 ml of tert-butanol and 150 ml of toluene. Then to the reaction solution was added dropwise to 5.00 g of 5-methoxyindole dissolved in 170 ml of toluene at room temperature. Bring the flax after 10 minutes to the reaction solution was added 4,79 ml under the conditions. Upon completion of the reaction, to the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate to separate an organic layer. The organic layer was then dried over anhydrous magnesium sulfate. After the organic layer was filtered through celite, was removed by filtration of the drying agent. After that, the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 2,08 g 5-methoxy-2,2-dimethylindoline. The obtained product was dissolved in 9 ml methanesulfonic acid. Then to the reaction solution was added of 2.45 g of methionine and the resulting mixture was heated to 110°C. Upon completion of the reaction, to the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate to separate an organic layer. The organic layer was then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain 1,41 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,24 (s, 6H), to 2.94 (s, 2H), 6,79-of 6.90 (m, 3H), 7,68 (DD, J=0,4, 8.0 Hz, 1H).

(2)1-{1-[2-(5-methoxy-2,2-dimethyl-1-oxonian-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound produces and 5-hydroxy-2,2-dimethylindoline ways, described in example 7, (1)-(4).

1H-NMR (CDCl3) δ (ppm): 1,25 (s, 6H), 2.00 in of 2.23 (m, 4H), 2,25-to 2.40 (m, 2H), 2,50-of 2.66 (m, 2H), 2,80-3,00 (m, 2H), 2.95 and (s, 2H), 3,15-to 3.33 (m, 2H), of 3.94 (s, 3H), 4,33-4,48 (m, 1H), return of 6.58 (d, J=3.2 Hz, 1H), 6,94 (d, J=8,4 Hz, 1H), was 7.36-7,46 (m, 2H), 7,65 (d, J=8,4 Hz, 1H), 7,69 (d, J=8,8 Hz, 1H), 8,12 (s, 1H).

Example 15

Synthesis of 1-{1-[2-(6-methoxy-2-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl})-N-methyl-1H-indole-6-carboxamide

The desired compound was synthesized using N-methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide, the method described in example 3 (5).

1H-NMR (CDCl3) δ (ppm): 2.13 in (users, 4H), 2,33 (users, 2H), 2,62 (s, 3H), 2,72 (users, 2H), of 3.07 (d, J=4,8 Hz, 3H), 3,02-3,18 (m, 2H), 3,20-to 3.34 (m, 2H), 3,90 (s, 3H), 4,34-4,48 (m, 1H), 6,24 (users, 1H), 6,56 (d, J=2,8 Hz, 1H), 6,89 (d, J=8,4 Hz, 1H), 7,32-of 7.48 (m, 3H), 7,63 (d, J=8.0 Hz, 1H), 8,04 (users, 1H).

Example 16

Synthesis of 1-{1-[2-(6-methoxy-2-methylbenzothiazol-5-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

The desired compound was synthesized using N-methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide, the method described in example 4 (4).

1H-NMR (CDCl3) δ (ppm): 2,12 (users, 4H), 2,30 (users, 2H), 2,60 (s, 3H), 2,62-to 2.74 (m, 2H), 2,94 (users, 2H), 3,06 (d, J=5,2 Hz, 3H), 3,12-3,30 (m, 2H), with 3.89 (s, 3H), 4,32 is 4.45 (m, 1H), 6,24 (users, 1H), 6,55 (d, J=3.2 Hz, 1H), of 6.99 (s, 1H), 7,32-7,42 (m, 2H), 7,43 (s, 1H), 7.62mm (d, J=8,4 Hz, 1H), 8,05 (users, 1H).

Example 17

Synthesis of 1-{1-[2-(6-methoxy-3-IU is albens[d]isoxazol-7-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

65 mg of 1-(1-(2-(6-Methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide, obtained in example 1 was dissolved in 1 ml N,N-dimethylformamide and then to the resulting solution was added 7.2 mg of 60% sodium hydride. The reaction solution was stirred at room temperature for 5 minutes and then added to it and 11.2 μl under the conditions. Upon completion of the reaction, to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (hexane/ethyl acetate) to give 17 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,11 (users, 4H), 2.26 and-to 2.42 (m, 2H), 2,54 (s, 3H), 2,68-2,82 (m, 2H), 3,06 (d, J=5,2 Hz, 3H), of 3.10-3.20 (m, 2H), 3,22-of 3.32 (m, 2H), 3,95 (s, 3H), 4,32-4,43 (m, 1H), 6.30-in (users, 1H), 6,55 (d, J=the 3.2 Hz, 1H), 6,95 (d, J=8,8 Hz, 1H), 7,34-7,42 (m, 2H), 7,43 (d, J=8,4 Hz, 1H), 7.62mm (d, J=8,4 Hz, 1H), 8,04 (s, 1H).

Example 18

Synthesis of 1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-5-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

The desired compound was synthesized using 1-(1-(2-(6-methoxy-3-methylbenzo[d-5-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide, obtained in example 2 by the method described in example 17.

1H-NMR (CDCl3) δ (ppm): 2.13 in (users, 4H), 2.21 are 2,39 (m, 2H), 2,54 (s, 3H), 2,60-by 2.73 (m, 2H), 2,88-3,00 (m, 2H), 3,06 (d, J=5,2 Hz, 3H), 3,15-3,30 (m, 2H), 3,93 (s, 3H), 4,32-to 4.46 (m, 1H), 6,28 (users, 1H), 6,56 (d, J=2,8 Hz, 1H), 6,97 (s, 1H), 7,32-7,40 (m, 3H), a 7.62 (d, J=8.0 Hz, 1H), 8,08 (s, 1H).

Example 19

Synthesis of 1-{1-[2-(2-methoxy-5-methoxyimino-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

200 mg of 5-(2,3-Dihydroxypropyl)-6-methoxy-1-tetralone, synthesized from 6-hydroxy-1-tetralone by the methods described in example 7, (1)-(4), was dissolved in a mixed solution consisting of 5 ml of methanol and 3 ml of tetrahydrofuran. Then to the reaction solution was added 401 mg methoxyamphetamine and 394 mg of sodium acetate and the resulting mixture was then stirred at room temperature. Upon completion of the reaction, to the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate to separate an organic layer. The obtained organic layer was washed saturated aqueous sodium bicarbonate and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 183 mg of O-methyloxime 5-(2,3-dihydroxypropyl)-6-methoxy-3,4-d the hydro-2H-naphthalene-1-it. From the obtained compound was obtained the desired compound by the method described in example 1 (4).

1H-NMR (CDCl3) δ (ppm): 1,80-1,90 (m, 2H), 2,15 (users, 4H), 2,32 (users, 2H), of 2.51 (users, 2H), 2,65 is 2.80 (m, 4H), 2,85-to 3.02 (m, 2H), 3,15-to 3.35 (m, 2H), 3,86 (s, 3H), of 3.97 (s, 3H), 4,34-4,48 (m, 1H), return of 6.58 (d, J=3.2 Hz, 1H), 6,77 (d, J=8,8 Hz, 1H), 7,38-7,46 (m, 2H), 7,65 (d, J=8.0 Hz, 1H), of 7.90 (d, J=8,8 Hz, 1H), 8,12 (s, 1H).

Example 20

Synthesis of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

126 mg of 8-Allyl-7-methoxy-2,2-dimethyl-4-oxoproline was dissolved in 12 ml of a mixture of tert-butanol-water (1:1) under nitrogen atmosphere. Then to the reaction solution was added to 0.72 g of AD-mix-β and the resulting mixture was then stirred at room temperature for 24 hours. Then to the reaction solution was added of 0.77 g of sodium sulfite while cooling on ice and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then filtered. The organic layer was then concentrated under reduced pressure to obtain 145 mg of 8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxoproline. This compound was used in next reaction without further purification.

145 mg of 8-(2,3-shall hydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxoproline was dissolved in 3 ml of tetrahydrofuran and 4 ml of methanol. Then to the reaction solution was added 7 ml of water containing 0,22 g metaperiodate sodium, while cooling on ice and the resulting mixture was then stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then filtered. The organic layer was then concentrated under reduced pressure to obtain 120 mg of (7-methoxy-2,2-dimethyl-4-exogamy-8-yl)acetaldehyde. This compound was used in next reaction without further purification.

120 mg of N-methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide and 120 mg of (7-methoxy-2,2-dimethyl-4-exogamy-8-yl)acetaldehyde was dissolved in 8 ml of methylene chloride. Then to the reaction solution were added 0.05 ml of acetic acid and 0.15 g of triacetoxyborohydride sodium and the resulting mixture was then stirred at room temperature for 1 hour. Then to the reaction solution was added saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then filtered. The filtrate is then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (methanol-ethyl acetate) to obtain 210 mg of the desired compound.

H-NMR (DMSO-d6) δ (ppm): 1,40 (s, 6H), 1,92 is 2.10 (m, 4H), 2,22 is 2.33 (m, 2H), 2.40 a-2,50 (m, 2H), 2,72 (s, 2H), 2,74-and 2.83 (m, 2H), 2,82 (d, J=4.4 Hz, 3H), is 3.08-3,17 (m, 2H), a 3.87 (s, 3H), 4,35-4,47 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 6.75 in (d, J=9,2 Hz, 1H), 7,51-to 7.59 (m, 2H), 7,62-of 7.69 (m, 2H), of 8.06 (s, 1H), 8,29-of 8.37 (m, 1H).

Example 22

Synthesis of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)7 Allyloxy-2,2-dimethyl-4-exogamy

9,74 g of 7-Hydroxy-2,2-dimethyl-4-oxoproline (CAS#: 17771-33-4) was dissolved in 150 ml of N,N-dimethylformamide. Then to the reaction solution was added to 10.5 g of potassium carbonate and of 7.36 g of allylbromide and the resulting mixture was stirred at room temperature overnight. After that, the reaction solution was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel (hexane-ethyl acetate) to obtain 11,0 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,45 (s, 6H), to 2.67 (s, 2H), 4.53-in-4,58 (m, 2H), 5,28 to 5.35 (m, 1H), lower than the 5.37-5,46 (m, 1H), 5,98-6,09 (m, 1H), 6,38 (d, J=2.4 Hz, 1H), 6,56 (DD, J=2,4, 8,8 Hz, 1H), 7,80 (d, J=8,8 Hz, 1H).

(2)8-Allyl-7-hydroxy-2,2-dimethyl-4-exogamy(a) and6-allyl-7-hydroxy-2,2-dimethyl-4-exogamy(b)

1,97 g 7 Allyloxy-2,2-dimethyl-4-oxoproline of restore and 5 ml of N,N-dimethylaniline in a nitrogen atmosphere and the reaction solution was heated at the boil under reflux for 6 hours. After that, the reaction solution was cooled to room temperature. Then it was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give a mixture of the desired compounds (a) and (b). The mixture was further purified by high-performance liquid chromatography (ODS-AM; acetonitrile-water) with the receipt of 1.05 g of the desired compound (a) and 95 mg of the desired compound (b).

The isomer (a)

1H-NMR (CDCl3) δ (ppm): the 1.44 (s, 6H), to 2.66 (s, 2H), 3,40-of 3.46 (m, 2H), 5,03-5,17 (m, 2H), of 5.55 (s, 1H), 5,86-6,00 (m, 1H), 6,47 (d, J=8,8 Hz, 1H), 7,71 (d, J=8,8 Hz, 1H).

The isomer (b)

1H-NMR (CDCl3) δ (ppm): the 1.44 (s, 6H), 2,65 (s, 2H), 3,34-3,37 (m, 2H), 5,14-to 5.21 (m, 2H), ceiling of 5.60 (s, 1H), 5,93-6,04 (m, 1H), 6,32 (s, 1H), 7,63 (s, 1H).

(3)8-Allyl-7-methoxy-2,2-dimethyl-4-exogamy

567 mg of 8-Allyl-7-hydroxy-2,2-dimethyl-4-oxoproline was dissolved in 15 ml of N,N-dimethylformamide. Then to the reaction solution was added 0.51 g of potassium carbonate and 0.42 g of iodomethane and the resulting mixture was then stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and then washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to obtain 582 mg tribunemedia.net.

1H-NMR (CDCl3) δ (ppm): the 1.44 (s, 6H), to 2.67 (s, 2H), 3,36 is 3.40 (m, 2H), 3,88 (s, 3H), 4.92 in-5,04 (m, 2H), of 5.84-5,95 (m, 1H), return of 6.58 (d, J=8,8 Hz, 1H), 7,80 (d, J=8,8 Hz, 1H).

(4) 1-(1-(2-(7-Methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide

150 mg of 8-allyl-7-methoxy-2,2-dimethyl-4-oxoproline was dissolved in 16 ml of a mixture of tert-butanol-water (1:1). Then to the reaction solution was added to 0.85 g of AD-mix-β and the resulting mixture was then stirred at room temperature overnight. Then to the reaction solution was added of 0.91 g of sodium sulfite while cooling on ice and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 171 mg of 8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxoproline. This compound was used in next reaction without further purification.

171 mg of 8-(2,3-Dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxoproline was dissolved in 4 ml of tetrahydrofuran and 4 ml of methanol. Then to the reaction solution were added 8 ml of water containing 0.26 g of metaperiodate sodium, while cooling on ice and the resulting mixture was then stirred at room temperature for 30 minutes. The reaction solution time is alali with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 163 mg of (7-methoxy-2,2-dimethyl-4-exogamy-8-yl)acetaldehyde. This compound was used in next reaction without further purification.

120 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide and 163 mg of (7-methoxy-2,2-dimethyl-4-exogamy-8-yl)acetaldehyde was dissolved in 10 ml of methylene chloride. Then to the reaction solution was added 0.06 ml of acetic acid and the resulting mixture was then stirred at room temperature for 15 minutes. Then to the reaction solution was added 157 mg triacetoxyborohydride sodium and the resulting mixture was then stirred at room temperature for 1 hour. Then to the reaction solution was added saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (methanol-ethyl acetate), followed by curing with ethyl acetate to obtain 220 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,40 (s, 6H), 1.93 and is 2.10 (m, 4H), 2,22 to 2.35 (m, 2H), 2,42-of 2.50 (m, 2H), 2,72 (s, 2H), 2,74-2,82 (m, 2H), is 3.08-3,17 (m, 2H), a 3.87 (s, 3H), 4,37-4,48 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 6.75 in (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), 7,65 (d, J=8,8 Hz, 1H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H) 8,13 (s, 1H).

Example 23

Synthesis of 1-{1-[2-(6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

(1)3-Methoxy-6-nitro-4-(2-propenyl)benzyl alcohol

of 8.40 g of 3-Hydroxy-4-(2-propenyl)benzyl alcohol (Tetrahedron, 56 (2000), 1873) was dissolved in 70 ml of acetic acid. Then to the reaction solution was added to 4.14 g of concentrated nitric acid and 0.6 ml of fuming nitric acid while cooling on ice and the resulting mixture was stirred at the same temperature for 20 minutes. After that, the reaction solution was brought to pH 6 by adding 5 N. aqueous sodium hydroxide solution while cooling on ice. Then was extracted with him ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel (hexane-ethyl acetate) to obtain 4.68 g of 3-hydroxy-6-nitro-4-(2-propenyl)benzyl alcohol.

4.68 g of 3-Hydroxy-6-nitro-4-(2-propenyl)benzyl alcohol was dissolved in 90 ml of N,N-dimethylformamide. Then to the reaction solution was added 3,71 g of potassium carbonate and 3,81 g iodomethane and the resulting mixture was stirred at whom atoi temperature during the night. The reaction solution was extracted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel (hexane-ethyl acetate) to obtain the 3,93 g of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 3,38 (d, J=6,8 Hz, 2H), of 3.94 (s, 3H), 4,87 (d, J=4,8 Hz, 2H), of 5.05-5,13 (m, 2H), 5,62 (t, J=4,8 Hz, 1H), of 5.89-of 6.02 (m, 1H), 7,42 (s, 1H), 7,94 (s, 1H).

(2)2-Amino-5-methoxy-4-(2-propenyl)benzyl alcohol

24 ml of a Mixture of ethanol-water (5:1) was added to 1.00 g of 3-methoxy-6-nitro-4-(2-propenyl)benzyl alcohol, and 1.00 g of iron and 2.00 g of ameriglide. The reaction solution was stirred at 90°C for 1 hour. After that, the reaction solution was cooled to room temperature and the insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 793 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): of 3.32 (d, J=6.0 Hz, 2H), 3,76 (s, 3H), with 4.64 (s, 2H), 5,00-5,09 (m, 2H), 5,88-6,00 (m, 1H), is 6.54 (s, 1H), only 6.64 (s, 1H).

(3)7-Allyl-6-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-he

677 mg 2-the Mino-5-methoxy-4-(2-propenyl)benzyl alcohol was dissolved in 20 ml of tetrahydrofuran in a nitrogen atmosphere. Then to the reaction solution was added 0.52 g of triphosgene and of 1.46 ml of triethylamine under cooling on ice. The resulting mixture was then stirred at room temperature for 30 minutes. Then to the reaction solution was added under cooling in ice-water and aqueous ammonia until stopped foaming. The reaction solution was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then was perioadele from ethyl acetate to obtain 485 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 3,26 (d, J=6,4 Hz, 2H), of 3.73 (s, 3H), 4,99-of 5.06 (m, 2H), with 5.22 (s, 2H), of 5.83-5,95 (m, 1H), 6,65 (s, 1H), 6,86 (s, 1H), 9,92 (users, 1H).

(4)7-Allyl-6-methoxy-1-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-he

210 mg of 7-Allyl-6-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-it was dissolved in 6 ml N,N-dimethylformamide. Then to the reaction solution was added 46 mg of 60% sodium hydride while cooling on ice. The resulting mixture was then stirred at room temperature for 20 minutes. After that, when cooled on ice was added to the reaction solution of 0.20 g of iodomethane. The resulting mixture was then stirred at room temperature within 2 hours. After that, the reaction solution was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 207 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 3,23 (s, 3H), 3,31-to 3.36 (m, 2H), 3,76 (s, 3H), 4,99 is 5.07 (m, 2H), 5,19 (s, 2H), of 5.89-6,00 (m, 1H), 6.87 in (s, 1H), 6,95 (s, 1H).

(5)1-{1-[2-(6-Methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

160 mg of 7-Allyl-6-methoxy-1-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-it was dissolved in 20 ml of a mixture of tert-butanol-water (1:1). Then to the reaction solution was added 0.96 g of AD-mix-β and the resulting mixture was then stirred at room temperature overnight. Then to the reaction solution was added to 1.03 g of sodium sulfite while cooling on ice and the resulting mixture was stirred at room temperature for 1 hour. Was added to the reaction solution, a saturated aqueous solution of sodium chloride, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 280 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-it. This connection line is arranged in the following reaction without further purification.

