Derivatives of nitrogen-containing heterocyclic compounds and pharmaceutical composition based on them

 

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 compounds of formula (I) possess agonistic activity against muscarinic receptors and can find application in medicine. 2 S. and 19 C.p. f-crystals, 1 tab., 2 Il.

The present invention relates to new compounds which are selective in relation to muscarinic acetylcholine receptor subtypes, as well as to methods of 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 azetilholinovy fericelli 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, they can perform certain functions in the Central nervous system associated with doganaleescort system.

In animal experiments to study the different muscarinic ligands (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 ).

Based on the presence of subtypes of muscarinic receptors in various tissues becomes obvious 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 established that the disease is associated with impaired cognitive 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 this detected face, to 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 as 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 who had undergone treatment. It was also found that taken cause significant hepatotoxicity, approximately 30% of patients seen increased transaminase levels (confirmed by 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-dimetional Alzheimer's disease in light and medium form (confirmed by P. Kasa et al., above). For this compound were not observed damaging effect on the liver, but it has effects on the gastrointestinal tract are 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 by 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).

To date muscarinic agonists (likely to be 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 by 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 the increase of motor activity, a significant improvement in mood and a significant reduction of anergy. However, it was later determined that the prospective m1 agonists are weak not completely selective agonists for receptors m2 and/or m3 subtypes (-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, greatly reducing the dose of drugs that can be prescribed 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 poznavatel is the to develop your connection that have improved the selectivity in respect of 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, C2-8the quinil, C1-8alkylidene, C1-8alkoxy, C1-8heteroalkyl, C1-8aminoalkyl, C1-8halogenation, C1-8alkoxycarbonyl, C1-8hydroxyalkoxy, C1-8hydroxyalkyl, -SH, C1-8alkylthio, -O-CH2-C5-6the aryl, -C(O)-C5-6the aryl, substituted C1-3by alkyl or halogen; C5-6the aryl or C5-6cycloalkyl, 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 Ohm, selected from N, O and S, and optionally substituted by halogen or C1-6the 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 is C5-12the aryl or C5-7cycloalkyl, 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, C2-6the quinil, C1-6alkoxy, C1-6heteroalkyl, C1-6aminoalkyl, C1-6halogenation, C1-6alkylthio, C1-6alkoxycarbonyl, -CN, -CF3, -Or SIG3, -COR3, NO2-The other3, -NHC(O)R3-C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3-C(O)R3R4, -O(CH2)qNR3, -NR3R4or -(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 Iliuta from h, normal or branched C1-8of alkyl,

or their pharmaceutically acceptable salt, ester and prodrug.

The present invention additionally relates to pharmaceutical compositions comprising an effective amount of the compounds of formula (I).

In addition, the invention relates to methods for treating symptoms of a disease or condition associated with reduced levels of acetylcholine, the method includes assigning a therapeutically effective amount of a composition comprising a compound of formula (I).

In an additional embodiment the present invention provides a method of treating 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 composition comprising a 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 cocktail recipes. what the lights).

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 of the present invention provides compounds of formula (I), where

X1, X2, X3, X4and X5are, or one of X1, 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, C1-8alkylidene, C1-8alkoxy, C1-8aminoalkyl, C1-8halogenation, C1-8alkoxycarbonyl is NR3R4where R3, R4and R5are the same or different, each independently selected from N and C1-6of alkyl, and s is an integer from 1 to 8;

n is 1, 2 or 3 and

And is phenyl or naphthyl,

where R2is a normal or branched C1-6the alkyl, C2-6alkenyl,2-6the quinil, C1-6alkoxy, C1-6aminoalkyl, C1-6halogenation, C1-6alkoxycarbonyl, -CN, -CF3-HE,- R3-The other3, -N(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3or - (CH2)qNR3R4where 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, C1-6alkoxy, C1-6heteroalkyl, C1-6aminoalkyl, C1-6halogenation, C1-6alkoxycarbonyl, -CN, -CF3-HE,- R3-The other3, N(O)R3-C(O)NR3R4, - NR3R4, -NR3C(O)NR4R5, -OC(O)R3or -(CH2)qNR3R4or their pharmaceutically acceptable salt, �ta/78/786845.gif">

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 -, or-OC(O)-. In another embodiment, X3is C. Preferably R1is alkyl, preferably where R2is alkyl, aminoalkyl, alkoxy or hydroxyl. In one embodiment, p is 3, the other R1is2-8the alkyl and R2is stands, hydroxyl or alkoxy.

