Polyheterocyclic compounds and use thereof as metabotropic glutamate receptor antagonists

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

 

The SCOPE of the INVENTION

The present invention relates to a new class of compounds, to pharmaceutical compositions containing these compounds and to the use of such compounds in therapy. The present invention also relates to methods of producing these compounds and to novel intermediate compounds used for their production.

PRIOR art

Glutamate is the major excitatory neurotransmitter in the Central nervous system of mammals (CNS). Glutamate exerts its effects on Central neurons by binding to receptors on the cell surface and thereby activate them. These receptors are divided into two main classes, ionotropic and metabotropic glutamate receptors, on the basis of structural characteristics of receptor proteins by which these receptors transmit signals into the cell, and pharmacological profiles.

Metabotropic glutamate receptors (mGluR) are receptors coupled with G-proteins that activate a number of intracellular secondary messengers after binding of glutamate. The mGluR activation in intact mammalian neurons causes one or more than one of the following responses: activation of phospholipase C; increased hydrolysis of phosphoinositide (P1); the release of intracellular cal is tion; activation of phospholipase D; activation or inhibition of adenylcyclase; increase or reduce the formation of cyclic adenosine monophosphate (camp); activation guanililcyclase; increase education of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increased release of arachidonic acid and increase or decrease the activity of voltage-dependent and ligand-dependent ion channels. Schoepp et al., Trends Pharmacol. Sci. 14-13 (1993), Schoepp, Neurochem. Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995), Bordi and Ugolini, Prog. Neurobiol. 59:55 (1999).

Eight separate mGluR subtypes, referred to as mGluRI to mGluR8 identified by molecular cloning. Nakanishi, Neuron 13:1031 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al., J. Med Chem. 38:1417 (1995). An additional variety of receptors exists due to the expression of alternative playerowner some forms of mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al., BBRC 199:1136 (1994), Joly et al., J. Neurosci. 15:3970 (1995).

Subtypes of metabotropic glutamate receptors can be divided into three groups, mGluR group I, group II and group III, on the basis of homology of amino acid sequences, systems of second messengers used by these receptors, and also on the basis of their pharmacological characteristics. mGluR group I include mGluR1, mGluR5 and their variants of alternative splicing. Agonist binding to these receptors leads as a result to the activation of phospholipase C and the subsequent mobilization of intracellular calcium.

Neurological, psychiatric and pain disorders

Attempts to assess the physiological role of mGluR group 1 suggested that activation of these receptors causes the excitation of neurons. Various studies have shown that mGluR agonists of group 1 can induce postsynaptic excitation when applied to neurons in the hippocampus, cerebral cortex, cerebellum and thalamus, as well as in other regions of the CNS. The data indicate that this excitation is the result of direct activation of postsynaptic mGluR, but also suggested that the activation of presynaptic mGluR, which results in an increased release of neurotransmitters. Baskys, Trends Pharmacol. Sci. 15:92 (1992), Schoepp, Neurochem. Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995), Watkins et al., Trends Pharmacol. Sci. 15:33 (1994).

Metabotropic glutamate receptors are involved in a number of normal processes in the Central nervous system of mammals. It is shown that mGluR activation is required for induction of long-term potentiation hippocampal and long-term suppression of the activity of the cerebellum. Bashir et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740 (1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377 (1994). Also demonstrated the role of mGluR activation in nociception and analgesia. Meller et al., Neuroreport 4:879 (1993), Bordi and Ugolini, Brain Res. 871:223 (1999). In addition, suggested that mGluR activation plays a modulatory role in several other normal process is s, including synaptic transmission, development of neuronal apoptotic death of neurons, synaptic plasticity, spatial learning, olfactory memory, the Central regulation of cardiac activity, the awakening, the regulation of motility and regulation vestibuloocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417 (1995).

In addition, suggested that metabotropic glutamate receptors group I play a role in a number of acute and chronic pathophysiological processes and disorders that affect the Central nervous system. These include stroke, head trauma, damage caused by hypoxia and ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease, psychiatric disorders and pain. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al., J. Med Chem. 36:1417 (1995), Spooren et al., Trends Pharmacol. Sci. 22:331 (2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43 (2002), Neugebauer Pain 98:1 (2002). Consider that much of the pathology of these conditions is the consequence of excessive excitation of neurons in the Central nervous system, induced by glutamate. Because it turns out that mGluR group I increase mediated by glutamate stimulation of neurons via postsynaptic mechanisms and enhanced presynaptic release of glutamate, activation, POS is but contributes to the pathology. Accordingly, selective antagonists of the receptor mGluR group I may be therapeutically useful for all States, based on excessive excitation of neurons in the Central nervous system, induced by glutamate, specifically as neuroprotective agents, analgesics or anti-seizure agents.

Recent advances in the neurophysiological explanation of the role of metabotropic glutamate receptors in General, and group 1 in particular has allowed to establish that these receptors are promising targets for drugs in therapy of acute and chronic neurological and psychiatric disorders, and chronic and acute pain disorders.

Gastrointestinal disorders

The lower esophageal sphincter (Les) is exposed to intermittent relaxation. As a result, the liquid from the stomach to enter the esophagus, as a mechanical barrier in such moments of temporarily disturbed, and this event is hereafter referred to as "gastro-intestinal (LCD) reflux".

Gastroesophageal reflux disease (GERD) is the most common disease of the upper parts of the gastrointestinal tract. The tasks of modern farmacoterapia are reducing the secretion of gastric acid or neutralization of acid in the esophagus. Believe that the main mechanism underlying the W is-reflux, depends on gipotonichnaya the lower esophageal sphincter. However, for example, in Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp.517-535 shown that the majority of reflux episodes occur at the time the temporary relaxation of the lower esophageal sphincter (VRNPS), i.e. relaxation, which are not run by the acts of swallowing. Also shown that patients with GERD the secretion of gastric acid is usually normal.

Suppose that the new compounds of the present invention are useful for the inhibition of transient relaxation of the lower esophageal sphincter (VRNPS) and, consequently, for the treatment of gastroesophageal reflux disease (GERD).

The phrase "VRNPS", temporary relaxation of the lower esophageal sphincter, is defined here in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp.601-610.

The wording "LCD reflux" is defined here as the ability of a fluid to pass from the stomach into the esophagus, because in this moment mechanical barrier temporarily lost.

The phrase "GERD", gastroesophageal reflux disease, defined here in accordance with van Heerwarden, M.A., Smout AJ.P.M., 2000; Diagnosis of reflux disease. Bailliere's Clin. Gastroenterol. 14, pp.759-774.

Because of their physiological and pathophysiological significance there is a need for new effective agonists and antagonists mGluR, who reavley high selectivity for subtypes of mGluR, in particular subtype receptors of group I.

SUMMARY of the INVENTION

In one aspect of the invention proposed compound of the formula I

where

R1selected from aryl and heteroaryl;

R1attached to R through a carbon atom on the ring R and is selected from the group consisting of: hydroxy, halogeno, nitro, C1-6alkylhalogenide, OC1-6alkylhalogenide, C1-6of alkyl,

OS1-6of alkyl, C2-6alkenyl, OS2-6alkenyl, C2-6the quinil, OS2-6the quinil,0-6alkyls3-6cycloalkyl, OS0-6alkyls3-6cycloalkyl,0-6alkylaryl, OS0-6alkylaryl, SNO, (CO)R5, O(CO)R5, O(CO)OR5, O(CNR5OR5With1-6R5With1-6R5With1-6alkyl(CO)R5OC1-6alkyl(CO)R5With0-6alkyls2R5OS1-6alkyls2R5With0-6alkylene, OS2-6alkylene, C0-6NR5R6,

OC2-6NR5R6C1-6alkyl(CO)NR5R6OC1-6alkyl(CO)NR5R6With0-6NR5(CO)R6,

OC2-6aNR5(CO)R6With0-6aNR5(CO)NR5R6With0-6SR5OS2-6SR5With0-6alkyl(SO)R5,

OS2-6alkyl(SO)R5With0-6the S 2R5OS2-6SO2R5C0-6alkyl(SO2)NR5R6OS2-6alkyl(SO2)NR5R6C0-6aNR5(SO2R6OC2-6aNR5(SO2R6With0-6aNR5(SO2)NR5R6OC2-6aNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6C0-6aNR5(CO)OR6OC2-6aNR5(CO)OR6, SO3R5and 5 - or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;

X1selected from the group consisting of: N, NR4and CR4;

X2selected from the group consisting of: C and N;

X3selected from the group consisting of: CR4, N and O;

X4selected from the group consisting of: CR4, N, NR4and;

X5selected from the group consisting of: communication, CR4R4', NR4, O, S, SO and SO2;

X6selected from the group consisting of: CR4and N;

X7selected from the group consisting of: C and N;

R4independently selected from the group consisting of hydrogen, hydroxy, C1-6of alkyl,

With0-6alkylene, oxo, =NR5, =NOR5With1-4alkylhalogenide, halogeno,3-7cycloalkyl, O(CO)1-4of alkyl, C1-4alkyl(SO)0-4of alkyl, C1-4alkyl(SO2)0-4Alki is a, (SO)0-4of alkyl, (SO2)0-4of alkyl, OC1-4of alkyl, C1-4R5and C0-4aNR5R6;

Q is selected from the group consisting of geterotsiklicheskie and heteroaryl;

R2and R3independently selected from the group consisting of: hydroxy, C0-6alkylene, oxo, =NR5, =NOR5With1-4alkylhalogenide, halogeno,1-6of alkyl, C3-7cycloalkyl,0-6alkylaryl,0-6alkylglycerol, C1-6alkylcyclohexane,0-6alkylchlorosilanes, OS1-4of alkyl, OC0-6alkylaryl, O(CO)1-4of alkyl, (CO)OS1-4of alkyl, C0-4alkyl(S)With0-4of alkyl, C1-4alkyl(SO)0-4of alkyl,

C1-4alkyl(SO2)0-4of alkyl, (SO)0-4of alkyl, (SO2)0-4of alkyl, C1-4R5With0-4aNR5R6and 5 - or 6-membered ring containing atoms independently selected from C, N, O and S, which may be condensed with a 5 - or 6-membered ring containing atoms independently selected from the group consisting of C, N and O, and where the specified ring and a specified condensed ring may be substituted by one or more A;

where any C1-6alkyl, aryl or heteroaryl defined under R1, R2and R3may be substituted by one or more than one;

And selected from the group SOS is oasa from: hydrogen, hydroxy, halogeno, nitro, oxo, C0-6alkylene,0-4alkyls3-6cycloalkyl, C1-6of alkyl, -OS1-6of alkyl, C1-6alkylhalogenide, OC1-6alkylhalogenide,2-6alkenyl,0-6alkylaryl,0-6R5OS2-6R5With0-6SR5OS2-6SR5, (CO)R5, O(CO)R5OS2-6alkylene, OS1-6alkyls2R5, O(CO)OR5OS1-6alkyl(CO)R5C1-6alkyl(CO)R5, NR5OR6C0-6NR5R6OC2-6NR5R6C0-6alkyl(CO)NR5R6OC1-6alkyl(CO)NR5R6OC2-6aNR5(CO)R6C0-6aNR5(CO)R6C0-6NR5(CO)NR5R6, O(CO)NR5R6C0-6alkyl(SO2)NR5R6OC2-6alkyl(SO2)NR5R6C0-6aNR5(SO2R6OC2-6aNR5(SO2R6, SO3R5C1-6aNR5(SO2)NR5R6OS2-6alkyl(SO2R5With0-6alkyl(SO2R5With0-6alkyl(SO)R5OS2-6alkyl(SO)R5and 5 - or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;

R5and R6independently selected from H, C1-6of alkyl, C3-7cycloalkyl and aryl is;

m is selected from 0, 1, 2, 3 or 4;

n is selected from 0, 1, 2, 3 or 4;

p is selected from 0, 1, 2, 3,or 4

and its salt or hydrate.

In an additional aspect of the invention proposed pharmaceutical composition containing a therapeutically effective amount of the compounds of formula I and a pharmaceutically acceptable diluent, excipients and/or inert carrier.

In yet another additional aspect of the invention proposed pharmaceutical composition comprising a compound of formula I for use in the treatment of disorders mediated by mGluR5 receptor, and for use in the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders.

In yet another additional aspect of the invention proposed compound of formula I for use in therapy, in particular for the treatment of disorders mediated by mGluR5 receptor, and for the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders.

Another aspect of the invention is the use of compounds of formula X for the manufacture of drugs for the treatment or prevention of obesity and conditions associated with obesity, as well as for the treatment of eating disorders by suppressing excessive food intake and obesity, which is its result, and the e complications related.

In another aspect of the invention the methods of obtaining compounds of formula I and intermediate compounds used for their production.

These and other aspects of the present invention are described in more detail below.

DETAILED description of the INVENTION

The present invention is to provide compounds exhibiting activity at metabotropic glutamate receptors (mGluR), in particular when mGluR5 receptors.

Listed below are definitions of various terms used in the description and the claims, to describe the present invention.

For the avoidance of doubt it should be understood that when in this description of the group referred to as 'defined here above', 'defined in the description above' or 'defined above', this group covers the first face and the most broad definition, and all and every other definitions for this group.

For the avoidance of doubt it should be understood that in this description of 'C1-6' means carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Similarly 'C1-3' means carbon group having 1, 2 or 3 carbon atoms.

In the case where the lower index represents the integer 0 (zero), the group to which the subscript indicates that this group is missing.

In this description, unless otherwise specified, the term "alkyl" includes both unbranched and branched alkyl groups and may consist of, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl or isohexyl, tert-hexyl. The term1-3alkyl has 1-3 carbon atoms and may represent a methyl, ethyl, W-propyl or isopropyl.

In this description, unless otherwise specified, the term "cycloalkyl" refers to substituted saturated cyclic hydrocarbon ring system. The term "C3-7cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In this description, unless otherwise specified, the term "alkoxy" includes both unbranched and branched alkoxygroup. C1-3alkoxy may represent, but is not limited to, methoxy, ethoxy, n-propoxy or isopropoxy.

In this description, unless otherwise specified, the term "communication" may be a saturated or unsaturated bond.

In this description, unless otherwise specified, the term "halogen" and "halogen" may be fluorine, chlorine, bromine or iodine.

In this description, unless otherwise specified, the term "alkylamino" means an alkyl group as defined above, which the traveler is replaced by halogen, as explained above. The term "C1-6alkylamino" may include, but is not limited to, vermeil, deformity, trifluoromethyl, foradil, defloratin or bromopropyl. The term "co1-6alkylamino" may include, but is not limited to, formatosi, deformedarse, triptoreline, floratone or diflorasone.

In this description, unless otherwise specified, the term "alkenyl" includes both unbranched and branched alkeneamine group. The term "C2-6alkenyl" refers to alkenylphenol group having from 2 to 6 carbon atoms and one or two double bonds, and may consist of, but is not limited to, vinyl, allyl, propenyl, Isopropenyl, butenyl, Isobutanol, crotyl, pentenyl, isopentenyl and hexenyl.

In this description, unless otherwise specified, the term "quinil" includes both unbranched and branched alkyline group. The term2-6quinil refers to alkenylphenol group having from 2 to 6 carbon atoms and one or two triple bond, and may consist of, but is not limited to, ethinyl, propargyl, butynyl, Isobutanol, pentenyl, isopentenyl and hexenyl.

In this description, unless otherwise specified, the term "aryl" refers to a possibly substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Sample and and suitable values of the term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, Intel and indenyl.

In this description, unless otherwise specified, the term "heteroaryl" refers to substituted monocyclic or bicyclic unsaturated ring system containing at least one heteroatom independently selected from N, O or S. Examples of "heteroaryl" may represent, but are not limited to, thiophene, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl and thiadiazolyl, benzoimidazolyl, benzoxazolyl, tetrahydrochloride, tetrahydropyrimidines, benzofuran, indolyl, isoindolyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazopyridine, oxazolopyridine, triazolopyridine, pyridyl, imidazopyridines, oxazolopyridine, triazolopyridazines and purines.

In this description, unless otherwise specified, the term "alkylaryl", "alkylglycerol and alkylsilanes" refers to the Deputy, which is attached via the alkyl group to an aryl, heteroaryl and cycloalkyl group.

In this description, unless otherwise specified, the term "heteroseksualci" refers to a possibly substituted, saturated cyclic hydrocarbon ring system, where one or more than one carbon atom is replaced by a heteroatom. The term "heterotic alkyl" includes, but not limited to, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, tetrahydrothiopyran.

In this description, unless otherwise specified, the term "5 - or 6-membered ring containing atoms independently selected from C, N, O or S, includes aromatic and heteroaromatic rings, as well as carbocyclic and heterocyclic rings which may be saturated, partially saturated or unsaturated. Examples of such rings may represent, but are not limited to, furyl, isoxazolyl, isothiazolin, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolyl, triazolyl, morpholinyl, piperazinil, piperidyl, piperidinyl, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydropyranyl, thiomorpholine, phenyl, cyclohexyl, cyclopentyl and cyclohexenyl.