280 mg of 7-(2,3-Dihydroxypropyl)-6-methoxy-1-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-it was dissolved in 4 ml of tetrahydrofuran and 4 ml of methanol. Then to the reaction solution were added 8 ml of water containing 0.29 grams of metaperiodate sodium, while cooling on ice and the resulting mixture was then stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate) to give 167 mg (6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)acetaldehyde.

80 mg of N-Methyl-1-(piperidine-4-yl)-1H-indole-6-carboxamide and 83 mg (6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)acetaldehyde was dissolved in 6 ml of methylene chloride. Then to the reaction solution was added 0.04 ml of acetic acid and 99 mg of triacetoxyborohydride sodium and the resulting mixture was then stirred at room temperature for 3 hours. Then to the reaction solution was added saturated aqueous sodium bicarbonate solution, and then were extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of the silica gel (methanol-ethyl acetate) to give 141 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,92-2,10 (m, 4H), 2,23 of-2.32 (m, 2H), of 2.51-2,61 (m, 2H), 2.77-to 2,85 (m, 2H), 2,82 (d, J=4.4 Hz, 3H), is 3.08-3.15 in (m, 2H), 3,26 (s, 3H), 3,79 (s, 3H), 4,37-4,47 (m, 1H), 5,19 (s, 2H), 6,50 (d, J=3.2 Hz, 1H), 6,94 (s, 1H), 6,99 (s, 1H), 7,52-to 7.59 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), of 8.06 (s, 1H), 8,30-of 8.37 (m, 1H).

Example 24

Synthesis of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 6-allyl-7-hydroxy-2,2-dimethyl-4-oxoproline the method described in example 22, (3) and (4).

1H-NMR (DMSO-d6) δ (ppm): of 1.39 (s, 6H), 1,92-of 2.08 (m, 4H), 2.21 are 2,31 (m, 2H), 2,45-of 2.56 (m, 2H), 2,65 is 2.75 (m, 2H), 2,69 (s, 2H), 3,06 is 3.15 (m, 2H), 3,85 (s, 3H), 4,37-4,47 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 6,53 (s, 1H), 7,20 (users, 1H), 7,50-of 7.60 (m, 2H), 7,53 (s, 1H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 25

Synthesis of 1-{1-[2-(5-methoxy-1-oxonian-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 5-hydroxy-1-indanone by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1.93 and is 2.10 (m, 4H), 2,24-of 2.34 (m, 2H), 2,47-to 2.57 (m, 2H), 2,58-to 2.65 (m, 2H), 2,80-2,87 (m, 2H), 3,03-3,17 (m, 4H), 3,91 (s, 3H), of 4.38-4,47 (m, 1H), 6,51 (d, J=3.2 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H), 7,21 (users, 1H), 7,51-to 7.61 (m, 3H), 7,68 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 26

Synthesis of 1-{1-[2-(6-methoxy-3-oxonian-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 5-hydroxy-1-indanone by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,92-2,07 (m, 4H), 2,21 of-2.32 (m, 2H), 2,50-2,61 (m, 4H), was 2.76-2,84 (m, 2H), 3,02-and 3.16 (m, 4H), to 3.92 (s, 3H), 4,36-4,47 (m, 1H), 6,50 (d, J=2,8 Hz, 1H), 7,13 (s, 1H), 7,21 (users, 1H), 7,46 (s, 1H), 7,52-to 7.61 (m, 2H), of 7.64-of 7.69 (m, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 27

Synthesis of 1-{1-[2-(5-methoxy-2-methylbenzothiazol-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 2-methyl-5-benzothiazol the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,94-of 2.09 (m, 4H), 2,24-of 2.34 (m, 2H), by 2.55 2.63 in (m, 2H), 2,78 (s, 3H), 3,13-3,30 (m, 4H), 3,88 (s, 3H), 4,37-4,47 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 7,16 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), 7,81 (d, J=8,8 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 28

Synthesis of 1-{1-[2-(5-methoxy-2-methylbenzothiazol-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 2-methyl-5-benzothiazol the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,93-of 2.09 (m, 4H), 2,23 of-2.32 (m, 2H), 2.57 m) 2.63 in (m, 2H), was 2.76 (s, 3H), 2,84-2,90 (m, 2H), is 3.08-and 3.16 (m, 2H), 3,88 (s, 3H), 4,37-4,48 (m, 1H), 6,50 (d, J=2,8 Hz, 1H), 7,20 (users, 1H), 7,47 (s, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (d, J=2,8 Hz, 1H), 7,80 (s, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 29

Synthesis of 1-{1-[2-(7-methoxyquinoline-8-yl)ethyl]piperidine-4-yl}-1H-ind the l-6-carboxamide

The desired compound was synthesized from 7-hydroxyquinoline solution by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,95-2,11 (m, 4H), 2.26 and-a 2.36 (m, 2H), 2,54 2.63 in (m, 2H), 3,17-of 3.25 (m, 2H), 3,40-3,47 (m, 2H), 3,99 (s, 3H), of 4.38-4,48 (m, 1H), 6,51 (d, J=3.2 Hz, 1H), 7,21 (users, 1H), 7,37 (DD, J=4,0, 8.0 Hz, 1H), 7,52-of 7.60 (m, 3H), 7,68 (d, J=3.2 Hz, 1H), 7,88 (d, J=9,2 Hz, 1H), 7,92 (users, 1H), 8,14 (s, 1H), 8,27 (DD, J=2,0, 8.0 Hz, 1H), 8,89 (DD, J=2.0 a, 4.0 Hz, 1H).

Example 30

Synthesis of 1-{1-[2-(6-methoxyquinoline-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 6-hydroxyquinoline solution by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,96-2,12 (m, 4H), 2,29-of 2.38 (m, 2H), 2,48-of 2.58 (m, 2H), 3,17-3,30 (m, 4H), 3,98 (s, 3H), 4,39-4,50 (m, 1H), 6,51 (d, J=3.6 Hz, 1H), 7,21 (users, 1H), 7,50 to 7.62 (m, 3H), 7,66-7,72 (m, 2H), 7,92 (users, 1H), 7,95 (d, J=9,2 Hz, 1H), 8,14 (s, 1H), 8,42 (d, J=9,2 Hz, 1H), 8,77-8,79 (m, 1H).

Example 31

Synthesis of 1-{1-[2-(7-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 6-hydroxy-1,4-benzodioxane (CAS#: 10288-72-9) by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,92-of 2.08 (m, 4H), 2,19-of 2.28 (m, 2H), 2,45-of 2.54 (m, 2H), 2,61-to 2.67 (m, 2H), 3,05-of 3.12 (m, 2H), 3,70 (s, 3H), 4,13-4,22 (m, 4H), 4,36-to 4.46 (m, 1H), 6.48 in (s, 1H), 6,50 (d, J=3.2 Hz, 1H), 6,69 (s, 1H), 7,21 (users, 1H), 7,54-of 7.60 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 users, 1H), 8,12 (s, 1H).

Example 32

Synthesis of 1-{1-[2-(6-methoxy-2,3-dihydrobenzo[1,4]dioxin-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 6-hydroxy-1,4-benzodioxane (CAS#: 10288-72-9) by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,92-of 2.09 (m, 4H), 2,19-of 2.30 (m, 2H), 2.40 a-2,48 (m, 2H), 2.71 to and 2.79 (m, 2H), 3,07-3,14 (m, 2H), and 3.72 (s, 3H), 4,13-4,19 (m, 2H), 4,23-to 4.28 (m, 2H), 4,37-to 4.46 (m, 1H), 6,47 (d, J=8,8 Hz, 1H), of 6.50 (d, J=3.2 Hz, 1H), 6,66 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 33

Synthesis of 1-{1-[2-(6-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-she (CAS#: 308110-07-8) by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,92-of 2.08 (m, 4H), 2.21 are 2,31 (m, 2H), 2,50-to 2.57 (m, 2H), 2,74-of 2.81 (m, 2H), equal to 2.94 (t, J=6.4 Hz, 2H), 3,07-3,14 (m, 2H), 3,51 (t, J=6.4 Hz, 2H), 3,85 (s, 3H), 4,37-4,47 (m, 1H), 6,50 (d, J=2,8 Hz, 1H), 6,86 (s, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (s, 1H), to 7.67 (d, J=2,8 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 34

Synthesis of 1-(1-(2-(6-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide

The desired compound was synthesized from 6-hydroxy-2-methyl-3,4-dihydro-2H-Sochi the Olin-1-she (CAS#: 308110-07-8) method, described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,93-of 2.09 (m, 4H), 2,23-of 2.34 (m, 2H), 2,38-2,48 (m, 2H), 2,78-2,87 (m, 2H), 2,94-3,03 (m, 2H), 3.00 and (s, 3H), 3,07-and 3.16 (m, 2H), 3.49 points of 3.56 (m, 2H), 3,85 (s, 3H), 4,37-4,47 (m, 1H), 6.48 in-6,53 (m, 1H), 6,97 (d, J=8,4 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), 7,68 (d, J=3.2 Hz, 1H), a 7.85 (d, J=8,4 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 35

Synthesis of 1-{1-[2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 7-hydroxy-4H-1-benzopyran-4-it (J. Med. Chem. 34 (1991) 1, 248) by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,95-2,07 (m, 4H), of 2.25 to 2.35 (m, 2H), 2,50-of 2.58 (m, 2H), 2,99 was 3.05 (m, 2H), 3,11-3,19 (m, 2H), 3.96 points (s, 3H), of 4.38-4,48 (m, 1H), 6,27 (d, J=6.0 Hz, 1H), 6,50 (d, J=2,8 Hz, 1H), 7,21 (users, 1H), to 7.25 (d, J=9,2 Hz, 1H), 7,54-of 7.60 (m, 2H), 7,66 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 7,94 (d, J=9,2 Hz, 1H), 8,13 (s, 1H), 8,31 (d, J=6,4 Hz, 1H).

Example 36

Synthesis of 1-{1-[2-(7-methoxy-2,3-dimethyl-4-oxo-4H-chromen-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)2,3-Dimethyl-7-hydroxy-4H-1-benzopyran-4-one

The desired compound was synthesized from 2',4'-dihydroxybenzophenone in accordance with Bull. Chem. Soc. Jpn., 67, 1972 (1994).

1H-NMR (DMSO-d6) δ (ppm): 1.91 a (s, 3H), of 2.36 (s, 3H), 6,76 (d, J=1.6 Hz, 1H), 6,86 (DD, J=1,6, 8,8 Hz, 1H), to 7.84 (d, J=8,8 Hz, 1H), at 10.64 (users, 1H).

(2)1-{1-[2-(7-Methoxy-2,3-dimethyl-4-oxo-4H-chromen-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carbox the amide

The desired compound was synthesized from 2,3-dimethyl-7-hydroxy-4H-1-benzopyran-4-it is the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,92-2,07 (m, 4H), of 1.94 (s, 3H), 2,27-of 2.36 (m, 2H), 2,43 (s, 3H), of 2.51-2,60 (m, 2H), 2,97 was 3.05 (m, 2H), 3,13-is 3.21 (m, 2H), 3,95 (s, 3H), of 4.38-4,48 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 7,19 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,53-of 7.60 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), 7,86-7,94 (m, 1H), to $ 7.91 (d, J=8,8 Hz, 1H), 8,13 (s, 1H).

Example 37

Synthesis of 1-{1-[2-(7-methoxy-3,3-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)7-Hydroxy-3,3-dimethyl-4-exogamy

The desired compound was synthesized from resorcinol and 3-chloropivaloyl acid in accordance with J. Org. Chem. 1994, 59, 1216.

1H-NMR (DMSO-d6) δ (ppm): 1,06 (s, 6H), 4,14 (s, 2H), of 6.31 (d, J=2.4 Hz, 1H), 6,50 (DD, J=2,4, 8,8 Hz, 1H), to 7.61 (d, J=8,8 Hz, 1H), 10,53 (users, 1H).

(2)1-{1-[2-(7-Methoxy-3,3-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 7-hydroxy-3,3-dimethyl-4-oxoproline the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,09 (s, 6H), 1,92-of 2.08 (m, 4H), 2,20-of 2.30 (m, 2H), 2,43-2,52 (m, 2H), was 2.76-2,84 (m, 2H), is 3.08-and 3.16 (m, 2H), 3,88 (s, 3H), 4,23 (s, 2H), 4,37-to 4.46 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), PC 6.82 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,54-to 7.61 (m, 2H), 7,65 (d, J=3.2 Hz, 1H), 7,69 (d, J=8,8 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 38

Synthesis of 1-{1-[2-(6-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline--yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

The desired compound was synthesized from 6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-she (CAS#: 308110-07-8) by the methods described in example 22, (1), (2) and (3) and example 23, (5).

1H-NMR (DMSO-d6) δ (ppm): 1,92-of 2.08 (m, 4H), 2.23 to-2,31 (m, 2H), 2,49-to 2.57 (m, 2H), 2,74-of 2.81 (m, 2H), 2,82 (d, J=4.4 Hz, 3H), equal to 2.94 (t, J=6.4 Hz, 2H), 2,99 (s, 3H), 3,07-and 3.16 (m, 2H), 3,51 (t, J=6.4 Hz, 2H), 3,86 (, 3H), 4,36-to 4.46 (m, 1H), 6,50 (d, J=2,8 Hz, 1H), 6.87 in (s, 1H), 7,51-7,58 (m, 2H), 7,66 (d, J=2,8 Hz, 1H), to 7.67 (s, 1H), of 8.06 (s, 1H), 8,30-of 8.37 (m, 1H).

Example 39

Synthesis of 1-{1-[2-(6-methoxymethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 7-allyl-6-methoxy-1-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-it is the method described in example 20 (4).

1H-NMR (DMSO-d6) δ (ppm): 1,93-of 2.08 (m, 4H), 2,22 of-2.32 (m, 2H), 2,52-2,61 (m, 2H), was 2.76-and 2.83 (m, 2H), is 3.08-3.15 in (m, 2H), 3,26 (s, 3H), 3,79 (s, 3H), 4,37-4,47 (m, 1H), 5,19 (s, 2H), 6,50 (d, J=3.2 Hz, 1H), 6,94 (s, 1H), 6,99 (s, 1H), 7,21 (users, 1H), 7,54-of 7.60 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 40

Synthesis of 1-{1-[2-(7-methoxy-2-methoxymethyl-2-methyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)8-Allyl-7-methoxy-2-methoxymethyl-2-methyl-4-exogamy

445 mg of 3'-Allyl-2'-hydroxy-4'-methoxyacetophenone and 0.57 g of methoxyacetone was dissolved in 10 ml of toluene. Then to the reactions nomu solution was added to 0.19 g pyrrolidine and to 0.19 ml of acetic acid. Then the reaction solution was boiled under reflux for 1 hour using the apparatus of Dean-stark. After that, the reaction solution was cooled to room temperature. Was added to the reaction solution of 1.14 g of methoxyacetone, 0,38 g pyrrolidine and 0.38 ml of acetic acid and the resulting mixture was still heated by boiling under reflux overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed sequentially 2 N. chloroethanol acid, 1 N. aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 194 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,36 (s, 3H), 2,53 (d, J=16.0 Hz, 1H), 2,98 (d, J=16.0 Hz, 1H), 3,34 is 3.40 (m, 2H), 3,41 (s, 3H), 3.43 points (d, J=8,8 Hz, 1H), 3,55 (d, J=8,8 Hz, 1H), 3,88 (s, 3H), 4.92 in-to 5.03 (m, 2H), of 5.84-5,95 (m, 1H), return of 6.58 (d, J=9,2 Hz, 1H), 7,79 (d, J=9,2 Hz, 1H).

(2)1-{1-[2-(7-Methoxy-2-methoxymethyl-2-methyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 8-allyl-7-methoxy-2-methoxymethyl-2-methyl-4-oxoproline the method described in example 22, (4).

1H-NMR (DMSO-d6) δ (ppm): 1,33 (s, 3H), 1,92 is 2.10 (m, 4H), 2,23-of 2.34 (m, 2H), 2.40 a-2,52 (m, 2H), 2,61 (d, J=16,8 Hz, 1H), 2,74-2,82 (m, 2H), 2,86 (d, J=16,8 Hz, 1H), 3,07-3,17 (m, 2H), and 3.31 (s, 3H), 3,49 (s, 2H), a 3.87 (s, 3H), 4,37-4,48 (m, 1H), 6,51 (d, J=3.2 Hz, 1H), 6.75 in (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.64 (d, J=8,8 Hz, 1H), 7,68 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 41

Synthesis of 1-{1-[2-(7-methoxy-4-oxaspiro(chroman-2,1'-cyclopentane)-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 3'-allyl-2'-hydroxy-4'-methoxyacetophenone the method described in example 40.

1H-NMR (DMSO-d6) δ (ppm): 1.60-to 1,90 (m, 6H), 1,90-2,10 (m, 6H), 2,22 of-2.32 (m, 2H), 2.40 a-2,48 (m, 2H), 2,73-of 2.81 (m, 2H), and 2.83 (s, 2H), is 3.08-3.15 in (m, 2H), 3,88 (s, 3H), 4,37-4,48 (m, 1H), 6,51 (d, J=3.2 Hz, 1H), 6,60 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), 7,66 (d, J=8,8 Hz, 1H), 7,68 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,14 (s, 1H).

Example 42

Synthesis of 1-{1-[2-(5,7-dimethoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)5,7-Dihydroxy-2,2-dimethyl-4-exogamy

40 ml Methanesulfonic acid was added to 1,99 g pentoxide Diaspora in nitrogen atmosphere. Then to the reaction solution was added a mixture of 3.15 g of 1,3,5-trihydroxybenzene and 3.3-dimethylacrylic acid, at 70°C. the Reaction solution was stirred at 70°C for 30 minutes and then was cooled to the room for the Noah temperature. The reaction solution was added to ice water, followed by extraction with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 2,81 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (s, 6H), 2,68 (s, 2H), of 5.53 (users, 1H), by 5.87 (d, J=2.4 Hz, 1H), to 5.93 (d, J=2.4 Hz, 1H), a 12.03 (s, 1H).

