Derivatives of nitrogen-containing heterocyclic compounds and medicinal agents based on thereof

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

 

The present invention relates to new compounds which are selective in relation to muscarinic acetylcholine receptor subtypes, as well as medicine, contributes to the activation of muscarinic receptors for the treatment or relief of diseases in which a positive is a modification of the activity of muscarinic receptors.

Muscarinic acetylcholine receptors play a leading role in the Central nervous system in higher cognitive functions, as well as in the peripheral parasympathetic nervous system. The resulting clone was found five distinct subtypes of muscarinic receptors (labeled m1-m5) (confirmed T.I. Bonner et al., Science 237, 1987, pp. 527-532; T.I. Bonner et al., Neuron 1, 1988, pp. 403-410). It was found that m1 is the predominant subtype in the cerebral cortex, and it is believed that he is involved in the regulation of cognitive functions, m2 is predominant in heart and it is believed that he is involved in the regulation of heart rhythm, in all probability, m3 involved in the stimulation of the gastrointestinal tract and urinary tract, as well as sweating and salivation, m4 is present in the brain, and m5 is in the brain, and can perform certain functions in the Central nervous system associated with doganaleescort system.

In animal experiments to study various musk rinevich ligand (confirmed S. Iversen, Life Sciences 60 (Nos. 13/14), 1997, pp. 1145-1152) it was shown that muscarinic compounds have a pronounced effect on cognitive function such as learning and memory. Based on this we can assume about the potential applicability of muscarinic agonists in improving cognitive function in diseases characterized by impaired cognitive functions, such as age-related (such as Alzheimer's disease or other dementia) and not associated with age (such as deficit hyperactive disorder attention).

Based on the presence of subtypes of muscarinic receptors in various tissues, it becomes apparent that the receptors m1-subtype is more common in the cerebral cortex, basal ganglia and the mediated, where their number is up to 35-60% of all binding sites of muscarinic receptors (confirmed by A. Levey, Proc. Natl. Acad. Sci. USA 93, 1996, pp. 13541-13546). It has been suggested that the m1-subtype (and possibly m4) plays a major role in the quality of postsynaptic muscarinic receptors (located in holinoretseptory neurons in the neocortex and mediated) in various types of cognitive and motor functions and, apparently, makes a major contribution to the response through the m1, in these parts of the brain.

Previously it was found that disease-related violation of poznavat the school functions, such as Alzheimer's disease, are accompanied by selective loss of acetylcholine in the brain. It is believed that this is the result of degeneration holinoliticheskih neurons in the basal part of the forebrain that innerviews (excite) the associative areas of the cerebral cortex and hippocampus involved in higher nervous activity (confirmed S.Iversen above). On the basis of the detected fact it is assumed that such conditions can be treated or at least to weaken drugs that enhance cholinergic function in the affected parts of the brain.

Treatment with acetylcholinesterase inhibitors (AChE), such as 9-amino-1,2,3,4-tetrahydropyridine (taken), increases acetylcholine in the brain, which indirectly causes stimulation of the muscarinic receptors. Treatment tacrine leads to moderate and temporary improvement in cognitive function in patients with Alzheimer's disease (confirmed by Kasa et al., above). On the other hand, it was found that taken has cholinergic side effects as a result of peripheral stimulation of acetylcholine. They include cramps in the abdomen, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Side effects from the gastrointestinal tract was observed in about one third of patients, which is s treated. It was also found that taken cause significant hepatotoxicity, approximately 30% of patients seen increased transaminase levels (confirmed P.Taylor, "Anticholinergic Agents", Chapter 8 in Goodman and Gilman: The Pharmacological Basis of Therapeutics, 9thEd., 1996, pp. 161-176). Side effects of tacrine largely limit its clinical applicability. Another AChE inhibitor (R,S)-1-benzyl-4-[5,6-dimethoxy-1-indanone-2-yl]methyl piperidine·HCl (donepezil) was recently approved for treating symptoms of Alzheimer's disease in light and medium form (confirmed P.Kasa et al., above). For this compound were not observed damaging effect on the liver, but it has effects on the gastrointestinal tract similar to those for tacrine, possibly as a result of stimulation of m3 receptors due to an increased parasympathetic tone.

Previously it has been suggested that because of muscarinic m1 receptors in the frontal cortex and hippocampus are intact, it is possible to cure or, at least, reduce the loss of acetylcholine in patients with Alzheimer's appointment of drugs acting as agonists of these muscarinic receptors (confirmed J.H.Brown and P.Taylor, "Muscarinic Receptor Agonists and Antagonists", Chapter 7 in Goodman and Gilman: The Pharmacological Basis of Therapeutics, 9thEd., 1996, pp. 147).

Until this lie is neither muscarinic agonists (likely selective for m1)proposed for treatment of Alzheimer's disease, such as arecoline not show higher efficiency in clinical trials than the AChE inhibitors (confirmed S.V.P.Jones et al., above). In one study (confirmed T.Sunderland et al., Brain Res. Rev. 13, 1988, pp. 371-389) it was found that arecoline does not have such a significant enhancement of cognitive functions in relation to behavioral changes, often observed in patients with Alzheimer's disease, such as a significant increase in physical activity, a significant increase in mood and a significant reduction of Energie. However, it was later determined that the prospective m1 agonists are weak incomplete selective agonists for receptors m2 and/or m3 subtypes (H.Bruner-Osborne et al., J. Med. Chem. 38, 1995, pp. 2188-2195). As mentioned above, it is assumed that the selectivity for the m2 receptor is responsible for the cardiovascular effects observed for these agonists, such as tachycardia and bradycardia, and believe that the activity for m3 receptors are responsible for side effects agonists gastro-intestinal tract.

Therefore, to date activity for the m2 and/or m3 receptors is a significant drawback for muscarinic agonists proposed for the treatment of Alzheimer's disease, a significant step is either reducing the dose of drugs, you can assign to patients, and which, therefore, have to obtain a suboptimal dose. In addition, the lack of selectivity in relation to subtypes and low efficiency of the present cholinergic compounds contributes to the manifestation of negative side effects and has a limited effect on cognitive function due to the weak and/or opposite effects in the brain. Therefore, it would be a great advantage to develop compounds that have improved selectivity in relation to the m1 subtype, but which have low or no activity for subtypes m2 and m3.

The present invention relates to compounds with the activity of the muscarinic agonist of General formula (I):

where

X1, X2, X3, X4and X5selected from S, N and O;

k is 0 or 1;

t is 0, 1 or 2;

R1is a normal or branched C1-8the alkyl, C2-8alkenyl,2-8the quinil,1-8alkylidene,1-8alkoxy, C1-8heteroalkyl,1-8aminoalkyl,1-8halogenation,1-8alkoxy carbonyl, C1-8hydroxyalkoxy,1-8hydroxyalkyl, -SH, C1-8alkylthio, -O-CH2-C5-6the aryl, -C(O)-C5-6the aryl, substituted C1-3alkalo is or halogen; With5-6the aryl or5-6cycloalkyl, optionally comprising 1 or more heteroatoms selected from N, S and O; -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -CR3R4, -OC(O)R3,-(O)(CH2)sNR3R4or -(CH2)sNR3R4where R3, R4and R5are the same or different, each independently selected from H, C1-6of alkyl; C5-6aryl, optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halogen or1-6by alkyl; C3-6cycloalkyl, or R3and R4together with the N atom, when available, form a cyclic ring structure, including 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8;

And is5-12the aryl or5-7cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;

R2is H, amino, hydroxyl, halogen or a normal or branched C1-6the alkyl, C2-6alkenyl,2-6the quinil,1-6alkoxy, C1-6heteroalkyl,1-6aminoalkyl,1-6halogenation,1-6alkylthio,1-6alkoxycarbonyl, -CN, -CF3, -OR3, -COR3, NO2-The other3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3 4R5, -OC(O)R3, -C(O)R3R4, -O(CH2)qNR3, -CNR3R4or -(CH2)qNR3R4where q is an integer from 1 to 6;

n is 0, 1, 2, 3 or 4, radicals R2where n > 1, are the same or different;

p is 0 or an integer from 1 to 5;

Y is O, S, CHOH, -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, NR7or-CH=N-, and R7is N or C1-4the alkyl or is absent; and

Z is CR8R9where R8and R9independently selected from h, normal or branched C1-8of alkyl; or

their pharmaceutically acceptable salt, ester and prodrug.

The present invention also relates to a pharmaceutical preparation comprising an effective amount of the compounds of formula (I)suitable for

treatment of symptoms of a disease or condition associated with reduced levels of acetylcholine, and said treatment includes the appointment of a therapeutically effective amount of a preparation comprising the compound of formula (I).