In this description, unless otherwise specified, the term ' =NR5" and "=NOR5includes imino - and oxime-group bearing a substituent R5or can represent a group or part of a group, including, but not limited to, aminoalkyl, aminoketone, aminoethoxy, amicin, hydroxyamides and alkoxyamines.

In the case where the lower index represents the integer 0 (zero), the group that applies to this is the lower index, indicates that this group is absent, i.e. there is a direct relationship between the groups.

In this description, unless otherwise specified, the term "condensed ring" refers to two rings that share two common atom.

In this description, unless otherwise specified, the term "bridge" means a molecular fragment that contains one or more than one atom or bond connecting two located at a distance from each other atom in the ring, forming, thus, either bi-or tricyclic system.

One embodiment of the invention relates to compounds of formula I

where

R1selected from aryl and heteroaryl;

R1attached to R through a carbon atom on the ring R and is selected from the group consisting of: hydroxy, halogeno, nitro, C1-6alkylhalogenide, OC1-6alkylhalogenide, C1-6of alkyl,

OC1-6of alkyl, C2-6alkenyl, OS2-6alkenyl,2-6the quinil, OS2-6the quinil,0-6alkyls3-6cycloalkyl, OS0-6alkyls3-6cycloalkyl,0-6alkylaryl, OS0-6alkylaryl, SNO, (CO)R5, O(CO)R5, O(CO)OR5C(CNR5OR5With1-6R5,

OS2-6OR5With1-6alkyl(CO)R5OC1-6alkyl(CO)R5With0-6alkyls2R5OS1-6alkyl is O 2R5With0-6alkylene, OS2-6alkylene,0-6NR5R6OS2-6NR5R6C1-6alkyl(CO)NR5R6OC1-6alkyl(CO)NR5R6C0-6NR5(CO)R6OC2-6aNR5(CO)R6With0-6aNR5(CO)NR5R6With0-6SR5OC2-6SR5With0-6alkyl(SO)R5OS2-6alkyl(SO)R5With0-6SO2R5OS2-6SO2R5,

C0-6alkyl(SO2)NR5R6OS2-6alkyl(SO2)NR5R6C0-6NR5(SO2R6OC2-6aNR5(SO2R6With0-6aNR5(SO2)NR5R6OC2-6aNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6C0-6aNR5(CO)OR6OC2-6aNR5(CO)OR6, SO3R5and 5 - or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;

X1selected from the group consisting of N, NR4and CR4;

X2selected from the group consisting of C and N;

X3selected from the group consisting of CR4, N and O;

X4selected from the group consisting of CR4, N, NR4and;

X5selected from the group consisting of ties, CR4R4 ', NR4, O, S, SO and SO2;

X6selected from the group consisting of CR4and N;

X7selected from the group consisting of C and N;

R4independently selected from the group consisting of hydrogen, hydroxy, C1-6of alkyl,

With0-6alkylene, oxo, =NR5, =NOR5With1-4alkylhalogenide, halogeno,3-7cycloalkyl, O(CO)1-4of alkyl, C1-4alkyl(SO)0-4of alkyl, C1-4alkyl(SO2)0-4of alkyl, (SO)0-4of alkyl, (SO2)0-4of alkyl, OC1-4of alkyl, C1-4R5and C0-4NR5R6;

Q is selected from the group consisting of geterotsiklicheskie and heteroaryl;

R2and R3independently selected from the group consisting of: hydroxy, C0-6alkylene, oxo, =NR5, =NOR5With1-4alkylhalogenide, halogeno,1-6of alkyl, C3-7cycloalkyl,0-6alkylaryl,0-6alkylglycerol, C1-6alkylcyclohexane,0-6alkylchlorosilanes, OS1-4of alkyl, OC0-6alkylaryl, O(CO)1-4of alkyl, (CO)OS1-4of alkyl, C0-4alkyl(S)With0-4of alkyl, C1-4alkyl(SO)0-4of alkyl,

C1-4alkyl(SO2)0-4of alkyl, (SO)0-4of alkyl, (SO2)0-4of alkyl, C1-4R5With0-4aNR5R6and 5 - or 6-membered ring containing atoms independently select the data from, N, O and S, which may be condensed with a 5 - or 6-membered ring containing atoms independently selected from the group consisting of C, N and O, and where the specified ring and a specified condensed ring may be substituted by one or more A;

where any C1-6alkyl, aryl or heteroaryl defined under R1, R2and R3may be substituted by one or more than one;

And selected from the group consisting of: hydrogen, hydroxy, halogeno, nitro, oxo, C0-6alkylene,0-4alkyls3-6cycloalkyl, C1-6of alkyl, -OC1-6of alkyl, C1-6alkylhalogenide, OC1-6alkylhalogenide,2-6alkenyl,0-3alkylaryl,0-6R5OS2-6R5With0-6SR5OC2-6SR5, (CO)R5, O(CO)R5OS2-6alkylene, OS1-6alkyls2R5, O(CO)OR5OS1-6alkyl(CO)R5C1-6alkyl(CO)R5, NR5OR6C0-6NR5R6OC2-6NR5R6C0-6alkyl(CO)NR5R6OC1-6alkyl(CO)NR5R6OC2-6aNR5(CO)R6With0-6NR5(CO)R6With0-6aNR5(CO)NR5R6, O(CO)NR5R6C0-6alkyl(SO2)NR5R6OS2-6alkyl(SO2)NR5R6C0-6aNR5(S 2R6OC2-6aNR5(SO2R6, SO3R5C1-6aNR5(SO2)NR5R6OS2-6alkyl(SO2R5With0-6alkyl(SO2R5With0-6alkyl(SO)R5OS2-6alkyl(SO)R5and 5 - or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;

R5and R6independently selected from H, C1-6of alkyl, C3-7cycloalkyl and aryl;

m is selected from 0, 1, 2, 3 or 4;

n is selected from 0, 1, 2, 3 or 4;

p is selected from 0, 1, 2, 3 or 4, and

their salts or hydrate.

Another embodiment of the invention relates to compounds:

4-(5-{2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)-pyridine;

3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine-1-carboxylic acid;

2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine;

2-[3-(3-chloro-phenyl-[1,2,4]oxadiazol-5-yl]-4-methyl-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine;

tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine-1-carboxylic acid;

2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine;

2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-4-methyl-piperazine;

2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-[1,2,4]triazole-3-yl}piperidine;

4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)pyridine;

2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-1-[5-(4-methoxyphenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]piperidine;

[4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)phenyl]dimethyl-amine;

[4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)-benzyl]-dimethyl-amine;

{2-[4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)-phenoxy]-ethyl}-dimethyl-amine;

(R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

(S)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

(R)-2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)-phenyl]-4-methyl-4H[1,2,4]triazole-3-yl}piperidine;

(S)-2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H[1,2,4]triazole-3-yl}piperidin;

(R)-4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)pyridine;

(S)-4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H[1,2,4]triazole-3-yl)pyridine;

4-[5-(5-{2-[5-(3-chlorophenyl)-isoxazol-3-yl]pyrrolidin-1-yl}-4-cyclopropyl-4H[1,2,4]triazole-3-yl)pyridine-2-yl]-morpholine;

4-[5-(542-[5-(3-chlorophenyl)-isoxazol-3-yl]pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)pyridine-2-yl]-morpholine;

3-(5-{2-[5-(3-chlorophenyl)-isoxazol-3-yl]pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-pyridine;

4-(5-{2-[5-(3-chlorophenyl)-isoxazol-3-yl]pyrrolidin-1-yl}-4-cyclopropyl-4H[1,2,4]triazole-3-yl)-pyridine;

3-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-4-(5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[5-(3-chlorophenyl)-isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-3-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[5-(3-chlorophenyl)-isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[5-(3-chlorophenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-3-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[5-(3-chlorophenyl)-isoxazol-3-yl]-4-[5-(6-methoxy-pyridin-3-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methoxypyridine-4-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(5-herperidin-3-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[5-(3-CHL is henyl)-isoxazol-3-yl]-4-[5-(5-herperidin-3-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-2-yl-4H[1,2,4]triazole-3-yl)-morpholine;

4-[5-(5-herperidin-3-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]morpholine;

3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H[1,2,4]triazole-3-yl)-morpholine;

3-[5-(3-chlorophenyl)-isoxazol-3-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine;

3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-3-yl-4H[1,2,4]triazole-3-yl)-morpholine and

3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-[5-(3,5-differenl)-4-methyl-4H[1,2,4]triazole-3-yl]-morpholine.

This invention relates to polycyclic compounds of the formula I, having the variable R. In embodiments of the invention, R represents aryl. In specific embodiments of the invention, R represents phenyl.

In embodiments of the invention m is 1 or 2.

In specific embodiments of the invention R is a phenyl having one or two substituent R1. In more specific embodiments of the invention, when there is one substituent R1this Deputy is in position 3 of the phenyl relative to the X2. In other specific embodiments of the invention, when there are two Deputy R1these substituents are in positions 2 and 5 of the phenyl relative to the X2.

In another embodiment of the invention R1selected from the group consisting of: in which of aroda, halogeno, C1-6alkylhalogenide, OC1-6alkylhalogenide, C1-6of alkyl, OC1-6of alkyl, C1-6R5With0-6alkylene,0-6NR5R6. In yet another embodiment of the invention R1selected from the group consisting of Cl, F, Me, OMe, CF3, OCF3and CN. In yet another embodiment of the invention R1represents Cl.

In embodiments of the invention X7is a C. In other embodiments of the invention X2is a C. In the preferred embodiments of the invention at least one of X2and X7is a C.

In another embodiment of the invention X3selected from N and O.

The invention additionally relates to compounds of formula I, where X2represents With. Embodiments of the invention include those in which X1represents N or CR4. In an additional embodiment of the invention, when X3represents Oh, then X4represents N, and when X3represents N, then X4represents O.

In another embodiment of the invention X2represents N. In a further embodiment of the invention X1represents N. In yet another additional embodiment of the invention X3represents N and X4represents N or CR4.

In another embodiment of the image is to be placed X 5selected from the group consisting of CR4R4', NR4, O, S, SO and SO2. In an additional embodiment of the invention X5selected from the group consisting of CR4R4', NR4and O. In yet another additional embodiment of the invention X5selected from the group consisting of O and NR4.

Specific embodiments of the invention include those in which the ring containing X1X2X3and X4selected so that the formed ring is tetrazole, triazole, oxadiazole, oxazole, isoxazole or imidazole ring. Preferably this ring is tetrazol, oxadiazole or isoxazol.

In embodiments of the invention X6represents N. In further embodiments of the invention X5selected from O and NR4. In further embodiments of the invention X5selected from CR4R4'.

In specific embodiments of the invention, when the ring containing X1X2X3and X4is tetrazol, X6represents N and X5represents CR4R4'. In another specific embodiment of the invention, when the ring containing X1X2X3and X4selected from oxadiazole and isoxazol, X6represents N and X5selected from O and NR4.

Another is lewinii invention R 4and R4independently selected from the group consisting of: hydrogen, C1-6of alkyl, C1-6alkylhalogenide, halogeno.

The present invention relates to compounds of formula I, having the ring Q. Embodiments of the invention include those in which Q represents heteroaryl. In preferred embodiments, Q is selected from the group consisting of:

a)b)in)

In a more preferred embodiment of the invention, the ring Q represents a

a)

Embodiments of the invention include those in which R1and R2selected from the group consisting of: hydrogen, C1-4alkylhalogenide,1-6of alkyl, C3-6cycloalkyl,0-6alkylaryl and C0-6alkylglycerol.

In one another embodiment of the invention any variable C1-6alkyl, aryl or heteroaryl defined under R1, R2and R3may be substituted by one or more than one Deputy A. Specific embodiments of the invention include those in which a is selected from the group consisting of: hydrogen, hydroxyl, halogeno,0-6alkylene, C1-6of alkyl, -OC1-6of alkyl, C1-6alkylhalogenide, OS1-6alkylhalogenide.

Embodiments of the invention include salts formed by compounds of formula I. the Salts for the applications in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in obtaining compounds of formula I.

A suitable pharmaceutically acceptable salt of the compounds according to the invention is, for example, salt accession acid, for example, inorganic or organic acids. In addition, a suitable pharmaceutically acceptable salt of the compounds according to the invention is a salt of an alkali metal, alkali earth metal salt or a salt with an organic base.

Other pharmaceutically acceptable salts and methods of obtaining these salts can be found, for example, in Remington''s Pharmaceutical Sciences (18thEdition, Mack Publishing Co.) 1990.

Some compounds of formula I may have chiral centres and/or geometric isomerism (E - and Z-isomers), and it should be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.

The invention also relates to any and all tautomeric forms of compounds of formula I.

The invention also relates to hydrate and solvate forms of the compounds of formula I.

The pharmaceutical composition

According to one aspect of the present invention proposed a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compounds of formula I or its salt, solvate or solvated salts in combination with one or more h is m one pharmaceutically acceptable diluent, excipients and/or inert carrier.

The composition may be in a form suitable for oral administration, such as tablets, pills, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration, for example, in the form of ointment, patch, or cream or for rectal administration, for example, in the form of a suppository.

In General, the above compositions can be manufactured in conventional manner using one or more than one of the common excipients, pharmaceutically acceptable diluents and/or inert carriers.

Suitable daily doses of the compounds of formula I in the treatment of a mammal, including humans, are from about 0.01 to 250 mg/kg body weight by oral administration and from about 0.001 to 250 mg/kg body weight at parenteral administration.

A typical daily dose of the active ingredients varies within a wide range and will depend on various factors, such as relevant indication, severity of the disease to be treated, the route of administration, age, weight and sex of the patient and specific applicable connection, and can be determined by the treating physician.

Medical use

Detected h what about the connection of the present invention exhibit a high degree of efficiency and selectivity in respect of individual subtypes of metabotropic glutamate receptors (mGluR). Accordingly, it is expected that compounds of the present invention are useful in the treatment of conditions associated with excitatory activation of mGluR5, and for inhibiting neuronal damage caused by excitatory activation of mGluR5. These compounds can be applied in order to cause the inhibitory effect against mGluR5 in mammals, including humans.

The receptor mGluR group I, including mGluR5, have high expression in the Central and peripheral nervous system and in other tissues. Therefore, expected that the compounds according to the invention are well suited for the treatment of mGluR5-mediated disorders such as acute and chronic neurological and psychiatric disorders, gastrointestinal disorders, and chronic and acute pain disorders.

The invention relates to compounds of formula I, as defined here above for use in therapy.

The invention relates to compounds of formula I, as defined here above, for use in the treatment of mGluR5-mediated disorders.

The invention relates to compounds of formula I, as defined here above, for use in the treatment of Alzheimer's disease, senile dementia, dementia caused by AIDS, Parkinson's disease, amyotrophic lateral sclerosis, horii's chorea, migraine, epilepsy, schizophrenia, depression, anxiety is, acute anxiety, ophthalmologic disorders such as retinopathy, diabetic retinopathy, glaucoma, auditory neuropathic disorders such as tinnitus, neuropathies induced by chemotherapy, post herpetic neuralgia and trigeminal neuralgia, tolerance, dependency syndrome fragile X-chromosome, autism, mental retardation, schizophrenia and down syndrome.

The invention relates to compounds of formula I, as defined here above, for use in the treatment of pain related to migraine, inflammatory pain, neurotic diseases pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, pain in the lower back, post-operative pain and pain associated with various conditions including angina, renal or biliary colic, menstruation, migraine and gout.

The invention relates to compounds of formula I, as defined here above, for use in the treatment of stroke, head injury, damage due to hypoxia and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.

The present invention also relates to the use of compounds of formula I, as defined here above, in the manufacture of drugs for the treatment of diseases mediated by the receptor mGluR group I, and any disorder of the item is listed above.

One of the embodiments of the invention relates to the use of compounds of formula I in the treatment of gastrointestinal disorders.

Another embodiment of the invention relates to the use of compounds of formula I for the manufacture of drugs for the inhibition of transient relaxation of the lower esophageal sphincter for the treatment of GERD, for the prevention LCD reflux, for the treatment of regurgitation, asthma, treatment of laryngitis, treatment of lung disease and to control bad gaining weight.

An additional embodiment of the invention is the use of compounds of formula I for the manufacture of drugs for the treatment or prevention of functional gastrointestinal disorders such as functional dyspepsia (FD). Another aspect of the invention is the use of compounds of formula I for the manufacture of drugs for the treatment or prevention of irritable bowel syndrome (IBS), such as irritable bowel syndrome prevalence of constipation, IBS with predominant diarrhea or IBS with alternating predominance of intestinal peristalsis.