(2)7 Allyloxy-5-hydroxy-2,2-dimethyl-4-exogamy

of 2.81 g of 5,7-Dihydroxy-2,2-dimethyl-4-oxoproline was dissolved in 60 ml of acetone. Then to the reaction solution was added 2,05 g of potassium carbonate and of 1.80 g of allylbromide and the resulting mixture was stirred at room temperature for 24 hours. Then to the reaction solution was added 0.20 g of potassium carbonate and 0.18 g of allylbromide and the resulting mixture was stirred at room temperature for 10 hours. Then to the reaction solution was added 0.20 g of potassium carbonate and 0.18 g of allylbromide and the resulting mixture was stirred at room temperature for 14 hours. Then to the reaction solution was added 0.20 g of potassium carbonate and 0.18 g of allylbromide and the resulting mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated the ri reduced pressure and the residue was diluted with ethyl acetate. The obtained product was washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 2,90 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): of 1.46 (s, 6H), 2,68 (s, 2H), to 4.52-of 4.57 (m, 2H), from 5.29 to 5.35 (m, 1H), lower than the 5.37-of 5.45 (m, 1H), 5,94-6,07 (m, 3H), 11,99 (s, 1H).

(3)7 Allyloxy-5-methoxy-2,2-dimethyl-4-exogamy

2,90 g 7 Allyloxy-5-hydroxy-2,2-dimethyl-4-exogamy was dissolved in 50 ml of N,N-dimethylformamide. Then to the reaction solution was added to 2.42 g of potassium carbonate and 2,32 g iodomethane and the resulting mixture was stirred at room temperature for 3 days. Then the reaction solution was diluted with ethyl acetate. The obtained product was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain and 2.79 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (s, 6H), 2,64 (s, 2H), a 3.87 (s, 3H), of 4.54 (d, J=5.6 Hz, 2H), 5,33 (DD, J=1,6, 10,0 Hz, 1H), 5,42 (DD, J=1,6, and 17.2 Hz, 1H), 5,98-6,10 (m, 1H), 6,03 (d, J=2.0 Hz, 1H), the 6.06 (d, J=2.0 Hz, 1H).

(4)1-{1-[2-(5,7-Dimethoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

the Desired compound was synthesized from 7-allyloxy-5-methoxy-2,2-dimethyl-4-oxoproline ways, described in example 22, (2), (3) and (4).

1H-NMR (DMSO-d6) δ (ppm): to 1.37 (s, 6H), 1,92 is 2.10 (m, 4H), 2,20-2,31 (m, 2H), 2,35 at 2.45 (m, 2H), 2,59 (s, 2H), 2,64-by 2.73 (m, 2H), 3,07-and 3.16 (m, 2H), 3,81 (s, 3H), with 3.89 (s, 3H), 4,37-4,47 (m, 1H), 6,28 (s, 1H), 6,50 (d, J=3.2 Hz, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 43

Synthesis of 1-{1-[2-(7-methoxy-4-oxaspiro(chroman-2,4'-oxan)-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)7-Hydroxy-4-oxaspiro(chroman-2,4'-oxan)

The desired compound was synthesized from resorcinol and (tetrahydropyran-4-ilidene)acetic acid by the method described in example 42, (1).

1H-NMR (CDCl3) δ (ppm): 1,72-to 1.82 (m, 2H), 1,94-2,02 (m, 2H), 2,69 (s, 2H), of 3.73-to 3.89 (m, 4H), 6,01 (users, 1H), gold 6.43 (d, J=2.4 Hz, 1H), of 6.49 (DD, J=2,4, and 8.4 Hz, 1H), 7,79 (d, J=8,4 Hz, 1H).

(2)1-{1-[2-(7-Methoxy-4-oxaspiro(chroman-2,4'-oxan)-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 7-hydroxy-4-oxaspiro(chroman-2,4'-oxan) by the method described in example 22.

1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (m, 4H), 1,94-2,12 (m, 4H), 2,27-of 2.36 (m, 2H), 2,47-to 2.57 (m, 2H), 2,77 (s, 2H), 2,83 of 2.92 (m, 2H), of 3.10-3.20 (m, 2H), 3,67-of 3.77 (m, 4H), to 3.89 (s, 3H), 4,40-4,50 (m, 1H), 6,51 (d, J=3.2 Hz, 1H), 6,78 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,54-to 7.61 (m, 2H), of 7.64-7,71 (m, 2H), to $ 7.91 (users, 1H), 8,15 (s, 1H).

Example 44

Synthesis of 1-{1-[2-(2-methoxynaphthalene-1-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

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While cooling on ice and 0.61 g of tert-butoxide potassium was added to 20 ml tetrahydropyranol suspension containing 2.28 g (methoxymethyl)triphenylmethylchloride, in nitrogen atmosphere. The resulting mixture was stirred for 5 minutes. Then to the reaction solution were added 600 mg of 2-methoxy-1-naphthaldehyde while cooling on ice. The resulting mixture was stirred at the same temperature for 20 minutes. The reaction solution was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 667 mg 2-methoxy-1-(2-methoxyphenyl)naphthalene containing a small amount of triphenylphosphine. This compound was used in next reaction without further purification.

120 mg of 2-Methoxy-1-(2-methoxyphenyl)naphthalene was dissolved in 4 ml of a mixture of 2 N. chloromethane acid-tetrahydrofuran (1:1). The resulting mixture was then stirred at 70°C for 2 hours. The reaction solution was cooled to room temperature and then was diluted with ethyl acetate. The obtained product was washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated at igenom pressure to obtain 115 mg (2-methoxynaphthalene-1-yl)acetaldehyde. This compound was used in next reaction without further purification.

70 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide and 115 mg (2-methoxynaphthalene-1-yl)acetaldehyde was dissolved in 2 ml of tetrahydrofuran. Then to the reaction solution was added to 0.03 ml of acetic acid and 91 mg of triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature overnight. Then added to the reaction solution, saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate-methanol) to obtain 72 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,98-2,14 (m, 4H), 2,30-to 2.40 (m, 2H), 2,50-2,60 (m, 2H), 3,18-to 3.38 (m, 4H), of 3.95 (s, 3H), 4,40-4,50 (m, 1H), of 6.52 (d, J=3.2 Hz, 1H), 7,22 (users, 1H), 7,33-7,40 (m, 1H), 7,45 (d, J=9,2 Hz, 1H), 7,50 to 7.62 (m, 3H), of 7.70 (d, J=3.2 Hz, 1H), 7,82-of 7.90 (m, 2H), 7,92 (users, 1H), of 7.97 (d, J=8,4 Hz, 1H), 8,15 (s, 1H).

Example 45

Synthesis of 1-{1-[2-(3-methoxynaphthalene-2-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 3-methoxy-2-naphthalenylbanned (CAS#: 56679-88-0) by the method described in example 44.

1H-NMR (DMSO-d6) δ (ppm): 1.93 and is 2.10 (m, 4H), of 2.25 to 2.35 (m, 2H), 2,63-2,70 (m, 2H), 2,90-2,96 (m, 2H), 3,11-3,19 (m, 2H), 3,93 (s, 3H), of 4.38-4,48(m, 1H), 6,50 (d, J=3.2 Hz, 1H), 7,21 (users, 1H), 7,28-7,35 (m, 2H), 7,37-7,44 (m, 1H), 7,53-of 7.60 (m, 2H), 7,68 (d, J=3.2 Hz, 1H), 7,72 (s, 1H), 7,75-7,81 (m, 2H), 7,92 (users, 1H), 8,14 (s, 1H).

Example 46

Synthesis of 1-{1-[2-(4-hydroxy-7-methoxypropan-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

52 mg of 1-(1-(2-(7-Methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide was dissolved in 6 ml of a mixture of methanol-tetrahydrofuran (1:1). Then to the reaction solution was added 5 mg of sodium borohydride while cooling on ice. The resulting mixture was then stirred at room temperature for 2 hours. After this was added to the reaction solution of 5 mg of sodium borohydride and 5 mg of sodium borohydride after 2 hours and 4 hours. Then the reaction solution was stirred at the same temperature throughout the night. Was added to the reaction solution, a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (ethyl acetate-methanol) to obtain 30 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,80-of 1.88 (m, 1H), 1,90-2,10 (m, 5H), 2,19-of 2.28 (m, 2H), 2,36 is 2.44 (m, 2H), 2,69-2,77 (m, 2H), 3,07 is 3.15 (m, 2H), 3,76 (s, 3H), 4,16-4,24 (m, 2H), 4,37-to 4.46 (m, 1H), 4,55-4,60 (m, 1H), 5,17 (d, J=5,2 Hz, 1H), 6,50 (d, J=3.2 Hz, 1H), 6,56 (d, J=8,8 Hz, 1H), and 7.1 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,54-of 7.60 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 47

Synthesis of 1-{1-[2-(7-methoxy-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

42 mg of 1-(1-(2-(7-Methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide was dissolved in 3 ml of methanol. Then to the reaction solution was added 15 mg of 10% palladium-on-carbon. The resulting mixture was then stirred at room temperature for 15 hours in a hydrogen atmosphere. After that I added to the reaction solution of 15 mg of 10% palladium-on-carbon. The resulting mixture was then stirred at the same temperature for 4 hours. After this palladium-on-carbon was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (ethyl acetate) to obtain 20 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,93-of 2.08 (m, 4H), 2,20-of 2.30 (m, 2H), 2,42-of 2.50 (m, 2H), 2,72 (t, J=6.3 Hz, 2H), 2,74-2,82 (m, 2H), is 3.08-and 3.16 (m, 2H), 3,88 (s, 3H), 4,37-4,47 (m, 1H), 4,54 (t, J=6.3 Hz, 2H), 6,50 (d, J=2,8 Hz, 1H), 6,80 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,55-of 7.60 (m, 2H), to 7.67 (d, J=2,8 Hz, 1H), 7,69 (d, J=8,8 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 48

Synthesis of 1-{1-[2-(4-hydroxy-7-methoxy-2,2-DIMETHYLPROPANE-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

259 mg 1(1-(2-(7-Methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl)piperidine-4-yl)-N-methyl-1H-indole-6-carboxamide was dissolved in 5 ml of methanol. Then to the reaction solution were added 60 mg of sodium borohydride while cooling on ice. The resulting mixture was then stirred at room temperature overnight. After this was added to the reaction solution, a saturated aqueous solution of sodium bicarbonate, followed by extraction of the mixture with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (ethyl acetate) and then was purified by chromatography on a column of silica gel (ethyl acetate-methanol) to give 216 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,24 (s, 3H), of 1.37 (s, 3H), 1,92 is 2.00 (m, 5H), and 2.26 (t, J=11.2 Hz, 2H), 2,37 is 2.46 (m, 2H), 2,68-2,77 (m, 2H), 2,82 (d, J=4.4 Hz, 3H), 3,07-and 3.16 (m, 2H, in), 3.75 (s, 3H), 4,36 is 4.45 (m, 1H), 4,60-of 4.66 (m, 1H), 5,17 (d, J=6.0 Hz, 1H), 6,50 (d, J=3.2 Hz, 1H), 6,55 (d, J=8,8 Hz, 1H), 7.23 percent (d, J=8,8 Hz, 1H), 7,51-7,58 (m, 2H), 7,66 (d, J=3.2 Hz, 1H), of 8.06 (s, 1H), 8,19-at 8.36 (m, 1H).

Example 49

Synthesis of 1-{1-[2-(1-hydroxy-5-methoxyindol-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 1-(1-(2-(5-methoxy-1-oxonian-4-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide by the method described in example 48.

1H-NMR (DMSO-d6) δ (ppm): 1,72 of-1.83 (m, 1H), 1,90-2,10 (m, 4H), 2,20-is 2.37 (m, 3H), 2.40 a-2,50 (m, 2H), 2,62-2,78 (m, 3H), 2,87-of 2.97 (m, 1H), 3,05-and 3.16 (m, 2H), of 3.77 (s, 3H), 4,36-4,47 (m, 1H), 4,6-of 5.05 (m, 2H), 6,47-6,53 (m, 1H), PC 6.82 (d, J=8.0 Hz, 1H), 7,13 (d, J=8.0 Hz, 1H), 7,21 (users, 1H), 7,52 to 7.62 (m, 2H), of 7.64-of 7.70 (m, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 50

Synthesis of 1-{1-[2-(3-hydroxy-6-methoxyindol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 1-(1-(2-(6-methoxy-3-oxonian-5-yl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide by the method described in example 48.

1H-NMR (DMSO-d6) δ (ppm): 1,72-to 1.82 (m, 1H), 1,90-2,10 (m, 4H), 2,20-of 2.36 (m, 3H), 2,44-to 2.57 (m, 2H), 2,63-and 2.79 (m, 3H), 2,85-to 2.94 (m, 1H), 3,07-and 3.16 (m, 2H), of 3.78 (s, 3H), 4,37-4,48 (m, 1H), to 4.98 (DD, J=5,6, 12.0 Hz, 1H), to 5.03 (d, J=5.6 Hz, 1H), 6,51 (d, J=3.2 Hz, 1H), PC 6.82 (s, 1H), 7,11 (s, 1H), 7,21 (users, 1H), 7,53 to 7.62 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), 7,92 (users, 1H), 8,13 (s, 1H).

Example 51

Synthesis of 1-{1-[2-(6-methoxyquinoline-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)1-Allyl-2-methoxy-5-nitrobenzene

The desired compound was synthesized from 2-allylphenol the method described in example 23, (1).

1H-NMR (CDCl3) δ (ppm): 3,42 (d, J=6,8 Hz, 2H), of 3.94 (s, 3H), 5,07-5,17 (m, 2H), 5,91-6,03 (m, 1H), make 6.90 (d, J=9,2 Hz, 1H), of 8.06 (d, J=2.4 Hz, 1H), 8,15 (DD, J=2,4, and 9.2 Hz, 1H).

(2)3-Allyl-4-methoxyaniline

15.0 g of 1-allyl-2-methoxy-5-nitrobenzene, and 33.4 g of ameriglide and 17.5 g of iron suspended in 270 ml of ethanol and 55 ml of water. The reaction solution was heated at the boil under reflux for 1 hour. Then p is a promotional solution was cooled to room temperature and was removed by filtration of insoluble materials. The filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 11.1 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): of 3.32 (d, J=6,4 Hz, 2H), 3,39 (users, 2H), 3,76 (s, 3H), 5,00-5,10 (m, 2H), 5,91-6,03 (m, 1H), 6,51-to 6.57 (m, 2H), 6,67-of 6.73 (m, 1H).

(3)6-Methoxyquinoline-7-carbaldehyde

6-Methoxy-7-(1-propenyl)quinoline with samaritano double bond was synthesized from 3-allyl-4-methoxyaniline according to Heterocycles, Vol. 54, No. 1, 105 (2001) (where the isomerization was carried out, providing 7-allyl-1-methanesulfonyl-6-methoxy-1,2-dihydroquinoline the opportunity to interact with potassium hydroxide at 80°C in dimethyl sulfoxide).

of 1.41 g of AD-mix-α and 93 mg of methanesulfonamide was dissolved in 12 ml of a mixture of tert-butanol-water (1:1). Then to the reaction solution were added 195 mg of 6-methoxy-7-(1-propenyl)quinoline and the mixture was stirred over night. Then added to the reaction solution of 2.0 g of sodium sulfite while cooling on ice and the resulting mixture was stirred at room temperature for 30 minutes. After that the reaction is near to the solution was added a saturated aqueous solution of sodium chloride, followed by extraction with methylene chloride. The extract is then washed 2 N. aqueous solution of potassium hydroxide. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 236 mg of 1-(6-methoxyquinoline-7-yl)propane-1,2-diol. This compound was used in next reaction without further purification.

236 mg 1-(6-Methoxyquinoline-7-yl)propane-1,2-diol was dissolved in 8 ml of tetrahydrofuran and 3 ml of methanol. Then to the reaction solution was added while cooling on ice and 4 ml of water containing 0,43 g metaperiodate sodium. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 149 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 4,06 (s, 3H), 7,18 (s, 1H), 7,44 (DD, J=4,4, 7,6 Hz, 1H), 8,05-8,11 (m, 1H), to 8.57 (s, 1H), 8,84-8,89 (m, 1H), 10,61-at 10.64 (m, 1H).

(4)1-{1-[2-(6-Methoxyquinoline-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 6-methoxyquinoline-7-carbaldehyde as described in example 44.

1H-NMR (DMSO-d6) δ (ppm): 1,94-2,10 (m, 4H), 2,27-of 2.86 (m, 2H), 2,66-by 2.73 (m, 2H), 2,96-to 3.02 (m, 2H), 3,12-3,20 (m, H), of 3.96 (s, 3H), 4,39-of 4.49 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 7,21 (users, 1H), 7,35 (s, 1H), 7,43 (DD, J=a 4.4, and 8.4 Hz, 1H), 7,53-to 7.61 (m, 2H), 7,68 (d, J=3.2 Hz, 1H), to 7.84 (s, 1H), 7,92 (users, 1H), 8,14 (s, 1H), 8,20-compared to 8.26 (m, 1H), 8,71 (DD, J=1,2, 4,4 Hz, 1H).

Example 52

Synthesis of 1-{1-[2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)7-[2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl]-6-methoxyquinoline

While cooling on ice 0,82 g of tert-butoxide potassium was added to 20 ml tetrahydropyranol suspension containing 2.50 g (methoxymethyl)triphenylmethylchloride, in nitrogen atmosphere. The resulting mixture was then stirred at the same temperature for 10 minutes. Then to the reaction solution was added while cooling on ice, 3 ml of tertrahydrofuran ring solution containing 545 mg 6-methoxyquinoline-7-carbaldehyde, and the resulting mixture is then stirred at the same temperature for 15 minutes. After that, the reaction solution was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (hexane-ethyl acetate) to obtain 1,41 g of 6-methoxy-7-(2-methoxyphenyl)quinoline containing triphenylphosphine. The connection used is Ali in the next reaction without further purification.

of 1.41 g of 6-Methoxy-7-(2-methoxyphenyl)quinoline was dissolved in 40 ml of a mixture of 2 N. chloromethane acid-tetrahydrofuran (1:1) and the resulting mixture is then stirred at 70°C for 2 hours. The reaction solution was cooled to room temperature. Diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 1.45 g (6-methoxyquinoline-7-yl)acetaldehyde containing triphenylphosphine. This compound was used in next reaction without further purification.

1.45 g (6-Methoxyquinoline-7-yl)acetaldehyde and 0.63 g of 1,4-dioxa-8 azaspiro[4,5]decane was dissolved in 20 ml of methylene chloride. After this was added to the reaction solution of 0.42 ml of acetic acid and 0.74 g of triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature for 3 hours. Then to the reaction solution was added saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform-methanol) to give 445 mg of the desired compound.

1H-NMR (CDCl ) δ (ppm): 1,75-to 1.86 (m, 4H), 2,59-2,77 (m, 6H), 2,97-of 3.07 (m, 2H), of 3.94 (s, 3H), of 3.97 (s, 4H), 7,00 (s, 1H), 7,29 (DD, J=a 4.4, and 8.4 Hz, 1H), to 7.84 (s, 1H), 8,01 (DD, J=1,6, and 8.4 Hz, 1H), 8,72 (DD, J=1,6, a 4.4 Hz, 1H).