The drug is also suitable for the treatment of symptoms of a disease or condition associated with elevated intraocular pressure such as glaucoma, where the method includes assigning a therapeutically effective amount of a preparation comprising the compound of formula (I).

Brief description of drawings

Figure 1 is a graph showing the raw data for screening 35000, small organic molecules using a 96-well plate in a test described in example XVI.

Figure 2 is a graph showing the data compared to the standard profile antagonist atropine cells, transfectional muscarinic m1 receptor, stimulated either by carbachol (open triangles)or compound a (example I) (closed triangles).

A detailed description of the invention

The present invention relates to compounds, preferably showing a relatively high selectivity with respect to the receptor subtype m1 compared to other muscarinic subtypes, which may have positive effects in the treatment of disorders of cognitive function, such as Alzheimer's disease or other conditions associated with age-related decline of cognitive functions, while avoiding the side effects of the drugs proposed to date for this purpose. Surprised by screening against receptors m1-m5 subtypes were selected compounds exhibiting this property.

According to one embodiment, the present invention provides compounds of formula (I), where x1, X2, X3, X4and X5are C; iliadin of X 1, X2, X3, X4and X5is O or N and the others are C;

k is 0 or 1;

t is 1;

R1is a normal or branched C1-8the alkyl, C2-8alkenyl,2-8the quinil,1-8alkylidene,1-8alkoxy, C1-8aminoalkyl,1-8halogenation,1-8alkoxycarbonyl, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3or -(CH2)sNR3R4where R3,R4and R5are the same or different, each independently selected from H and C1-6of alkyl; and s is an integer from 1 to 8;

n is 1, 2 or 3; and

A is a phenyl or naphthyl;

where R2is a normal or branched C1-6the alkyl, C2-6alkenyl,2-6the quinil,1-6alkoxy, C1-6aminoalkyl,1-6halogenation,1-6alkoxycarbonyl, -CN, -CF3, -OH, -COR3-The other3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3or -(CH2)qNR3R4; where q is an integer from 1 to 6; or

And is aryl containing 1 or more heteroatoms selected from N, S and O;

R2is H, halogen, normal or branched C1-6the alkyl, C2-6alkenyl,2-6the quinil,1-6 alkoxy, C1-6heteroalkyl,1-6aminoalkyl,1-6halogenation,1-6alkoxycarbonyl, -CN, -CF3, -OH, -COR3-The other3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3or -(CH2)qNR3R4; or

their pharmaceutically acceptable salt, ester or prodrug.

In one preferred embodiment the compound has the formula (II):

Preferred variants of compounds of formula (II) include compounds of formulas (IIa) and (IIb):

Preferably, in the compounds of formulas I, II, IIa and IIb t is 1, and Y is-C(O)-, -NHC(O)-, S, O, or-OC(O)-. In another embodiment, X3is C. Preferably R1is alkyl, preferably where R2is alkyl, aminoalkyl, alkoxy or hydroxyl. In one embodiment, R is 3. In another, R1is2-8the alkyl, and R2is stands, hydroxyl or alkoxy.

In one embodiment n is 1 or 2; Y is-C(O)- or O, and t is 1. Preferably R2is a halogen. According to other embodiments, t is 0, or R1is alkoxy, benzyl or phenyl.

X3can also be N, where according to one embodiment R1is alkyl Il is alkoxy; or R1is benzyl or phenyl, where R2is alkyl or alkoxy.

According to another embodiment of the X3is About, where t may be equal to, for example, 0. Preferably R2is alkyl or alkoxy; or R2is halogen.

Preferred embodiments of the invention include:

4-Methoxy-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4 Ethoxy-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Propoxy-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4 Butoxy-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methoxymethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Ethoxymethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Propoxymethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-(2-Methoxyethyl)-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-(2-Ethoxyethyl)-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methoxy-4-methyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methoxy-4-ethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methoxy-4-propyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methoxy-4-n-butyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4 Ethoxy-4-methyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4 Ethoxy-4-ethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4 Ethoxy-4-propyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4 Ethoxy-4-n-butyl-1-[4-(2-were)-4-oxo-1-Buti is]piperidine;

4-Propoxy-4-methyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Propoxy-4-ethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Propoxy-4-propyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Propoxy-4-n-butyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-n-Butoxy-4-methyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-n-Butoxy-4-ethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-n-Butoxy-4-propyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-n-Butoxy-4-n-butyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

2-[3-(4-n-Butylpiperazine)propoxy]toluene;

2-[3-(4-n-Butylpiperazine)propanesulfonyl]toluene;

2-[3-(4-n-Butylpiperazine)propanesulfonyl]toluene;

3-(4-n-Butylpiperazine)-o-tolyl-butane-1-tion;

3-(4-n-Butylpiperazine)-o-tolylamino;

N-(4-(4-n-Butylpiperazine)-1-o-tributyl)hydroxylamine;

4-n-Butyl-1-[4-(2-chlorophenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-bromophenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-forfinal)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-mercaptophenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-sulfonylmethane)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-sulfenylation)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-AMINOPHENYL)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-methylaminophenol)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-ethylaminomethyl)-4-oxo-1-butyl]piperidine;

4-what-Butyl-1-[4-(2-dimethylaminophenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-diethylaminophenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(1-H-imidazol-2-yl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(1-imidazol-1-yl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(1-thiazol-2-yl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-([1,2,3]triazole-1-yl)-4-oxo-1-butyl]piperidine;

2-[4-n-butyl-piperidine-1-ethyl]-8-methyl-3,4-dihydro-2H-naphthalen-1-it;

2-[4-n-butyl-piperidine-1-ethyl]-7-methyl-indan-1-it;

3-[4-n-butyl-piperidine-1-ethyl]-chromen-4-one;

2-[4-n-butyl-piperidine-1-ethyl]-1H-benzoimidazol;

4-n-Butyl-1-[4-(4-fluoro-2-were)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-hydroxyphenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-methoxyphenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(1-thiophene-2-yl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-ethylphenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-ethoxyphenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2,4-dimetilfenil)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2,3-dimetilfenil)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(3-methoxyphenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(4-were)-4-oxo-1-butyl]piperidine;

4-n-Butyl-N-phenylbutyramide;

4-Methyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(naphthalen-1-yl)-4-oxo-1-butyl]piperidine;

4-Benzyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

1-[4-(2-methylphen is)-4-oxo-1-butyl]pyrrolidin;

4-Benzyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

2-Propyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

2-Ethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-n-Propyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

3,5-Dimethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

4-n-Hexyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

4-Hydroxyethyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

4-Ethyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

4-Benzyl-1-[4-(4-forfinal)-4-oxo-1-butyl]piperidine;

4-Benzyl-1-[4-(4-bromophenyl)-4-oxo-1-butyl]piperidine;

4-Phenyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine;

3-Hydroxymethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Methyl-1-[4-(4-bromophenyl)-4-oxo-1-butyl]piperidine;

1-[4-(2-were)-4-oxo-1-butyl]piperidine;

2-Hydroxymethyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

4-Benzyl-1-[4-(2-were)-4-oxo-1-pentyl]piperazine;

4-n-Hexyl-1-[4-(2-were)-4-oxo-1-pentyl]piperazine;

4-(piperidine-1-yl)-1-[4-(2-were)-4-oxo-1-butyl]piperidine;

1-[4-(2-were)-4-oxo-1-butyl]-2,3-dihydro-1H-indole;

4-Benzyl-1-[5-(2-were)-5-oxo-1-pentyl]piperidine;

4-n-Butyl-1-[5-(2-were)-5-oxo-1-pentyl]piperidine;

4-n-Butyl-1-[4-(2,6-dimetilfenil)-4-oxo-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-methoxymethyl)-4-oxo-1-butyl]piperidine;

3,5-Dimethyl-1-[5-(2-were)-5-oxo-1-pentyl]piperidine;

3,5-Dimethyl-1-[4-(4-forfinal)-4-oxo-1-butyl]piperidine;

1-[4-(4-Forfinal)-4-oxo-1-butyl]pyrrolidin;

4-Benzyl-1-[6-(2-were)-6-oxo-1-hexyl]piperazine;

3,5-Dimethyl-1-[6-(2-were)-6-oxo-1-butyl]piperidine;

4-Benzyl-1-[5-(2-methoxyphenyl)-5-oxo-1-pentyl]piperazine;

4-Benzyl-1-[3-phenyl-3-oxo-1-propyl]piperazine;

4-n-Butyl-1-[5-(2-methoxyphenyl)-5-oxo-1-pentyl]piperidine;

3,5-Dimethyl-1-[4-(4-fluoro-2-were)-4-oxo-1-butyl]piperidine;

3-n-Butyl-1-[4-(2-were)-4-oxo-1-butyl]azetidin;

4-n-Butyl-1-[4-(2-were)-4-oxo-2-methyl-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-were)-4-oxo-2,2-dimethyl-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-were)-4-oxo-2-ethyl-1-butyl]piperidine;

4-n-Butyl-1-[4-(2-were)-4-oxo-2-propyl-1-butyl]piperidine; and

4-n-Butyl-1-[4-(2-were)-4-oxo-2,2-diethyl-1-butyl]piperidine.