In an additional aspect of the invention proposed pharmaceutical composition containing a therapeutically effective amount of the compounds of formula I and a pharmaceutically acceptable diluent, excipients and/or inert carrier.

In yet another further the recreational aspect of the invention proposed pharmaceutical composition, containing the compound of the formula I, for use in the treatment of disorders mediated by mGluR5 receptors, and for use in the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders.

In yet another additional aspect of the invention proposed compound of formula I for use in therapy, in particular for the treatment of disorders mediated by mGluR5 receptors and for the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders.

An additional aspect of the invention is the use of compounds of formula I for the manufacture of drugs for the treatment or prevention of obesity and conditions associated with obesity, as well as for the treatment of eating disorders by suppressing excessive eating and obesity, which is its outcome, and complications associated with it.

In another aspect of the invention the methods of obtaining compounds of formula I and intermediate compounds used for their production.

These and other aspects of the present invention are described in more detail here below.

The invention is also a method of treatment of mGluR5-mediated disorders and any disorder listed above in a patient suffering from specified when standing or with the risk of such disorders, includes introduction to the patient an effective amount of the compounds of formula I, as defined here above.

The dose required for therapeutic or prophylactic treatment of a particular disorder will necessarily vary depending on the host organism, which are treated, route of administration and the severity of the disorder to be treated.

In the context of the present description, the terms "therapy" and "treatment" include the prevention or prophylaxis if there is no specific guidance on the opposite. The terms "therapeutic" and "therapeutically" should be understood accordingly.

In this description, unless otherwise specified, the term "antagonist" and "inhibitor" should indicate a connection that is in any way, partially or completely blocks the biochemical path signal conversion, resulting in response by ligand.

The term "disorder", unless otherwise indicated, means any condition and disease associated with the activity of metabotropic glutamate receptors.

Non-medical use

In addition to their use in therapeutic medicine, the compounds of formula I, their salts or hydrates are also useful as pharmacological tools in the development and standardisation of test systems in vitro and in vivo to assess the effects of inhibitors of the activity associated with mGlu, in laboratory animals, such as cats, dogs, rabbits, monkeys, rats and mice, as part of studies of new therapeutic agents.

Ways to get

In another aspect of the present invention the methods of obtaining compounds of the formula I or their salts, or hydrates. Here we describe methods for obtaining compounds of the present invention.

Throughout the description of such methods should be clear that various reagents and intermediate compounds administered, where appropriate, the protective groups and their subsequent destruction in a way that is easily understandable to experts in the field of organic synthesis. Generally accepted methods of use of such protective groups, and examples of suitable protective groups are described, for example, in "Protective Groups in Organic Synthesis, T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York (1999). You should also understand that the transformation of a group or substituent to another group or Deputy by chemical manipulations can be performed at any intermediate connection or the final product on the synthetic route to the final product, in which the possible type of transformation is limited only by your own incompatibility with other functional groups, which carries the molecule at this stage, conditions or reagents used in the transformation. Such self-incompatibility is the way to overcome them by appropriate transformations and stages of synthesis in an appropriate order will be easily understood by experts in the field of organic synthesis. Examples of the transformations below, and it should be clear that the described transformation is not limited to only conventional groups or substituents, which are examples of transformations. Links and descriptions to other suitable transformations are given in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" R.C.Larock, VHC Publishers, Inc. (1989). Links and descriptions to other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4thEd. McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill (1994). Methods purification of intermediates and final products include, for example, chromatography with normal and reversed phase column or rotating plate, recrystallization, distillation and extraction liquid-liquid or solid-liquid extraction, which will be easily understood by professionals in this area of technology. Definitions of the substituents and groups are as in formula I, except in those cases where they are defined differently. The term "room temperature" and "ambient temperature" should be marked, if not stated otherwise, the temperature from 16 to 25°C.

The term "flavobacteria", unless otherwise specified, should be identified, with reference to the solvent used, the temperature at the boiling point of the specified solvent or higher.

Reduction

aq.water
bar.atmosphere
BINAP2.2 bis(diphenylphosphino)-1,1'-binaphthyl
Boc, the BOCtert-butoxycarbonyl
CDIN,N'-carbonyldiimidazole
dbadibenzylideneacetone
DCCN,N-dicyclohexylcarbodiimide
DHMdichloromethane
DEAN,N-diisopropylethylamine
DIBAL-Hdiisobutylaluminum
DICN,N'-diisopropylcarbodiimide
DMAPN,N-dimethyl-4-aminopyridine
DMFdimethylformamide
DMSOthe sulfoxide
DPPF1,1'-bis(diphenylphosphino)ferrocene
EA or EtOActhe ethyl acetate
EDC, EDCIthe hydrochloride of N-[3-(dimethylamino)propyl]-N'-
ethylcarbodiimide
Etethyl
Et2Odiethyl ether
Etliodata
EtOHethanol
Et3Nthe triethylamine
Fmoc, FMOC9-fluorenylmethoxycarbonyl
hhour(s)
HBTUO-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate
HetArheteroaryl
HOBtN-hydroxybenzotriazole
HPLChigh performance liquid chromatography
LCMSHPLC mass spectrum
MCPBA meta-chlorbenzene acid
Memethyl
MeCNacetonitrile
Mellogmean
MeMgClMetalmania chloride
MeOHmethanol
minminutes
NaOAcsodium acetate
nBunormal butyl
nBuLi, n-BuLi1-utility
NCSN-chlorosuccinimide
NMRnuclear magnetic resonance
in the so-calledduring the night
SLAacetate
OMsester mesilate or methanesulfonate
OTsester tosylate, toluensulfonate or 4-methylbenzenesulfonate
PPTS pyridinium para-toluensulfonate
pTsOHpair-toluensulfonate acid
CT, CT, K.T.room temperature
us.rich
TPVsolid-phase extraction (usually containing silica gel)
TBAFtetrabutylammonium fluoride
tBu, t-Butert-butyl
tBuOH, t-BuOHtert-butanol
TEAthe triethylamine
THFtetrahydrofuran

The intermediate compounds

Intermediate compounds obtained in the following ways synthesis, useful for further compounds of formula I. Other source materials either are commercially available or can be obtained by methods described in the literature. The following synthesis pathway are non-limiting examples of a receipt that you can use. Specialists in the art will understand that you can use the others who Ooty.

Synthesis of isoxazoles

Aldehydes of formula vi where X5is the same as defined in formula I, can be used to obtain isoxazoles. A commercially available derivative of the acid of formula ii, where X5represents O, S, S, N-R2and N-G2(G2represents a protective group, orthogonal to G1), can be subjected to N-protection with obtaining compounds of formula iii, where G1represents a protective group such as BOC or Fmoc, using methods well known in the art. The acid group in the compounds of formula iii can be converted to alkilany ether of the formula iv, such as, for example, methyl or ethyl ester, which can be converted to aldehydes of formula vi using a mild reducing agent such as DIBAL-H in a solvent such as toluene, at a low temperature, for example -78°C. higher temperatures or stronger reducing agents can lead to the formation of primary alcohols of the formula v, either exclusively or mixed with aldehydes of the formula vi. Other functional groups such as a primary alcohol in compounds of formula v, nitrile in the compounds of formula vii and an amide group Weinrebe (Weinreb) in the compounds of formula viii can be converted to aldehydes of formula vi using techniques developed in the art. In addition, the acid of formula ii can be converted into NITRILES of the formula vii by methods known in the art, for example by conversion of the acid primary amide followed by dehydration to the nitrile.

The aldehydes of the formula vi can be converted to oximes of formula ix by treatment with hydroxylamine in a solvent such as pyridine, at a temperature of from 0°C. to room temperature. Isoxazoles of formula x can be obtained by chlorination Asimov formula ix using a reagent such as N-chlorosuccinimide (NCS), with subsequent 1,3-dipolar-cyclopentadiene with suitable R-substituted acetylene, where R can be either (R1)m-P or a masking group which can subsequently be converted into (R1)m-P (Steven, R. V. et al. J. Am. Chem. Soc. 1986, 108, 1039). Intermediate isoxazol x can then be subjected to removal of protection with obtaining xi standard methods.

Isoxazoles of formula x, where R is a masking group, can be obtained in this way, and the masking group can be converted into (R1)m-P after the formation of isoxazoline rings. For example, in the use of trialkylaluminium formed trialkylsilanes, which can be subjected to reactions such to the to, for example, cross combination type of Calm, for the introduction of aryl substituents by combining with the corresponding arylalkenes.

Synthesis of [1,2,4]-oxadiazole

Carboxylic acids of formula iii can be used to obtain the corresponding 3-R-substituted [1,2,4]oxadiazole formula xii by activation of the acid group, attaching an appropriate R-substituted of hydroxyamine with the formation of ester followed by cyclization to oxadiazole. [Cm. Tetrahedron Lett., 2001, 42, 1495-98, Tetrahedron Lett., 2001, 42, 1441-43, and Bioorg. Med. Chem. Lett. 1999, 9, 1869-74]. The acid may be activated in the form of a mixed anhydride using alkylchloride, such as isobutylparaben, in the presence of a base, such as triethylamine, in a suitable solvent, such as THF. Alternative you can use other well-known techniques of acid activation, including activation of the acid in situ by using a reagent, such as EDCI, DCC, DIC, or HBTU in the presence or in the absence of coreagent, such as HOBt or DMAP, in a suitable solvent, such as DMF, DHM, THF or MeCN, at a temperature of from -20 to 100°C. the Cyclization can be accomplished by heating in a solvent such as pyridine or DMF, under microwave irradiation or by the use of catalysts, such as TBAF. R-substituted hydroxyamine can is to be obtained from NITRILES by addition of hydroxylamine hydrochloride in the presence of a base, such as NaOH, NaHCO3or Na2CO3with the formation of free hydroxylamine in a solvent such as ethanol or methanol or the like, at temperatures from room temperature to 100°C.

For compounds of formula ii, where X is a N-G2, offered a convenient way to obtain the free NH of the compounds of formula I. for Example, a commercially available derivative of the acid of formula iia, where X represents the N-Boc, can be subjected to the orthogonal N-protective group G, such as, for example, Fmoc. The resulting intermediate compound iiia can be transformed into the corresponding [1,2,4]-oxadiazole using the above methods. When Fmoc is used as one of the protective groups, the means of education [1,2,4]-oxadiazole ring comprising a base, such as activating chloroformate in the presence of triethylamine, or ring closure in pyridine, can ensure the removal of the protective group to obtain xiiia directly without isolation of the intermediate 2-(3-R-[1,2,4]oxadiazol-5-yl)-piperazine.

5-R-substituted [1,2,4]oxadiazole formula xiib can be obtained from the NITRILES of the formula vii by efficient rearrangement of substituents attached to the [1,2,4]-oxadiazole. The NITRILES of the formula vii interact with hydroxylamine to the described above, obtaining intermediate hydroxyamide and can be turned into [1,2,4]oxadiazole formula xiib using Alliluyeva agent containing the group R, using the method described above for the conversion of compounds of formula iii, the compounds of formula xii.

Synthesis of tetrazolo

The NITRILES of the formula vii can be used in obtaining the appropriate tetrazolo formula xviii by treatment with azide, such as NaN3, LiN3, azide trialkylamine or trimethylsilylmethyl, preferably with a catalyst, such as oxide dibutylamine or ZnBr2in solvents such as DMF, water or toluene, at a temperature of from 80 to 200°C. by conventional heating or microwave radiation [see J. Org. Chem. 2001, 7945-7950; J. Org. Chem. 2000, 7984-7989 or J. Org. Chem. 1993, 4139-4141].

N2-atilirovanie 5-substituted tetrazoles described in the literature using a range of partners combinations. The compounds of formula xviii, where R represents an aryl group, can be obtained using, for example, Baranovich acids of formula xv [grouped IN(OH)2], or the corresponding iodonium salts of formula xvii [with grouping I+-Ar], or the relevant diacetato of triarylbismuth [grouped Bi(OAc)2Ar2] as progress agents, mediated by transition metals [see Tetrahedron Lett. 2002, 62216223; Tetrahedron Lett. 1998, 2941-2944; Tetrahedron Lett. 1999, 2747-2748]. With baronowie acids using stoichiometric amount of Cu(II)-acetate and pyridine in solvents such as dichloromethane, DMF, dioxane or THF, at temperatures from room temperature to 100°C. With iodonium salts using catalytic amounts of Pd(II)-compounds, such as Pd(dba)2or Pd(OAc)2together with catalytic amounts of Cu(II)-carboxylates, such as Cu(II)-phenylcyclopropanecarboxylic, and bidentate ligands such as BINAP or DPPF, in solvents such as t-BuOH at a temperature of from 50 to 100°C. diacetate of triarylbismuth can be used in catalytic amounts of copper acetate in the presence of N,N,N',N'-tetramethylguanidine in a suitable solvent, such as THF, when heated at a temperature of 40-60°C. Itaniemi salt of the formula xvi can be obtained, for example, from the corresponding acids Baranovich by treating aromatic compounds, substituted hypervalent iodine, such as hydroxyl(tosyloxy)iadanza or Phl(OAc)2×2TfOH, in dichloromethane or the like [see Tetrahedron Lett. 2000, 5393-5396]. Diacetate of triarylbismuth can be obtained from ariline bromides with trichloride bismuth in a suitable solvent, such as THF, boiling under reflux, with getting triarylbismuth which is then oxidised to diacetate, ISOE is isua oxidizing agent, such as perborate sodium, acetic acid [Synth. Commun. 1996, 4569-75].

Synthesis of [1,2,3]triazoles

The keto-aldehydes of the formula xix can be obtained from compounds of formula ii via activation of the acid group, interaction with diazomethane with the formation of intermediate alpha diazoketone and trapping acid, such as acetic acid, with formation of an intermediate alpha-acetylated ketone, which can be converted into compounds of formula xix by hydrolysis and oxidation [Cm. Bioorg. Med. Chem. 2002, 10, 2199-2206]. The keto-aldehydes of the formula xix will interact with arylhydrazines with acetic acid and water at a temperature of from -20 to 120°C with the formation of bis-hydrazones of formula XX, which can undergo cyclization in the presence of copper sulfate (II) in aqueous mixtures, for example, dioxane or THF at a temperature from -20 to 120°C with the formation of [1,2,3]triazoles of formula xxi [Cm. J. Med. Chem. 1978, 21, 1254-60 and J. Org Chem. 1948, 13, 807-14]. Protection of compounds of formula xxi can be removed, as described above, to obtain the secondary amine of formula xxii.

Synthesis of ring Q: amino-triazole

Amines of formula xi, xiii, xviii and xxii to the remote protection can be subjected to successive formation of the thiourea, the methylation and the formation of a triazole with obtaining compounds of formula I where ring Q, not only is em a triazole, attached to the newly protected secondary amine. Thiourea of formula xxiv can be obtained by a well-developed methods using, for example, isothiocyanate, R2SCN or 1,1-thiocarbonyl-diimidazole in the presence of R2NH2in a solvent such as methanol, ethanol and the like, at temperatures from room temperature to 100°C and is usually carried out at 60°C. Alkylation of the intermediate thioureas can be performed using alkylating agents, such as itmean or Iodate, in a solvent such as DMF, acetone, CH2Cl2at room temperature or at elevated temperatures getting estimacion formula xxv. When used yodaiken, the product can be isolated in the form of salts hydroiodide [see Synth. Commun. 1998, 28, 741-746]. The compounds of formula xxv can interact with acylhydrazines or with hydrazine and then with allermuir agent with the formation of intermediate compounds that can be cyklinowanie to 3-aminotriazole formula xxvi by heating at 50-200°C. in a suitable solvent, such as pyridine or DMF.

Conversion to other functional groups

It should be clear that, when additional functional groups present in the compounds of formula I or any predecessor, this functional group is s can be used to introduce other substituents or functional groups of the ways, developed in the art, when no other incompatible reactive sites. For example, in compounds of formula xxvii, which can be obtained from orthogonal substituted bis-amine xiiia described above, the secondary amine obtained by removing protection G2, can undergo alkylation or reductive amination with the formation of the tertiary amine of formula xix. In addition, other substituents, are not depicted in detail on the schemes, may be present, as described in formula I, provided that such substituents do not affect the reaction described above.