(2)1-acetyl-7-[2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl]-6-methoxy-1,2,3,4-tetrahydroquinolin

445 mg of 7-(2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxyquinoline was dissolved in 10 ml of methanol. Then to the reaction solution was added 100 mg of 10% palladium-on-carbon. The resulting mixture was stirred for 6 hours in an atmosphere of hydrogen at a pressure of 4 kg/cm2. After this palladium-on-carbon was removed by filtration and the filtrate was concentrated under reduced pressure. The reaction solution was stirred under these conditions for 10 hours 3 times and then concentrating it under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 459 mg of 7-(2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline. This compound was used in next reaction without further purification.

3 ml of acetic anhydride and 3 ml of pyridine was added to 251 mg of 7-(2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline and the resulting mixture was then stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (hexane-ethyl acetate) and then by chromatography on a column of silica gel (ethyl acetate-methanol) to give 162 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,73 of-1.83 (m, 4H), 1,88-of 1.97 (m, 2H), 2,18 (users, 3H), 2,54-by 2.73 (m, 8H), 2,75-2,84 (m, 2H), 3,70-of 3.80 (m, 2H), of 3.78 (s, 3H), of 3.95 (s, 4H), 6,60 (s, 1H), 6,88 (users, 1H).

(3)1-{1-[2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

162 mg of 1-Acetyl-7-(2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline was dissolved in 6 ml of a mixture of 2 N. chloromethane acid-tetrahydrofuran (1:1) and the reaction solution is then stirred at 70°C for 10 hours. The reaction solution was cooled to room temperature and was added saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 127 mg of 1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidine-4-it. This connection is used the next reaction without further purification.

172 mg of 3-Amino-4-(2,2-dimethoxymethyl)benzamide and 127 mg of 1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidine-4-it was dissolved in 5 ml of acetic acid. Then to the reaction solution was added 0.65 g of sodium sulfate and the resulting mixture was stirred at room temperature for 1 hour. Then added to the reaction solution of 0.16 g of triacetoxyborohydride sodium and the resulting mixture was stirred for 1 hour. Then to the mixture was added 5 ml of water and the resulting mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, then concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform-methanol) and chromatography on a column with NH silica gel (ethyl acetate-methanol) to give 146 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,78-1,89 (m, 2H), 1.91 a-to 2.06 (m, 4H), and 2.14 (s, 3H), 2,19-of 2.30 (m, 2H), 2,47-to 2.57 (m, 2H), 2,63-2,77 (m, 4H), 3,06-3,13 (m, 2H), 3,63 (t, J=6.4 Hz, 2H), of 3.78 (s, 3H), 4,37-to 4.46 (m, 1H), 6,50 (d, J=2,8 Hz, 1H), 6,78 (users, 1H), 7,06-7,26 (m, 2H), 7,53-of 7.60 (m, 2H), 7,65 (d, J=2,8 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 53

Synthesis of 1-{1-[2-(6-methoxy-1-methyl-1,2,3,4-t is trihydroxysilyl-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)7-[2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl]-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin

445 mg of 7-(2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxyquinoline was dissolved in 10 ml of methanol. Then to the reaction solution was added 100 mg of 10% palladium-on-carbon. The resulting mixture was stirred for 6 hours in an atmosphere of hydrogen at a pressure of 4 kg/cm2. Palladium-on-carbon was removed by filtration, followed by concentration under reduced pressure. The reaction solution was stirred under these conditions for 10 hours, 3 times, followed by concentration under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 459 mg of 7-(2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline. This compound was used in next reaction without further purification.

196 mg of 7-(2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline was dissolved in 5 ml of acetonitrile. Then to the reaction solution was added 1 ml of 37% formalin, 190 mg cyanoborohydride sodium and 0.15 ml of acetic acid and the resulting mixture was stirred at anatoy temperature for 1 hour. Then the reaction solution was diluted with ethyl acetate, then washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (hexane-ethyl acetate) to obtain 100 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,52-to 1.63 (m, 3H), 1,75-of 1.88 (m, 3H), 1,94 is 2.01 (m, 2H), 2,52-of 2.86 (m, 8H), of 2.81 (s, 3H), 3,07-of 3.12 (m, 2H), and 3.72 (s, 3H), of 3.97 (s, 4H), 6.48 in (s, 1H), 6,51 (s, 1H).

(2)1-{1-[2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

100 mg of 7-(2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 6 ml of a mixture of 2 N. chloromethane acid-tetrahydrofuran (1:1). The reaction solution was stirred at 70°C for 7 hours. The reaction solution was cooled to room temperature. After this was added to the reaction solution, a saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 87 mg of 1-(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidine-4-it. This compound was used in next reaction without further purification.

129 mg of 3-amine which is 4-(2,2-dimethoxymethyl)benzamide and 87 mg of 1-(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidine-4-it was dissolved in 4 ml of acetic acid. Then to the reaction solution was added 0,49 g of sodium sulfate and the resulting mixture was stirred at room temperature for 1 hour. Then added to the reaction solution of 0.12 g of triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature for 1 hour. After that I added to the reaction solution 4 ml of water and then the resulting mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, followed by concentration under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate-methanol) and chromatography on a column with NH silica gel (ethyl acetate) to obtain 70 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,83 is 1.91 (m, 2H), 1,92-of 2.08 (m, 4H), 2,20-to 2.29 (m, 2H), 2,47-of 2.54 (m, 2H), 2.63 in-a 2.71 (m, 4H), was 2.76 (s, 3H), 3,02-3,13 (m, 4H), 3,68 (s, 3H), 4,37-to 4.46 (m, 1H), 6.48 in (s, 1H), 6,50 (d, J=3,2 Hz, 1H), 6,56 (s, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 54

Synthesis of 1-{1-[2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)Allyl-6-methoxyquinoline

The desired compound was synthesized from 6-hydroxyquinoline solution methods described in example 22, (1), (2) and (3).

1H-NMR (CDCl3) δ (ppm): 3,80-of 3.85 (m, 2H), of 3.97 (s, 3H), 4,87-of 4.95 (m, 1H), equal to 4.97-5,02 (m, 1H), 5,95-the 6.06 (m, 1H), 7,35 (DD, J=4.0 a, and 8.4 Hz, 1H), 7,50 (d, J=9,2 Hz, 1H), 8,01 (d, J=9,2 Hz, 1H), 8,21-of 8.27 (m, 1H), 8,76 (DD, J=1,6, 4.0 Hz, 1H).

(2)5-[2-(1,4-Dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl]-6-methoxyquinoline

1.24 g of 5-Allyl-6-methoxyquinoline was dissolved in 5 ml of tert-butanol. Then to the reaction solution was added 70 ml of tert-butanol-water (1:1) solution containing 10.3 g of AD-mix-αand the resulting mixture is then stirred at room temperature overnight. Then added to the reaction solution of 15 g of sodium sulfite and the mixture was stirred at room temperature for 30 minutes while cooling on ice. Was added to the reaction solution, a saturated aqueous solution of sodium chloride, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to get 1,69 g of 3-(6-methoxyquinoline-5-yl)propane-1,2-diol. This compound was used in next reaction without further purification.

0,81 g of 3-(6-Methoxyquinoline-5-yl)propane-1,2-diol was dissolved in 24 ml of tetrahydrofuran and 8 ml of methanol. Then to the reaction solution was added while cooling on ice 12 ml of water containing 1,49 g metaperiodate, then the resulting mixture was stirred at room temperature for 45 minutes. Then to the reaction solution was added saturated aqueous solution of sodium chloride, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to get to 0.72 g (6-methoxyquinoline-5-yl)acetaldehyde. This compound was directly used in the next reaction without further purification.

0,72 g (6-Methoxyquinoline-5-yl)acetaldehyde and 0.75 g of 1,4-dioxa-8 azaspiro[4,5]decane was dissolved in 30 ml of methylene chloride. Then to the reaction solution was added to 0.50 ml of acetic acid and 0,89 g triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature overnight. Thereafter, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (hexane-ethyl acetate) to give 1.01 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,77-to 1.87 (m, 4H), 2,53-2,77 (m, 6H), 3,23-of 3.32 (m, 2H), of 3.97 (s, 3H), 3,98 (s, 4H), 7,37 (DD, J=4.0 a, and 8.4 Hz, 1H), 7,47 (d, J=8,8 Hz, 1H), 8,00 (d, J=8,8 Hz, 1H), compared to 8.26-8.34 per (m, 1H), 8,76 (DD, J=1,6, 4.0 Hz, 1H).

(3)1-{1-[2-(1-Acetyl-6-methoxy-1,2,3,4-tetrahydro inolin-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 5-(2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxyquinoline the methods described in example 52, (2) and (3).

1H-NMR (DMSO-d6) δ (ppm): 1,80-of 1.92 (m, 2H), 1.93 and with 2.14 (m, 4H), 2,24 is 2.33 (m, 2H), 2,38 is 2.46 (m, 2H), 2,55-by 2.73 (m, 2H), 2.77-to 2,85 (m, 2H), is 3.08-and 3.16 (m, 2H), 3,63 (t, J=6.4 Hz, 2H), 3,80 (s, 3H), 4,37-4,47 (m, 1H), 6,51 (d, J=3.2 Hz, 1H), 6,83 (d, J=8,4 Hz, 1H), 7,06-7,26 (m, 2H), 7,54-to 7.61 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 55

Synthesis of 1-{1-[2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 5-(2-(1,4-dioxa-8 azaspiro[4,5]Decan-8-yl)ethyl)-6-methoxyquinoline the methods described in example 53, (1) and (2).

1H-NMR (DMSO-d6) δ (ppm): 1,87-2,10 (m, 6H), 2,23 of-2.32 (m, 2H), 2,35-to 2.42 (m, 2H), 2,66-2,78 (m, 4H), to 2.75 (s, 3H), 3.00 and-a 3.06 (m, 2H), 3,07-and 3.16 (m, 2H), 3,69 (s, 3H), 4,36-4,47 (m, 1H), 6,46 (d, J=8,8 Hz, 1H), 6,51 (d, J=3.2 Hz, 1H), 6,69 (d, J=8,8 Hz, 1H), 7,21 (users, 1H), 7,54-to 7.61 (m, 2H), 7,68 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 56

Synthesis of 1-{1-[2-(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)(4-Allyl-5-methoxy-2-nitrobenzyloxy)-tert-butyldimethylsilyl

229 mg of 4-Allyl-5-methoxy-2-nitrobenzyl alcohol was dissolved in 5 ml of N,N-dimethylformamide. Then to the reaction solution were added while cooling n the ice 0.17 g of imidazole and 0.23 g of tert-butyldimethylsilyloxy. The resulting mixture was stirred at room temperature for 2 hours. After that I added to the reaction solution of 34 mg of imidazole and 46 mg of tert-butyldimethylsilyloxy. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and then washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 330 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 0,15 (s, 6H), and 0.98 (s, 9H), 3,37-to 3.41 (m, 2H), 3,93 (s, 3H), of 5.05-5,14 (m, 2H), 5,12 (s, 2H), of 5.89-6,01 (m, 1H), 7,42 (s, 1H), 8,01 (s, 1H).

(2)tert-Butyl[4-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-5-methoxy-2-nitrobenzyloxy]dimethylsilane

of 1.37 g of AD-mix-β was dissolved in 10 ml of a mixture of tert-butanol-water (1:1) and then to the reaction solution was added 2 ml of tert-butanolato solution containing 330 mg of (4-allyl-5-methoxy-2-nitrobenzyloxy)-tert-butyldimethylsiloxy. The resulting mixture was then stirred at room temperature overnight. Was added to the reaction solution of 1.5 g of sodium sulfite while cooling on ice and the resulting mixture was stirred at room temperature for 1 hour. To the reaction races who the thief was added a saturated aqueous solution of sodium chloride, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 390 mg of 3-(4-(tert-butyldimethylsilyloxy)-2-methoxy-5-nitrophenyl)propane-1,2-diol. This compound was directly used in the next reaction without further purification.

390 mg of 3-(4-(Tert-butyldimethylsilyloxy)-2-methoxy-5-nitrophenyl)propane-1,2-diol was dissolved in 8 ml of acetone. Then to the reaction solution was added 0.33 g of dimethoxypropane and 26 mg p-toluensulfonate pyridinium. The resulting mixture was then stirred at room temperature for 41 hours. After that, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 358 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 0,15 (s, 6H), 0,99 (s, 9H), of 1.34 (s, 3H), USD 1.43 (s, 3H), 2,87 (DD, J=6,0, to 13.6 Hz, 1H), 2,96 (DD, J=6,0, to 13.6 Hz, 1H), 3,64 (DD, J=6,8, 8.0 Hz, 1H), 3,92 (s, 3H), 3,99 (DD, J=5,6, 8.0 Hz, 1H), 4,33-to 4.41 (m, 1H), 5,12 (s, 2H), 7,43 (s, 1H), 8,08 (s, 1H).

(3)4-[(2,2-Dimethyl-[1,3]dioxolane-4-yl)methyl]-5-methoxy-2-nitrobenzaldehyde

358 mg of Tert-butyl(4-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-5-methoxy-2-nitrobenzyloxy)di is lilliana was dissolved in 10 ml of tetrahydrofuran. While cooling on ice to the reaction solution was added 1 ml of tertrahydrofuran ring solution containing 1,0 M tetrabutylammonium, and the resulting mixture was then stirred at room temperature for 3 hours. After that, the reaction solution was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 253 mg (4-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanol.

After that, 253 mg (4-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanol was dissolved in 10 ml of methylene chloride. Then to the reaction solution was added 2.5 g of activated manganese dioxide and the mixture was stirred at room temperature for 66 hours. After that, the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 137 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): of 1.34 (s, 3H), USD 1.43 (s, 3H), 2.91 in-3,03 (m, 2H), 3,65 (DD, J=6,0, 8.0 Hz, 1H), 3,98 (s, 3H), 4,06 (DD, J=6,0, 8.0 Hz, 1H), 4,34-4,43 (m, 1H), 7,32 (s, 1H), 8,07 (s, 1H), 10,47 (s, 1H),

(4)7-[(2,2-Dimethyl-[1,3]dioxolane-4-yl)methyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-2-he

137 mg of 4-((2,2-Dimethyl-[1,3]dioxolane-4-yl)methyl)-5-meth is XI-2-nitrobenzaldehyde was dissolved in 5 ml of toluene. Then to the reaction solution was added 204 mg ethoxycarbonylmethylene and the resulting mixture is then heated at the boil under reflux for 1 hour. The reaction solution was cooled to room temperature. After that, the reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to give 168 mg of 3-(4-((2,2-dimethyl-[1,3]dioxolane-4-yl)methyl)-5-methoxy-2-nitrophenyl)acrylate.

After 168 mg of 3-(4-((2,2-dimethyl-[1,3]dioxolane-4-yl)methyl)-5-methoxy-2-nitrophenyl)ethyl acrylate was dissolved in 5 ml of ethanol. Then to the reaction solution was added 30 mg of 10% palladium-on-carbon and the resulting mixture was then stirred in an atmosphere of hydrogen for 4 hours. Palladium-on-carbon was removed by filtration and the filtrate is then concentrated under reduced pressure. The residue was dissolved in 5 ml of ethanol. The reaction solution was stirred at 50°C for 17 hours. Then, they were heated at the boil under reflux for 30 minutes. The reaction solution was cooled to room temperature, then concentrated under reduced pressure. The residue was perioadele from a mixture of diethyl ether-hexane to obtain 110 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): of 1.23 (s, 3H), of 1.33 (s, 3H), 2,36 is 2.43 (m, 2H), 2,63-2,77 (m, 2H), 2,80-2,87 (m, 2H), 3,53 (DD, J=6,4, 8.0 Hz, 1H), 3,74 (s, 3H), 3,90 (DD, J=5,6, 8.0 Hz, 1H), 4,15-to 4.23 (m, 1H), of 6.68 (s, 1H), PC 6.82 (s, 1H), 9,84 (users, 1H).

(5)1-{1-[2-(6-Methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

109 mg of 7-((2,2-Dimethyl-[1,3]dioxolane-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-it was dissolved in 4 ml of a mixture of methanol-tetrahydrofuran (1:1). When cooled on ice was added to the reaction solution 1 ml 2 N. chloroethanol acid and the resulting mixture was then stirred at room temperature for 3 hours. After that, the reaction solution was concentrated under reduced pressure to obtain 110 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-it. This compound was directly used in the next reaction without further purification.

110 mg of 7-(2,3-Dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-it was dissolved in 2 ml methanol and 1 ml of tetrahydrofuran. Then to the reaction solution was added while cooling on ice, 2 ml of water containing 0.16 g of metaperiodate sodium. The resulting mixture was stirred at room temperature for 30 minutes. Was added to the reaction solution, a saturated aqueous solution of sodium chloride, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 87 mg of (6-methoxy-2-oxo-12,3,4-tetrahydroquinolin-7-yl)acetaldehyde. This compound was directly used in the next reaction without further purification.

100 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide and 87 mg (6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde suspended in 5 ml of methylene chloride. Then to the reaction solution were added 0.05 ml of acetic acid and 0.13 g of triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature overnight. Then added to the reaction solution, a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform-methanol) and chromatography on a column with NH silica gel (chloroform-methanol) and then perioadele from ethyl acetate to obtain 18 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,92-2,10 (m, 4H), 2,20-of 2.30 (m, 2H), 2.40 a (t, J=7,6 Hz, 2H), 2,45 is 2.55 (m, 2H), 2,65-of 2.72 (m, 2H), and 2.83 (t, J=7,6 Hz, 2H), 3,06-of 3.12 (m, 2H, in), 3.75 (s, 3H), 4,37-4,47 (m, 1H), 6,50 (d, J=the 3.2 Hz, 1H), 6,69 (s, 1H), for 6.81 (s, 1H), 7,21 (users, 1H), 7,53-to 7.61 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H), 9,85 (s, 1H).

Example 57

Synthesis of 1-{1-[2-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)7-[(2,2-Dimethyl-[1,3]dioxolane-4-the l)methyl]-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-he

300 mg of 7-((2,2-Dimethyl-[1,3]dioxolane-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-it was dissolved in 6 ml N,N-dimethylformamide. When cooled on ice was added to the reaction solution of 49 mg of 60% sodium hydride and the resulting mixture was then stirred at room temperature for 30 minutes. Then to the reaction solution was added while cooling on ice 0.29 grams of iodomethane. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (hexane-ethyl acetate) to give 310 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): of 1.34 (s, 3H), USD 1.43 (s, 3H), 2,58-of 2.66 (m, 2H), 2,80-2,89 (m, 3H), equal to 2.94 (DD, J=6,0, of 14.0 Hz, 1H), 3,32 (s, 3H), of 3.65 (DD, J=6,0, 7,6 Hz, 1H), 3,80 (s, 3H), of 3.97 (DD, J=5,6, and 7.6 Hz, 1H), 4,32-4,39 (m, 1H), 6,65 (s, 1H), for 6.81 (s, 1H).