In one embodiment n is 1 or 2; Y is-C(O)- or 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 or 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-ethylphenyl)-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-butyl]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-butylphenyl)-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-toolbutton-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-n-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-(1H-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-Butylpiperazine-1-ethyl]-8-methyl-3,4-dihydro-2H-naphthalen-hypericin-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-Were)-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-ocso-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;

1-(2-Were)-2-(4-benzylpiperazine-1-yl)Etalon;

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-Benzo[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. the connection, where (CH2)p-Y - is -(CH2)3-C(O)- or -(CH2)3-S - and X1- X5are With; so-A-(R2)nand R1are not together on-and were n-bootrom respectively; the phenyl and n-bootrom respectively, or p-florfenicol and-O-(CH2)2CH3respectively.

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 volume formula n-butylpiperazine)propanesulfonyl]toluene and 4-propyloxy-1-[4-(4-forfinal)-4-oxo-1-butyl]piperidine).

The present invention additionally relates to pharmaceutical compositions 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, age-related 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. prostranstvo 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 of agonist muscarinic receptor m1 by the number of agonist, is 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 radical with 1-6 carbon atoms in the chain, such as 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” DL is used, the terms “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 rings, 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 radicals included in the definition of R2above. It is clear that the Vice-C1-6alkyl, C1-6alkenyl, C1-6quinil, C1-6alkoxy, C1-6heteroalkyl, C1-8aminoalkyl, C1-6halogenated or C1-6alkoxycarbonyl can, if present, to be substituted by one or more hydroxyl, C1-4alkoxy, halogen, cyano, amino or nitro.

As the estuaries and the raised 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); Foye, W. O. 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 Century, J. Cromatog. 407:1-18 (1987), which are incorporated by reference in their entirety. You can get labeled with isotopes of the compounds having formula (XX), for example, using tritium-labeled reducing agent for rehabilitation amination or by using14With the unification of the formula (XXII) can be restored, for example, AN3, 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 by nucleophilic substitution of the 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-chlorosuccinimide or SGAs3-H2SO4or Nickel peroxide or a metal (Al, K) or DCC-DMSO.

When Y in the formula (XXXII) is-O-, this compound can be obtained by 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.

The suitable is that you can get, 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 sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium; salts formed suitable organic ligands, e.g. Quaternary ammonium salts. Examples of pharmaceutically acceptable salts include the acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, 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-methylglucamine salt of ammonium, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannat, tartrate, tosylate, Tr is the Oia. 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 are intended 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 is possible to divide the usual method is entrusted 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 achieved using a 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 compositions and, accordingly, schemes doses established in this about what eception.

The present invention also relates to pharmaceutical compositions comprising one or more compounds according to the invention together with a pharmaceutically acceptable diluent or excipient. Preferably these compositions 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 can be made appropriately and in accordance with accepted practice, as described in Remington''s Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1990. Alternative compositions can 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 prep the items for local use, for example, in eyes or on skin, or mucous.

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, 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 compositions such as tablets, the active ingredient of the Pach diluents, for example with 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 composition so that the composition can be easily divided into equal effective unit dosage forms such as tablets, pills and capsules. Solid composition 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 be to provide dosage forms that provide the advantage of prolonged action. For example, the tablet or pill may include an inner core containing the active compound, 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 intestinal sh acids with the usual substances, such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which you can include these compositions 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 despergiruemaya agents that can be used include glycerin and the like. For parenteral administration is desirable sterile suspensions and solutions. When it is desirable intravenous use of isotonic preparations, which usually contain suitable preservatives. The composition can also be in the form of ophthalmic solutions or suspensions, i.e., eye drops, intraocular injection.