The invention additionally relates to the following compounds, which can be used as intermediates in obtaining the compounds of the formula I:

methyl-4-dimethylaminomethyl-benzoate

ethyl-4-(2-dimethylamino-ethoxy)-benzoate

hydrazide 4-dimethylaminomethyl-benzoic acid

the hydrazide of 4-(2-dimethylamino-ethoxy)-benzoic acid

hydrazide 4-deformedarse-benzoic acid

Tris-(3-chloro-phenyl)-visaton

the diacetate of Tris-(3-chloro-phenyl)-vimochana

tert-butyl ester 2-hydroxymethyl-piperidine-1-carboxylic acid

4-tert-butyl ether morpholine-3,4-dicarboxylic acid

4-tert-butyl ester 1-(N-fluoren-9-ylmethyl)ether piperazine-1,2,4-tricarboxylic acid

<> tert-butyl ester 2-formyl-piperidine-1-carboxylic acid

4-tert-butyl ester 3-methyl ester morpholine-3,4-dicarboxylic acid

tert-butyl ether 3-formyl-morpholine-4-carboxylic acid

tert-butyl ester 2-cyano-piperidine-1-carboxylic acid

tert-butyl ester 2-(1H-tetrazol-5-yl)-piperidine-1-carboxylic acid

tert-butyl ester 2-(hydroxyimino-methyl)-piperidine-1-carboxylic acid

tert-butyl ether 3-(hydroxyimino-methyl)-morpholine-4-carboxylic acid

tert-butyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid

tert-butyl ester 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carboxylic acid

tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic acid

tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperazine-1-carboxylic acid

tert-butyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic acid

2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine

3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine

3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine

2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine

methylamide 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioate

methylamide 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carbothioate

methylamide 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl-morpholine-4-carbothioate

tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methylthiocarbamate-piperazine-1-carboxylic acid

methylamide 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioate

methyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-piperidine-1-carboxymethylate

methyl ester of 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-M-methyl-morpholine-4-carboxymethylate

methyl ester of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-methylmorpholin-4-carboxymethylate

tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methylsulfonyl-methyl)-piperazine-1-carboxylic acid

methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate

Examples

Hereinafter the invention will be illustrated by the following non-limiting examples.

General methods

All source materials are commercially available or previously described in the literature.

Spectra1H NMR and13With NMR were recorded on a spectrometer or Bruker 300 or a Bruker DPX400 or Varian +400, operating at 300, 400 and 400 MHz for1H NMR, respectively, using TMS or the residual signal of the solvent as a comparison, in deuterated chloroform as solvent unless otherwise stated. All chemical shifts are quoted in ppm on the δ-scale and fine splitting of the signals specified, it is to be seen from the account (s: singlet, br s: broad singlet; d: doublet; t: triplet; q: Quartet; m: multiplet).

Separation using analytical flow liquid chromatography with subsequent definitions of the mass spectrum was carried out on the installation of Waters LCMS, consisting of an Alliance 2795 (LC) and odnokletochnogo mass spectrometer ZQ. The mass spectrometer was equipped with a source of electrocapillary ions, operating in the regime of positive and/or negative ion. The voltage of the sputtering ions were ±3 kV and the mass spectrometer was scanned from m/z 100-700 when the scan time of 0.8 sec On column X-Terra MS, Waters, C8, and 2.1×50 mm, 3.5 mm, was applied a linear gradient from 5% to 100% acetonitrile in 10 mm ammonium acetate (aq.) or in 0.1% TFU (aq.). Preparative chromatography with reversed phase was carried out on automated preparative HPLC Gilson diode digital detector, using an XTerra MS C8, 19×300 mm, 7 mm, as a column.

Purification using chromatotron was performed on glass plates coated with silica gel/gypsum (Merck, 60 PF-254 with calcium sulfate) with the coating layer is 1, 2 or 4 mm, using chromatotron TC Research 7924T. Cleaning products also was performed using flash chromatography glass columns Packed with silica gel, or plastic SPE tubes pre-filled with silica gel.

Microwave heating was performed in a microwave resonator Smith Syntheizer Single-mode, giving continuous radiation at 2450 MHz (Personal Chemistry AB, Uppsala, Sweden).

Example 1

Methyl-4-dimethylaminomethyl-benzoate

Methyl-4-(methyl bromide)benzoate (4,58 g, 20 mmol) was mixed with 45% dimethylamine (5,57 ml, 2.5 mmol) in THF (50 ml) at room temperature for 30 minutes the mixture was concentrated in vacuo and the residue was diluted with water and was extracted with ether. The organic layer was dried MgSO4and concentrated in vacuum to obtain compound indicated in heading (4.0 g), as pale yellow oil.1H NMR (CDCl3) δ (m-1): 8.01 (d, 2H), 7.40 (d, 2H), 3.92 (s, 3H), 3.48 (s, 2H) and 2.26 (s, 6H).

Example 2

Ethyl-4-(2-dimethylamino-ethoxy)-benzoate

Ethyl-4-hydroxy-benzoate (16.6 g, 0.1 mol) was mixed with hydrochloride (2-chloro-ethyl)-dimethyl-amine (40 g, 0.28 mol) and K2CO3(100 g, 0,724 mol) in DMF. This mixture was heated to 150°C for 4 h and then was poured into ice water and the product was extracted into ethyl acetate. An ethyl acetate layer was washed with brine, the product was acidified using 1 N. HCl (130 ml) and an ethyl acetate layer was discarded. The acidified aqueous layer was washed with ethyl acetate, then podslushivaet 2M sodium carbonate (100 ml) and the product was again extracted into ethyl acetate. The organic layer was washed with brine, dried MgSO4, filtered and concentrated to obtain the compound indicated in heading (12,6 g, 53%) as a sticky bright yellow-max is the new oil. 1H NMR (CDCl3), δ (m-1): 8.01 (d, 2H), 6.95 (d, 2H), 4.36 (q, 2H), 4.13 (t, 2H), 2.76 (t, 2H), 2.36 (s, 6H) and 1.39 (t, 3H).

Example 3

Hydrazide 4-dimethylaminomethyl-benzoic acid

Methyl-4-dimethylaminomethyl-benzoate (4.0 g, 20 mmol) was mixed with hydrazine hydrate (9.7 ml, 200 mmol) in methanol at 80°C during the night. The mixture was concentrated in vacuo and the residue triturated with ether to obtain the connection specified in the header (3,37 g, 84,2%) as a white solid.1H NMR (DMSO-d6), δ (m-1): 9.75 (w, 1H), 7.76 (d, 2H), 7.35 (d, 2H), 4.50 (w, 2H), 3.41 (s, 2H) and 2.13 (s, 6H).

Example 4

The hydrazide of 4-(2-dimethylamino-ethoxy)-benzoic acid

Ethyl-4-(2-dimethylamino-ethoxy)-benzoate (12,6 g, 53 mmol) was mixed with hydrazine hydride (26.5 g, 0.5 mol) in ethanol at 100°C in a sealed flask overnight. The mixture was concentrated and triturated with ether to obtain the connection specified in the header (9,83 g, 82,9%) as a pale yellow solid.1H NMR (DMSO-d6), δ (m-1): 9.62 (s, 1H), 7.77 (d, 2H), 6.97 (d, 2H), 4.45 (b, 2H), 4.08 (t, 2H), 2.61 (t, 2H), and 2.20 (s, 6H).

Example 5

Hydrazide 4-deformedarse-benzoic acid

HOBt (2.2 g, 15.9 mmol) and EDCl (3.1 g, 15.9 mmol) was added to 4-deformedarse-benzoic acid (2.5 g, 13.3 mmol) in acetonitrile (25 ml) at room temperature. After two hours, was added dropwise a solution of hydrazine monohydrate (0,493 ml, 10.2 mmol) and cyclohexane 0.33 ml) in acetonitrile (5.0 ml) at 0°C. After stirring at room temperature for 2 hours the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate (4 times), dried over sodium sulfate, filtered and concentrated to obtain the compound indicated in heading (2,12 g, 79%, white solid).1H NMR (DMSO-d6), δ (m-1): 9.80 (bs, 1H), 7.88 (m, 2H), 7.34 (t, 1H), 7.23 (m, 2H), 4.50 (bs, 2H).

Example 6

Bis-(3-chloro-phenyl)-iodone tetrafluoroborate

Bis(atomic charges)(3-chlorophenyl)-λ-3-jodan received, as described in the literature [Kazmierczak, P.; Skulski, L, Synthesis 1998, 12, 1721-1723]. To a stirred mixture of 3-Chlorfenvinphos acid 0,821 g (a 5.25 mmol) and BF3·Et2O (0,78 g, 5.5 mmol) in dichloromethane (50 ml) at 0°C was added a solution of bis(atomic charges)(3-chlorophenyl)-λ-3-jodan (1.78 g, 5 mmol) in dichloromethane (50 ml) in an argon atmosphere and the reaction mixture was stirred for 1.5 hours at 0°C. was Added saturated aqueous NH4BF4(10.5 g, 100 mol) and the reaction mixture was stirred for one hour, poured into water and was extracted with dichloromethane. The organic layer was concentrated to obtain a solid residue, which is triturated with diethyl ether to obtain the connection specified in the header (whitish solid, 1.70 g, 78%).1H NMR (CDCl3), δ (m-1): 8.02 (m, 4H), 7.58 (dm, 2H), 7.4 (t, 2H).

Example 7

2 Fenell coproantibodies copper(II)

Sodium hydroxide (0,81 g, 20,25 mmol) in water (10 ml) was added to 2-phenylcyclopropanecarboxylic (32,4 g, 20 mmol) and the mixture was stirred until until the solid is fully dissolved. Was added dropwise copper sulfate(II) (2,44 g, 10 mmol) in water. The mixture was stirred for 2 h and the blue precipitate was collected by filtration, dried in vacuum and used without further purification.

Example 8

tert-Butyl ester 2-hydroxymethyl-piperidine-1-carboxylic acid

Di-tert-BUTYLCARBAMATE (8,3 g of 38.2 mmol) was added to a stirred solution of piperidinemethanol (4.0 g, or 37.4 mmol) in CH2Cl2(50 ml) was added 1 N. NaOH (50 ml, 50 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic phase was washed with water (30 ml) and brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuo to obtain the crude product, which was triturated with hexane to obtain the connection specified in the header, in the form of a white solid (4.8 g, 64%).

Example 9

4-tert-Butyl ether morpholine-3,4-dicarboxylic acid

Di-tert-BUTYLCARBAMATE (3.33 g, and 15.3 mmol) was added to a solution of morpholine-3-carboxylic acid (1.7 g, 10.2 mmol), potassium carbonate (? 7.04 baby mortality g, 51 m is ol) in acetone (5 ml) and water (10 ml) at 0°C. The resulting mixture was stirred at room temperature for 24 h, diluted with water (50 ml) and was extracted with diethyl ether (2×50 ml). The aqueous phase was treated with hydrochloric acid (2M aqueous, 100 ml), was extracted with dichloromethane (2×50 ml). The combined organic phase was washed with water (50 ml), brine (50 ml), dried (sodium sulfate), filtered and concentrated in vacuum with the separation of the desired product as a white solid (1.98 g, 84%).1H NMR (CDCl3), δ (m-1): 4.46 (m, 2H), 3.80 (m, 3H), 3.53 (m, 1H), 3.31 (m, 1H), 1.48 (d, 9H).

Example 10

4-tert-Butyl ester 1-(N-fluoren-9-ymetray)ether piperazine-1,2,4-tricarboxylic acid

A solution of 9-fluorenylmethoxycarbonyl (2,72 g, 10.5 mmol) in 1,4-dioxane (19 ml) was added dropwise to a solution of 1-tert-butyl ether piperazine-1,3-dicarboxylic acid (2.20 g, 9.6 mmol) and N,N-diisopropylethylamine (4,2 ml of 23.9 mmol) in water (9.5 ml) in an ice bath. After stirring over night at room temperature the reaction mixture was diluted with water and was extracted with chloroform (4 times). The organic layer was washed with saturated sodium bicarbonate and water, and then 1 N. HCl and water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4-tert-butyl ester 1-(N-fluoren-9-Eletropaulo) ether piperazine-1,2,4-tricarboxylic acid (4.3 g).

Example 1

tert-Butyl ester 2-formyl-piperidine-1-carboxylic acid

DMSO (7,14 ml, 98 mmol) was added dropwise to a stirred solution of oxalicacid (30 ml, 2M in CH2Cl2, 60 mmol) in CH2Cl2(60 ml) at -78°C. After 5 minutes the solution was added tert-butyl ester 2-hydroxymethyl-piperidine-1-carboxylic acid in CH2Cl2(25 ml) and the reaction mixture was stirred at -78°C for 0.5 h, then was added Et3N (25 ml, 181 mmol) and the mixture was left to slowly warm to room temperature with stirring. Then the mixture was poured into water (100 ml) and the organic layer was separated. Then the organic extract washed with NaHCO3(saturated). The aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic phase was washed with water (30 ml) and brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuum. In the chromatography product was received as specified in the header, in the form of a yellow oil (3,27 g, 73%).

Example 12

4-tert-Butyl ester 3-methyl ester morpholine-3,4-dicarboxylic acid

Logmean (0,32 ml, 5,19 mmol) was added to a solution of 4-tert-butyl ether morpholine-3,4-dicarboxylic acid (1 g, 4,32 mmol) and potassium carbonate in DMF (15 ml). The resulting mixture was stirred at room temperature for 4 h, diluted with diethyl ether (100 ml) and the settlement of adavale washed with water (3×100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuum with the release of the desired compound as a transparent oil (0,99 g, 94%).1H NMR (CDCl3), δ (m-1): 4.40 (m, 2H), 3.75 (m, 6H), 3.39 (m, 2H), 1.46 (d, 9H).

Example 13

tert-Butyl ether 3-formyl-morpholine-4-carboxylic acid

Diisobutylaluminum (1M in toluene) was added dropwise to a solution of 4-tert-butyl ester 3-methyl ester morpholine-3,4-dicarboxylic acid (992 mg, of 4.05 mmol) in toluene (10 ml) at -78°C and left to mix at -78°C for 1 h, the Reaction mixture was suppressed by slow addition of decahydrate sodium sulfate (0.6 g) under stirring at 80°C for 40 minutes. The mixture was filtered hot through the gasket celite using ethyl acetate. The filtrate was concentrated in vacuo and chromatography (silica gel, 8% acetone in hexano) received the product specified in the header, in the form of a white solid (539 mg, 62%).1H NMR (CDCl3), δ (m-1): 9.68 (s, 1H), 4.45 (m, 2H), 3.86 (m, 2H), 3.70 (dd, 1H), 3.51 (m, 1H), 3.23 (m, 1H), 1.48 (m, 9H).

Example 14

a) tert-Butyl ester 2-cyano-piperidine-1-carboxylic acid

1-tert-Butyl ether piperidine-1,2-dicarboxylic acid (12.8 g, at 55.6 mmol) and THF (170 ml) was added to a 500 ml round bottom flask equipped with a magnetic stirrer. The solution was cooled to -20°C was added triethylamine (10.1 ml, 72,3 mmol),and then ethylchloride (5,32 ml, at 55.6 mmol). The resulting white precipitate was allowed to mix at -10°C for 1 h In the above reaction mixture was added aqueous ammonia (22,6 ml, 1168 mmol) and the clear reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum and the selected residue was dissolved in ethyl acetate (300 ml). The organic phase is then washed with water (300 ml) and brine (200 ml), dried (sodium sulfate), filtered and concentrated in vacuum emitting transparent resin. This resin was ground with hexane emitting carbamate (9.4 g, 74%) as a white solid.1H NMR (CDCl3), δ (m-1): 6.03 (bs, 1H), 5.55 (bs, 1H), 4.77 (bs, 1H), 4.05 (bs, 1H), 2.81 (t, 1H), 2.27 (bs, 1H), 1.47 (m, 14H).

Acetonitrile (220 ml) and DMF (3,82 ml, 49.4 mmol) was added to a 500 ml round bottom flask equipped with a magnetic stirrer. The mixture was cooled to -5°C and added to it oxalicacid (24,7 ml, 49.4 mmol, 2 M in dichloromethane). The resulting mixture was stirred for 15 minutes After this solution was added tert-butyl ester 2-carbarnoyl-piperidine-1-carboxylic acid (9.4 g, 41.2 mmol) in acetonitrile (50 ml) and pyridine (8,3 ml, 103 mmol). The reaction mixture was allowed to mix at room temperature over night. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (00 ml). The organic phase is then washed with water (300 ml) and brine (200 ml), dried (sodium sulfate), filtered and concentrated in vacuum with the release of the connection specified in the header (8,44 g, 97%) as a yellow solid.1H NMR (CDCl3), δ (m-1): 5.23 (bs, 1H), 4.03 (bs, 1H), 2.93 (t, 1H), 1.75 (m, 5H), 1.46 (m, 10H).

b) tert-Butyl-3-cyanobacterin-4-carboxylate

The triethylamine (1,808 ml, 12,97 mmol) and ethylchloride (0,909 ml, 9,514 mmol) was added to a cooled (0°C.) solution of 4-tert-butyl ether morpholine-3,4-dicarboxylic acid (2.00 g, 8,65 mmol) in THF (25 ml). This reaction mixture was heated to room temperature and left to mix for 2 h, then was cooled to 0°C. was added ammonium hydroxide (4 ml). The resulting mixture was heated to room temperature and was stirred for a further 1 h the Solvent was removed in vacuum and the product was extracted from the aqueous phase with dichloromethane. The combined organic substance was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain tert-butyl ester 3-carbarnoyl-morpholine-4-carboxylic acid (whitish solid, 1,37 g, 69%).1H NMR (300 MHz, CDCl3) δ=1.51 (s, 9H); 3.19 (m, 1H); 3.52 (m, 2H); 3.88 (m, 2H); 4.50 (d, J=11.4, 1H); 5.81 (s broad, 1H); 6.05 (s broad, 1H).