(2)1-{1-[2-(6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 7-((2,2-dimethyl-[1,3]dioxolane-4-yl)methyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-it is the method described in example 56, (5).

1H-NMR (DMSO-d6) δ (ppm): 1,92-2,9 (m, 4H), 2,22 of-2.32 (m, 2H), 2,45-2,60 (m, 4H), 2,72-of 2.86 (m, 4H), is 3.08-3.15 in (m, 2H), 3,24 (s, 3H), of 3.78 (s, 3H), 4,37-4,48 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), to 6.88 (s, 1H), of 6.96 (s, 1H), 7,22 (users, 1H), 7,53-7,60 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 58

Synthesis of 1-{1-[2-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

The desired compound was synthesized from 7-((2,2-dimethyl-[1,3]dioxolane-4-yl)methyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-it is the method described in example 56, (5).

1H-NMR (DMSO-d6) δ (ppm): 1.93 and is 2.10 (m, 4H), 2,22-2,31 (m, 2H), 2,47-2,60 (m, 4H), 2,74-to 2.85 (m, 4H), 2,82 (d, J=4.4 Hz, 3H), is 3.08-3.15 in (m, 2H), 3,24 (s, 3H), of 3.78 (s, 3H), 4,36-to 4.46 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), to 6.88 (s, 1H), of 6.96 (s, 1H), 7,51-7,58 (m, 2H), to 7.67 (d, J=3.2 Hz, 1H), with 8.05 (s, 1H), 8,30-of 8.37 (m, 1H).

Example 59

Synthesis of 1-{1-[2-(1-ethyl-6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 7-((2,2-dimethyl-[1,3]dioxolane-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-it is the method described in example 57.

1H-NMR (DMSO-d6) δ (ppm): of 1.13 (t, J=7.2 Hz, 3H), 1,94-2,07 (m, 4H), 2.21 are of 2.30 (m, 2H), 2,46 at 2.59 (m, 4H), 2,74-and 2.83 (m, 4H), is 3.08-and 3.16 (m, 2H), of 3.78 (s, 3H), 3,99 (sq, J=7.2 Hz, 2H), 4,37-4,47 (m, 1H), 6,50 (d, J=the 3.2 Hz, 1H), 6,86 (s, 1H), 7,00 (s, 1H), 7,21 (users, 1H), 7,54-of 7.60 (m, 2H), 7,65 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,12 (s, 1H).

Example 60

Synthesis of 1-{1-[2-(3-ethyl--methoxy-2-oxo-2,3-dihydroisoxazole-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)3-Ethyl-6-methoxy-5-(3-methyl-2-butenyl)-3H-benzoxazol-2-he

231 mg of 6-Methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazole was dissolved in 5 ml of tetrahydrofuran in a nitrogen atmosphere. Then to the reaction solution were added over 20 minutes, 0.4 ml tertrahydrofuran ring of a solution containing 0.12 g sodium borohydride and 0.1 ml of acetic acid, and the resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of ammonium chloride followed by extraction with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to obtain 80 mg of 2-ethylamino-5-methoxy-4-(3-methyl-2-butenyl)phenol, containing the product, whose structure was unknown. This compound was directly used in the next reaction without further purification.

80 mg 2-Ethylamino-5-methoxy-4-(3-methyl-2-butenyl)phenol was dissolved in 5 ml of tetrahydrofuran in a nitrogen atmosphere. Then to the reaction solution was added 0.11 g of 1,1'-carbonyldiimidazole and the resulting mixture was stirred at room temperature for the of 1 hour. After that, the mixture was stirred at 50°C for a further 1 hour. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate) to obtain 60 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): to 1.35 (t, J=6.8 Hz, 3H), 1,72 (s, 3H), of 1.75 (s, 3H), of 3.33 (d, J=7.2 Hz, 2H), 3,82 (s, 3H), 3,84 (sq, J=6,8 Hz, 2H), 5,23-of 5.29 (m, 1H), 6.73 x (s, 1H), 6,80 (s, 1H).

(2)1-{1-[2-(3-Ethyl-6-methoxy-2-oxo-2,3-dihydroisoxazole-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

The desired compound was synthesized from 3-ethyl-6-methoxy-5-(3-methyl-2-butenyl)-3H-benzoxazol-2-it is the method described in example 4 (4).

1H-NMR (DMSO-d6) δ (ppm): 1.26 in (t, J=7.2 Hz, 3H), 1.93 and-of 2.08 (m, 4H), 2,24 of-2.32 (m, 2H), 2,50-2,60 (m, 2H), 2.77-to 2,84 (m, 2H), is 3.08-3.15 in (m, 2H), 3,80 (s, 3H), 3,82 (sq, J=7.2 Hz, 2H), 4,37-4,47 (m, 1H), 6,50 (d, J=the 3.2 Hz, 1H), 7,14 (s, 1H), 7,17-7,24 (m, 1H), 7,20 (s, 1H), 7,54-of 7.60 (m, 2H), 7,66 (d, J=3.2 Hz, 1H), to $ 7.91 (users, 1H), 8,13 (s, 1H).

Example 61

Synthesis of 1-{1-[2-(7-methoxy-3-methyl-2-oxo-3,4-dihydro-1,3-benzoxazin-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)2 Allyloxy-4-hydroxybenzaldehyde

15,23 g of 2,4-Dihydroxybenzaldehyde was dissolved in 20 ml of methyl ethyl ketone. Then to the reaction solution was sequentially added 15,54 g of potassium carbonate, 9,73 ml allylbromide, 18,67 g of potassium iodide and 3.55 g tetrabutylammonium. This reaction solution was heated at the boil under reflux in nitrogen atmosphere for 1.5 hours. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and water to separate the organic layer. The organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 13,72 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 4,58-4,60 (m, 2H), 5,32 and 5.36 (m, 1H), 5.40 to-5,46 (m, 1H), 5,99-between 6.08 (m, 1H), 6,44 (d, J=2.4 Hz, 1H), 6,56 (DD, J=2,4, 8,8 Hz, 1H), 7,44 (d, J=8,8 Hz, 1H), 9,72 (s, 1H), 11,47 (s, 1H).

(2)3-Allyl-2,4-dihydroxybenzaldehyde

3,10 g 2 Allyloxy-4-hydroxybenzaldehyde was dissolved in 6 ml N,N-dimethylaniline and the reaction solution was heated at boiling under reflux in a nitrogen atmosphere. After about 2.5 hours the reaction solution was set to cool. Then to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained org is practical layer was washed 5 N. chloroethanol acid, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 0.88 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3,48-to 3.50 (m, 2H), 5,15-5,23 (m, 2H), by 5.87 (s, 1H), 5,94-6,04 (m, 1H), 6,50 (d, J=8,4 Hz, 1H), 7,35 (d, J=8,4 Hz, 1H), to 9.70 (s, 1H), 11,76 (s, 1H).

(3)8-Allyl-7-hydroxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-he

0.88 g of 3-Allyl-2,4-dihydroxybenzaldehyde was dissolved in 10 ml of methanol. To the resulting solution was added with 1.92 ml of a methanol solution containing methylamine (40%), and the resulting mixture was then stirred at room temperature for about 30 minutes. Thereafter, this reaction solution was cooled on ice and then was added slowly sodium borohydride. The reaction solution was stirred at room temperature for 15 minutes. After this was removed under reduced pressure the solvent. To the residue was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of Phil what trevanian desiccant organic layer was concentrated under reduced pressure. To the residue was added to 2.40 g of 1,1'-carbonyldiimidazole and 30 ml of anhydrous tetrahydrofuran and the resulting mixture is then heated at the boil under reflux for 2.5 hours. The reaction solution was cooled to room temperature and then added to it 5 ml of methanol. Was removed under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 0.66 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3,11 (s, 3H), 3,52-of 3.54 (m, 2H), 4,39 (users, 2H), 5,11-by 5.18 (m, 2H), 5,24 (s, 1H), of 5.92-of 6.02 (m, 1H), 6,62 (d, J=8,2 Hz, 1H), 6,85 (d, J=8,2 Hz, 1H).

(4)8-Allyl-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-he

0.66 g of 8-Allyl-7-hydroxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-it was dissolved in 6 ml N,N-dimethylformamide. To the resulting solution was added to 0.63 g of potassium carbonate and 0.94 ml under the conditions and the resulting mixture was then stirred at room temperature overnight under nitrogen atmosphere. Then to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with an aqueous solution of sodium thiosulfate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified of chromatography the th on a column of silica gel (hexane/ethyl acetate) to obtain the gain of 0.58 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3,11 (s, 3H), 3.46 in-of 3.48 (m, 2H), 3,83 (s, 3H), 4,40 (users, 2H), 4,94-of 5.05 (m, 2H), of 5.89 of 5.99 (m, 1H), only 6.64 (d, J=8.6 Hz, 1H), make 6.90 (d, J=8.6 Hz, 1H).

(5)8-(2,3-Dihydroxypropyl)-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-he

12 ml of Tert-butanol and 10 ml of water was dissolved in 0,58 g of 8-allyl-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-it. To the resulting solution was added 2,48 g of AD-mix-β and the resulting mixture was stirred at room temperature overnight. After confirming the disappearance of the starting material, was added to the reaction solution of 2.97 g of sodium sulfite and the mixture was then stirred for approximately 45 minutes. Then to the reaction solution were added water and chloroform to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate/methanol) to obtain 0.55 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,92-to 3.02 (m, 2H), 3,11 (s, 3H), 3,50 (DD, J=5,8, 12.0 Hz, 1H), 3,60 (DD, J=3,6, 12.0 Hz, 1H), 3,85 (s, 3H), 3,92-of 3.96 (m, 1H), and 4.40 (s, 2H), 6,66 (d, J=8,4 Hz, 1H), 6,94 (d, J=8,4 Hz, 1H).

(6)1-{1-[2-(7-Methoxy-3-methyl-2-oxo-3,4-dihydro-1,3-benzoxazin-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-Carbo who said

114 mg of 8-(2,3-Dihydroxypropyl)-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-it was dissolved in 2 ml of tetrahydrofuran, 2 ml of methanol and 1.3 ml of water. Then to poluchennom solution was added 182 mg metaperiodate sodium and the mixture was vigorously stirred. After confirming the disappearance of the material was added to the reaction solution, water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 135 mg of the crude aldehyde.

135 mg of the indicated crude aldehyde, dissolved in 4 ml of dichloromethane and 40.5 μl of acetic acid was sequentially added 86 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide and the mixture then was stirred for 10 minutes. Then to the reaction solution was added 112 mg triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature overnight. Then added to the reaction solution, 10% aqueous sodium carbonate solution and chloroform to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of Phil what trevanian desiccant organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (ethyl acetate/methanol) to give 124 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,04-to 2.40 (m, 4H), 2,28-of 2.38 (m, 2H), 2,58-of 2.66 (m, 2H), 2.95 and-2,99 (m, 2H), 3,12 (s, 3H), 3,21 of 3.28 (m, 2H), of 3.84 (s, 3H), 4,32-and 4.40 (m, 2H), and 4.40 (s, 2H), 5.56mm (users, 1H), 6,29 (users, 1H), 6,55 (d, J=3.3 Hz, 1H), only 6.64 (d, J=8,4 Hz, 1H), make 6.90 (d, J=8,4 Hz, 1H), 7,38 (d, J=3.3 Hz, 1H), 7,45 (userd, 1H), 7,63 (d, J=8.0 Hz, 1H), 8,08 (users, 1H).

Example 62

Synthesis of 1-{1-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihydro-2H-1,3-benzoxazin-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)Methyl 4-(allyloxy)-2-hydroxybenzoate

20,05 g of Methyl 2,4-dihydroxybenzoate was dissolved in 250 ml of acetone and then to the reaction solution was sequentially added 17,31 g of potassium carbonate and 12.4 ml of allylbromide. The resulting mixture was stirred at room temperature under nitrogen atmosphere for approximately 2.5 days. After this was removed by filtering the precipitate and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 20,36 g of the desired compound. In the NMR spectrum was slightly noticeable peak, presumably representing isomer (methyl 4-(allyloxy)-2-hydroxybenzoate).

1H-NMR (CDCl3) δ (ppm): 3,91 (s, 3H), 4,54-of 4.57 (m, 2H), 530-5,33 (m, 1H), 5,39-of 5.45 (m, 1H), 5,99-between 6.08 (m, 1H), 6,44-6,47 (m, 2H), 7,72 to 7.75 (m, 1H), 10,96 (s, 1H).

(2)Methyl 3-allyl-2,4-dihydroxybenzoate

for 9.47 g of Methyl 4-(allyloxy)-2-hydroxybenzoate was dissolved in 25 ml of N,N-dimethylaniline and the mixture was then heated at the boil under reflux in a nitrogen atmosphere. After about 2.5 hours the reaction mixture was cooled to room temperature. Then to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed 5 N. chloroethanol acid, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 2.30 g of the desired compound. In the NMR spectrum was slightly noticeable peak, presumably representing isomer (methyl 5-(allyloxy)-2,4-dihydroxybenzoic).

1H-NMR (CDCl3) δ (ppm): 3,48-to 3.50 (m, 2H), 3,91 (s, 3H), 5,11-by 5.18 (m, 2H), 5.56mm (s, 1H), 6,38 (d, J=8,8 Hz, 1H), 7,65 (d, J=8,8 Hz, 1H), 11,27 (s, 1H).

(3)Methyl 3-allyl-2-hydroxy-4-methoxybenzoate

2.30 g of Methyl 3-allyl-2,4-dihydroxybenzoate was dissolved in 30 ml of acetone and then to the resulting solution was added to 1.83 g of potassium carbonate and 0,76 ml under the conditions. The resulting mixture C is the was stirred at room temperature under nitrogen atmosphere overnight. Then to the reaction solution was added 5% aqueous solution of sodium hydrosulphate, water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with an aqueous solution of sodium thiosulfate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give to 1.83 g of the desired compound. In the NMR spectrum was slightly noticeable peak, presumably representing isomer (methyl 5-(allyloxy)-2-hydroxy-4-methoxybenzoate).

1H-NMR (CDCl3) δ (ppm): 3,41-of 3.43 (m, 2H), 3,86 (s, 3H), 3,91 (s, 3H), 4,93-5,02 (m, 2H), 5,90-6,00 (m, 1H), 6,45 (d, J=8,8 Hz, 1H), 7,73 (d, J=8,8 Hz, 1H), 11,05 (s, 1H).

(4)Methyl 3-allyl-4-methoxy-2-(methoxyethoxy)benzoate

Sodium hydride (60%) was washed with n-hexane and then suspended in 2 ml of anhydrous tetrahydrofuran. The resulting suspension was cooled on ice and then stirred in a nitrogen atmosphere. To this suspension was added 2.30 g of methyl 3-allyl-2-hydroxy-4-methoxybenzoate dissolved in 8 ml of anhydrous tetrahydrofuran. The reaction solution was stirred at room temperature for about 1 hour. Then to the reaction solution was added 1.25 ml of CHL is methylotroph simple ether and the resulting mixture was still stirred over night. Then to the reaction solution was added 10% aqueous sodium carbonate solution and ethyl acetate to separate an organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give to 1.32 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3,49-3,51 (m, 2H), to 3.58 (s, 3H), 3,86 (s, 6H), 4,94-5,00 (m, 2H), 5,04 (s, 2H), 5,90-6,00 (m, 1H), of 6.68 (d, J=8,8 Hz, 1H), 7,79 (d, J=8,8 Hz, 1H).

(5)3-Allyl-4-methoxy-2-(methoxyethoxy)benzoic acid

1,32 g of Methyl 3-allyl-4-methoxy-2-(methoxyethoxy)benzoate was dissolved in 12 ml of methanol and the resulting mixture is then stirred while cooling on ice. Then to the reaction mixture were added 2,97 ml 5 N. aqueous sodium hydroxide solution and the resulting mixture was stirred at room temperature overnight. The reaction solution was cooled on ice and added to it the ethyl acetate. Then the mixture was brought to approximately pH 5 by the addition of 5% aqueous solution of sodium hydrosulphate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined. The combined organic layer washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 1.19 g of the desired compound. This compound was used in next reaction without further purification.

1H-NMR (CDCl3) δ (ppm): 3,44-of 3.46 (m, 2H)and 3.59 (s, 3H), with 3.89 (s, 3H), 4.95 points-to 5.03 (m, 2H), 5,13 (s, 2H), of 5.92-6,01 (m, 1H), 6,79 (d, J=8,8 Hz, 1H), 8,02 (d, J=8,8 Hz, 1H), 10,8 (users, 1H).

(6)8-Allyl-7-methoxy-3-methyl-2H-1,3-benzoxazin-2,4(3H)-dione

1.20 g of 3-Allyl-4-methoxy-2-(methoxyethoxy)benzoic acid was dissolved in 15 ml of anhydrous tetrahydrofuran and then to the resulting solution was added 0.84 g of 1,1'-carbonyldiimidazole. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 25 minutes. Then to the reaction solution was added to 11.8 ml of methylamine (2.0 M tertrahydrofuran ring solution) and the resulting mixture was stirred at room temperature for approximately 5 hours. Then the reaction mixture was cooled on ice and added to it 2.5 ml of concentrated chloroethanol acid. The resulting mixture was stirred at room temperature for 15 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water 3 times and then washed with a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride. The resulting product was then dried over betw denim magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. To the obtained residue were added 20 ml of anhydrous tetrahydrofuran and then to the mixture was added 1,53 g of 1,1'-carbonyldiimidazole. The reaction mixture was heated at the boil under reflux in nitrogen atmosphere for about 2 hours. The reaction solution was cooled to room temperature, then was removed under reduced pressure the solvent. To the residue was added ethyl acetate and water to separate the organic layer. The obtained organic layer was washed with water twice and then with a saturated solution of sodium chloride. The resulting product was then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was perioadele from a mixture of ethyl acetate-n-hexane to obtain 0.97 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 3,45 (s, 3H), 3,52-of 3.54 (m, 2H), of 3.94 (s, 3H), equal to 4.97-of 5.06 (m, 2H), 5,85-5,95 (m, 1H), make 6.90 (d, J=8,8 Hz, 1H), of 7.96 (d, J=8,8 Hz, 1H).