Therefore, the present invented the effect 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 experiment.

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, Kotor 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 impaired cognitive functions, such as scarce impaired attention, or neurodegenerative diseases such as Alzheimer's disease, other forms of age-related decline in cognitive functions, such as senile dementia, or related dementia symptoms, such as decreased motor activity, mood changes, anergy, apathy, anxiety, and aggressive behavior. Now suppose that musculinity 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, which is 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, uses of the compounds of 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 asking in 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 to 50 mg of active ingredient, preferably about 1 to 10 mg of the active ingredient. An effective amount of a drug is typically delivered at a dose of from about 0.0001 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 to 1 mg/kg of body weight per day. Connection, you can enter a rate of 1-4 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 ulula 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 detected by elevated levels of the marker is 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 90C for 30 min, while not over the release of hydrogen. The suspension is cooled in an ice bath for 20 min with subsequent domawnie 15 min at room temperature. Within 30 minutes slowly added 3-benzyl-4-piperidone 1 (14.0 g, 74 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (200 ml) followed by extraction with heptane (4100 ml) and ethyl acetate (2100 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, so Kip. 101-105(0.1 mm, RT. Art.).

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, was 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, boiled away and the residue was dissolved in N2O (40 ml) and NaOH (20 ml, 2 M) followed by extraction with ethyl acetate (3100 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 address chronic of 1.65 (DD, 2N), of 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 H2O (15 ml). The mixture was extracted with ethyl acetate (330 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: t (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-of 2.97 (d, 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 magnesium turnings (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 the aOH (6 ml, 2 M). The reaction mixture was extracted with ethyl acetate (350 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:CH3HE (99:1)], getting a net 5 (0,42 g, 26%).

1H NMR (CDCl3): or 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-Hydroxyethylpiperazine-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-bromobutyronitrile (0,90 ml, 9 mmol). The reaction mixture was stirred at room temperature for 12 hours the Mixture was filtered and boiled away the dryness. After adding H2O (20 ml) were extracted with ethyl acetate (320 ml) and the combined organic phases were dried (gSO4) 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 suchilin and 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(320 ml) and the organic phase was dried (gSO4) and evaporated to dryness, obtaining 0,41 g of crude 7. The crude product was subjected to preparative HPLC [eluent buffer A: 0.1% of TFA; buffer B: 80% of CH3SP + 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-Propylpiperidine-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)basics dried (gSO4) and evaporated to dryness, obtaining raw 8. The crude product was subjected to column chromatography [eluent - CH2Cl2: MeOH (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 magnesium turnings (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 μl, 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 H2SO4(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 (350 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), dried (gSO4) 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 CH3SP + 0,1% TFA], having Anil] piperidine (11)

In dried in a drying Cabinet flask with a capacity of 10 ml was added magnesium turnings (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 μl, 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 H2SO4(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 (350 ml), the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), dried (gSO4) 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% 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 capacity is,18 mmol), potassium iodide (10 mg) and 4-bromo-4-chlorobutyrophenone (785 mg, was 2.76 mmol). The reaction mixture stood at 110C for 12 h, followed by dissolving in N2About (10 ml). The reaction mixture was extracted with Et2O (315 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 In 80% of CH3SP + 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 magnesium turnings (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 under reflux for 1 h Via a 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 peremeci which was extracted with ethyl acetate (320 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 CH3SP + 0,1% TFA], having obtained analytically pure sample of compound 13. LC-MS [M+NG]+231 (visit. 231.3 of which).