Oxalicacid (a 3.87 ml, 2M in DHM, 7,73 mmol) was added to a cooled (0°C) rest the ru of dimethylformamide (0,598 ml, 7,73 mmol) in acetonitrile (15 ml). This solution was stirred for 20 min at 0°C. a Solution of tert-butyl methyl ether 3-carbarnoyl-morpholine-4-carboxylic acid (1,37 g, 5,95 mmol) in acetonitrile (6 ml) and pyridine (0,481 ml, 5,95 mmol) was added to the first solution. This mixture was left to warm to room temperature and was stirred for 30 minutes the Solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane and washed with water. The aqueous phase is re-extracted with dichloromethane. The combined organic substance was dried (Na2SO4), filtered and concentrated under reduced pressure to get the connection specified in the header (whitish crystals, 1.24 g, 98%).1H NMR (300 MHz, CDCl3) δ=1.51 (s, 9H); 3.26 (m, 1H); 3.55 (td, J=11.8 Hz, 2.7 Hz, 1H); 3.41 (dd, J=11.8 Hz, 3.3 Hz, 1H); 3.83 (m, 1H), 3.98 (d, J=11.4 Hz, 1H); 4.08 (d, J=12 Hz, 1H); 5.32 (m, 1H).

Example 15

a) tert-Butyl 2-(2H-tetrazol-5-yl)piperidine-1-carboxylate

tert-Butyl-2-cyanopiperidine-1-carboxylate (2.10 g, 10 mmol) was mixed with sodium azide (0,715 g, 11 mmol) and ammonium chloride (0,588 g, 11 mmol) in DMF (7.5 ml) and heated at 100°C during the night. The reaction mixture was extinguished with water and was extracted with ethyl acetate. The organic layer was washed with water three times, and then brine, dried and concentrated to obtain the compound indicated in heading (white solid, was 2.34 g, 92,5). 1H NMR (CDCl3), δ (m-1): 5.7 (m, 1H), 4.02 (m, 1H), 2.93 (m, 1H), 2.35 (m, 1H), 2.07 (m, 1H), 1.74 (m, 3H), 1.49 (m+s, 11H).

The following compound was obtained in the same way:

b) tert-Butyl 3-(2H-tetrazol-5-yl)morpholine-4-carboxylate

tert-Butyl-3-cyanobacterin-4-carboxylate (2,74 g, 12.9 mmol) was mixed with sodium azide (0,923 g of 14.2 mmol) and ammonium chloride (0,759 g of 14.2 mmol) in DMF (8 ml) and heated at 100°C for 6 h and left to mix at room temperature over night. The reaction mixture was extinguished with water, acidified to pH 3 and extracted with ethyl acetate. The organic layer was washed with water three times, and then brine, dried and concentrated to obtain the compound indicated in heading (white solid, 2.64 g, 80.7 per cent).1H NMR (CDCl3), δ (m-1): 5.5 (br s, 1H), 4.45 (d, 1H), 3.8-3.98 (m, 3H), 3.62 (t, 1H), 3.3 (brs, 1H), 1.46 (s, 9H).

Example 16

tert-Butyl ester 2-(hydroxyimino-methyl)-piperidine-1-carboxylic acid

tert-Butyl ester 2-formyl-piperidine-1-carboxylic acid (1.0 g, 4.7 mmol) in pyridine (1.3 ml) was added to a solution of hydroxylamine hydrochloride (407 mg, 5.9 mmol) in pyridine (5.0 ml) at 0°C and the mixture was stirred at room temperature for 12 hours the Mixture was diluted with water (50 ml), was extracted with dichloromethane (3×25 ml). The combined organic phase was washed with brine (50 ml), dried (sodium sulfate), filtered and conc is listed in the vacuum with the release of the desired compound as a pale yellow oil (1.0 g).

Example 17

tert-Butyl ether 3-(hydroxyimino-methyl)-morpholine-4-carboxylic acid

A solution of tert-butyl methyl ether 3-formyl-morpholine-4-carboxylic acid (539 mg, of 2.50 mmol) in pyridine (1.3 ml) was added to a solution of hydroxylamine hydrochloride (217 mg, of 3.13 mmol) in pyridine (2.5 ml) at 0°C. the Mixture was heated to room temperature and was stirred for 12 h, diluted with water (50 ml) and was extracted with dichloromethane (3×25 ml). The combined organic phase was washed with brine (50 ml), dried (sodium sulfate), filtered and concentrated in vacuum with the release of the desired compound as a pale yellow oil (578 mg).

Example 18

tert-Butyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid

N-Chlorosuccinimide (643 mg, 4,82) in DMF (6 ml) was added to tert-butyl ether, 2-(hydroxyimino-methyl)-piperidine-1-carboxylic acid (1.0 g, of 4.38 mmol) in dimethylformamide (10 ml) at 40°C. This mixture was stirred at 40°C for 1.5 h, cooled to room temperature, diluted with diethyl ether (75 ml) and then washed with water (3×100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuum to obtain intermediate compound as a yellow oil.

This is an intermediate compound in dichloromethane (5 ml) was added to 3-chloro-1-ethynylbenzene (1,24 ml, 10 IMO is b) the triethylamine (1,05 ml, rate of 7.54 mmol) and dichloromethane (5 ml) at 0°C and the mixture was stirred at room temperature for 12 h and concentrated in vacuum. The residue was dissolved in ethyl acetate (75 ml) and then washed with water (3×50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 2% ethyl acetate in dichloromethane) received the connection specified in the header, in the form of a yellow solid (236 mg).1H NMR (CDCl3), δ (m-1): 7.75 (dd, 1 H), 7.64 (m, 1H), 7.40 (m, 2H), 6.37 (s, 1H), 5.48 (br, 1H), 4.08 (m, 1H), 2.83 (m, 1H), 2.35 (m, 1H), 2.00-1.53 (m, 5H), 1.52 (s, 9H).

Example 19

tert-Butyl ester 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carboxylic acid

A solution of N-chlorosuccinimide in dimethylformamide (6 ml) was added to a solution of tert-butyl methyl ether 3-(hydroxyimino-methyl)-morpholine-4-carboxylic acid (578 mg, 2.51 mmol) in dimethylformamide (10 ml) at 40°C and the mixture was stirred at 40°C. for 1.5 hours, the Reaction mixture was cooled to room temperature, diluted with diethyl ether (75 ml), then washed with water (3×100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuum emitting intermediate compound as a clear oil.

This is an intermediate compound in dichloromethane (5 ml) was added the solution of 3-chloro-1-ethynylbenzene (1,24 ml, 10 mmol), triethylamine (1,05 ml, rate of 7.54 mmol) in dichloromethane (5 ml) at 0°C and the mixture was stirred at room temperature for 12 hours the Reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (75 ml) and then washed with water (3×50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 2% ethyl acetate in dichloromethane) received the connection specified in the header, in the form of a yellow solid (236 mg).1H NMR (CDCl3), δ (m-1): 7.76 (bs, 1H), 7.67 (m, 1H), 7.43 (m, 2H), 6.51 (s, 1H), 5.24 (m, 1H), 4.39 (d, 1H), 3.88 (m, 3H), 3.60 (dt, 1H), 3.24 (m, 1H), 1.52 (s, 9H).

Example 20

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic acid

Isobutylparaben (0,42 ml, 3,24 mmol) was added to a solution of 4-tert-butyl ether morpholine-3,4-dicarboxylic acid (500 mg, of 2.16 mmol) and triethylamine (0,805 ml, 5,79 mmol) in THF (15 ml) at 0°C. This mixture was heated to room temperature within 2 hours. Was added 3-chloro-N-hydroxy-benzamidine (368 mg, of 2.16 mmol) and the mixture was stirred over night at room temperature, then cooled and diluted with ethyl acetate (350 ml). The organic layer was washed with water (2×30 ml) and brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The result chromatography (silica compound is a gel, 30-40% ethyl acetate in hexano) received ether (755 mg, 91%).1H NMR (CDCl3), δ (m-1): 7.73 (s, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.38 (dd, 1H), 5.25 (d, 2H), 4.4-4.8 (m, 2H), 4.1-3.2 (m, 5H), 1.50 (s, 9H).

The solution of this ester in DMF was heated at 127°C for 2 hours. The product was extracted into ethyl acetate (100 ml) and the organic layer was washed with water (3×20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The connection specified in the header (783 mg), obtained with a quantitative yield.1H NMR (CDCl3), δ (m-1): 8.09 (s, 1H), 7.98 (d, 1H), 7.46 (m, 2H), 4.50 (s, 1H), 4.2-3.2 (m, 6H), 1.49 (s, 9H).

Example 21

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperazine-1-carboxylic acid

4-tert-Butyl ester 1-(N-fluoren-9-ymetray) ether piperazine-1,2,4-tricarboxylic acid (4.3 g, 9.6 mmol), 3-chloro-N-hydroxy-benzamidine (1.8 g, 10.5 mmol), HOBt (1.4 g, 10.5 mmol) and EDCl (2.0 g, 10.5 mmol) in DMF (25 ml) was stirred at room temperature overnight. This reaction mixture was diluted with ethyl acetate, washed with water (3 times), saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (20 ml)and then was heated at 135°C for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous self the volume of sodium was filtered and concentrated. The result chromatography (silica gel, hexane - 1:1 hexane: dichloromethane - 1:3:4 ethyl acetate: hexane: dichloromethane - 3:1:4 ethyl acetate: hexane: dichloromethane) received the connection specified in the header (1.35 g, 39%).1H NMR (CDCl3), δ (m-1): 8.12 (m, 1H), 8.00 (m, 1H), 7.47 (m, 2H), 4.21 (m. 2H), 3.81 (m, 1H), 3.25 (m, 2H), 2.81 (m, 2H), 2.38 (bs, 1H), 1.50 (bs, 9H).

Example 22

a) tert-Butyl-2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-carboxylate

A mixture of tert-butyl 2-(2H-tetrazol-5-yl)piperidine-1-carboxylate (253 mg, 1 mmol), tert-butyl sodium (96 mg, 1 mmol), racemic BINAP (24,9 mg, 0.04 mmol), Pd2(dba)3 (10.4 mg, 0.01 mmol), 2-phenylcyclopropanecarboxylic copper(II) (7,72 mg, 0.02 mmol) and bis-(3-chloro-phenyl)-iodone of tetrafluoroborate (436,8 mg, 1 mmol) was boiled under reflux in tert-butanol (20 ml) in an argon atmosphere for 2 hours. After removal of solvent in vacuo resulting chromatography (5% ethyl acetate in hexano) received the connection specified in the header (pale yellow sticky oil, 237,8 mg, 65.3 per cent).1H NMR (CDCl3), δ (m-1): 8.14 (d, 1H), 8.03 (dm, 1H), 7.46 (m, 2H), 5.75 (brs, 1H), 4.1 (m, 1H), 3.05 (m, 1H), 2.43 (d, 1 H), 1.99 (tm, 1 H), 1.7 (t, 2H), 1.53 (m+s, 11 H).

The following compound was obtained in the same way:

b) tert-Butyl-3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]morpholine-4-carboxylate

A mixture of tert-butyl 3-(2H-tetrazol-5-yl)morpholine-4-carboxylate (701 mg, 2,74 mm is l), tert-butyl sodium (264 mg, is 2.74 mmol), racemic BINAP (68,5 mg, 0.11 mmol), Pd2(dba)3(28.4 mg, 0,0274 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic copper(II) (21.2 mg, 0,059 mmol) and bis-(3-chloro-phenyl)-iodone of tetrafluoroborate (1200 mg, is 2.74 mmol) was boiled under reflux in tert-butanol (40 ml) in an argon atmosphere for two hours. After removal of solvent in vacuo resulting chromatography (5-20% ethyl acetate in hexano) received the connection specified in the header (colorless sticky oil, 840 mg, 83.7 percent).1H NMR (CDCl3), δ (m-1): 8.14 (s, 1H), 8.03 (dm, 1H), 7.48 (m, 2H), 5.40 (br s, 1H), 4.56 (d, 1H), 3.94 (dd, 1H), 3.90 (m, 2H), 3.62 (td, 1H), 3.47 (brs, 1H).

Example 23

2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine

Triperoxonane acid (5 ml) was added to tert-butyl ether 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid (500 mg, 1.38 mmol) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 1 h, concentrated until dry and the residue was dissolved in sodium hydroxide (1 N. aqueous, 30 ml). The aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic phase was washed with water (30 ml) and brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of a light yellow oil (292 mg, 81%).1H NMR (CDCl3), δ (m-1): 7.75 (dd, 1H, 7.65 (m, 1H), 7.41 (m, 2H), 6.60 (s, 1H), 3.94 (dd, 1H), 3.17 (m, 1H), 2.83 (m, 1H), 2.35 (m, 1H), 2.00-1.53 (m, 6H).

Example 24

3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-morpholine

Triperoxonane acid (2 ml) was added to tert-butyl ether, 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carboxylic acid (236 mg, of 0.65 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 1 h, concentrated until dry and the residue was dissolved in sodium hydroxide (1 N. aqueous, 30 ml). The aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic phase was washed with water (30 ml) and brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of a light yellow oil (171 mg, 99%).1H NMR (CDCl3), δ (m-1): 7.72 (s, 1H), 7.62 (m, 1H), 7.37 (m, 2H), 6.59 (s, 1H), 4.18 (dd, 1H), 4.00 (dd, 1H), 3.87 (dt, 1H), 3.62 (m, 2H), 3.03 (m, 2H), 2.10 (bs, 1H).

Example 25

3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine

A solution of tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic acid (783 mg, 2,19 mmol) was dissolved in minimum amount of dichloromethane and then cooled to 0°C in an ice bath. Solution was added 1:1 triperoxonane acid: dichloromethane (10 ml), the mixture was stirred at 0°C for 15 minutes and heated the mixture up CT scan within 45 minutes. Added ice cold water (20 ml) and the mixture is neutral is hosted saturated sodium bicarbonate. The product was extracted into dichloromethane (2×25 ml) and washed with brine (2×25 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The result chromatography (silica gel) has received the connection specified in the header (429 mg, 74%).1H NMR (CDCl3), δ (m-1): 8.11 (s, 1H), 8.00 (d, 1H), 7.47 (m, 2H), 3.6-4.4 (m, 6H), 3.0-3.3 (m, 2H).

Example 26

a) 2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine

tert-Butyl 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-carboxylate (237 mg, 0,651 mmol) was mixed with triperoxonane acid (0,85 ml) and dichloromethane (0,85 ml) at 0°C for 0.5 hours. This mixture was poured into saturated sodium carbonate and was extracted with dichloromethane. The result chromatography (20-100% ethyl acetate in hexano) received 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-piperidine (white solid, 113 mg, 65.8 per cent).1H NMR (CDCl3), δ (m-1): 8.16 (s, 1H), 8.03 (dm, 1H), 7.46 (m, 2H), 4.17 (dm, 1H), 3.21 (dm, 1H), 2.84 (to, 1H), 2.18 (dm, 1H), 2.15 (m, 1H), 1.94 (m, 1H), 1.8 (m, 1H), 1.68 (m, 1H), 1.59 (m, 2H).

The following compound was obtained in the same way:

b) 3-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-morpholine

tert-Butyl-3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]morpholine-4-carboxylate (840 mg, 2,296 mmol) was mixed with triperoxonane acid (6 ml) and dichloromethane (6 ml) at 0°C for 1.5 hours. This mixture was poured into saturated sodium carbonate and was extracted with dichloromethane, dried and concentrated to obtain the connection is to be placed, specified in the header (pale yellow sticky oil, 550 mg, 90%).1H NMR (CDCl3), δ (m-1): 8.18 (s, 1H), 8.06 (dm, 1H), 7.52 (m, 2H), 4.45 (dd, 1H), 4.24 (dd, 1H), 3.92 (dt, 1H), 3.87 (dd, 1H), 3.72 (ddd, 1H), 3.14 (m,2H), 2.11 (brs, 1H).

Example 27

Methylamide 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioate

Methylisothiocyanate (63 mg, 0.86 mmol) was added to 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine (150 mg, or 0.57 mmol) in CH2Cl2(4 ml) and the resulting mixture was stirred at room temperature for 12 hours the mixture was concentrated in vacuum and the selected residue is triturated with 50% diethyl ether in hexano emitting the desired compound in the form of a whitish solid (quantitative).