(7)3-Allyl-2-hydroxy-4-methoxy-N-methylbenzamide

3.94 g of AD-mix-β was added to a mixture of 0.97 g of 8-allyl-7-methoxy-3-methyl-2H-1,3-benzoxazin-2,4(3H)-dione, 30 ml of tert-butanol and 20 ml of water. The resulting mixture was stirred at room temperature overnight. Then to the reaction solution add the Yali to 4.73 g of sodium sulfite and the mixture was stirred for 50 minutes. The reaction solution was brought to approximately pH 5 by the addition of 1 N. chloroethanol acid and then the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. To the obtained residue was added 8 ml of methanol and 4 ml of tetrahydrofuran and then to the mixture was added of 1.44 ml of 5 N. aqueous sodium hydroxide solution. The reaction mixture then was stirred for 10 minutes. The reaction solution was cooled on ice, and then add to it 1 N. chloroethanol acid to bring the pH to about 6. Was added to the reaction solution in ethyl acetate for extraction. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to get 0,81 g of the desired compound. NMR analysis showed the presence of two conformers in the form of a mixture. The ratio was approximately 2:1. The following measurement data shows the number of hydrogen atoms, wherein the sum of the conformers is one molecule.

1H-NMR (CDCl3) δ (ppm): 2,99 (s, 2H), 3,02 (who, 1H), 3,42-3,44 (m, 2H), 3,85 (s, 3H), 4,94-5,04 (m, 2H), 5,93-of 6.02 (m, 1H), 6,14 (users, 1H), 6,41 (d, J=8,8 Hz, 1H), 7,21 (d, J=8,8 Hz, 0,33H), 7,21 (d, J=8,8 Hz, 0,67H), 12,69 (users, 1H).

(8)3-Allyl-2-(benzyloxy)-4-methoxy-N-methylbenzamide

0.15 g of sodium Hydride was washed with n-hexane and then suspended in 0.5 ml of anhydrous tetrahydrofuran. The suspension was cooled on ice and then stirred in a nitrogen atmosphere. Then to the resulting suspension were added 0,81 g of 3-allyl-2-hydroxy-4-methoxy-N-methylbenzamide dissolved in 5 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was cooled on ice and added to it 520 μl of benzylbromide. The resulting mixture was stirred at room temperature for 40 minutes. Then to the reaction solution was added 3 ml of N,N-dimethylformamide and the resulting mixture was still stirred for 1 hour. Was added to the reaction mixture with ice followed by extraction with ethyl acetate. The organic layer was washed with water 3 times and then with a saturated solution of sodium chloride. Then the obtained product was dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was perioadele from a mixture of ethyl acetate-n-hexane to obtain of 0.49 g of the desired compound. NMR analysis showed the presence of two to the formers in the form of a mixture. The ratio was approximately 1:1. The following measurement data shows the number of hydrogen atoms, wherein the sum of the conformers is one molecule.

1H-NMR (CDCl3) δ (ppm): 2,84 (s, 1,5H), 2,85 (s, 1,5H), 3,51-of 3.53 (m, 2H), 3,88 (s, 3H), 4,84 (s, 2H), equal to 4.97-5,02 (m, 2H), 5,98-6,07 (m, 1H), for 6.81 (d, J=8,8 Hz, 1H), 7,38 was 7.45 (m, 5H), 7,63 (userd, 1H), 8,01 (d, J=8,8 Hz, 1H)

(9)2-Benzyloxy-3-(2,3-dihydroxypropyl)-4-methoxy-N-methylbenzamide

of 1.57 g of AD-mix-β was added to a mixture consisting of of 0.49 g of 3-allyl-2-(benzyloxy)-4-methoxy-N-methylbenzamide, 14 ml of tert-butanol and 12 ml of water. The resulting mixture was stirred at room temperature overnight. Then to the reaction solution was added 1.88 g of sodium sulfite and the mixture was then stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate twice. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give to 0.47 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,90 (d, J=4,8 Hz, 3H), of 2.93 (DD, J=6,0, to 13.6 Hz, 1H), 3,01 (DD, J=3,0, to 13.6 Hz, 1H), 3,47 (DD, J=5,2, and 11.6 Hz, 1H)and 3.59 (DD, J=3,6, and 11.6 Hz, 1H), 3,91 (s, 3H), 3,94-4,00 (m, 1H), 484 (d, J=a 10.6 Hz, 1H), 4,89 (d, J=a 10.6 Hz, 1H), 6,83 (d, J=8,8 Hz, 1H), 7,39-7,47 (m, 5H), 8,01 (d, J=8,8 Hz, 1H).

(10)1-{1-[2-(2-(Benzyloxy)-6-methoxy-3-((methylamine)carbonyl)phenyl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

of 0.47 g of 2-Benzyloxy-3-(2,3-dihydroxypropyl)-4-methoxy-N-methylbenzamide was dissolved in 6 ml of tetrahydrofuran, 6 ml of methanol and 4 ml of water. Then, to the obtained solution was added 0,57 g metaperiodate sodium and the mixture was vigorously stirred. After confirming the disappearance of the starting material, was added to the reaction solution, water and ethyl acetate to separate an organic layer. The aqueous layer was extracted with ethyl acetate and combined with the above organic layer. The combined layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to get 0,49 g of the crude aldehyde.

0.27 g of 1-(piperidine-4-yl)-1H-indole-6-carboxamide was dissolved in 20 ml of dichloromethane. Then, to the obtained reaction solution was sequentially added 0,49 g of the above crude aldehyde and 129 μl of acetic acid. The mixture then was stirred for 20 minutes. Then to the reaction solution was added 0.36 g of triacetoxyborohydride sodium and the resulting mixture was stirred at ControlTemplate during the night. Then to the reaction solution was added 10% aqueous sodium carbonate solution and chloroform to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH silica gel (ethyl acetate/methanol) to obtain the 0,49 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,04-2,52 (m, 4H), 2,25 is 2.51 (m, 2H), 2,60-of 2.64 (m, 2H), 2,87 (d, J=4,8 Hz, 3H), 2,97-to 2.99 (m, 2H), 3,18 (userd, 2H), 3,90 (s, 3H), 4,35 was 4.42 (m, 1H), 4,88 (s, 2H), 5,59 (users, 1H), 6,15 (users, 1H), 6,57 return of 6.58 (m, 1H), 6,80 (d, J=8,8 Hz, 1H), 7,30-7,46 (m, 7H), 7,56 (userd, 1H), 7,65 (d, J=8,4 Hz, 1H), to 7.99 (d, J=8,8 Hz, 1H), 8,12 (s, 1H).

(11)1-{1-[2-(2-Hydroxy-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

15 ml of methanol and 10 ml of tetrahydrofuran was added to 486 mg of 1-(1-(2-(2-(benzyloxy)-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide for its dissolution. Then, to the obtained solution was added 74 mg of 10% Pd-C (containing water) and the resulting mixture was stirred at room temperature in hydrogen atmosphere overnight. Then, Pd-C was removed by filtration and was removed under reduced pressure, the solvent to obtain 408 mg of the desired compound.

1H-YAM who (DMSO-d 6) δ (ppm): 1,94-of 2.08 (m, 4H), 2,23-of 2.30 (m, 2H), 2,43-2,47 (m, 2H), was 2.76 is 2.80 (m, 5H), 3,12 (userd, 2H), 3,83 (s, 3H), of 4.38-to 4.46 (m, 1H), of 6.49 (d, J=2,8 Hz, 1H), 6,56 (userd, 1H), 7,20 (s, 1H), 7,53-7,58 (m, 2H), 7,66-of 7.69 (m, 2H), of 7.90 (s, 1H), 8,11 (s, 1H), 8,17 (users, 1H).

(12)1-{1-[2-(7-Methoxy-3-methyl-2,4-dioxo-3,4-dihydro-2H-1,3-benzoxazin-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

30 ml of anhydrous tetrahydrofuran was added to 408 mg of 1-(1-(2-(2-hydroxy-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl)piperidine-4-yl)-1H-indole-6-carboxamide. Then to the mixture was added 294 mg of 1,1'-carbonyldiimidazole. The resulting mixture was then heated at the boil under reflux in nitrogen atmosphere for 5 minutes. Then to the reaction solution was added 5 ml of N,N-dimethylformamide and the resulting mixture was heated at the boil under reflux in nitrogen atmosphere for 45 minutes. The reaction solution was cooled to room temperature, then was removed under reduced pressure the solvent. Then to the residue was added 294 mg of 1,1'-carbonyldiimidazole. The reaction mixture was heated at the boil under reflux in nitrogen atmosphere for 30 minutes. The reaction solution was cooled to room temperature and was then removed under reduced pressure the solvent. To the residue was added water and collected by filtration the precipitate. The precipitate was washed with diethyl ether. After that it suspendido the Ali in ethanol was removed under reduced pressure the solvent. To the residue was added ethyl acetate, after which the solution was filtered with getting 451 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,94-2,07 (m, 4H), 2,25 is 2.33 (m, 2H), 2,50 is 2.55 (m, 2H), 2,89 of 2.92 (m, 2H), 3,14 (userd, 2H), 3.27 to (s, 3H), of 3.96 (s, 3H), 4,39-4,47 (m, 1H), 6,50 (d, J=3,4 Hz, 1H), 7,14 (d, J=8,8 Hz, 1H), 7,21 (s, 1H), 7,54-of 7.60 (m, 2H), 7,66 (d, J=3,4 Hz, 1H), 7,87 (d, J=8,8 Hz, 1H), to $ 7.91 (s, 1H), 8,13 (s, 1H).

Example 63

Synthesis of 1-{1-[2-(2-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)6-(Allyloxy)-3,4-dihydronaphthalene-1(2H)-he

3,30 ml allylbromide was added to a mixture consisting of 5,62 g of 6-hydroxy-3,4-dihydroxynaphthalene-1(2H)-is it at 5.27 g of potassium carbonate and 60 ml of acetone. The resulting mixture was heated at boiling under reflux in a nitrogen atmosphere over night. The reaction solution was cooled to room temperature and the precipitate was removed by filtration. Was removed under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain 6,35 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,08-of 2.15 (m, 2H), 2,59-2,62 (m, 2H), 2,92 (t, J=6.0 Hz, 2H), 4,58-4,60 (m, 2H), and 5.30-of 5.34 (m, 1H), 5.40 to-the 5.45 (m, 1H), 6,00-6,10 (m, 1H), 6,72 (d, J=2.6 Hz, 1H), at 6.84 (DD, J=2,4, 8,8 Hz, 1H), of 8.00 (d, J=8,8 Hz, 1H).

(2)5-Allyl-6-hydroxy-3,4-dihydronaphthalene-1(2H)-he

1.13 g of 6-(Allyloxy)-3,4-dihydronaphthalene-1(2H)-it was dissolved in 8 ml of N,N-d is methylaniline. The resulting mixture was heated at the boil under reflux in nitrogen atmosphere for 5 hours. Similarly, a total of 5.21 g of 6-(allyloxy)-3,4-dihydronaphthalene-1(2H)-it was dissolved in 40 ml of N,N-dimethylaniline and the mixture was heated at the boil under reflux in nitrogen atmosphere for 7 hours. The resulting reaction solution was cooled to room temperature. Two reaction solution was mixed, then added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed 5 N. chloroethanol acid, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate and tert-butyl methyl ether, after which the solution was filtered with getting to 3.52 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,07-and 2.14 (m, 2H), 2.57 m-2,61 (m, 2H), 2,89 (t, J=6.0 Hz, 2H), 3,45-3,47 (m, 2H), equal to 4.97-5,02 (m, 1H), 5,07-5,11 (m, 1H), 5,65 (s, 1H), 5,91-6,01 (m, 1H), 6,78 (d, J=8,8 Hz, 1H), 7,95 (d, J=8,8 Hz, 1H).

(3)5-Allyl-6-methoxy-3,4-dihydronaphthalene-1(2H)-he

901 µl under the conditions added to the mixture, composed of 1.46 g of 5-allyl-6-hydroxy-3,4-dihydronaphthalene-1(2H)-it 1.20 g of potassium carbonate and 15 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature at which osphere nitrogen during the night. Then to the reaction solution were added water and ethyl acetate to separate an organic layer. The obtained organic layer was washed with water (5 times) and a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 1.51 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): to 2.06 and 2.13 (m, 2H), 2.57 m-2,61 (m, 2H), 2,89 (t, J=6.0 Hz, 2H), 3.43 points-of 3.46 (m, 2H), 3,88 (s, 3H), 4,87-is 4.93 (m, 1H), equal to 4.97-5,00 (m, 1H), 5,85-5,94 (m, 1H), 6,86 (d, J=8,8 Hz, 1H), 8,03 (d, J=8,8 Hz, 1H).

(4)5-(2,3-Dihydroxypropyl)-6-methoxy-3,4-dihydronaphthalene-1(2H)-he

Mixed of 6.99 g of AD-mix-β, 15 ml of tert-butanol and 20 ml of water. 1.51 g of 5-allyl-6-methoxy-3,4-dihydronaphthalene-1(2H)-it was dissolved in 14 ml of tert-butanol and the resulting solution was added to the mixture obtained before. The resulting mixture was then stirred at room temperature overnight. After this was added to the mixture scored 8.38 g of sodium sulfite and the mixture was stirred for approximately 1 hour, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer conc who was narrowly under reduced pressure. To the residue was added ethyl acetate and hexane, after which the solution was filtered to obtain 1.51 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,09-of 2.15 (m, 2H), 2,59-2,62 (m, 2H), 2.91 in was 3.05 (m, 4H), 3,52 (DD, J=6,0, 11.2 Hz, 1H), 3,66 (DD, J=3,4, 11.2 Hz, 1H), 3,89-of 3.97 (m, 1H), 3,92 (s, 3H), to 6.88 (d, J=8,8 Hz, 1H), of 8.06 (d, J=8,8 Hz, 1H).

(5)1-{1-[2-(2-Methoxy-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

of 0.13 g of 5-(2,3-Dihydroxypropyl)-6-methoxy-3,4-dihydronaphthalene-1(2H)-it was dissolved in a mixed solution consisting of 2 ml of tetrahydrofuran, 2 ml of methanol and 1.3 ml of water. Then, to the obtained solution were added 224 mg metaperiodate sodium and the resulting mixture was vigorously stirred for 30 minutes. After confirming the disappearance of the starting material, was added to the reaction solution, water and ethyl acetate to separate an organic layer. The aqueous layer was extracted with ethyl acetate and the resulting aqueous layer was mixed with the above organic layer. The combined layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 129 mg of the crude aldehyde.

105 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide was dissolved in 4 ml of dichloromethane. Then to the reaction solution were added a sequence is correctly 129 mg of the indicated crude aldehyde, 49.4 μl of acetic acid and the resulting mixture was stirred for 15 minutes. After that 137 mg triacetoxyborohydride sodium was added to the reaction solution and the resulting mixture was stirred at room temperature overnight. Then to the reaction solution was added 10% aqueous sodium carbonate solution and chloroform to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate, followed by filtration. The organic layer was concentrated under reduced pressure and dried. To the residue was added ethyl acetate and tert-butyl methyl ether, after which the solution was filtered to obtain 142 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,05-of 2.16 (m, 6H), 2,32 (users, 2H), 2,50 is 2.55 (m, 2H), 2,60 2.63 in (m, 2H), 2,92 are 2.98 (m, 4H), 2,25 (userd, 2H), 3,91 (s, 3H), of 4.38 is 4.45 (m, 1H), 5,62 (users, 1H), 6,17 (users, 1H), 6,58-6,59 (m, 1H), 6,86 (d, J=8,8 Hz, 1H), 7,39-the 7.43 (m, 2H), 7,65 (d, J=8.0 Hz, 1H), 8,04 (d, J=8,8 Hz, 1H), 8,13 (s, 1H).

Example 64

Synthesis of 1-{1-[2-(2-methoxy-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

(1)6-Methoxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-he

A mixture consisting of 7,12 g of tert-butoxide potassium, 20 ml of tert-butanol and 50 ml of toluene, cooled on ice and then stirred in a nitrogen atmosphere. To this mixture was added 5,02 g of 6-hydroxy-2,2-dimethyl-3,4-dinately-1(2H)-she RA is solved in 100 ml of toluene. Ten minutes to the reaction solution was added to 3.99 ml under the conditions and the resulting mixture was stirred at room temperature overnight. Then to the reaction solution were added water and ethyl acetate to separate an organic layer. The resulting organic layer was sequentially washed with water (5 times), 10% aqueous sodium carbonate solution and a saturated solution of sodium chloride. The resulting product was then dried over anhydrous sodium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain of 3.69 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): to 1.21 (s, 6H), to 1.96 (t, J=6.4 Hz, 2H), 2,95 (d, J=6,4 Hz, 2H), 3,85 (s, 3H), 6,66 is 6.67 (m, 1H), 6,83 (DD, J=2,8, 8,8 Hz, 1H), 8,02 (d, J=8,8 Hz, 1H).

(2)6-Hydroxy-3,4-dihydronaphthalene-1(2H)-he

of 3.69 g of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-it was dissolved in 70 ml of anhydrous methylene chloride. The resulting solution was cooled in a bath of dry ice and acetone. Then to the solution was added 36 ml of tribromide boron (1,0 M methylenechloride solution) and the resulting mixture was stirred at room temperature overnight. Then the reaction solution was again cooled in a bath of dry ice and acetone. Was added to a solution of 36 ml of tribromide boron (1,0 M methylenchlorid the hydrated solution) and the resulting mixture was stirred at room temperature overnight. After that, the reaction solution was poured on ice and then added to it the chloroform. Was removed by filtration of the insoluble residue. The organic layer was separated and then dried over anhydrous sodium sulfate. The resulting solution was passed through a glass filter filled with silica gel, and was removed at reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to give 1.52 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,20 (s, 6H), 1,94-of 1.97 (m, 2H), 2,92 (t, J=6.4 Hz, 2H), to 5.57 (s, 1H), 6,62-6,63 (m, 1H), 6,74 (DD, J=2,8, and 8.4 Hz, 1H), of 7.97 (d, J=8,4 Hz, 1H).

(3)6-(Allyloxy)-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-he

830 μl of allylbromide was added to a mixture of 1.52 g of 6-hydroxy-3,4-dihydronaphthalene-1(2H)-she, 1.22 g of potassium carbonate and 15 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. To the reaction solution were added water and ethyl acetate to obtain an organic layer. The resulting organic layer was sequentially washed with water (4 times) and a saturated solution of sodium chloride and then dried over anhydrous sodium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 1,69 Griboedova connection.

1H-NMR (CDCl3) δ (ppm): 1,20 (s, 6H), to 1.96 (t, J=6.4 Hz, 2H), equal to 2.94 (t, J=6.4 Hz, 2H), 4,58-4,60 (m, 2H), and 5.30-5,33 (m, 1H), 5.40 to-the 5.45 (m, 1H), 6,00-6,10 (m, 1H), of 6.68 (d, J=2.4 Hz, 1H), at 6.84 (DD, J=2,4, and 8.4 Hz, 1H), 8,01 (d, J=8,4 Hz, 1H).