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

4-(4-Methylpiperazin-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 (325 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 the synthesis of compound 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 magnesium turnings (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 is and 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(320 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 CH3SP + 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-Butylpiperazine-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 mixture was stirred at room temperature for 12 h followed by addition of H2O (20 ml) and was extracted with ethyl acetate (325 ml). The combined organic phases were washed with brine (25 ml), dried (MgSO4) and evaporated to dryness, obtaining 0,89 g crude 16, the cat who yl]piperazine (17). In dried in a drying Cabinet flask with a capacity of 10 ml was loaded magnesium turnings (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 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(320 ml) and the organic phase was dried (gSO4) 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 CH3SP + 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-ethoxyphenyl)-4-oxo-1-util]piperidine (18)

In dried in a drying Cabinet flask with a capacity of 10 ml was added magnesium turnings (94 mg, 3.8 mmol), which are activated when using TeV 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 40C for another 3 hours, the Reaction mixture was repaid by adding a2SO4(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 (350 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), 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 magnesium turnings (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 (5 ml) with spontaneous boiling and the reaction mixture is boiled under reflux is 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 (350 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), 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)] received 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 magnesium turnings (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 mixture p is a promotional mix podslushivaet the addition of NaOH (20 ml, 2 M). After adding THF (20 ml) were extracted with ethyl acetate (350 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), the organic phase was dried (gSO4) and evaporated to dryness, obtaining and 0.61 g of crude 20. The crude product was subjected to column chromatography [eluent CH2CL2: Meon (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 magnesium turnings (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 N2SO4(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 (350 the ub>4) and evaporated to dryness received 0.75 g of crude 21. The crude product was subjected to column chromatography [eluent CH2CL2: Meon (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 magnesium turnings (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 (350 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), the organic phase was dried (MgSO4) and evaporated to dryness, obtaining 0.51 g of crude 22. The crude product was subjected to colloect. 331,5).

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

Methyl ester of 4-(4-butylpiperazine-1-yl)butyric acid (23). Into the reaction flask with a capacity of 25 ml was added methyl ether 4-pamakani 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 CH3SP (10 ml). The reaction mixture was stirred over night at room temperature, followed by filtering and evaporating to dryness. After adding H2O (50 ml) were extracted with ethyl acetate (3100 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: Meon (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 -78C. 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 up to the Ali ethyl acetate (625 ml) and the combined organic phases were dried (MgSO4and boiled away the dry, receiving 0.31 g of crude 24. The crude product was subjected to column chromatography [eluent CH2CL2: Meon (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-iadanza (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 N2O (50 ml) were extracted with ethyl acetate (350 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 magnesium turnings (123 mg, 5.1 mmol), which is activated when the heat of the gun in a vacuum. In the inert atoli under reflux for 3.5 hours A solution of 4-(4-n-butylpiperazine-1-yl)Botanical 4 (of 0.53 g, 2.5 mmol) in CH2Cl2(3 ml) was added to the reaction mixture and stirred at 40With during the night. The reaction mixture was repaid by the addition of H2SO4(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 (350 ml) and the combined organic phases were washed with brine (10 ml) and NaOH (10 ml, 2 M), the combined organic phases were dried (gSO4) and evaporated to dryness, obtaining 1.28 g of crude 26. The crude product was subjected to column chromatography [eluent - tol: tO (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 were introduced H2when 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 is yennie organic phase was washed with brine (10 ml) and NaOH (10 ml, 2 M), dried (MgSO4) and evaporated to dryness, obtaining 0,42 g crude 27. The crude product was subjected to column chromatography [eluent CH2CL2: Meon (99:1)], getting a net 27 (0.21 mg, 58%). LC-MS [M+H]+303 (visit. 303,2).

Example XVI. The 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 3T3 (obtained from American standard culture collection under the number of ATSS CRL 1658) were grown at 37With 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 2106the 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 chimerae 363, 1993, p. 274).

On the first day the cells were transfectional using reagent for transfection with Superfect (obtained from Qiagen, Valencia, CA) according to the manufacturer's instructions. The Cup made a DNA receptor DNA-gal (pSI-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 overnight at 37C 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%bretwalda 100% merged layer.

The analysis of cells NIH 3T3, transfection muscarinic receptors subtypes (General method). DMEM containing 2% Cyto-SF3, was heated at 37C in a water bath under sterile conditions. Sterile uterine solutions of the test compounds, which were subjected to analysis were prepared by dilution of compounds in DMEM to 8the final concentrations for testing. In the test as a positive control was used connection (carbachol) and have also bred in DMEM to 8final 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 37C and 5% CO2.