Example 28

Methylamide 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carbothioate

Methylisothiocyanate (46.2 mg, to 0.63 mmol) was added to 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine (145 mg, 0.55 mmol) in CHCl3(4 ml) and the resulting mixture was stirred at room temperature for 12 hours the mixture was concentrated in vacuum and the selected residue is triturated with 50% diethyl ether in hexano emitting the desired compound in the form of a whitish solid (181 mg, 97%).1H NMR (CDCl3), δ (m-1): 7.78 (m, 1H), 7.67 (m, 1H), 7.45 (m, 2H), 6.75 (s, 1H), 6.28 (m, 1H), 5.80 (m, 1H), 4.57 (d, 1H), 4.29 (d, 1H), 4.09 (dd, 1H), 3.99 (dd, 1H), 3.75 (dt, 1H), 3.45 (dt, 1H), 3.23 (d, 3H).

Example 29

Methylamide 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carbothioate

Methylisothiocyanate (161 mg, 2.2 mmol) and Et3N (0,61 mg, 4.4 mmol) was added to a solution of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine (294 mg, 1.1 mmol) in CH2Cl2(4 ml) and the mixture was stirred at room temperature for 12 h and concentrated in vacuum. In the chromatography got the connection specified in the header, in the form of a sticky oil (313 mg, 84%).1H NMR (CDCl3), 6 (m-1): 8.06 (d, 1H), 7.96 (dd, 1H), 7.48 (dd, 1H), 7.45 (t, 1H), 6.88 (dd, 1H), 6.01 (br, m, 1H), 4.57 (d, 1H), 3.99 (m, 2H), 3.80 (m, 2H), 3.67 (ddd, 1H), 3.26 (d, 3H).

Example 30

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methylthiocarbamate-piperazine-1-carboxylic acid

Methylisothiocyanate (256 mg, 3.50 mmol) was added to a solution of tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperazine-1-carboxylic acid (1,11 g, 3.04 from mmol) in chloroform (17 ml) at room temperature. After stirring overnight the mixture was concentrated and the resulting chromatography (silica gel, 1:3:4 ethyl acetate: hexane: dichloromethane - 1,5:2,5:4 ethyl acetate: hexane: dichloromethane) received the connection specified in the header (796 mg, 60%).1H NMR (CDCl3), δ (m-1): 8.05 (m, 1H), 7.95 (m, 1H), 7.45 (m, 2H), 6.01 (m, 1H), 4.68 (m, 1H), 4.22 (m, 1H), 3.80 (m, 2H), 3.51 (m, 1H), 3.25 (m, 3H), 3.07 (m, 1H), 1.30 (bs, 9H).

Example 31

Methylamide 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-the l]-piperidine-1-carbothioate

2-({2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}methyl)pyridine (600 mg, of 2.38 mmol) was mixed with methylisothiocyanate (250 mg, to 3.41 mmol) in chloroform (10 ml) at room temperature over night. The reaction mixture was concentrated and triturated with ether to obtain the connection specified in the header, in the form of a white solid (676 mg, 88%).1H NMR (CDCl3), δ (m-1): 8.13 (s, 1H), 8.03 (m, 1H), 7,51 (m, 2H), 6.93 (w, 1H), 6.06 (w, 1H), 4.24 (m, 1H), 3.34 (m, 1H), 3.23 (d, 3H), 2.46 (m, 1H), 2.11 (m, 1H), 1.60-1.95 (m, 4H).

Example 32

Methyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-methyl-piperidine-1-carboxymethylate

Logmean (50 μl, 0.80 mmol) was added to methylamide 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioate (181 mg, 0.54 mmol) in methanol (4 ml) and the resulting mixture was stirred at 75°C for 3 hours the Mixture was cooled to room temperature, diluted with saturated sodium bicarbonate (aqueous, 30 ml), was extracted with dichloromethane (3×20 ml). The combined organic phase was washed with brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of a yellow oil (0,19 g, 100%).1H NMR (CDCl3), δ (m-1): 7.73 (dd, 1H), 7.64 (m, 1H), 7.38 (m, 2H), 6.60 (s, 1H), 5.37 (m, 1H), 4.25 (m, 1H), 3.95 (m, 2H), 3.67 (m, 2H), 3.32 (m, 1H), 3.25 (s, 3H), 2.36 (s, 3H).

Example 33

Methyl ester of 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-M-m the Teal-morpholine-4-carboxymethylate

Logmean (50 μl, 0.80 mmol) was added to methylamide 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carbothioate (181 mg, 0.54 mmol) in methanol (4 ml) and the resulting mixture was stirred at 75°C for 3 hours the Mixture was cooled to room temperature, diluted with saturated sodium bicarbonate (aqueous, 30 ml), was extracted with dichloromethane (3×20 ml). The combined organic phase was washed with brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of a yellow oil (0,19 g, 100%).1H NMR (CDCl3), δ (m-1): 7.73 (dd, 1H), 7.64 (m, 1H), 7.38 (m, 2H), 6.60 (s, 1H), 5.37 (m, 1H), 4.25 (m, 1H), 3.95 (m, 2H), 3.67 (m, 2H), 3.32 (m, 1H), 3.25 (s, 3H), 2.36 (s, 3H).

Example 34

Methyl ester of 3-[3-(3-chloro-phenyl)-(1,2,4]oxadiazol-5-yl]-methylmorpholin-4-carboxymethylate

Logmean (212 mg, 1.5 mmol) was added to a solution of methylamide 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carbothioate (313 mg, of 0.92 mmol) in methanol (10 ml) and the mixture was stirred at 75°C for 3 hours the Mixture was cooled to room temperature, diluted with saturated sodium bicarbonate (aqueous, 30 ml), was extracted with dichloromethane (3×20 ml). The combined organic phase was washed with brine (30 ml), dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of a white solid which CSOs substances (248 mg, 76%).1H NMR (CDCl3), δ (m-1): 8.08 (d, 1H), 7.95 (dd, 1H), 7.47 (dd, 1H), 7.43 (t, 1H), 5.47 (dd, 1H), 4.36 (d, 1H), 3.40-4.00 (m, 5H), 3.21 (s, 3H), 2.36 (s, 3H).

Example 35

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methylsulfonyl-methyl)-piperazine-1-carboxylic acid

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methylthiocarbamate-piperazine-1-carboxylic acid (796 mg, 1.82 mmol) and jodean (0,170 ml, 2,73 mmol) in methanol (11 ml) was heated at 75°C in a tightly closed bottle within 2 hours. After cooling, the mixture was concentrated and then the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, 25% ethyl acetate in hexano) received the connection specified in the header (632 mg, 77%).1H NMR (CDCl3), δ (m-1): 8.08 (m, 1H), 7.97 (m, 1H), 7.44 (m, 2H), 5.51 (m, 1H), 4.49 (m, 1H), 4.01 (m, 2H), 3.49 (m, 2H), 3.20 (s, 3H), 3.15 (m, 1H), 2.37 (s, 3H), 1.38 (bs, 9H).

Example 36

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate

Methylamide 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioate (676 mg, 2.0 mmol) was mixed with iodomethane (0.4 ml) in methanol (15 ml) in a tightly closed bottle at 80°C for 2 hours. This reaction mixture was concentrated using retornos the evaporator. The residue was podslushivaet saturated sodium bicarbonate and was extracted with dichloromethane. The organic layer was dried MgSO4obtaining the connection specified in the header, in the form of a sticky pale yellow oil (700 mg, 100%).1H NMR (CDCl3), δ (m-1): 8.15 (s, 1H), 8.04 (d, 1H), 7.48 (m, 2H), 5.75 (m, 1H), 3.22 (m, 1H), 3.22 (m, s, 4H), 2.04 (s, m, 4H), 2.10 (m, 1H), 1.69 (m, 4H).

Example 37

a) 4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-pyridine

The isonicotinic acid hydrazide (42,3 mg, 0.31 mmol) was added to methyl ether 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-1-piperidine-1-carboxymethylate (90 mg, 0.26 mmol) in ethanol (1.5 ml). This mixture was stirred at 75°C for 12 h and then was diluted with dichloromethane (8 ml). The organic phase is then washed with water (4×10 ml) and brine (10 ml), dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 10% methanol in ethyl acetate) has received a yellow oil, which was triturated with 30% hexane in diethyl ether to obtain the connection specified in the header, in the form of a whitish solid (50 mg).1H NMR (CDCl3), δ (m-1): 8.72 (d, 2H), 7.69 (s, 1H), 7.59 (m, 3H), 7.36 (m, 2H), 6.54 (s, 1H), 4.79 (dd, 1H), 3.64 (s, 3H), 3.28 (m, 2H), 2.20 (m, 2H), 1.90-1.73 (m, 4H).

The following compounds were obtained in a similar way:

b) 3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-(5-feast of the DIN-4-yl-4H-[1,2,4]triazole-3-yl)-morpholine; output 40,2 mg, 24%, yellow powder;1H NMR CDCl3(300 MHz): 3.37 (m, 1H); 3.59 (m, 1H); 3.75 (s, 3H); 3.97 (m, 1H); 4.08 (m, 2H); 4.32 (dd, J=11.7 Hz, 3.3 Hz, 1H); 5.00 (m, 1H); 7.45 (t, J=8 Hz), 7.56 (d, J=8 Hz, 1H); 7.62 (d, J=4.8 Hz, 2H); 7.94 (d, J=7.8 Hz, 1H); 8.04 (m, 1H); 8.75 (br. s, 2H).

The enantiomers were separated using column Chiralpak AD of 4.6×250 mm, elwira iPrOH/0,05% Et2NH at a flow rate of 1 ml/min with getting 12.5 mg of enantiomer 1, Rt (retention time) 7,39 min, and 12.7 mg of enantiomer 2, Rt 12,57 minutes

C) 3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-3-yl-4H-1,2,4-triazole-3-yl)-morpholine; yield of 63.5 mg, 27%, white solid;1H NMR CDCl3(300 MHz): 9.07 (s, 1H), 8.71 (d of t, 1H), 8.16 (d of t, 1H), 7.75 (d, 1H), 7.64 (m, 1H), 7.41 (m, 3H), 6.83 (s, 1H), 5.18 (t, 1H), 4.25 (d, 2H), 4.12 (m, 1H), 3.99 (m, 1H), 3.72 (m, 1H), 3.49 (m, 1H), 3.38 (m, 1H), 1.30 (m, 1H), 1.14 (m, 2H), 0.60 (m, 1H).

The enantiomers were separated using column Chiralpak AD of 4.6×250 mm, elwira IPrOH at a flow rate of 1 ml/min, to obtain the enantiomers of 1 in the form of a whitish solid, 14,4 mg, Rt 5,9 min, enantiomer 2 in the form of a whitish solid, and 16.7 mg, Rt of 23.7 minutes

g) 3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-yl)morpholine; output 103,4 mg, 43%, white solid;1H NMR CDCl3(300 MHz): 8.75 (d, 2H), 7.76 (m, 3H), 7.64 (m, 1H), 7.41 (m, 2H), 6.83 (s, 1H), 5.19 (t, 1H), 4.25 (d, 2H), 4.13 (m, 1H), 3.99 (t of d, 1H), 3.73 (t of d, 1H), 3.50 (m, 1H), 3.41 (m, 1H), 1.28 (m, 1H), 1.15 (m, 2H), 0.62 (m, 1H).

e) 3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2,4-Tria is ol-3-yl)morpholine; output 85,0 mg, 35%, white solid;

1H NMR CDCl3(300 MHz): 8.90 (d, 1H), 8.72 (m, 1H), 8.05 (d of t, 1H), 7.73 (m, 1H), 7.61 (m, 1H), 7.41 (m, 3H), 6.67 (s, 1H), 4.82 (m, 1H), 4.25 (d of d, 1H), 4.08 (m, 3H), 3.67 (s, 3H), 3.48 (m, 1H), 3.40 (m, 1H).

e) 3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(6-methoxy-pyridin-3-yl)-4-methyl-4H-[1,2,4]triazole-3-yl]morpholine; yield and 73.2 mg, 29%, white solid;1H NMR CDCl3(300 MHz): 8.40 (d, 1H), 7.88 (d of d, 1H), 7.69 (s, 1H), 7.59 (m, 1H), 7.38 (m, 2H), 6.84 (d, 1H), 6.65 (s, 1H), 4.79 (m, 1H), 4.20 (d of d, 1H), 4.04 (m, 3H), 3.98 (s, 3H), 3.61 (s, 3H), 3.44 (m, 1H), 3.36 (m, 1H).

g) 3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methoxypyridine-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]morpholine; yield 26.6 mg, 5,8%, yellow oil;1H NMR CDCl3(300 MHz): 8.31 (d, 1H), 8.04 (t, 1H), 7.95 (dt, 1H), 7.44 (m, 2H), 7.24 (d, 1H), 7.02 (s, 1H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.05 (m, 2H), 4.02 (s, 3H), 3.73 (s, 3H), 3.7 (m, 1H), 3.34 (m, 1H).

C) 3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]morpholine; yield of 42.3 mg, 9.6%, as a yellow oil;1H NMR CDCl3(300 MHz): 8.64 (br, 1H), 8.02 (t, 1H), 7.94 (dt, 1H), 7.44 (m, 4H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.03 (m, 2H), 3.74 (s, 3H), 3.7 (m, 1H), 3.38 (m, 1H), 2.66 (s, 3H).

3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(5-herperidin-3-yl)-4-methyl-4H-1,2,4-triazole-3-yl]morpholine; yield 285 mg, and 63.9%, yellow oil;1H NMR CDCl3(300 MHz): 8.72 (s, 1H), 8.59 (d, 1H), 8.03 (t, 1H), 7.94 (dt, 1H), 7.82 (dq, 1H), 7.45 (m, 2H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.05 (m, 2H), 3.75 (s, 3H), 3.7 (m, 1H), 3.38 (m, 1H).

K) 3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(5-herperidin-3-yl)-4-Mei is-4H-1,2,4-triazole-3-yl]morpholine; yield 40 mg, 38%, white solid;1H NMR CDCl3(300 MHz): 8.73 (s, 1H), 8.59 (d, 1H), 7.83 (m, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 7.41 (m, 2H), 6.68 (s, 1H), 4.83 (m, 1H), 4.25 (m, 1H), 4.08 (m, 3H), 3.71 (s, 3H), 3.45 (m, 2H).

l) 3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-2-yl-4H-1,2,4-triazole-3-yl)morpholine; yield 68 mg, 14,3%, yellow oil; 90% purity by NMR;1H NMR CDCl3(300 MHz): 8.64 (d, 1H), 8.22 (d, 1H), 8.01 (s, 1H), 7.93 (d, 1H), 7.78 (td, 1H), 7.28 (m, 3H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.03 (m, 2H), 4.02 (s, 3H), 3.66 (m, 1H), 3.34 (m, 1H).

m) 4-[5-(5-Herperidin-3-yl)-4-methyl-4H-1,2,4-triazole-3-yl]-3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]morpholine; yield 103 mg, 36.2 per cent, a clear oil;1H NMR CDCl3(300 MHz): 8.74 (s, 1H), 8.61 (d, 1H), 8.38 (t, 1H), 8.02 (dt, 1H), 7.84 (dq, 2H), 7.21 (t, 1H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.03 (m, 2H), 3.75 (s, 3H), 3.70 (m, 1H), 3.38 (m, 1H)

h) 3-[3-(3-Itfinal)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-yl)morpholine; output to 99.6 mg, 37.3 per cent, a clear oil;

1H NMR CDCl3(300 MHz): 8.78 (dd, 2H), 8.38 (t, 1H), 8.02 (dt, 1H), 7.84 (dt, 1H), 7.63 (dd, 2H), 7.21 (t, 1H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.18 (m, 1H), 4.03 (m, 2H), 3.76 (s, 3H), 3.71 (m, 1H), 3.37 (m, 1H).

o) 3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]morpholine; yield of 5.6 mg, 5%, yellow oil;1H NMR CDCl3(300 MHz): 8.64 (d, 1H), 7.72 (m, 1H), 7.5 (m, 1H), 7.41 (m, 1H), 7.38 (m, 3H), 6.66 (s, 1H), 4.81 (m, 1H), 4.24 (m, 1H), 4.09 (m, 3H), 3.68 (s, 3H), 3.52 (m, 2H), 2.63 (s, 3H).

Example 38

3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)morpholine

Hydrase the isonicotinic acid (56,1 mg, 0.41 mmol) was added to methyl ether 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-morpholine-4-carboxymethylate (96 mg, 0.27 mmol) in ethanol. The resulting mixture was allowed to mix at 75°C for 12 h and then was diluted with dichloromethane (8 ml). The organic phase is then washed with water (4×10 ml) and brine (10 ml), dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 10% methanol in ethyl acetate) has received a yellow oil, which was triturated with 30% hexane in diethyl ether to obtain the connection specified in the header, in the form of a whitish solid (46 mg).1H NMR (CDCl3), δ (m-1): 8.76 (d, 2H), 7.72 (dd, 1H), 7.62 (m, 3H), 7.42 (m, 2H), 6.67 (s, 1H), 4.82 (dd, 1H), 4.25 (dd, 1H), 4.07 (m, 3H), 3.71 (s, 3H), 3.45 (m, 2H).