The compounds per se, are specifically excluded from the scope of formula I are 4-n-butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine; 4-n-butyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine; 2-[3-(3-n-butylpiperazine)propanesulfonyl]toluene and 4-propyloxy-1-[4-(4-forfinal)-4-oxo-1-butyl]piperidine (i.e. compounds where (CH2)p-Y - is -(CH2)3-C(O)- or -(CH2)3-S-; and X1to X5are With; so-And-(R2)nand R1are not together about-me what inveniam and n-bootrom respectively; the phenyl and n-bootrom, respectively, or p-florfenicol and-O-(CH2)2CH3, respectively).

The present invention additionally relates to a method for exposure to agonist at muscarinic receptor comprising contacting the receptor with an effective amount of the compounds of formula (I), including all connections in the scope of formula (I) (i.e. including 4-n-butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine, 4-n-butyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine, 2-[3-(3-n-butylpiperazine)propanesulfonyl]toluene and 4-propyloxy-1-[4-(4-forfinal)-4-oxo-1-butyl]piperidine).

The present invention additionally relates to pharmaceutical preparations comprising an effective amount of the compounds of formula (I), including all connections in the scope of formula (I) (i.e. including 4-n-butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine, 4-n-butyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine, 2-[3-(3-n-butylpiperazine)propanesulfonyl]toluene and 4-propyloxy-1-[4-(4-forfinal)-4-oxo-1-butyl]piperidine).

The present invention also relates to methods of treating symptoms of a disease or condition associated with reduced levels of acetylcholine, the method includes assigning a therapeutically effective amount of a composition described herein. Examples of diseases or conditions include neurodegenerative disease, impaired cognitive function, Otradnoe decline of cognitive function or dementia.

It was also shown that the compounds of the present invention have the ability to reduce intraocular pressure and, therefore, can be used to treat diseases such as glaucoma. Glaucoma is a disease in which there is an abnormality in the mechanism of regulation of the circulation of aqueous humor that fills the anterior chamber, i.e. the space formed between the cornea and the crystalline lens. This leads to increased watery moisture, and increased intraocular pressure, leading respectively to the defect of the field of vision and even blindness as a result of compulsive and reduction of the optic nerve papilla.

Compounds of the present invention preferably show a selective agonist activity in relation to the m1 receptor. Such an agonist is defined as a compound that increases the activity of muscarinic receptor m1 when it is in contact with the receptor. Selectivity is defined as the property agonists, muscarinic receptor m1 by the number of agonist effective to enhance the activity of m1 receptors to cause minor or even no increased activity of the receptor m3 and m5 subtypes and preferably m2 and m4 subtypes.

As used herein, the term "alkyl" means normal or branched alkanoyl glad the feces with 1-6 carbon atoms in the chain, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc. the Term "heteroalkyl" is intended to denote alkangovolo radical containing 1 or 2 heteroatoms selected from O, S or N.

As used herein, the term "alkenyl" means normal or branched Allenby radical with 2-6 carbon atoms in the chain; the term "quinil" is intended to indicate a normal or branched olkinuora radical with 2-6 carbon atoms in the chain.

As used herein, the term "aryl" and "cycloalkyl" preferably refers to mono - and bicyclic ring structures containing 5 to 12 carbon atoms, more preferably to a monocyclic ring containing 5 to 6 carbon atoms. Where such rings include one or more heteroatoms selected from N, S and O (i.e. heterocyclic ring, such rings include, in General, from 5 to 12 atoms, more preferably from 5 to 6 atoms. Heterocyclic rings include, but are not limited to fullam, pirrallo, pyrazolyl, teinila, imidazolium, isoxazolyl, oxazolyl, thiazolyl, isothiazolines, pyridium, piperidinium, piperazinil, pyridazinyl, pyrimidinyl, pyrazinium, morpholinium, oxadiazolyl, thiadiazolyl, imidazolinium, imidazolidinyl and the like. The ring may be substituted by one or more rad is Kalami included in the definition of R2above. It is clear that alternates With1-6alkyl, C1-6alkenyl,1-6quinil,1-6alkoxy, C1-6heteroalkyl,1-6aminoalkyl,1-6halogenated or1-6alkoxycarbonyl can, if present, to be substituted by one or more hydroxyl,1-4alkoxy, halogen, cyano, amino or nitro.

As used herein, the term "halogen" or "halo" includes chlorine, fluorine, iodine or bromine.

It is clear that the ring represented by the structure

can be saturated or unsaturated.

Compounds of the present invention can be obtained by methods similar to the methods disclosed in the patent UK 1142143 and U.S. patent 3816433. Path modifications of these methods, involving the incorporation of other reagents, etc. will be understood by experts in this field. For example, the compounds of formula I can be obtained as shown in the following reaction scheme.

Starting compound having the formula (X)can be obtained by the General methods of organic synthesis. For General methods of preparing compounds of the formula (X), seek Fuller R.W. et al., J. Med. Chem. 14:322-325 (1971); W.O. Foye et al., J. Pharm Sci. 68:591-595 (1979); Bossier J.R. et al., Chem. Abstr. 66:46195h and 67:21527a (1967); Aldous F.A.B., J. Med. Chem. 17:1100-1111 (1974); Fuller R.W. et al., J. Pharm. Pharmacol 25:828-829 (1973); Fuller R.W. et al., Neuropharmacology 14:739-746 (1975); Conde S. et al., J. Med. Chem. 21:978-981 (1978); I. Lukovits et al., Int. J. Quantum Chem. 20:429-438 (1981); and Law B., J. Cromatog. 407:1-18 (1987), which are incorporated by reference in their entirety. You can get labeled isotopes of the compounds having formula (XX), for example, using labeled with tritium reducing agent for rehabilitation amination or by using14C-labeled original substance.

Alternative where the original substance includes a carbonyl group, the compound of formula (XXII) can be restored, for example, AlH3, DIBORANE:metilsulfate or other standard reducing agents for carbonyl group to obtain a ligand of the formula (XXX).

The receptor ligands of the formula (XXXII) can be obtained nucleophilic substituted electrophile (E) derivatives (XXXI). Examples of electrophiles that can be used for this purpose include halide, such as I, Cl, Br, tosylate or mesilate.

When Y in the formula (XXXII) is-C(O)-, this compound can be obtained by oxidation of the secondary alcohol, for example, chlorbromuron pyridinium or N-chloro-succinimide or CrO3-H2SO4or Nickel peroxide or a metal (Al, K) or DCC-DMSO.

When Y in the formula (XXXII) is-O-, then this connection can get the ü alkylation of an alcohol arylhalides, for example, when Cu catalysis.

When Y in the formula (XXXII) is-S-, this compound can be obtained by alkylation of the thiol arylhalides, for example, when Cu catalysis.

When Y in the formula (XXXII) is NON-, this compound can be obtained by recovering the corresponding ketone by catalytic hydrogenation or by using NaBH4or when using LiAlH4.

Suitable pharmaceutically acceptable salts of the compounds of this invention include acid additive salts that can be obtained, for example, by mixing a solution of the compounds according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds according to the invention have an acid group, suitable pharmaceutically acceptable salts may include alkali metal salts, for example, salts of sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium; and salts formed suitable organic ligands, e.g. Quaternary ammonium salts. Examples of pharmaceutically acceptable salts include the acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bi is artrit, borate, bromide, calcium, carbonate, chloride, clavulanate, citrate, dihydrochloride, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, nitrate, N-methyl glucagonoma salt of ammonium, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannat, tartrate, tosylate, triethiodide and valerate.

In the scope of the present invention include prodrugs of the compounds according to this invention. Basically, these prodrugs are inactive derivatives of the compounds according to the present invention, which are easily converted in vivo into the required compound. Conventional methods of selection and obtain a suitable prodrugs are described, for example, in "Design of Prodrugs", ed. H.Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species formed during the introduction of the compounds according to the invention in a biological environment.

If the compounds according to the invention have at least one chiral center, they may be in the form of a racemate or in the form of enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. In addition, some of the crystalline forms of the compounds of the present invention can be in the form of polymorphic forms, and they also Ave naznachayutsya for inclusion in the present invention. In addition, some compounds of the present invention may form a solvate with water (i.e. hydrates) or common organic solvate. Such a solvate is also included in the scope of the present invention.