After incubation the medium was removed when you turn the tablet for micrometrology and their soft shaking, after �p://img.russianpatents.com/chr/946.gif">-D-galactopyranoside, 0,5% nonidet NP-40 in phosphate buffered saline solution) and the plates were incubated at 30With until he received the maximum absorption at 405 nm. Of all the values subtracted absorption holes of the main controls and controls on the tablet.

Results. Using the General procedure described above, cells NIH 3T3 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 but four compounds which 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 of the five subtypes.

Connection And additionally tested for agonist activity against several other receptors on-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 does not inhibit the reaction-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 is and the maximum response was defined as a response to 10 μm carbachol). The results are presented in the following table.

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.

Claims

1. The compound of the formula I

where X1, X2, X3, X4and X5denote SN2or one of them denotes NH, and the other X1- X5are CH2;

k is 0 or 1;

R1is a normal or branched C1-8alkie or different;

And denotes phenyl or pyridinyl;

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

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-C(O)-;

Z is CH2,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where X1, X2, X3, X4and X5are CH2or one of X1, X2, X3, X4or X5are NH, and the others are CH2; k is 0 or 1; t is 1; R1is a normal or branched C1-8by alkyl; n is 1, 2 or 3; a is a phenyl, where R2is a normal or branched C1-6the alkyl, C1-6alkoxy, or a is pyridium; R2is H, halogen, normal or branched C1-6the alkyl, C1-6alkoxy, or its pharmaceutically acceptable salt.

3. Connection under item 1 or 2, where Z is CH2and p is 2.

4. Connection to one of the preceding paragraphs, where k is equal to 0.

5. Connection at one PM.1-3, representing a compound of formula II

img src="https://img.russianpatents.com/img_data/78/786855.gif">

the values of the radicals defined in paragraph 1.

7. Connection on p. 5, representing a compound of formula IIb

the values of the radicals defined in paragraph 1.

8. Connection at one PM.5-7, where X3equals CH2.

9. Connection to one of the preceding paragraphs, where R1is alkyl.

10. Connection on p. 9, where R2is alkyl, alkoxy or hydroxyl.

11. Connection on p. 10, where R2is alkyl or alkoxy.

12. Connection at one PM.1-10, where R1is2-8the alkyl and R2is stands, hydroxyl or alkoxy.

13. Connection to one of the preceding paragraphs, where n in formula I or formula II is 1 or 2, Y is-C(O)- and t is 1.

14. Connection on p. 13, where R2is halogen.

15. Connection at one PM.1-12, where t is 0.

16. Connection at one PM.5-7 and 9 to 15, when the compound has formula II, IIA or IIb, where X3is NH.

17. Connection to one of the preceding paragraphs, where Z-(CH2)p-Y - is-CH2-CH2-CH2WITH-.

18. Connection on p. 1, where a is pyridium.

19. Pharmaceutical composition having agonistic active in paragraph 1, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

20. The composition according to p. 19, where the compound is as defined in one of the paragraphs.2-18.

21. Connection on p. 1, which has the structural formula IA

where R1is a normal or branched C1-8the alkyl or C1-8hydroxyalkoxy;

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

the radicals R2when n > 1, are the same or different,

p is 0 or an integer from 1 to 5;

Y is-C(O)-;

Z is CH2,

provided that

(a) when t is 1, R1is not the stands,

(b) when-Z-(CH2)p-Y - is -(CH2)3-C(O)-, -A-(R2)nand R1are not together,

(i) o-stands-phenyl and n-bootrom respectively,

(ii) phenyl or n-bootrom respectively,

or its pharmaceutically acceptable salt.

 

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< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 3-intellipedia formula I, where R1, R2, R3and R4denote H, A, OH, OA, F, Cl, Br, J, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA, or R1and R2and R3and R4together denote methylenedioxy, R5Is H or OH, R6- H or R5and R6together denote a bond, And represents C1- C6-alkyl, n denotes a number from 2 to 6, and their physiologically acceptable salts
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