(4)5-Allyl-6-hydroxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-he

1,69 g of 6-(allyloxy)-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-it was dissolved in 10 ml of N,N-dimethylaniline and the mixture was boiled under reflux in nitrogen atmosphere for 7 hours. The reaction solution was cooled to room temperature. To the reaction solution were added water and ethyl acetate to obtain an organic layer. The obtained organic layer is successively washed with 5 N. chloroethanol acid (3 times), water (4 times) and a saturated solution of sodium chloride. The resulting product was then dried over anhydrous sodium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. To the residue was added hexane, and then collected by filtration the precipitate to obtain 1.06 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,19 (s, 6H), 1,95 (t, J=6.4 Hz, 2H), 2,89 (t, J=6.4 Hz, 2H), 3,44-3,47 (m, 2H), equal to 4.97-to 5.03 (m, 1H), 5,07-5,10 (m, 1H), of 5.92-6,01 (m, 1H), 6, 78 (d, J=8.6 Hz, 1H), 7,94 (d, J=8.6 Hz, 1H).

(5)5-Allyl-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-he

575 μl under the conditions added to a mixture of 1.06 g of 5-allyl-6-hydroxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-it, 0,77g of potassium carbonate and 10 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. To the reaction solution were added water and ethyl acetate to obtain an organic layer. The obtained organic layer was washed with water (5 times) and a saturated solution of sodium chloride and then dried over anhydrous sodium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate) to obtain the 1,09 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,19 (s, 6H), was 1.94 (t, J=6.4 Hz, 2H), 2,89 (t, J=6.4 Hz, 2H), 3,42 is-3.45 (m, 2H), 3,88 (s, 3H), 4,87-is 4.93 (m, 1H), 4,96-5,00 (m, 1H), 5,85-5,95 (m, 1H), 6.87 in (d, J=9.0 Hz, 1H), 8,03 (d, J=9,0 Hz, 1H).

(6)5-(2,3-Dihydroxypropyl)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-he

4,47 g of AD-mix-β was added to a mixture consisting of of 1.09 g of 5-allyl-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-she, 17 ml of tert-butanol and 17 ml of water. The resulting mixture was stirred at room temperature overnight. Then to the reaction solution was added lower than the 5.37 g of sodium sulfite and the mixture was stirred for 35 minutes, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous sodium sulfate. After removal by filtration Assicurazioni the solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate/methanol) to obtain 1.25 g of the desired compound.

1H-NMR (CDCl3) δ (ppm): 1,19 (s, 3H), 1,19 (s, 3H), of 1.97 (t, J=6,7 Hz, 2H), 2,14 (users, 1H), 2,37 (users, 1H), 2,90 was 3.05 (m, 4H), 3,51-3,55 (m, 1H), 3,65 at 3.69 (m, 1H), 3,89-of 3.96 (m, 1H), 3,91 (s, 3H), 6.89 in (d, J=8,8 Hz, 1H), with 8.05 (d, J=8,8 Hz, 1H).

(7)1-{1-[2-(2-Methoxy-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide

of 0.13 g of 5-(2,3-Dihydroxypropyl)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalene-1(2H)-it was dissolved in a mixed solution consisting of 2 ml of tetrahydrofuran, 2 ml of methanol and 1.3 ml of water. Then, to the obtained solution was added 197 mg metaperiodate sodium and the resulting mixture was vigorously stirred for 30 minutes. After confirming the disappearance of the starting material, was added to the reaction solution, water and ethyl acetate to separate an organic layer. The aqueous layer was extracted with ethyl acetate and the resulting aqueous layer was mixed with the above organic layer. The resulting layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure to obtain 117 mg of the crude aldehyde.

93 mg of 1-(piperidine-4-yl)-1H-indole-6-carboxamide was dissolved in 4 ml of dichloromethane. Then p is a promotional solution was added sequentially 117 mg of the above crude aldehyde and 43.8 μl of acetic acid and the resulting mixture then was stirred for 10 minutes. Then to the reaction solution was added 122 mg triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature for 50 minutes. Then to the reaction solution was added 10% aqueous sodium carbonate solution and chloroform to separate the organic layer. The obtained organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration the organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate and tert-butyl methyl ether, after which the solution was filtered to obtain 153 mg of the desired compound.

1H-NMR (DMSO-d6) δ (ppm): 1,11 (s, 6H), 1,92-of 2.08 (m, 6H), 2,29 is 2.33 (m, 2H), 2,43-2,47 (m, 2H), 2,83-2,87 (m, 2H), 2,94-of 2.97 (m, 2H), 3,14 (userd, 2H), 3,88 (s, 3H), 4,39-4,47 (m, 1H), 6,51 (d, J=2,8 Hz, 1H), 7,03 (d, J=8,8 Hz, 1H), 7,22 (s, 1H), 7,55-to 7.61 (m, 2H), to 7.67 (d, J=3.6 Hz, 1H), to 7.84 (d, J=8,8 Hz, 1H), 7,92 (s, 1H), 8,13 (s, 1H).

Example 65

Synthesis of {1-[1-(3,4-dihydro-7-methoxy-1(2H)-naphtalene-8-yl)ethylpiperidine-4-yl]-(1H)-indol-6-yl}carboxamide

(1)3,4-Dihydro-7-methoxy-8-(2-propenyl)-1(2H)-naphtalene

160 mg of 3,4-dihydro-7-hydroxy-8-(2-propenyl)-1(2H)-naftalina (CAS No. 122076-30-6), 140 mg of iodomethane and 400 mg of potassium carbonate was dissolved in 15 ml of acetone. The reaction solution is then stirred at 70°C for 1.5 hours. The mixture was filter and then washed with acetone. Next, the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with getting out of the eluate ethyl acetate-hexane (1:10) 140 mg of the desired compound.

1H-NMR (CDCl3) δ (ppm): 2,05 (DDD, J=6,0, 6,4, 7.2 Hz, 2H), 2.63 in (DD, J=6,4, 7.2 Hz, 2H), 2,88 (DD, J=6,0, 6.4 Hz, 2H), 3,83 (s, 3H), 3,85-3,88 (m, 2H), 4,91-of 5.05 (m, 2H), 5,97-between 6.08 (m, 1H), 7,01 (d, J=8,4 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H).

(2){1-[1-(3,4-Dihydro-7-methoxy-1(2H)-naphtalene-8-yl)ethylpiperidine-4-yl]-(1H)-indol-6-yl}carboxamide

130 mg of 3,4-Dihydro-7-methoxy-8-(2-propenyl)-1(2H)-naftalina was dissolved in 6 ml of tetrahydrofuran and 3 ml of water. Then to the resulting solution were added at room temperature with 0.2 ml of a 3.3% aqueous solution of osmium tetroxide, and then the resulting mixture was stirred for 15 minutes. Then to the mixture was added 600 mg of sodium perchlorate and the resulting mixture was stirred at room temperature for 4 hours. The mixture was distributed between ethyl acetate and water and an ethyl acetate layer was separated. An ethyl acetate layer was washed with 5% sodium thiosulfate solution, water and saturated sodium chloride solution. The resulting product was then dried over magnesium sulfate. The mixture was filtered and the organic layer was concentrated under reduced pressure. The residue was passed through a short column with silica gel to obtain 110 mg of the corresponding crude aldehyde is on the product.

A mixture of 110 mg of the obtained aldehyde, 90 mg of 1-(piperidine-4-yl-1H-indol-6-yl)carboxamide and 100 mg of acetic acid, was dissolved in 5 ml of tetrahydrofuran and the resulting mixture was then stirred at room temperature for 15 minutes. Then to the reaction solution was added 200 mg of triacetoxyborohydride sodium and the resulting mixture was stirred for 1.5 hours. Then to the reaction solution was added 10% potassium carbonate solution, followed by extraction with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride and then dried over magnesium sulfate, followed by filtration. Then the layer was concentrated under reduced pressure. The residue was purified flash chromatography on silica gel with getting out of the eluate methylene chloride-methanol (10:1) 38 mg of the desired compound as a pale yellow solid.

1H-NMR (CDCl3) δ (ppm): 2,10-of 2.26 (m, 6H), 2,41-to 2.57 (m, 2H), 2.63 in (DD, J=6,4, 7.2 Hz, 2H), 2,62-2,78 (m, 2H), 2,85 (DD, J=6,0, 6.4 Hz, 2H), 3,28-3,44 (m, 4H), 3,83 (s, 3H), 4,36-to 4.46 (m, 1H), to 6.57 (d, J=3.6 Hz, 1H), 7,01 (d, J=8,4 Hz, 1H), 7,12 (d, J=8,4 Hz, 1H), 7,41 (d, J=3.6 Hz, 1H), 7,46 (DD, J=1,2, 8,8 Hz, 1H), to 7.64 (d, J=8,8 Hz, 1H), 8,11 (users, 1H).

Example 66

Synthesis fumarata 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-exogamy-8 and the)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (1,00 g) and fumaric acid (0,249 g) was dissolved in a mixed solvent, consisting of acetone (5 ml) and water (15 ml) at 60°C. the resulting mixture was left at room temperature for 1 hour. Precipitated precipitated solid substance was collected by filtration, and the obtained product is then washed with a mixed solvent consisting of acetone (2.5 ml) and water (7.5 ml), to obtain the desired compound (1,09 g).

1H-NMR (DMSO-d6) δ (ppm): 1,40 (s, 6H), 1,94-2,11 (m, 4H), 2,27-is 2.37 (m, 2H), 2,45-of 2.56 (m, 2H), 2,72 (s, 2H), 2,75-2,84 (m, 5H), 3,12-3,20 (m, 2H), a 3.87 (s, 3H), of 4.38-4,47 (m, 1H), 6.48 in-6,51 (m, 1H), 6,60 (s, 1,5H), to 6.75 (d, J=9.6 Hz, 1H), 7,50-7,58 (m, 2H), 7,63-to 7.67 (m, 2H), 8,05 (users, 1H), 8,29-8,35 (m, 1H).

Example 67

Synthesis of L-(+)-tartrate 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (100 mg) was dissolved in a mixed solvent consisting of tetrahydrofuran (1 ml) and diethyl ether (25 ml). Then to the reaction solution was added a mixed solvent consisting of tetrahydrofuran (1 ml) and diethyl ether (25 ml)containing L-(+)-tartaric acid (31 mg)at room temperature. Precipitated precipitated solid substance was collected by filtration, and the obtained product is then washed with diethyl ether to obtain the desired compound (110 mg).

1H-NMR (DMSO-d6) δ (ppm): 1,40 (s, 6H), 1,97 with 2.14 (m, 4H), 2,40-2,60 (m, 4H), of 2.72 (s, 2H), 2,78-2,84 (m, 5H), 3,20-3,30 (m, 2H), a 3.87 (s, 3H), 4,20 (s, 2H), 4,43-a 4.53 (m, 1H), 6,50 (d, J=3.2 Hz, 1H), 6.75 in (d, J=8,4 Hz, 1H), 7,50-7,58 (m, 2H), 7,63-to 7.67 (m, 2H), 8,05 (users, 1H), 8,28-to 8.34 (m, 1H).

Example 68

Synthesis maleate of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (105 mg) was dissolved in tetrahydrofuran (10 ml). Then to the reaction solution was added tertrahydrofuran ring solution (10 ml)containing maleic acid (25 mg)at room temperature. Then to the mixture was added at room temperature, tert-butyl methyl ether and the resulting mixture was concentrated under reduced pressure. To the residue for solidification was added diethyl ether. The resulting suspension was stirred for 10 minutes while cooling on ice, after which the solid was collected by filtration. The solid is washed with diethyl ether to obtain the desired compound (117 mg).

1H-NMR (DMSO-d6) δ (ppm): the 1.44 (s, 6H), 2,17 of-2.32 (m, 4H), 2,45 is 2.55 (m, 4H), was 2.76 (s, 2H), and 2.83 (d, J=7.2 Hz, 3H), 2,94 was 3.05 (m, 2H), 3.25 to 3.40 in (m, 2H), 3,91 (s, 3H), 4,74-is 4.85 (m, 1H), 6,02 (s, 1,5H), 6,54-6,59 (m, 1H), PC 6.82 (d, J=8.0 Hz, 1H), 7,50 to 7.62 (m, 3H), 7,73 (d, J=8.0 Hz, 1H), of 8.09 (s, 1H), 8,28-8,35 (m, 1H).

Example 69

Synthesis fumarata 1-{1-[2-(7-m the toxi-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide

Fumarate of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (2,05 g) was dissolved in a mixed solvent consisting of n-propanol (6 ml) and water (18 ml)at 60°C. thereafter, the reaction solution was kept at room temperature and then at 0°C. Precipitated precipitated crystals were collected by filtration. The collected crystals were dried at room temperature under reduced pressure for 30 minutes to obtain the desired compound (2,02 g).

Example 70

Synthesis fumarata 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (crystals A-type)

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (1,00 g) and fumaric acid (0,249 g) was dissolved in a mixed solvent consisting of acetone (5 ml) and water (15 ml)at 60°C. thereafter, the reaction solution was kept at room temperature for 1 hour. Precipitated precipitated solid substance was collected by filtration. The collected crystals were washed mixed solvent consisting of acetone (2.5 ml) and water (7.5 ml), to obtain the desired compound (1,09 g).

[X-ray powder diffractometry crystals a-type]

Crystals (crystal form A), obtained as described above crystallization, crushed in agate the new mortar. The obtained sample was placed on the table of the x-ray powder diffractometer and perform the analysis under the following conditions (1).

The measurement conditions

Table 8
The sample holderGlass or copper
TargetCopper
DetectorScintillation counter
The voltage on the tube40 kV
Current tube200 mA
The slitDSI/2°, RS 0.3 mm, SSI/2°
The scanning speed2°/min
The sampling interval0,02°
The scan interval5° to 40°
The goniometerVertical goniometer

Example 71

Synthesis fumarata 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (crystal B-type)

Fumarate of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (2,05 g) was dissolved in a mixed solvent consisting of n-propanol (6 ml) and water (18 ml)at 60°C. thereafter, the reaction solution was kept at room temperature and then at 0°C. Dropped the precipitated crystals was collected by filtration. The collected crystals were dried at room temperature under reduced pressure for 30 minutes to obtain the desired compound (2,02 g).

[X-ray powder diffractometry crystals of b-type]

Crystals (crystalline form), obtained as described above crystallization, were crushed in an agate mortar. The obtained sample was placed on the table of the x-ray powder diffractometer and perform the analysis under the following conditions (figure 2).

The measurement conditions

Table 9
The sample holderGlass or copper
TargetCopper
DetectorScintillation counter
The voltage on the tube40 kV
Current tube200 mA
The slitDSI/2°, RS 0.3 mm, SSI/2°
The scanning speed2°/min
The sampling interval0,01°
The scan interval5° to 40°
The goniometerVertical goniometer

Example 72

Synthesis fumarata 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-CT is oksamida (crystalline form C)

Fumarate of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (100 mg) was weighed and placed in a round bottom flask. Connection once was dissolved in a mixed solvent consisting of water (1 ml) and methanol (0.6 ml), while heating. The reaction solution is then kept at room temperature. Precipitated precipitated crystals were collected by filtration. The collected crystals were dried at 60°C to obtain the desired compound (68 mg).

[X-ray powder diffractometry crystals With a-type]

Crystals (crystals With a-type), obtained as described above crystallization, were crushed in an agate mortar. The obtained sample was placed on the table of the x-ray powder diffractometer and perform the analysis under the following conditions (figure 3).

The measurement conditions

Table 10
The sample holderGlass or copper
TargetCopper
DetectorScintillation counter
The voltage on the tube40 kV
Current tube200 mA
The slitDSI/2°, RS 0.3 mm, SSI/2°
The scanning speed° /min
The sampling interval0,01°
The scan interval5° to 40°
The goniometerVertical goniometer

Example 73

Synthesis fumarata 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (crystals of D-type)

Fumarate of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide (100 mg) was weighed and placed in a round bottom flask. Connection once was dissolved in 2-propanol (1 ml) under heating. The reaction solution is then kept at room temperature. Precipitated precipitated crystals were collected by filtration. The collected crystals were dried at 60°C to obtain the desired compound (80 mg).

[X-ray powder diffraction of crystals of D-type]

Crystals (crystals of D-type), obtained as described above crystallization, were crushed in an agate mortar. The obtained sample was placed on the table of the x-ray powder diffractometer and perform the analysis under the following conditions (figure 4).

The measurement conditions

Table 11
The sample holderGlass or copper
TargetHoney is
DetectorScintillation counter
The voltage on the tube40 kV
Current tube200 mA
The slitDSI/2°, RS 0.3 mm, SSI/2°
The scanning speed2°/min
The sampling interval0,01°
The scan interval5° to 40°
The goniometerVertical goniometer

Examples of the manufacture of dosage forms

Below are examples of the manufacture of dosage forms comprising compounds of the present invention. But the examples do not limit the manufacture of dosage forms of the compounds of the present invention.

Example 1 manufacture of dosage forms

The compound of example 2045 (parts)
High viscosity magnesium oxide15
Lactose75

The above compounds are thoroughly mixed to obtain a powder or powder consisting of fine granules with a size of 350 μm or less. Powder was placed in a sealed container, receiving the capsule.

Example 2 production of Les is arctonyx forms

The compound of example 24 (1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide)45 (parts)
Starch15
Lactose16
Crystalline cellulose21
Polyvinyl alcohol : 3
Distilled water30

The above compounds are thoroughly mixed. The resulting mixture was granulated by grinding and then drying. After that, the obtained product was separated by sieving to obtain granules ranging in size from 1410 to 177 μm.

Example 3 manufacture of dosage forms

Got granules by the method similar to that described in example 2 production. Then to 96 parts of the obtained granules were added 4 parts of calcium stearate, and then carried out molding by pressing obtaining tablets with a diameter of 10 mm

Example 4 manufacture of dosage forms

To 90 parts of the granules obtained by the method similar to that described in example 2 production, was added 10 parts of crystalline cellulose and 3 parts of calcium stearate. The resulting mixture was subjected to molding by pressing obtaining tablets with a diameter of 8 mm, then on tablets nano is or suspension, containing glutinously syrup and precipitated calcium carbonate, to obtain tablets with a sugar coating.

Example 5 manufacture of dosage forms

The compound of example 22 (1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide)0.6 parts
Nonionic surfactant2,4
Saline97

These components were mixed while heating and the resulting mixture was then placed in a vial. Then it was sterilized with getting the dosage form for injection.