If the means of obtaining the compounds according to the invention give a mixture of stereoisomers such isomers can be divided in the usual ways, such as preparative chiral chromatography. Compounds can be obtained in racemic form, or individual enantiomers can be obtained stereoselective synthesis or by separation. The connection can, for example, be divided into their components-enantiomers by standard means, such as education diastereoisomeric pairs in the formation of salts with optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. Connections can also be divided in the formation diastereoisomeric esters or amides, followed by chromatographic separation or removal of the chiral auxiliary substances.

When carrying out any of the methods of obtaining the compounds of the present invention may be necessary and/or desirable to protect sensitive or reactive groups on any of the relevant molecules. This can be the to achieve with conventional protective groups such as described in "Protective Groups in Organic Chemistry", ed. J.F.W.McOmie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, "Ptotective Groups in Organic Synthesis", John Wiley & Sons, 1991. The protective group can be removed at the appropriate subsequent stage using methods known in this field.

Compounds of the present invention can be introduced in any of the above drugs and consequently schemes doses established in this area, in those cases that require specific pharmacological modification of the activity of muscarinic receptors.

The present invention also relates to pharmaceutical preparations comprising one or more compounds according to the invention together with a pharmaceutically acceptable diluent or excipient. Preferably, such preparations are in unit dosage forms such as tablets, pills, capsules (including songs with the continuous release or delayed release), powders, granules, elixirs, tinctures, syrups and emulsions, sterile solutions or suspensions for parenteral administration, aerosol or liquid sprays, drops, ampoules, a device for Samovodene or suppositories; for oral, parenteral (e.g. intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal administration, or for administration by inhalation or insufflate, and mo is ut to be properly prepared and in accordance with common practice, as described in Remington''s Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1990. Alternative medicines may be in the form of a continuous release formulation suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as decanoate, can be adapted to provide drug depot for intramuscular injection. The present invention also relates to preparations suitable for topical application, for example, in eyes or on skin or mucous membranes.

For example, for oral administration in the form of tablets or capsules, the active ingredient of a drug can be combined with non-toxic pharmaceutically acceptable inert carrier for oral administration, such as ethanol, glycerol, water and the like. Moreover, when it is desirable or necessary, the mixture can also include suitable binders, lubricants, disintegrating agents, flavoring agents and coloring agents. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural or synthetic gums, such as Arabian gum, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, the sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Loosening substances include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

For solid preparations such as tablets, the active ingredient is mixed with a suitable pharmaceutical excipient, for example, as described above, and other pharmaceutical diluents, e.g. water, to obtain a solid composition for the subsequent formation containing a homogeneous mixture of the compounds of the present invention or its pharmaceutically acceptable salt. The term "homogeneous" is meant that the active ingredient is evenly distributed in the product so that it can be easily divided into equal effective unit dosage forms such as tablets, pills and capsules. Solid preparation for the subsequent formation can then be subdivided into unit dosage forms of the type described above containing from 0.1 to about 50 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be covered with membrane or otherwise make to obtain pharmaceutical form prolonged action. For example, the tablet or pill may include an inner core containing the asset to the second connection, and the outer layer in the form of a shell covering the core. The outer shell may be enteric layer which serves to protect it from disintegration in the stomach and allows the inner core to pass intact into the duodenum or slowly released. For such enteric layers or shells, you can use a variety of substances, including a number of polymeric acids and mixtures of polymeric acids with conventional substances such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which you can include these medicinal preparations for oral or injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as oil of cotton seeds, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, such as tragakant, Arabian gum, alginate, dextran, sodium carboxymethyl cellulose, gelatin, methylcellulose or polyvinylpyrrolidone. Other dispersing agents that can be used include glycerin and the like. For parenteral administration is desirable STERI the performance communications suspensions and solutions. When it is desirable intravenous use of isotonic preparations, which usually contain suitable preservatives. Drugs can also be in the form of ophthalmic solutions or suspensions, i.e. eye drops, intraocular injection.

Therefore, the present invention also relates to the relief or treatment of a disease or condition in which the positive effect of the modification of the activity of the muscarinic receptor, in particular, the activity of the m1 receptor, the appointment of a therapeutically effective amount of the compounds of the present invention to a subject in need of such treatment. Such diseases or conditions may, for example, occur as a result of inadequate stimulation or activation of muscarinic receptors. It is expected that the use of compounds that are selective for a particular subtype of muscarinic receptors, in particular m1, can largely avoid problems with side effects observed with the known muscarinic drugs such as tachycardia or bradycardia, or gastrointestinal effects.

The term "subject"used here, refers to an animal, preferably a mammal, most preferably to a person who is the object of treatment, observation or experience is of amenta.

The term "therapeutically effective amount"used here means the amount of active substance or pharmaceutical agent that causes a response of the biological or medicinal response in a tissue, system, animal or human, which is the goal of the researcher, veterinarian, medical doctor or other Clinician, which includes relieving symptoms of the disease to be treated.

Preferably, compounds of General formula I are subtitulo selectivity for muscarinic receptors m1-subtype. Also the compounds exhibit selectivity for muscarinic receptors m1-subtype compared to other tested associated with G-protein receptors, including serotonin, histamine, dopamine, or adrenergic receptors. One important value of this selectivity is that these compounds can be effective for the treatment or attenuation of a number of diseases or disorders of the Central nervous system without undesirable side effects previously observed with non-selective compounds.

The ability of the compounds of the present invention show selectivity for muscarinic receptors m1-subtype makes them potentially very useful for the treatment of diseases or disorders characterized by a disturbance in Navalny functions such as scarce impaired attention, or neurodegenerative diseases such as Alzheimer's disease, other forms of age-related decline in cognitive function, for example, senile dementia, or related dementia symptoms, such as decreased motor activity, mood changes, anergia, apathy, anxiety, and aggressive behavior. Now suppose that the muscarinic m1 receptor may also be involved in the regulation of intraocular pressure and, therefore, muscarinic m1 agonists can be used for the treatment or relief of eye diseases such as glaucoma.

Mainly compounds of the present invention can be introduced in a single daily dose or the total daily dose may be administered in divided doses two, three or four times a day. In addition, the compounds of the present invention can be introduced in intranasal form via topical application suitable carriers for intranasal or through the skin, using such forms of bread on the skin for transdermal passage, well known to specialists in this field. When assigning the form of a system for delivery through the skin introduction will be more continuous than discontinuous during the course introduction.

Course introduction, in which the compounds are applied by N. the present invention, is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the disease that is being treated, the route of administration, the condition of the kidneys and liver of the patient and the specific substance. A physician or veterinarian of ordinary skill can easily determine or assign an effective amount of a drug required to prevent, counter or stop the progression of diseases or disorders that can be treated.

Daily introduction of products may vary within a wide range from 0.01 to 100 mg per adult human per day. For oral administration, the preferred compositions are in the form of tablets containing 0,01, 0,05, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0 or 50.0 mg of active ingredient for the symptomatic regulation of dosage for a patient who undergoes treatment. A single dose usually contains from about 0.001 mg to 50 mg of active ingredient, preferably from about 1 mg to 10 mg of the active ingredient. An effective amount of a drug is typically delivered at a dose of approximately from 0.0001 mg/kg to about 25 mg/kg of body weight per day. Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day. Connection, you can enter corcom 4 times a day.

Compounds of the present invention can be used per se in appropriate doses, certain conventional testing for optimal pharmacological effect on muscarinic receptor, in particular, muscarinic receptor m1-subtype, at the same time minimizing any potential toxic or other undesirable effects. In addition, in some cases it may be desirable joint or sequential introduction of other agents that enhance the effect of the connection.

Pharmacological properties and selectivity of the compounds according to this invention for muscarinic receptors specific subtype can be demonstrated using a variety of methods of analysis using the recombinant receptor subtypes, preferably receptors person, if any are available, for example, conventional methods secondary carrier or binding. Especially convenient and functional system for the test is the selection and amplification of receptor disclosed in U.S. patent 5707798, which describes a method of screening for bioactive compounds when using the ability of cells transfection DNA receptor, for example, the coding of different muscarinic subtypes, to amplify in the presence of ligand receptor. Cell amplification is detected by increasing the n levels of the marker, also expressed by the cells.

The invention hereinafter disclosed in the following examples, which in no way intended to limit the scope of the invention in accordance with the invention.