The enantiomers were separated using column Chiralpak AD of 4.6×250 mm, elwira IPrOH at a flow rate of 1 ml/min, to obtain the enantiomers of 1 as a white solid, 9 mg, Rt 5,6 min, enantiomer 2 in the form of a white solid, 9 mg, Rt to 9.9 minutes

Example 39

3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-morpholine

Pyridine (30 μl) and hydrazide 4-deformedarse-benzoic acid (57,9 mg, 0.29 mmol) was added to a solution of methyl ester of 3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-morpholine-4-carboxymethylate (960 mg, 0.27 mmol) in ethanol. This mixture is eremetical at 75°C for 48 h, and then was diluted with dichloromethane (8 ml). The organic phase is then washed with water (4×10 ml) and brine (10 ml), dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 10% dichloromethane in ethyl acetate) received the connection specified in the header, in the form of a clear oil (18 mg).1H NMR (CDCl3), δ (m-1): 7.67 (m, 4H), 7.39 (m, 2H), 7.23 (d, 2H), 6.66 (s, 1H), 6.58 (t, 1H), 4.80 (dd, 1H), 4.25 (dd, 1H), 4.07 (m, 3H), 3.61 (s, 3H), 3.40 (m, 2H).

Example 40

3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-morpholine

Pyridine (30 ml), and isonicotinic acid hydrazide (60 mg, 0.29 mmol) was added to methyl ether 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-methylmorpholin-4-carboxymethylate (101 mg, 0.44 mmol) in ethanol and the mixture was stirred at 75°C for 48 h and the mixture was diluted with dichloromethane (8 ml). The organic phase is then washed with water (4×10 ml) and brine (10 ml), dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 10% dichloromethane in ethyl acetate) received the connection specified in the header, in the form of a clear oil (40 mg, 33%).1H NMR (CDCl3) 6 (m-1): 8.78 (d, 2H), 8.03 (d, 1H), 7.92 (dd, 1H), 7.63 (d, 2H), 7.46 (dd, 1H), 7.40 (t, 1H), 5.14 (dd, 1H), 4.35 (d, 1H), 4.14 (m, 3H), 3.75 (s, 3H), 3.73 (m, 1H), 3.39 (m, 1H).

Example 41

3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-morpholine

Methyl ester of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-N-methyl-morpholine-4-carboxymethylate (100 mg, 0.28 mmol), hydrazide 4-deformedarse-benzoic acid (60,2 mg, 0.30 mmol) and pyridine (4 drops) in ethanol (10 ml) was heated at 75°C for 24 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and then washed with water (5 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, 1-2% methanol in dichloromethane) received the connection specified in the header (for 99.5 mg, 73%).1H NMR (CDCl3) δ (m-1): 8.03 (m, 1H), 7.93 (m, 1H), 7.67 (m, 2H), 7.46 (m, 1H), 7.42 (m, 1H), 7.25 (m, 2H), 6.59 (t, 1H), 5.13 (m, 1H), 4.37 (m, 1H), 4.16 (m, 1H), 4.01 (m, 2H), 3.66 (m, 1H), 3.67 (s, 3H), 3.36 (m, 1H).

Example 42

tert-Butyl ester 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine-1-carboxylic acid

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methylsulfonyl-methyl)-piperazine-1-carboxylic acid (211,6 mg, 0.47 mmol) and isonicotinoyl hydrazide (96,5 mg, 0.70 mmol) in ethanol (6 ml) was heated at 80°C for 24 hours. After cooling, the mixture was diluted with ethyl acetate and washed with water (5 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, 0-5% 2 M methanolic ammonia in a mixture of 1:1 ethyl acetate:dichlo is methane) received connection specified in the header (168,5 mg, 69%, colorless oil).1H NMR (CDCl3) δ (m-1): 8.77 (m, 2H), 8.04 (s, 1H), 7.94 (m, 1H), 7.62 (m, 2H), 7.44 (m, 2H), 5.08 (m, 1H), 4.15 (m, 1H) 4.06 (m, 1H), 3.75 (m, 3H), 3.73 (s, 3H), 3.32 (m, 1H), 1.43 (bs, 9H).

Example 43

2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine

Triperoxonane acid (1.5 ml) was added to a solution of tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine-1-carboxylic acid (164 mg, 0.31 mmol) in dichloromethane (3 ml) at 0°C and was stirred for 2.5 hours. After concentrating the mixture, the residue was diluted with dichloromethane, and then washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound indicated in heading (109 mg, 83%, white foamy solid).1H NMR (CDCl3) δ (m-1): 8.75 (m, 2H), 8.02 (m, 1H), 7.93 (m, 1H), 7.62 (m, 2H), 7.43 (m, 2H), 5.01 (m, 1H), 3.73 (s, 3H), 3.62 (m, 2H), 3.40 (m, 1H), 3.22 (m, 3H).

Example 44

2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine

Formic acid (0.1 ml), formaldehyde (37% mass/mass of solution in water, 0.1 ml) and cyanoborohydride sodium (1.0 M in THF, 0.1 ml) was added to a solution of 2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine (50,3 mg, 0.12 mmol) in methanol(0.8 ml) at room temperature. After stirring for 30 minutes the mixture was diluted with water and was extracted with chloroform (4 times), dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, 1-5% 2 M methanolic ammonia in dichloromethane) received the connection specified in the header (90%).1H NMR (CDCl3) δ (m-1): 8.77 (m, 2H), 8.03 (m, 1H), 7.93 (m, 1H), 7.63 (m, 2H), 7.42 (m, 2H), 5.21 (m, 1H), 3.74 (s, 3H), 3.70 (m, 1H), 3.43 (m, 1H), 3.09 (m, 2H), 2.70 (m, 2H), 2.41 (s, 3H).

Example 45

tert-Butyl ester 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine-1-carboxylic acid

tert-Butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methylsulfonyl-methyl)-piperazine-1-carboxylic acid (211,3 mg, 0.47 mmol), hydrazide 4-deformedarse-benzoic acid (99,2 mg, 0.49 mmol) and pyridine (8 drops) in ethanol was heated at 75°C for three days. After cooling, the reaction mixture was diluted with ethyl acetate, and then washed with water (5 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, ethyl acetate:hexane:dichloromethane 3:1:4 to 100% ethyl acetate) received the connection specified in the header.

Example 46

2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine

Triperoxonane KIS the GTC (1.5 ml) was added to a solution of tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]piperazine-1-carboxylic acid at 0°C and was stirred for 2.5 hours. After concentrating the mixture, the residue was diluted with dichloromethane, and then washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, 3-4% 2 M methanolic ammonia in dichloromethane) received the connection specified in the header (white solid, yield 31% over two stages).1H NMR (CDCl3) δ (m-1); 8.05 (m, 1H), 7.95 (m, 1H), 7.69 (m, 2H), 7.47 (m, 1H), 7.42 (m, 1H), 7.26 (m, 2H), 6.59 (t, 1H), 5.01 (m, 1H), 3.63 (m, 5H), 3.39 (m, 1H), 3.20 (m, 3H).

Example 47

2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-4-methyl-piperazine

Formic acid (0.1 ml), formaldehyde (37% wt./wt. in water, 0.1 ml) and cyanoborohydride sodium (1.0 M in THF, 0.1 ml) was added to a solution of 2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine (27.3 mg, 0,056 mmol) in methanol (0.8 ml) at room temperature. After stirring for 30 minutes the mixture was diluted with water and was extracted with chloroform (3 times), dried over anhydrous sodium sulfate, filtered and concentrated. The result chromatography (silica gel, 1-3% methanol in dichloromethane) received the connection specified in the header (57%).1H NMR (CDCl3) δ (m-1): 8.03 (m, 1H), 7.93 (m, 1H), 7.68 (m, 2H), 7.46 (m, 1H), 7.42 (m, 1H), 7.25 (m, 2H), 6.59 (t, 1H), 5.20 (m, 1H), 3.68 (m, 1H), 3.66 (s, 3H), 3.40 (m, 1H), 3.12 (m, 1H), 302 (m, 1H), 2.69 (m, 2H), 2.40 (s, 3H).

Example 48

2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-1,2,4-triazole-3-yl}piperidine

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate (70 mg, 0.2 mmol) was mixed with hydrazide 4-deformedarse-benzoic acid (40,4 mg, 0.2 mmol) in ethanol at 80°C during the night. This reaction mixture was diluted with water and was extracted with dichloromethane. The dichloromethane layer was dried and purified by chromatography (ethyl acetate) to obtain the compound indicated in heading (37 mg, 38%).1H NMR (CDCl3) δ (m-1): 8.09 (s, 1H), 7.99 (m, 1H), 7.66 (d, 2H), 7.46 (m, 2H), 7.24 (d, 2H), 6.58 (t, 1H), 5.10 (m, 1H), 3.66 (s, 3H), 3.48 (m, 1H), 3.30 (m, 1H), 1.70-2.30 (m, 6H).

Example 49

4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)pyridine

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate (70 mg, 0.2 mmol) was mixed with isonicotinic acid hydrazide (33,2 mg, 0.2 mmol) in ethanol at 80°C during the night. This reaction mixture was diluted with water and was extracted with dichloromethane. The dichloromethane layer was dried and purified by chromatography (ethyl acetate) to obtain the compound indicated in heading (34 mg, 40.3 per cent).1H NMR (CDCl3) δ (m-1): 8.74 (d, 2H), 8.07 (s, 1H), 7.96 (m, 1H), 7.61 (d, 2H), 7.45 (m, 2H), 5.11 (m, 1H), 3.73 (s, 3H), 3.48 (m, 1H), 3.30 (m, 1H), 1.70-2.30 (m, 6H).

Example 50

2-[2-(3-the ENT-phenyl)-2H-tetrazol-5-yl]-1-[5-(4-methoxyphenyl)-4-methyl-4H-1,2,4-triazole-3-yl]piperidine

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate (70 mg, 0.2 mmol) was mixed with a hydrazide of 4-methoxy-benzoic acid (33,2 mg, 0.2 mmol) in ethanol at 80°C during the night. This reaction mixture was diluted with water and was extracted with dichloromethane. The dichloromethane layer was dried and purified by chromatography (ethyl acetate) to obtain the compound indicated in heading (20.2 mg, 22.4 percent).1H NMR (CDCl3) δ (m-1): 8.09 (s, 1H), 7.98 (m, 1H), 7.57 (d, 2H), 7.45 (m, 2H), 7.99 (d, 2H), 5.10 (m, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 3.48 (m, 1H), 3.29 (m, 1H), 1.70-2.30 (m, 6H).

Example 51

[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)phenyl]dimethylamine

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate (70 mg, 0.2 mmol) was mixed with a hydrazide of 4-methoxy-benzoic acid (27.4 mg, 0.2 mmol) in ethanol at 80°C during the night. This reaction mixture was diluted with water and was extracted with dichloromethane. The dichloromethane layer was dried and purified by chromatography (ethyl acetate) to obtain the compound indicated in heading (20.2 mg, 21.6 per cent).1H NMR (CDCl3) δ (m-1): 8.10 (s, 1H), 7.97 (m, 1H), 7.48 (m, 4H), 6.75 (d, 2H), 5.09 (m, 1H), 3.63 (s, 3H), 3.48 (m, 1H), 3.29 (m, 1H), 3.02 (s, 3H), 1.70-2.30 (m, 6H).

The enantiomers were separated using column Chiralpak AD of 4.6×250 mm, elwira iPrOH at a flow rate of 2 ml/min, to obtain the enantiomers of 1 as white the foam, 2.6 mg, Rt 6,3 min, enantiomer 2 in the form of a white foam, 2.6 mg, Rt7,1 min

Example 52

[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)benzyl]dimethylamine

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate (to 49.9 mg, 0,1422 mmol) was mixed with hydrazide 4-dimethylaminomethyl-benzoic acid (30 mg, 0,156 mmol) in ethanol (1.2 ml) at 100°C during the night. This reaction mixture was diluted with ethyl acetate, washed with water 3 times, was purified by chromatography (2~3% 2 M methanolic ammonia in chloroform) to obtain the compound indicated in heading (9,2 mg, 13.5 per cent).1H NMR (CDCl3) δ (m-1): 8.09 (s, 1H), 7.98 (m, 1H), 7.60 (d, 2H), 7.45 (m, 4H), 5.11 (m, 1H), 3.66 (s, 3H), 3.48 (s plus m, 3H), 3.30 (m, 1H), 2.28 (s, 6H), 1.60-2.20 (m, 6H).

Example 53

(2-[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-phenoxy]-ethyl}-dimethylamine

Methyl ester 2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboxymethylate (85 mg, 0,242 mmol) was mixed with a hydrazide of 4-(2-dimethylamino-ethoxy)-benzoic acid (75,7 mg, 0,339 mmol) in ethanol (1.2 ml) at 100°C during the night. This reaction mixture was diluted with dichloromethane, washed with water (X3), was purified by chromatography (2~3% 2 M methanolic ammonia in chloroform) to obtain the compound indicated in heading (32 mg, 26%).1H NMR (CDCl3) δ (m-1): 8.09 (s, 1H) 7.97 (m, 1H), 7.56 (d, 2H), 7.44 (m, 2H), 7.01 (d, 2H), 5.09 (m, 1H), 4.11 (t, 2H), 3.62 (s, 3H), 3.65 (m, 1H), 3.44 (m, 1H), 2.76 (t, 2H), 2.36 (s, 6H), 1.60-2.30 (m, 6H).

Examples 54A and 54b

(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-morpholine and

(S)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-morpholine

Two enantiomers were isolated from the racemic 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-research using chiral HPLC column (Chiralpak AD) using hexane/isopropanol (20: 80); enantiomer 1 showed a retention time of 7.5 minutes, while the enantiomer 2 showed a retention time of 8.7 minutes.

Examples 55A and street, 55A

(R)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-[1,2,4]triazole-3-yl}piperidine and

(S)-2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-[1,2,4]triazole-3-yl}piperidine

2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-[1,2,4]triazole-3-yl}piperidine were separated using a Chiralpak AD (4,6×250)using ethanol:isopropanol (1:1) at a flow rate of 1.0 ml/min to obtain the two enantiomers of 13.3 mg (Rt=14,2 min) and 11.9 mg (Rt=18,7 min).

Examples 56a and b

(R)-4-(542-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl}pyridine and

(S)-4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl}pyridine

The product was separated using Chiralpak AD (4,6×250), using ethanol: isopropanol (1:1) at a flow rate of 1.0 ml/min to obtain the two enantiomers of 9.5 mg (Rt=11,6 min) and 10.8 mg (Rt=16,8 min).

Example 57

5-Formicariidae

Hydrazine monohydrate 98%, with 4.9 ml, 101,1 mmol) was added to a solution of ethyl-5-fornicating (1,71 g, 10.1 mmol) in EtOH (35 ml) in an argon atmosphere. The reaction mixture was allowed to mix at room temperature for five hours. The reaction mixture was concentrated and triturated with hexane to obtain compound indicated in heading (light yellow solid, 1,462 g, 93%).1H NMR CD3OD δ (m-1): 8.82 (s, 1H), 8.65 (m, 1H), 8.01 (dm, 1H).

Example 58

2-Methylsemicarbazide

HOBt (950 mg, of 6.99 mmol) and EDCl (1,34 g of 6.99 mmol) was added to a suspension of 2-chloro-6-methylethanolamine acid (1 g, 5.83 mmol) in acetonitrile (15 ml) at room temperature. After 1 h the solution was added hydrazine monohydrate (of 0.56 ml, 11,66 mmol) and cyclohexene (0.15 ml, 1.5 mmol) in acetonitrile (5 ml) dropwise at 0°C. the mixture was stirred over night and left to warm to room temperature. The solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to obtain 2-chloro-6-methylsemicarbazide (yellow solid, 1.1 g, used without dal is Asa cleaning). A balloon filled with hydrogen was attached to the flask containing 2-chloro-6-methylpyridin-4-carboxylic acid (1.12 g, 6,03 mmol), palladium 10% wt./wt. on activated carbon (0.56 g), triethylamine (3.4 ml) and ethanol (20 ml)and then stirred over night at room temperature. The reaction mixture was filtered through celite, washed with methanol and concentrated. The residue is triturated with dichloromethane and then filtered to obtain 2-methylsemicarbazide (light yellow solid, the crude product is used without further purification).