Example 6 manufacture of dosage forms

Mixed compound of example 20 (1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide), lactose, corn starch and nitrosamino hydroxypropylcellulose. Then, using hydroxypropylcellulose dissolved in a suitable amount of distilled water, was carried out by wet granulation. Resulting granulated product was dried and then classified. Then, to the obtained granules were added nitrosamino hydroxypropylcellulose and magnesium stearate, and these components are then mixed to follow what they manufacture tablets. The resulting tablets were coated with an aqueous solution containing base coating (Opadry yellow). The number of materials per tablet shown in the table below.

Table 12
The material used1 mg tablet10 mg tablet60 mg tablet
Connection 1 according to the present invention1 mg10 mg60 mg
Lactose122 mg113 mg63 mg
Corn starch20 mg20 mg20 mg
Nizkozameshhennoj hydroxypropylcellulose20 mg20 mg20 mg
Hydroxypropylcellulose6 mg6 mg6 mg
Distilled wateran appropriate numberan appropriate numberan appropriate number
Nizkozameshhennoj hydroxypropylcellulose10 mg10 mg10 mg
Crystalline cellulose20 mg20 mg20 mg
Magnesium stearate1 mg1 mg1 mg
Yellow Opadry (note)8 mg8 mg8 mg
Total208 mg208 mg208 mg

(Note) a Pre-mixed material formed by mixing 56% hydroxypropylmethylcellulose 2910, 28% talc, 10% of Macrogol 6000, 4% of titanium oxide and 2% yellow half iron oxide.

Industrial applicability

The compound of the present invention represented by the General formula (I), has the effect of binding to 5-HT1A receptor, as well as antagonistic effect against the specified receptor. Therefore, it is applicable as a means for the treatment or prevention of symptoms of the lower urinary tract and, in particular, fast urination, urinary incontinence or the like.

Brief description of drawings

[1] - x ray powder crystal type As obtained in example 70. The horizontal axis shows the angle of diffraction (2θ), and the vertical axis maximum strength;

[2] - x ray powder crystal type, obtained in example 71. The horizontal axis shows the angle of diffraction (2θ), and the vertical axis maximum strength;

[3] - x ray powder crystal of the type obtained in example 71. On the horizontal axis pokazanova diffraction (2θ ), and the vertical axis is the maximum strength;

[4] powder x-ray crystal type D obtained in example 72. The horizontal axis shows the angle of diffraction (2θ), and the vertical axis is the maximum strength.

1. The compound represented by the following formula (I)or its pharmacologically acceptable salt

where R1and R2represent substituents adjacent to each other, and together with the two carbon atoms to each of which they are attached, form a group represented by the following formula:

1),or

2),,,,,,,,or

3)or

4),,or

where a hydrogen atom in each cyclic group can be substituted by 1-4 substituents, selected the data from the following group of substituents B1,

R3represents a hydrogen atom or methyl group; and

R6is a Deputy selected from the following group A1 deputies,

group A1 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

the group V1 of substituents: (1) hydrogen atom, (2) hydroxyl group, (3) oxoprop, (4) C1-C6 alcoolica group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where specified C1-C6 alkyl group may be substituted by C1-C6 alkoxygroup), (7) C1-C6 alkoxygroup, (8) C1-C6 alkoxyimino, (9) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same and the same carbon atom, and (10) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the carbon atom.

2. The compound according to claim 1 or its pharmacologically acceptable salt, where R1and R2represent substituents adjacent to each other, and together with the two carbon atoms to each of which they are attached, form a group represented by the following formula:

1),or

2), ,,,,,,,or

3)or

4),,or

where a hydrogen atom in each cyclic group can be substituted by 1-4 substituents, selected from the following group of substituents B1, the group V1 of substituents: (1) hydrogen atom, (2) hydroxyl group, (3) oxoprop, (4) C1-C6 alcoolica group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where specified C1-C6 alkyl group may be substituted by C1-C6 alkoxygroup), (7) C1-C6 alkoxygroup, (8) C1-C6 alkoxyimino, (9) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (10) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the carbon atom.

3. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-a-1), formula (I-is -2), formula (I-a-3) or formula (1-a-4)

where R3represents a hydrogen atom or methyl group; R4aand R5arepresent substituents selected from the following group V1 of substituents; R6is a Deputy selected from the following group A1 substituents; R11arepresents a hydroxyl group, R12arepresents a hydrogen atom or C1-C6 alkyl group, or R11aand R12arepresent a carbonyl group or a group of the formula C=N-OR8c(where R8crepresents a C1-C6 alkyl group), together with the carbon atoms to which are attached R11aand R12a; Xandrepresents a methylene group or an oxygen atom; and nandis an integer from 1 to 3,

group A1 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup; group V1 of substituents: (1) hydrogen atom, (2) hydroxyl group, (3) oxoprop, (4) C1-C6 alcoolica group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where specified C1-C6 alkyl group may be substituted by C1-C6 alkoxygroup), (7) C1-C6 alkoxygroup, (8) C1-C6 alkoxyimino, (9) C5-C6 cycloalkyl group, the way the bathroom two C1-C3 alkyl groups, attached to the same carbon atom, and (10) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the carbon atom.

4. The compound according to claim 3 or its pharmacologically acceptable salt, where R11aand R12aform a carbonyl group together with the carbon atoms to which R11aand R12aattached.

5. The compound according to claim 3 or 4, or its pharmacologically acceptable salt, where R4aand R5arepresent substituents selected from the following group B2 substituents, and R6is a Deputy selected from the following group A2 deputies, group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B2 deputies: (1) hydrogen atom, (2) hydroxyl group, (3) C1-C6 alkyl group, (4) C1-C6 alkoxygroup, (5), C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (6) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the above carbon atom.

6. The compound according to claim 3 or its pharmacologically acceptable salt, where R4aand R5aimagine what a Deputy, selected from the following group B5 substituents, and R6is a Deputy selected from the following group A4 deputies, group A4 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B5 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (4) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the carbon atom.

7. The compound according to claim 3 or its pharmacologically acceptable salt, where Xandrepresents an oxygen atom.

8. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-b-1), formula (I-b-2), formula (I-b-3) or formula (I-b-4)

where R4aand R5arepresent substituents selected from the following group B5 substituents, and R6is a Deputy selected from the following group A4 deputies,

group A4 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B5 substituents: (a) a hydrogen atom, (2) C1-C6 alkyl group, (3) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (4) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the carbon atom.

9. The compound according to claim 3 or its pharmacologically acceptable salt, where R11arepresents a hydroxyl group, and R12arepresents a hydrogen atom or C1-C6 alkyl group.

10. The connection according to claim 9 or its pharmacologically acceptable salt, where R4aand R5arepresent substituents selected from the following group B2 substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, (3) hydroxyl group, (4) C1-C6 alkoxygroup, (5), C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, and (6) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together with the oxygen atom and the carbon atom.

11. The connection according to claim 9 or 10, or its pharmacologically acceptable salt, where Xandrepresents an oxygen atom.

12. The compound according to claim 3 or its pharmacologically acceptable salt, where R11aand R12atogether form a group of formula =N-OR8c(where R8crepresents a C1-C6 alkyl group).

13. Connection on p. 12 or its pharmacologically acceptable salt, where R4aand R5arepresent substituents selected from the following group v3 of substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, and (3) C1-C6 alkoxygroup;

group OT deputies: (1) hydrogen atom, (2) hydroxyl group, (3) C1-C6 alkoxygroup.

14. Connection on p. 12 or 13 or its pharmacologically acceptable salt, where Xandrepresents an oxygen atom.

15. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-c-1) or formula (I-c-2)

where R3represents a hydrogen atom or methyl group and R4d, R5dand R6represent substituents selected from the following group A1 deputies,

group A1 deputies: (1) atom of the water is kind, (2) C1-C6 alkoxygroup.

16. Connection on p. 15 or its pharmacologically acceptable salt, where R4dand R5drepresent substituents selected from the following group V4 of substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B4 deputies: (1) hydrogen atom, (2) C1-C6 alkyl group, and (3) C1-C6 alkoxygroup.

17. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-d-1) or formula (I-d-2)

where R3represents a hydrogen atom or methyl group; R4eand R5erepresent substituents selected from the following group A1 substituents; R6is a Deputy selected from the following group A1 substituents; and each of Xeand Yerepresents (1) an oxygen atom, (2) methylene group, (3) -CONR7e- (where R7erepresents (1) hydrogen atom or (2) C1-C6 alkyl group), (4) -NR7eCO- (where R7eis above a certain value), (5) -NR8e- (where R8erepresents (1) C1-C6 alkyl group, or (2) C1-C6 acyl group), or (6) single bond, the group A1 deputies: (1) the atom is odorata, (2) C1-C6 alkoxygroup.

18. Connection on p. 17 or its pharmacologically acceptable salt, where R4eand R5erepresent substituents selected from the following group v3 of substituents, and R6is a Deputy selected from the following group A2 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

the group v3 of substituents: (1) hydrogen atom, (2) hydroxyl group, (3) C1-C6 alkyl group, and (4) C1-C6 alkoxygroup.

19. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-e-1) or formula (I-e-2)

where R3represents a hydrogen atom or methyl group; R6is a Deputy selected from the following group A1 substituents; R7frepresents (1) hydrogen atom, (2) C1-C6 alkyl group, (3) C3-C8 cycloalkyl group, (4) C2-C6 alkenylphenol group, (5) C2-C6 alkylamino group, or (6) C1-C6 alkoxy-C1-C6 alkyl group; and each of Xfand Yfrepresents (1) a single bond, (2) a methylene group which may have a Deputy, selected from the following group A1 substituents, or (3) a carbonyl group, group A1 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup.

20. Link is in p. 19 or its pharmacologically acceptable salt, where R6is a Deputy selected from the following group A2 substituents; R7fis a Deputy selected from the following group V4 of substituents; and each of Xfand Yfrepresents (1) a single bond, (2) a methylene group which may have a Deputy, selected from the following group V4 of substituents, or (3) a carbonyl group, group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B4 deputies: (1) hydrogen atom, (2) hydroxyl group, (3) C1-C6 alkyl group, and (4) C1-C6 alkoxygroup.

21. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-f-1), formula (I-f-2), formula (I-f-3), formula (I-f-4), formula (I-g-1), formula (I-g-2), formula (I-h-1), formula (I-h-2), formula (I-h-3) or formula (I-h-4)

where R3represents a hydrogen atom or methyl group and R6and R7gprovide the amount deputies, selected from the following group A1 substituents (but the case when R7grepresents a hydroxyl group is excluded),

group A1 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup.

22. Connection item 21 or its pharmacologically acceptable salt, where R6is a Deputy selected from the following group A2 substituents, and R7gis a Deputy selected from the following group V7 deputies,

group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B7 deputies: (1) a hydrogen atom, and (2) C1-C6 alkyl group.

23. The connection to item 21 or 22 or its pharmacologically acceptable salt, where R6is a Deputy selected from the following group A4 substituents, and R7gis a Deputy selected from the following group 6 substituents,

group A4 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

group B6 deputies: (1) a hydrogen atom, and (2) C1-C6 alkyl group.

24. The compound according to claim 1 or its pharmacologically acceptable salt, which is represented by formula (I-i-1) or formula (I-i-2)

where R3represents a hydrogen atom or methyl group and R6, R9hand R10hpresented Aut a Deputy, selected from the following group A1 substituents; and Xhand Yhrepresent (1) a methine group or (2) a nitrogen atom, a group A1 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup.

25. Connection on p. 24 or its pharmacologically acceptable salt, where R9h, R10hand R6represent substituents selected from the following group A2 substituents, and Xhand Yhrepresent (1) a methine group or (2) a nitrogen atom, group A2 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup.

26. The compound according to claim 1, selected from the following group, or its pharmacologically acceptable salt:

1) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide,

2) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

3) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

4) 1-{1-[2-(6-methoxy-3-oxonian-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

5) 1-{1-[2-(6-methoxy-2-methylbenzothiazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

6) 1-{1-[2-(6-methoxy-2-methylbenzothiazole-7-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

7) 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

8) 1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol--yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide,

9) 1-{1-[2-(5-methoxy-1-oxonian-4-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide and

10)1-{1-[2-(7-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide.

27. The compound according to claim 1, selected from the following group, or its pharmacologically acceptable salt:

1) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-N-methyl-1H-indole-6-carboxamide,

2) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-8-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide and

3) 1-{1-[2-(7-methoxy-2,2-dimethyl-4-exogamy-6-yl)ethyl]piperidine-4-yl}-1H-indole-6-carboxamide.

28. Pharmaceutical composition having inhibitory activity against serotonin 1A receptors containing as an active ingredient the compound represented by the following formula (I)or its pharmacologically acceptable salt

where R1and R2represent substituents adjacent to each other, and together with the two carbon atoms to each of which they are attached, form

1),or

2),,,, ,,,,or

3)or

4),,or

where a hydrogen atom in each cyclic group can be substituted by 1-4 substituents, selected from the following group of substituents B1,

R3represents a hydrogen atom or methyl group; and

R6is a Deputy selected from the following group A1 deputies,

group A1 deputies: (1) hydrogen atom, (2) C1-C6 alkoxygroup;

the group V1 of substituents: (1) hydrogen atom, (2) hydroxyl group, (3) oxoprop, (4) C1-C6 alcoolica group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where specified C1-C6 alkyl group may be substituted by C1-C6 alkoxygroup), (7) C1-C6 alkoxygroup, (8) C1-C6 alkoxyimino, (9) C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attached to the same and the same carbon atom, and (10) tetrahydropyranyl group formed by two C1-C3 alkyl groups attached to the same carbon atom, together the ones with the oxygen atom and the carbon atom.

29. The pharmaceutical composition according p, characterized in that it is a tool for the treatment or prevention of symptoms of the lower urinary tract.

30. The pharmaceutical composition according to clause 29, characterized in that it is a tool for the treatment or prevention of symptoms and delay urination.

31. The pharmaceutical composition according to clause 29 or 30, characterized in that it is a tool for the treatment or prevention of heart urination or urinary incontinence.

32. The pharmaceutical composition according p, characterized in that it is a tool for the treatment or prevention of a decrease in cognitive ability associated with Alzheimer's disease or senile dementia, reduced learning ability or memory disorder, or anxiety disorder.

33. The pharmaceutical composition according p, characterized in that it is a tool for the treatment or prevention of schizophrenia, emotional disorders, alcohol and/or cocaine addiction, symptoms associated with withdrawal from the ingestion of nicotine or Smoking, or disorders of visual attention.

34. The pharmaceutical composition according p, characterized in that it is a tool for the treatment or prevention of sleep disorders, migraine, temperature instability, eating disorders, vomiting, gastro-intestinal the Sam is STS or genital failure.



 

Same patents:

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) or their pharmaceutically acceptable salts wherein R1 and R2 are similar or different and chosen independently from group comprising aryl and heteroaryl. Each of them as a substitute comprises optionally from one to sic groups chosen from group comprising the following groups: (a) halogen atom; (b) -OCF3 or -OCHF2; (c) -CF3; (d) -CN; (e) alkyl; (f) R18-heteroaljyl; (k) hydroxyl; (l) alkoxyl comprising cyclopropylmethoxyl, and (s) trifluoroalkoxyl; R3 means hydrogen atom (H); R4, R5, R7 and R8 are similar or different and chosen independently from group comprising H, -OH, alkyl, heteroalkyl and

under condition that if Z and/or X means nitrogen atom (N) then all radicals R4, R5, R7 and R8 don't mean -OH; R6 means -C(O)R15; R9 and R10 mean H; R11 is chosen from group comprising H and alkyl; R12 is chosen from group comprising H and alkyl; R13 is chosen from group comprising alkyl and alkoxyl; R14 means H; R15 is chosen from group comprising -NR16R17, -OR16 and alkyl wherein R16 and R17 are similar or different and chosen independently from group comprising H and alkyl; R18 means a substitute chosen from group comprising lower alkyl, halogen alkyl, halogenalkyl, alkoxycarbonyl, dialkylamino-group and piperidinyl; X and Z are similar or different and chosen independently from carbon atom (C) and N. Proposed compounds possess properties of inhibitor of 17β-hydroxysteroid dehydrogenase of type 3. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical composition.

16 cl, 23 tbl, 651 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines represented by the formula (I): wherein n means 2, 3 or 4; R1 means hydrogen atom or alkyl with 1-4 carbon atoms; R2 means pyridyl or thiazolyl that can be substituted with alkyl with 1-4 carbon atoms, halogen atom, amino-, dimethylamino-, acetylamino-, guanidino-, pyridylamino-group, thienyl, pyridyl, morpholinyl and thiazolyl substituted if necessary with alkyl with 1-4 carbon atoms or phenyl comprising if necessary up to three substitutes as halogen atom, alkyl with 1-4 carbon atoms or alkoxy-group with 1-4 carbon atoms, and to their salts, hydrates, salt hydrates and solvates, and also to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine of the formula (I) possessing properties of agonist of A1-adenosine receptors. Also, invention describes a medicinal agent possessing properties of agonist of A1-adenosine receptors. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal and pharmacological properties of compounds and drug.

7 cl, 3 tbl, 27 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to 2-thio substituted derivatives of imidazole with formula I , where R1 represents aryl, which can be substituted by a halogen atom or halogen-C1-C6-alkyl; R2 is chosen from a group, containing a) aryl-C1-C4-alkyl, and b) C1-C6-alkyl; R3 is chosen from a group, containing (a) NR4R10, (b) NR7COR10, (c) OR10, (d) NH2; R4 represents H; R3 and R6, which can be the same or different, represent H, halogen, OH, C1-C6-alkoxy, C1-C6-alkyl or halogen-C1-C6-alkyl; R7 represents R4; R10 has one of the following values: (a) A-B, (b)-(e), (f) C1-C6-alkyl, which is substituted with 2 phenyl groups; A represents linear or branched C1-C6-alkylene; B is chosen from a group, containing (a) H, (b)-(e), (f) OC1-C6-alkyl, (g) OH; Hy represents 3-10-member non-aromatic, mono-, bi- or tricyclic carbocycle, which can be or not be condensed with a benzene ring; Ar represents 5- or 6- member aromatic heterocycle, which has 1 heteroatom, chosen from a group, consisting of O, S, and N, and which may not be condensed with a benzene ring, Het represents 5- or 6-member non-aromatic heterocycle, which has 1 heteroatom, which represents O, which may not be condensed with a benzene ring; m is 0,1 or 2; or its optical isomers or physiologically used salts. Compounds with formula I are used when making pharmaceutical compositions with inhibiting effect on release of cytokines.

EFFECT: obtaining of derivatives, which have inhibiting action to release of cytokine action.

13 cl, 4 tbl, 148 ex

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