EXAMPLES

Example I - 4-n-Butyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine (5)

1-Benzyl-4-n-butylidenephthalide (2). 3-necked flask with a capacity of 500 ml equipped with a stirrer, was loaded sodium hydride (1,61 g, 67 mmol) and DMSO (40 ml). The resulting suspension was heated to 90°C for 30 min, while not over the release of hydrogen. The suspension is cooled in an ice bath for 20 min followed by the addition of a suspension of the bromide butyldiphenylsilyl (26,6 g, 67 mmol) in DMSO (70 ml). The red mixture was stirred for 15 min at room temperature. Within 30 minutes slowly added 1-benzyl-4-piperidone 1 (14.0 g, 74 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture were added N2O (200 ml) followed by extraction with heptane (4 × 100 ml) and ethyl acetate (2 × 100 ml). The combined organic phase was dried and evaporated to dryness, obtaining of 38.1 g of a yellow oil. Oil surpassed received 14.9 g (88%) 2, BP. 101-105°C (0.1 mm Hg).1H NMR (CDCl3) 0,90-0,95 (t, 3H), 1,25-of 1.41 (m, 2H), 1,90-of 2.20 (m, 2H), 2,18-of 2.30 (m, 4H), 2.40 a at 2.45 (m, 4H), 2.50 each (s, 2H), 5,17 (t, 1H), 7,20-7,42 (m, 5H).

4-n-Butylpiperazine (3). In a flask with a capacity of 500 ml equipped with a stirrer, added a suspension of 2 (13,2 g, 58 mmol) and 10% palladium on coal (1.2 g) in ethanol (70 ml) followed by the addition of concentrated hydrochloric acid (1.5 ml). From the reaction flask was pumped out the air and introduced the hydrogen. In General spent 2,5 DM3of hydrogen. The reaction mixture was filtered and evaporated and the residue was dissolved in N2O (40 ml) and NaOH (20 ml, 2M), followed by extraction with ethyl acetate (3 × 100 ml). The combined organic phases were washed with brine (30 ml) and evaporated to dryness, obtaining of 7.1 g of crude 3. The crude product was subjected to column chromatography [eluent:heptane:EtOAc (4:1)], getting a net 3 (2.7 g, 33%).1H NMR (CDCl3) of 0.85 (t, 3H), from 1.0 to 1.38 (m, N), of 1.65 (DD, 2H), 2,38 (s, 1H), 2,55 (dt, 2H), 3.04 from (dt, 2H).

4-(4-n-Butylpiperazine-1-yl)Botanical (4). In a flask with a magnetic stir bar with a capacity of 100 ml was placed 3 (2.3 g, 16.4 mmol), 4-bromobutyronitrile (2.4 g, 16.4 mmol), powdered potassium carbonate (2.5 g, 18 mmol) in acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 5 h followed by addition of N2About (15 ml). The mixture was extracted with ethyl acetate (3 × 30 ml) and the combined organic phases are evaporated to dryness, obtaining of 3.9 g of crude 4. The crude product was subjected to column chromatography [eluent:heptane:EtOAc (1:1)], getting a net 4 (2.3 g, 87%).1H NMR (CDCl3) of 0.82 (t, 3H), 1,19-to 1.37 (m, N), of 1.64 and 1.75 (d, 2H), 1,84 is 2.01 (m, 4H), 2,39-of 2.54 (m, 4H), 2,89-2,97 (who, 2H).

4-n-Butyl-1-[4-(2-were)-4-oxo-1-butyl]piperidine (5). In dried in a drying Cabinet flask with a capacity of 25 ml was loaded Mg shavings (125 mg, 5.2 mmol), which is activated when the heat of the gun. In an inert atmosphere was added a suspension of 2-yoganidra (1.13 g, 5.2 mmol) in Et2O (4 ml) and the reaction mixture was stirred at room temperature for 1 h was Added compound 4 (720 mg, 3.4 mmol)dissolved in Et2O (4 ml)and the mixture is boiled under reflux during the night. Added THF (15 ml) and sulfuric acid (4 ml, 2 M) and the reaction mixture was stirred for 4 h followed by addition of NaOH (6 ml, 2M). The reaction mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic phases are evaporated to dryness, obtaining 1.2 g of crude 5. The crude product was subjected to column chromatography [eluent:CH2Cl2:CH3OH (99:1)], getting a net 5 (0,42 g, 26%).1H NMR (CDCl3) of 0.83 (t, 3H), 1,20-of 1.42 (m, N), 1,65-of 1.73 (d, 2H), 1,96-of 2.20 (m, 4H), of 2.53 (t, 2H), 3,02-3,17 (m, 4H), to 3.89 (s, 3H), 6,95-7,01 (m, 2H), 7,44 (t, 1H), 7,65 (d, 1H).

Example II - 3-Hydroxymethyl-[4-(2-were)-4-oxo-1-butyl]piperidine (7)

4-(3-Hydroxymethyl-piperidine-1-yl)-butyronitrile (6). In dried in a drying Cabinet flask with a capacity of 25 ml was added piperidine-3-yl-methanol (1.12 g, 10 mmol) in acetonitrile (10 ml) followed by addition of potassium carbonate (1,38 g, 10 mmol) and 4-bambuterol is trela (0,90 ml, 9 mmol). The reaction mixture was stirred at room temperature for 12 hours the Mixture was filtered and evaporated to dryness. After adding N2O (20 ml) were extracted with ethyl acetate (3 × 20 ml) and the combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining 1.50 g of crude 6, which was used without further purification in the synthesis of compound 7.

3-Hydroxymethyl-[4-(2-were)-4-oxo-1-butyl]piperidine (7). In dried in a drying Cabinet flask with a capacity of 50 ml was added Mg shavings (780 mg, 32 mmol), which is activated when the heat of the gun in vacuum followed by the addition of anhydrous THF (7 ml). In an inert atmosphere was added a suspension of 2-iodotoluene (5,3 g, 24 mmol) in THF (10 ml) and the reaction mixture is boiled under reflux for 4 hours Through a syringe was added to a suspension of compound 6 (1.50 g, 8 mmol) in THF (5 ml) followed by addition of CuBr (23 mg, 0.16 mmol, 2 mol%) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of N2SO4(20 ml, 2 M) and stirred at room temperature for 2 h followed by addition of NaOH (8 ml, 2 M). After adding THF (15 ml) was extracted with CH2Cl2(3 × 20 ml) and the organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0,41 g of crude 7. The crude product is t was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound 7. LC-MS [M+H]+275 (visit. 275,2).

Example III - 2-Propyl-[4-(2-were)-4-oxo-1-butyl]piperidine (9)

4-(2-propyl-piperidine-1-yl)-butyronitrile (8). A mixture of 2-propylpiperidine (550 mg, 4.3 mmol), 4-bromobutyronitrile (430 mg, 3.0 mmol) and potassium carbonate (550 mg, 4.0 mmol) in acetonitrile (5 ml) was stirred at room temperature for 12 h followed by the addition of saturated brine (25 ml). The reaction mixture was extracted with ethyl acetate (3 × 25 ml) and the combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining raw 8. The crude product was subjected to column chromatography [eluent:CH2Cl2:Meon (99:1)], getting a net 8 (0,48 g, 83%); LC-MS [M+H]+194 (visit. 194,2).

2-Propyl-[4-(2-were)-4-oxo-1-butyl]piperidine (9). In dried in a drying Cabinet flask was added Mg shavings (97 mg, 4.1 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 2-iodotoluene (380 mg, 2.8 mmol) in Et2O (3 ml) and the reaction mixture is boiled under reflux for 1 h using a syringe was added to a mixture of compound 8 (of 0.43 g, 2.2 mmol) in CH2Cl2(3 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of N2 SO4(10 ml, 2 M) and stirred at room temperature for 12 h followed by the addition of NaOH (10 ml, 2 M). After adding THF (15 ml) were extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), dried (MgSO4) and evaporated to dryness, obtaining of 0.43 g of crude 9. The crude product was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound (9); LC-MS [M+H]+287 (visit. 287,2).

Example IV-1-[4-(2-were)-4-oxo-1-butyl]piperidine (11)

In dried in a drying Cabinet flask with a capacity of 10 ml was added Mg shavings (97 mg, 4.1 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 2-iodotoluene (380 mg, 3.0 mmol) in Et2O (3 ml) and the reaction mixture is boiled under reflux for 1 h Via a syringe was added to a suspension of 4-piperidine-1-yl-butanetriol (10) (Dahlbom et al., Acta. Chem. Scand. 1951, 5, 690-697) (0,305 mg, 2.0 mmol) in CH2Cl2(3 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of N2SO4(10 ml, 2 M) and stirred at room temperature for 12 h followed by the addition of NaOH (12 ml, 2 M). After adding THF (15 ml) were extracted with ethyl acetate (3 × 0 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M) and dried (MgSO4) and evaporated to dryness, obtaining 0.21 g of crude 11. The crude product was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound (11); LC-MS [M+H]+245 (visit. 245,2).

Example V - 4-Methyl-1-[4-(4-bromophenyl)-4-oxo-1-butyl]piperidine (12)

In a dried flask with a capacity of 10 ml was added 4-methylpiperidine (719 mg, 6 mmol), dioxane (5 ml) followed by addition of potassium carbonate (0,30 g of 2.18 mmol), potassium iodide (10 mg) and 4-bromo-4-chlorobutyrophenone (785 mg, was 2.76 mmol). The reaction mixture stood at 110°C for 12 h, followed by dissolving in N2About (10 ml). The reaction mixture was extracted with Et2O (3 × 15 ml) and the combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining 0.50 g of crude 12. The crude product was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound 12; LC-MS [M+H]+322 (visit. 323,1).

Example VI - 1-[4-(2-were)-4-oxo-1-butyl]pyrrolidin (13)

In dried in a drying Cabinet flask with a capacity of 10 ml was loaded Mg shavings (30 mg, 1.2 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 2-iodotoluene (0,22 g, 1.0 mmol) in Et2O (2 ml) and the reaction mixture is boiled with reverse cold what linecom within 1 hour Through syringe was added 4-pyrrolidin-1-yl-butyronitrile (Burckhalter et al., J. Org. Chem. 1961, 26, 4070-4076) (0.14 g, 1.0 mmol) in CH2Cl2(2 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of N2SO4(10 ml, 2 M) and stirred at room temperature for 2 h followed by addition of NaOH (10 ml, 2 M). After adding THF (15 ml) were extracted with ethyl acetate (3 × 20 ml)and the organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0.12 g of crude 13. The crude product was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound 13; LC-MS [M+H]+231 (visit. 231.3 of which).

Example VII - 4-Methyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine (15)

4-(4-Methyl-piperazine-1-yl)butyronitrile (14). In a flask with a capacity of 25 ml made 1-methylpiperazine (0.52 g, 5.1 mmol), 4-bromobutyronitrile (0,78 g, 5.3 mmol) and potassium carbonate (0.71 g, 5.3 mmol)suspended in acetonitrile (5 ml). The reaction mixture was stirred at room temperature for 4 h followed by addition of N2O (20 ml) and was extracted with ethyl acetate (3 × 25 ml). The combined organic phases were washed with brine (25 ml), dried (MgSO4) and evaporated to dryness, getting to 0.72 g of crude 14, which was used without further purification in cinesexuality 15.

4-Methyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine (15). In dried in a drying Cabinet flask with a capacity of 10 ml was added Mg shavings (116 mg, 4.0 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a mixture of 2-iodotoluene (0.65 g, 3.0 mmol) in Et2O (3 ml) and the reaction mixture is boiled under reflux for 1 h Via a syringe was added a solution of compound 14 (0.33 g, 2.0 mmol) in CH2Cl2(3 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of H2SO4(6 ml, 2 M) and stirred at room temperature for 2 h followed by addition of NaOH (8 ml, 2 M). After adding THF (15 ml) was extracted with CH2Cl2(3 × 20 ml). The organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0.26 g of crude 15. The crude product was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound 15; LC-MS [M+H]+260 (visit. 260,4).

Example VIII - 4-n-Butyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine (17)

4-(4-Butyl-piperazine-1-yl)butyronitrile (16). In a flask with a capacity of 25 ml made 1-butylpiperazine (712 mg, 5.0 mmol), 4-bromobutyronitrile (779 mg, 5.3 mmol) and potassium carbonate (687 mg, 5.0 mmol)suspended in acetonitrile (5 ml). The reaction is mesh was stirred at room temperature for 12 h followed by addition of N 2O (20 ml) and was extracted with ethyl acetate (3 × 25 ml). The combined organic phases were washed with brine (25 ml), dried (MgSO4) and evaporated to dryness, obtaining 0,89 g crude 16, which was used without further purification in the synthesis of compound 17.

4-n-Butyl-1-[4-(2-were)-4-oxo-1-butyl]piperazine (17).

In dried in a drying Cabinet flask with a capacity of 10 ml was loaded Mg shavings (100 mg, 4.0 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a mixture of 2-iodotoluene (0.66 g, 3.0 mmol) in Et2O (3 ml) and the reaction mixture is boiled under reflux for 1 h using a syringe was added to a suspension of compound 16 (of 0.43 g, 2.0 mmol) in CH2Cl2(3 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of N2SO4(6 ml, 2 M) and stirred at room temperature for 2 h followed by addition of NaOH (8 ml, 2 M). After adding THF (15 ml) was extracted with CH2Cl2(3 × 20 ml) and the organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0.50 g of crude 17. The crude product was subjected to preparative HPLC [eluent:buffer A:0.1% of TFA; buffer B:80% of CH3CN + 0,1% TFA], having obtained analytically pure sample of compound 17; LC-MS [M+H]+302 (visit. 302,5).

Example IX - 4-n-Butyl-1-[4-(2-atok fenil)-4-oxo-1-butyl]piperidine (18)

In dried in a drying Cabinet flask with a capacity of 10 ml was added Mg shavings (94 mg, 3.8 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 1-ethoxy-2-yogashala (0.71 g, 2.9 mmol) in Et2O (3 ml) and the reaction mixture is boiled under reflux for 3 hours Connection 4 (0.40 g, 1.9 mmol) was dissolved in CH2Cl2(3 ml) and the mixture was stirred at 40°C for another 3 hours, the Reaction mixture was repaid by the addition of H2SO4(10 ml, 2 M) and left under stirring at room temperature overnight followed by the addition of NaOH (20 ml, 2 M) to alkaline reaction. The reaction mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M) and the combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining of 0.60 g of crude 18. The crude product was subjected to column chromatography [eluent:tol:EtOAc (1:1)], getting a net 18 (0.32 g, 34%); LC-MS [M+H]+331 (visit. 331,5).

Example X - 4-n-Butyl-1-[4-(2,3-dimetilfenil)-4-oxo-1-butyl]piperidine (19)

In dried in a drying Cabinet flask with a capacity of 10 ml was added Mg shavings (94 mg, 3.8 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 1-iodine-2,3-xylene (0,69 g, 3.0 mmol) in Et2O ( ml) with spontaneous boiling and the reaction mixture is boiled under reflux for 4 hours A suspension of compound 4 (of 0.41 g, 2.0 mmol) in CH2Cl2(2 ml) was added to the reaction mixture and left at room temperature overnight. The reaction mixture was repaid by the addition of H2SO4(7 ml, 2 M) and stirred at room temperature for 3 h followed by addition of NaOH (20 ml, 2 M) to alkaline reaction. The reaction mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2M) and the organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0,69 g raw 19. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (99:1)], getting a net 19 (0.40 g, 64%); LC-MS [M+H]+315 (visit. 315,5).

Example XI - 4-n-Butyl-1-[4-(2,4-dimetilfenil)-4-oxo-1-butyl]piperidine (20)

In dried in a drying Cabinet flask with a capacity of 10 ml was loaded Mg shavings (95 mg, 3.9 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 1-iodine-2,4-xylene (0,69 g, 2.9 mmol) in Et2O (4.5 ml) with spontaneous boiling and the reaction mixture is boiled under reflux for 3 hours Connection 4 (of 0.41 g, 2.0 mmol)dissolved in CH2Cl2(2 ml), was added in an inert atmosphere in the reaction mixture left under stirring at room temperature overnight. The reaction sociosocio the addition of H 2SO4(8 ml, 2 M) and stirred at room temperature for 4 h, then the reaction mixture was podslushivaet the addition of NaOH (20 ml, 2 M). After adding THF (20 ml) were extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), and the organic phase was dried (MgSO4) and evaporated to dryness, obtaining and 0.61 g of crude 20. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (99:1)], getting a net 20 (0.21 g, 35%); LC-MS [M+H]+315 (visit. 315,5).

Example XII 4-n-Butyl-1-[4-(2-methoxyphenyl)-4-oxo-1-butyl]piperidine (21)

In dried in a drying Cabinet flask with a capacity of 10 ml was loaded Mg shavings (0.12 g, 4.9 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 1-bromo-2-ethylbenzene (0.66 g, 3.6 mmol) in Et2O (2 ml) and the reaction mixture is boiled under reflux for 2 hours Through a syringe was added to a suspension of compound 4 (0.50 g, 2.4 mmol) in CH2Cl2(2 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of H2SO4(14 ml, 2 M) and stirred at room temperature for 2 h followed by addition of NaOH (20 ml, 2 M). After adding THF (20 ml) were extracted with ethyl acetate (3 × 50 ml) and the combined PR is adicheskie phase was washed with brine (10 ml) and NaOH (10 ml, 2 M) and the organic phase was dried (MgSO4) and evaporated to dryness received 0.75 g of crude 21. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (99:1)], getting a net 21 (0.68 g, 90%); LC-MS [M+H]+315 (visit. 315,5).

Example XIII - 4-n-Butyl-1-[4-(2,4-dimetilfenil)-4-oxo-1-butyl]piperidine (22)

In dried in a drying Cabinet flask with a capacity of 10 ml was loaded Mg shavings (88 mg, 3.6 mmol) and activated when the heat of the gun in a vacuum. In an inert atmosphere was added a suspension of 1-iodine-2-methoxymethanol (0,67 g, 2.7 mmol) in Et2O (4 ml)and the reaction mixture is boiled under reflux for 1 h Via a syringe was added to a suspension of compound 8 (0,38 g, 1.8 mmol) in CH2Cl2(4 ml)and the reaction mixture was stirred at room temperature overnight. The reaction mixture was repaid by the addition of H2SO4(10 ml, 2 M) and stirred at room temperature for 2 h followed by addition of NaOH (10 ml, 2 M). After adding THF (15 ml) were extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M) and the organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0.51 g of crude 22. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (99:1)], getting a net 22 (0.14 g, 23%); LC-MS [M+H]+ 331 (visit. 331,5).

Example XIV - 4-n-Butyl-1-[4-(2-pyridinyl)-4-oxo-1-butyl]piperidine (24)

Methyl ester of 4-(4-butyl-piperidine-1-yl)butyric acid (23). Into the reaction flask with a capacity of 25 ml was added methyl ether 4-bromo-butyric acid (2,04 g, and 11.2 mmol), compound 3 (1.51 g, the 10.8 mmol) and potassium carbonate (1.63 g, and 11.8 mmol), suspended in CH3CN (10 ml). The reaction mixture was stirred over night at room temperature, followed by filtering and evaporating to dryness. After adding N2About (50 ml) were extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining 2,84 g raw 23. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (99:1)], getting a net 23 (1,93 g, 75%); LC-MS [M+H]+241 (visit. 241,2).

4-n-Butyl-1-[4-(2-pyridinyl)-4-oxo-1-butyl]piperidine (24). In a dry reaction flask with a capacity of 25 ml was added 2-bromopyridine (200 mg, 1.3 mmol)dissolved in CH2Cl2(3 ml), and the temperature brought to -78°C. After stirring for 20 min was added n-BuLi (from 0.84 ml, 1.4 mmol) under inert atmosphere. After another 30 minutes and was added to the solution 23 in CH2Cl2(2 ml). The reaction mixture is allowed to warm to room temperature over night before maturity N2SO4(5 ml, 1 M). The reaction mixture was extracted with ethyl acetate (6 × 25 ml) and the combined organic phases were dried (MgSO 4) and evaporated to dryness, obtaining 0.31 g of crude 24. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (10:1)], getting a net 24 (75 mg, 12%); LC-MS [M+H]+288 (visit. 288,2).

Example XV - 4-n-Butyl-1-[4-(2-hydroxyphenyl)-4-oxo-1-butyl]piperidine (27)

1-benzyloxy-2-iodine-benzene (25). In dried in a drying Cabinet flask with a capacity of 25 ml was dissolved 2-itfinal (1,03 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) in dry acetone (10 ml). The mixture was stirred for 15 min followed by the addition of benzylbromide (and 0.61 ml, 5.2 mmol) and left overnight at room temperature. After adding N2About (50 ml) were extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining 1.7 g of crude 25. The crude product was subjected to column chromatography [eluent:heptane:EtOAc (9:1)], getting a net 25 (1.2 g, 81%); LC-MS [M+H]+310 (visit. 310,0).

4-n-Butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1-butyl]piperidine (26). In dried in a drying Cabinet flask with a capacity of 25 ml was added Mg shavings (123 mg, 5.1 mmol), which is activated when the heat of the gun in a vacuum. In an inert atmosphere was added a solution of 1-benzyloxy-2-iodine-benzene (25) (1.18 g, 3.8 mmol) in Et2O (10 ml) and the reaction mixture is boiled under reflux for 3.5 hours a Solution of 4-(4-n-butylpiperazine-1-yl)Botanical 4(0,53 g, 2.5 mmol) in CH2Cl2(3 ml), was added to the reaction mixture and stirred at 40°With during the night. The reaction mixture was repaid by the addition of N2SO4(10 ml, 2 M) and left to mix for 1 h followed by addition of NaOH (20 ml, 2 M) to alkaline reaction. The reaction mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M) and the combined organic phases were dried (MgSO4) and evaporated to dryness, obtaining 1.28 g of crude 26. The crude product was subjected to column chromatography [eluent:tol:EtOAc (1:1)], getting a net 26 (0.51 g, 51%); LC-MS [M+H]+393 (visit. 393,7).

4-n-Butyl-1-[4-(2-hydroxyphenyl)-4-oxo-1-butyl]piperidine (27). Into the reaction flask with a capacity of 25 ml was added a solution of 4-n-butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1-butyl]piperidine (26) (49 mg, 1.2 mmol) in dry EtOH (10 ml) and concentrated HCl (0.1 ml) followed by addition of palladium on coal (40 mg). In the reaction flask was introduced N2when using a cylinder and left to mix at room temperature overnight in an atmosphere of H2. The reaction mixture was podslushivaet the addition of NaOH (2 ml, 2.0 M) and was filtered through celite. The aqueous phase was extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), dried (MgSO4) and evaporated dash is, having 0,42 g crude 27. The crude product was subjected to column chromatography [eluent:CH2Cl2:MeOH (99:1)], getting a net 27 (0.21 mg, 58%); LC-MS [M+H]+303 (visit. 303,2).

Example XVI - a Screening of the test compounds in the test with the use of muscarinic receptor subtypes m1, m2, m3, m4 and m5

Transfection of cells with DNA muscarinic receptors (General method). Cells NIH T (obtained from American standard culture collection under the number of ATSS CRL 1658) were grown at 37°in thermostat with a humidified atmosphere (5% CO2in a modified method of Dulbecco environment Needle (DMEM) supplemented with 4.5 g/l glucose, 4 mm glutamine, 50 u/ml penicillin, 50 u/ml streptomycin (obtained from Advanced Biotechnologies, Inc., Gaithersburg, MD) and 10% calf serum (obtained from Sigma, St. Louis, MI). Cells were treated with trypsin-EDTA, quickly poured and seeded at a concentration of 2×106the Cup size is 15 cm in 20 ml DMEM containing 10% calf serum.

Muscarinic receptors m1-m5 subtypes cloned essentially as described by Bonner et al., Science 237, 1987, p. 527, and Bonner et al., Neuron 1, 1988, p. 403. For receptors m2 and m4 cells was co-transfectional with DNA coding Chimera protein Gq and five amino acids with the terminal carboxyl group of the protein Gi (design Gq-i5 describes Conklin et al., Nature 363, 1993, p. 274).

On the first day the cells were transfectional using reagent for tra is speccie Superfect (obtained from Qiagen, Valencia, CA) according to the manufacturer's instructions. The Cup made a DNA receptor, DNA β-gal (pSI-β-galactosidase obtained from Promega, Madison, WI), chimeric DNA Gq-i5-receptor subtypes m2 and m4 and sperm DNA salmon (obtained from Sigma, St. Louis, MI) as filler, in General, 20 μg DNA. Before inclusion in the Cup to DNA was added 60 μl of Superfect and thoroughly mixed by set and lowering the pipette fluid several times. The mixture is incubated at room temperature for 10-15 minutes Wednesday aspirated and cups added 12 ml of fresh, DMEM containing 10% calf serum and 50 u/ml penicillin/streptomycin. The solution of the DNA-Superfect again mixed by pipette and introduced into cups that were turning to evenly distribute the mixture of DNA on the surface. Cells were incubated over night at 37°C and 5% CO2.

After incubation, the medium aspirated and cups washed once with 15 ml of buffered saline Hanks. Cup upset to ensure thorough rinsing. In the Cup was added 20 ml of fresh medium DMEM, enriched with 10% calf serum and 50 u/ml penicillin/streptomycin. Cells were incubated for 24-28 hours, until the cups were not formed 100% of the merged layer.

The analysis of cells NIH T, transfection muscarinic receptors subtypes (General method). DMEM containing 2% Cyto-SF3, was heated at 37°on the waters of the Noah bath in sterile conditions. Sterile uterine solutions of the test compounds, which were subjected to analysis were prepared by dilution of compounds in DMEM to 8× final concentration for testing. In the test as a positive control was used connection (carbachol) and have also bred in DMEM to 8× final concentration. 50 μl of DMEM containing 2% Cyto-SF3, introduced into each well of 96-well plate to micrometrology in sterile conditions. Then in the upper wells of tablets added to 16 μl of solutions of compounds and diluted solutions, selecting 16 μl of solutions of compounds of the top holes and making them a pipette in the next series of holes. This procedure was repeated with each subsequent adjacent holes, except that 50 μl of the same medium introduced into the wells of the main control wells that contained medium and cells, but no test compound) and the wells of the control on the tablet (wells containing medium, but not the test compound and cells). The tablets were placed in a thermostat at 37°to balance temperature and pH.

When the cell culture reached 100% livenote, the medium aspirated and each Cup washed with 15 ml of buffered saline Hanks (HBS). Cells left in thermostat for about 10-15 minutes until HBS did not become slightly yellow. Then HBS aspirated and each Cup was added 1 ml of trypsin and turned so that th is would completely cover the Cup. Cup gently shook several times to separate the cells. After cells were shifted from the surface, was added 8 ml DMEM containing 10% calf serum and 50 u/ml penicillin and 50 u/ml streptomycin for the inhibition of trypsin. Cups washed this medium and the cells were transferred by pipette into a test tube. The cells were attentively at 1000 rpm for 5-10 min in a centrifuge IEC Centra CL2 (made Sorvall). After this Wednesday carefully aspirated so as not to dislodge cells. Cellular precipitate suspended in 1600 µl of DMEM containing 10% calf serum and 50 u/ml penicillin and 50 u/ml streptomycin, and then made a 20 ml DMEM, with the addition of 2% Cyto-SF3. In wells of 96-well plate to micrometrology, prepared as described above, made of 50 μl of this cell suspension (except for the holes of the control on the tablet). The plates were incubated for 4 days at 37°C and 5% CO2.

After incubation the medium was removed when you turn the tablet for micrometrology and their soft shaking, after which they were wet absorbent paper. Each well has made a chromogenic substrate (3.5 mm o-nitrophenyl-β-D-galactopyranoside, 0,5% nonidet NP-40 in phosphate buffered saline solution) and the plates were incubated at 30°until he received the maximum absorption at 405 nm. Of all the values subtracted absorption of l is the LCM of the basic controls and controls on the tablet.

Results. Using the General procedure described above, cells NIH T together was transfectional DNA that encodes the receptor m1, m3 and m5 subtypes. Library compounds containing approximately 35,000 small organic compounds (1 per well) was subjected to screening against the receptor by the method described above. The figure 1 presents data obtained from a single 96-well plate in a screening. This tablet two compounds were active against one or more transfection receptors. In General, the screening identified four related compounds have shown activity. In order to determine which receptor was activated in screening, the connection is tested, as described above, each of the receptors, transfection in a separate cell cultures. Connection And enable only the m1 receptor-subtype, for which it had a strong partial agonist inducyruya weaker response than the standard connection carbachol.

In subsequent experiments it was found four compounds that are selectively activated m1-receptor without the presence of significant activity by muscarinic receptors m2, m3, m4 or m5. The most active compound, compound a, was not an antagonist-induced carbachol responses muscarinic receptors five is Antipov.

Connection And additionally tested for agonist activity against several other receptors on α-adrenergic receptor subtypes 1D, 1B, 1A, 2A, 2B and 2C, histamine H1 and serotonin subtypes 5-HT1A and 5-NTA. The connection in these tests did not show significant activity. In the experiments for the evaluation of antagonistic activity of the compound And not inhibited response α-adrenergic receptor subtypes 2A, 2B or 2C, or serotonin receptor subtypes 5-HT1A or 5-NTA. As shown in figure 2, the response induced by the connection And blocked muscarinic antagonist atropine with the same efficiency as the response induced by muscarinic agonist-carbajosa.

Example XVII - Test R-SAT

Put tests R-SAT (see U.S. patent No. 5707798 included here as a source of literature), in which cells transfection receptors m1, m3 or m5, was subjected to seven compounds at a concentration of 1.5 μm. The reaction cells were expressed as percentage of the maximum response was defined as a response to 10 μm carbachol). The results are presented in the following table.

ConnectionReceptor and concentration
m1

1.5 M
m3

1.5 M
m5

1.5 M
And

(example I)
107+/-97+/-83+/-8
In

(example IX)
76+/-117+/-9-6+/-10
With

(example XV)
91+/-94+/-90+/-12
D

(example X)
72+/-913+/-72+/-15
E

(example XI)
42+/-139+/-3-3+/-2
F

(example XII)
65+/-99+/-75+/-11
G*66+/-1916+/-127+/-11
* 4-n-Butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine

As indicated above, the compounds are selective agonists for the m1 receptor.

Described and claimed here that the invention is not limited in the amount disclosed here certain embodiments, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments included in the scope of the invention. Indeed, various modifications of the invention in addition to presented and described it will be clear to experts in this field from the above description. Such modifications are also intended to fall within scope of the applied claims.

Here cited various sources of literature, the disclosure of which is cited as the source literature completely.

1. The compound of the formula I used for getting medicines for ionizatsii muscarinic receptor formula

where X1X2, X3, X4and X5are CH2or one of them is NH and the other X1-X5are CH2;

k is 0 or 1;

t is 0, 1 or 2, the radicals R1when t is 2, are the same or different;

R1is normal Il is branched C 1-8the alkyl or C1-8hydroxyalkoxy;

A is a phenyl or pyridinyl;

R2is H, hydroxyl, halogen or a normal or branched C1-6the alkyl, C1-6alkoxy;

n is 0, 1, 2, 3 or 4, radicals R2where n>1, are the same or different;

p is 0 or an integer from 1 to 5;

Y is-OC(O)-;

Z is CH2,

or its pharmaceutically acceptable salt.

2. Drug for the treatment of diseases and conditions associated with reduced activity of muscarinic receptors ml-comprising compound (I) according to claim 1.

3. Drug for the treatment of symptoms of a disease or condition associated with reduced levels of acetylcholine, comprising the compound (I) according to claim 1.

4. The drug according to claim 2 or 3, where the disease or condition is a neurodegenerative disease, impaired cognitive function, age-related decline in cognitive function or dementia.

5. Drug for the treatment of symptoms of a disease or condition associated with elevated intraocular pressure, comprising the compound (I) according to claim 1.

6. The drug according to claim 5, where the disease is glaucoma.



 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

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FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.

EFFECT: valuable medicinal properties of compounds and composition.

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SUBSTANCE: invention relates to new derivatives of 4-phenylpyridine of the general formula: (I) wherein R means halogen or halogen atom; R1 means -(C≡C)mR1' or -(CR'=CR'')mR1'; X means -C(O)N(R8)-, -N(R8)C(O)- or -N(R8)-(CH2)p- wherein m = 0-4 and p = 1-2; values of radicals R1', R2, R3', R3, R4, R4', R8, R' and R'' are given above, and to their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. New compounds are neurokinine-1 antagonists and can be used as medicinal agents in treatment of diseases mediated by neurokinine-1 receptors.

EFFECT: valuable medicinal properties of derivatives.

13 cl, 119 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention relates to a new method for preparing derivative of pyridine of the formula [d]: wherein values of R1, R3 and R4 are given below. Method involves interaction of a new derivative of pyridone of the formula [a]: wherein R3 represent halogen atom, cyano-group or nitro-group; R4 represents hydrogen atom or halogen atom with derivative of α-diazoester of the formula [f]: -N2CHCOR1 [f] wherein R1 represents (C1-C6)-alkoxy-group, and this interaction is carried out in the presence of acid. Proposed method is suitable and profit method for preparing derivatives of pyridine of the formula [d] possessing with specific system of substitutes and eliciting the herbicide activity.

EFFECT: improved preparing method.

8 cl, 2 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

The invention relates to peptide compositions with delayed release, representing a compound (I) containing the compound (A) formula

and the polymer containing lactide links, glycolide links and links tartaric acids - which are found in the polymer at the next sootnoshenii: lactide units constitute from about 71% to about 73%, glycolide links from about 26% to about 28%; and the parts of tartaric acid from about 1% to 3%, and the amino group of the compound (a) relate ionic bond with the carboxyl groups of the acid units of the polymer; the particles of compound I, an average size of from about 10 microns to about 100 microns; pharmaceutical composition with delayed release and two methods of treatment of various diseases, including the introduction to the patient an effective amount of compound A, or microparticles

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of General formula

where X1-X5denote SN2or one of them denotes NH, and the other X1-X5are CH2; k is 0 or 1, R1is1-8the alkyl, C1-8hydroxyalkoxy; t is 0, 1 or 2; And represents phenyl or pyridinyl; R2is H, hydroxyl, halogen or1-6the alkyl, C1-6alkoxygroup; n is 0, 1-4; p is 0 or an integer from 1 to 5, Y is-C(O)-; Z is CH2or their pharmaceutically acceptable salts

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance
The invention relates to a method for producing 2-trifluoromethyl-10-[3-(1-methyl-piperazinil-4)-propyl)] -fenotiazina used to treat diseases of the Central nervous system

The invention relates to new benzoylpyridine having biological activity

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

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