Example 59

2-Ethoxyethylacetate

HOBt (1.73 g, 12,79 mmol) and EDCl (2,45 g, 12,79 mmol) was added to a suspension of 2-chloro-6-methoxyethylamine acid (2 g, 10,66 mmol) in acetonitrile (25 ml) at room temperature. After 1 h the solution was added hydrazine monohydrate (of 1.03 ml, one-21.32 mmol) and cyclohexene (0.2 ml, 2.0 mmol) in acetonitrile (5 ml) dropwise at 0°C. the mixture was stirred over night and left to warm to room temperature. The solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to obtain 2-chloro-6-methoxysalicylaldehyde (light yellow solid, 2,03 g, 95%). A balloon filled with hydrogen was attached to the flask containing 2-the PRS-6-methylpyridin-4-carboxylic acid (1,83 g, 9,07 mmol), palladium 10% wt./wt. on activated carbon (0,91 g), triethylamine (5.5 ml) and ethanol (30 ml)and then stirred over night at room temperature. The reaction mixture was filtered through celite, washed with methanol and concentrated. The residue is triturated with dichloromethane and then filtered to obtain 2-methoxysalicylaldehyde (light yellow solid, the crude product is used without further purification).

Example 60

3-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methylmorpholin-4-carbothioamide

To a stirred solution of 3-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]the research (550 mg, 2,07 mol) in chloroform (8 ml) was added methylisothiocyanate (227 mg, 3.1 mmol). This solution was stirred at room temperature over night, concentrated and triturated with diethyl ether to obtain the connection specified in the header, in the form of a white solid (608 mg, 86.7 per cent).1H NMR (CDCl3) δ (m-1): 8.13 (s, 1H), 8.03 (dm, 1H), 7.5 (m, 2H), 6.69 (m, 1H), 6.04 (m, 1H), 4.58 (d, 1H), 4.02 (m, 3H), 3.74 (m, 2H), 3.24 (d, 3H).

Example 61

Methyl-3-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methylmorpholin-4-carbimidoyl

To a solution of 3-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methylmorpholin-4-thioamide group by forming (608 mg, to 1.79 mmol) in methanol (12 ml) was added CH3l (224 μl and 3.59 mmol). This solution was heated to flavobacteria for 1.5 h, then cooled to room temperature the market and was diluted with dichloromethane and washed with NaHCO 3(aq.). The aqueous phase is re-extracted with dichloromethane and the combined organic substance was dried (Na2SO4), filtered and concentrated under reduced pressure to get the connection specified in the header, with a quantitative yield.1H NMR (300 MHz, CDCl3) δ (million1): 8.15 (s, 1H), 8.04 (dm, 1H), 7.48 (m, 2H), 5.65 (t, 1H), 4.45 (dd, 1H), 4.03 (dd, 1H), 3.93 (dt, 1H), 3.79 (dm, 1H), 3.72 (td, 1H), 3.59 (tm, 1H), 3.25 (s, 3H), 2.38 (s, 3H).

Example 62

tert-Butyl ether 3-(N-hydroxycarbamoyl)-morpholine-4-carboxylic acid

tert-Butyl ether 3-cyano-morpholine-4-carboxylic acid (600 mg, and 2.83 mmol) in methanol (20 ml) was added to a solution of hydroxylamine hydrochloride (982 mg, 14,13 mmol) and sodium carbonate (1,498 g, 14,19 mmol) in deionized water (20 ml). The resulting solution was heated to flavobacteria overnight, then cooled to room temperature and methanol was removed in vacuum. The product was extracted twice with ethyl acetate, then a third time after adding sodium chloride to saturate the aqueous phase. The solvent was removed in vacuum to obtain compound indicated in heading (sticky whitish solids, 466,8 mg, 67%).1H NMR (300 MHz, CDCl3) δ (m-1): 1.50 (s, 9H); 3.23 (td, J=11 Hz, 3 Hz, 1H); 3.55 (m, 2H); 3.81 (m, 2H); 4.58 (s, broad, 1H); 4.92 (s, broad, 1H).

Example 63

tert-Butyl ester 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol the-3-yl]-morpholine-4-carboxylic acid

To a stirred solution of tert-butyl methyl ether 3-(N-hydroxycarbamoyl)-morpholine-4-carboxylic acid (300 mg, 1,22 mmol), 3-chloro-benzoic acid (193,4 mg, 1,24 mmol) and HOBt (181,8 mg, 1.35 mmol) in dimethylformamide (4 ml) was added EDCl (236,8 mg of 1.24 mmol). This solution was stirred over night at room temperature, then was diluted with dichloromethane and washed with water. The aqueous phase is re-extracted with dichloromethane and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude intermediate compound was filtered through silica gel using 10% methanol in dichloromethane, to remove traces of HOBt. Eluent was concentrated under reduced pressure, then dissolved in dimethylformamide (3 ml) and heated to 130°C for 90 min after removal of the solvent in vacuo got the connection specified in the header (300 mg, 67%).1H NMR (300 MHz, CDCl3) δ (m-1): 1.51 (s, 9H); 3.54 (m, 3H); 3.89 (m, 2H); 4.51 (m, 2H); 7.47 (m, 1H); 7.58 (m, 1H); 8.02 (m, 2H).

Example 64

3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine

The solution triperoxonane acid (4 ml) in dichloromethane (2 ml) was added to a solution of tert-butyl ester 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carboxylic acid (approximately 200 mg) in dichloromethane (2 ml). The resulting solution was stirred at the room for the Noah temperature for 30 min, then was diluted with dichloromethane and a small amount of water. The aqueous phase was neutralized with solid sodium bicarbonate was then added to deionized water and the organic phase was separated. The aqueous phase is re-extracted with dichloromethane and the combined organic phases were dried, filtered and concentrated under reduced pressure to get the connection specified in the header (144,9 mg, quantitatively).1H NMR (300 MHz, CDCl3) δ (m-1): 3.10 (m, 2H); 3.72 (m, 1H); 3.85 (m, 2H); 4.18 (dd, J=11 Hz, 3 Hz, 1H); 4.27 (dd, J=8 Hz, 3 Hz, 1H); 7.49 (t, J=8 Hz, 1H); 7.60 (m, 1H); 8.04 (m, 2H).

Example 65

Methylamide 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carbothioate

To a stirred solution of 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-research (184,8 mg, 0,696 mol) in chloroform (5 ml) was added methylisothiocyanate (54,7 ál HDI, 0.800 mmol). This solution was stirred at room temperature overnight, diluted with dichloromethane and washed with water. The aqueous phase is re-extracted with dichloromethane and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was subjected to chromatography in 60% ethyl acetate in hexano with getting the connection specified in the header, in the form of whitish crystals.1H NMR (300 MHz, CDCl3) δ (m-1): 3.06 (d, J=4.2 Hz, 3H); 3.61 (quintet of d, J=12 Hz, 3 Hz, 2H); 3.92 (m,3H); 4.51 (d, J=12 Hz, 1H); 6.51 (s, broad, 2H); 7.42 (t, J=7.5 Hz, 1H); 7.51 (m, 1H); 7.92 (m, 1H); 8.01 (m, 1H).

Example 66

Methyl ester of 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-N-methyl-morpholine-4-carboxymethylate

To a solution of methylamide 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carbothioate (137, 6mm mg, 0.41 mmol) in methanol (3 ml) was added CH3l (50,6 μl, 0.82 mmol). This solution was heated to flavobacteria for 1.5 h, then cooled to room temperature and was diluted with dichloromethane and washed with NaHCO3(aq.). The aqueous phase is re-extracted with dichloromethane and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to get the connection specified in the header, with a quantitative yield.1H NMR (300 MHz, CDCl3) δ (m-1): 2.34 (s, 3H); 3.24 (s, 3H); 3.61 (quintuplet of d, J=12 Hz, 3.3 Hz, 2H); 3.80 (d, J=12 Hz, 1H); 3.91 (m, 2H); however, 4.40 (dd, J=12 Hz, 2 Hz, 1H); 5.46 (s, broad, 1H); 7.43 (t, J=8.1 Hz, 1H); 7.52 (m, 1H); 7.96 (d, J=7.5 Hz, 1H); 8.07 (m, 1H).

Example 67

tert-Butyl-3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]morpholine-4-carboxylate

Isobutylparaben (1,56 ml of 12.0 mmol) was added to a solution of 4-tert-butyl ether morpholine-3,4-dicarboxylic acid (2,528 g, 10.9 mmol) and triethylamine (3.8 ml, 27,3 mmol) in THF (35 ml) at 0°C and the mixture was stirred for 2 hours. Added 3-iodine-N-hydroxy-benzamidine (2.86 g, 10.9 mmol), the mixture p is remedial for 1 h at room temperature and the solvent was removed in vacuum. Acyclic ether intermediate compound used without further purification. Was added DMF (25 ml) and the mixture was heated at 120°C during the night. The product was extracted into ethyl acetate and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The result chromatography (silica gel, 10-20% ethyl acetate in hexane) received the connection specified in the header (light yellow oil, 3,0403 g, 61%)as a mixture of rotamers by NMR.1H NMR (CDCl3) δ (m-1): 8.44 (s, 1H), 8.06 (d, 1H), 7.85 (d, 1H), 7.23 (t, 1H), 5.41 (br s, 0.5H), 5.24 (brs, 0.5H), 4.52 (brs, 1H), 3.9 (m, 3H), 3.6 (t, 1H), 3.49 (m, 1H), 1.53 (s, 4.5H), 1.46 (s, 4.5H).

Example 68

3-[3-(3-Itfinal)-1,2,4-oxadiazol-5-yl]morpholine

The solution triperoxonane acid (9.6 ml) in dichloromethane (25 ml) was added to a solution of tert-butyl 3-[3-(3-iodine-phenyl)-1,2,4-oxadiazol-5-yl]morpholine-4-carboxylate (3.04 from g, 6.05 mmol) in dichloromethane (30 ml) and the mixture was stirred at room temperature overnight and concentrated until dry. The residue was dissolved in ethyl acetate and washed with sodium hydroxide (1 N. water, 15 ml). The organic phase was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuum. The result chromatography (silica gel, 5% 2 M methanolic ammonia in dichloromethane) received the connection specified in the header (yellow oil, 2,1599 g, 1%). 1H NMR (CDCl3) δ (m-1): 8.48 (s, 1H), 8.08 (d, 1H), 7.86 (d, 1H), 7.24 (t, 1H), 4.34 (m, 1H), 4.2 (d, 1H), 3.86-3.99 (m, 2H), 3.74 (t, 1H), 3.18 (d, 1H), 3.05 (t, 1H).

Example 69

3-[3-(3-Itfinal)-1,2,4-oxadiazol-5-yl]-M-methylmorpholin-4-carbothioamide

Methylisothiocyanate (575 mg, 7,86 mmol) was added to 3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]morpholine (2.16 g, 6.05 mmol) in CHCl3(50 ml) and the resulting mixture was stirred at 60°C for 7 h and left at room temperature over the weekend. The mixture was concentrated in vacuum and the selected residue triturated with diethyl ether in hexano with the release of the connection specified in the header (yellow oil, 2.6 g, 100%).1H NMR (CDCl3) δ (m-1): 8.38 (s, 1H), 8.02 (d, 1H), 7.83 (d, 1H), 7.2 (t, 1H), 6.86 (m, 1H), 6.18 (m, 1H), 4.56 (d, 1H), 3.99 (m, 2H), 3.78 (t, 2H), 3.63 (m, 1H), 3.03 (d, 3H).

Example 70

Methyl-3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]-N-methylmorpholin-4-carbimidoyl

Logmean (0,11 ml of 1.74 mmol) was added to 3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]-N-methylmorpholin-4-carbothioamide (465 mg, of 1.08 mmol) in methanol (5 ml) and the resulting mixture was stirred at 75°C for 4 h the Mixture was cooled to room temperature, concentrated in vacuo, diluted with saturated sodium bicarbonate (aqueous), was extracted with dichloromethane. The combined organic phase was dried (sodium sulfate), filtered and concentrated in vacuum to obtain compound, specified in the header, in the form of a yellow oil (460 mg, 96%).1H NMR (CDCl3) δ (m-1): 7.44 (s, 1H), 8.05 (d, 1H), 7.84 (d, 1H), 7.22 (t, 1H), 5.46 (m, 1H), 4.36 (dm, 1H), 3.96 (m, 2H), 3.65-3.86 (m, 3H), 3.22 (s, 3H), 2.37 (s, 3H).

Example 71

tert-Butyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-carboxylic acid

A solution of tert-butyl methyl ether 2-formyl-pyrrolidine-1-carboxylic acid (4,2 g, 21.1 mmol) (commercially available from PharmaCore, Inc., 4180 Mendenhall Oaks Parkway, Suite 160. High Point, NC 27265, USA, or it is synthesized according to the method Beak et. al. J. Org. Chem. 1993, 58, 1109) in anhydrous pyridine (8 ml) was added to a cooled on ice to a solution of hydroxylamine hydrochloride (1.90 g, a 27.4 mmol) in anhydrous pyridine (25 ml). This solution was stirred at room temperature overnight. Was added water (500 ml) and the solution was extracted with dichloromethane (3×200 ml). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuum. The residue was dissolved in anhydrous DMF (50 ml) and was heated to 40°C. was Added a solution of N-chlorosuccinimide (3,10 g, 23.2 mmol) in anhydrous DMF (30 ml) and the reaction mixture was stirred at 40°C for 1.5 h and then at room temperature overnight. Added additional 844 mg (6.3 mmol) of N-chlorosuccinimide and the reaction mixture was stirred at 40°C. for 1.5 hours, the Reaction mixture was left to cool, diluted with diethyl ether (500 ml) and washed in the water (3×300 ml), and then brine (100 ml). The organic layer was dried (sodium sulfate), filtered and concentrated in vacuum. The residue was dissolved in anhydrous dichloromethane (30 ml) and added to a cooled on ice to a solution of 1-chloro-3-ethinyl-benzene and triethylamine in anhydrous dichloromethane (25 ml). The reaction mixture was stirred over night at room temperature and the solvent was removed in vacuum. The residue was dissolved in ethyl acetate (300 ml) and washed with water (3×100 ml) and brine (100 ml). The organic layer was dried (sodium sulfate), filtered and concentrated in vacuum. The residue was purified flash chromatography (heptane:ethyl acetate 8:1-4:1) to obtain the compound indicated in heading (3,48 g, 48%), in the form of oil, which hardened on standing.1H NMR (400 MHz, CDCl3, rotamer) δ (m-1): 1.10-1.69 (m, 9H); 1.71-2.44 (m, 4H); 3.34-3.68 (m, 2H); 4.90-5.10 (m, 1H); 6.40-6.55 (m, 1H); 7.37 (bs, 2H); 7.67 (m, 1H); 7.72 (bs, 1H).

Example 72

5-(3-Chloro-phenyl)-3-pyrrolidin-2-yl-isoxazol

tert-Butyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-carboxylic acid (3,45 g, 9.9 mmol) was dissolved in dichloromethane (15 ml) and added triperoxonane acid (15 ml). This solution was stirred at room temperature for 1 h, and then concentrated in vacuum.

The residue was dissolved in dichloromethane (200 ml) and washed with 1 M aqueous NaOH (200 ml). The aqueous layer was extracted with dichloromethane (2×100 ml) and yedinenye organic layers were washed with water (100 ml) and brine (100 ml), was dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header (2,12 g, 86%).1H NMR (400 MHz, CDCl3) δ (m-1): 1.88 (m, 3H); 2.1 (s, 1H); 3.62 (m, 1H); 3.12 (m, 1H); 4.32 (dd, 1H); 6.51 (s, 1H); 7.35 (m, 1H); 7.61 (m, 1H); 7.72 (s, 1H).

Example 73

Methylamide 2-[5-(3-chlorophenyl)isoxazol-3-yl]-pyrrolidin-1-carbothioate

Methylisothiocyanate (329 mg, 4.5 mmol) was added to 5-(3-chloro-phenyl)-3-pyrrolidin-2-yl-isoxazol (746 mg, 3.0 mmol) in anhydrous dichloromethane (20 ml) at room temperature. The reaction mixture was stirred overnight and concentrated in vacuum. The residue was purified flash chromatography using a gradient of 20-80% ethyl acetate in heptane, to obtain the compound indicated in heading (580 mg, 60%).1H NMR

(400 MHz, CDCl3) δ (m-1): 2.21 (m, 3H); 2.37 (m, 1H); 3.11 (d, 3H); 3.79 (m, 2H); 5.53 (bs, 1H); 6.57 (s, 1H); 7.39 (m, 1H), 7.68 (m, 1H); 7.73 (m, 1H).

Example 74

Cyclopropylamine 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-carbothioate

Cyclopropylacetylene (446 mg, 4.5 mmol) was added to 5-(3-chloro-phenyl)-3-pyrrolidin-2-yl-isoxazol (746 mg, 3.0 mmol) in anhydrous dichloromethane (20 ml) at room temperature. The reaction mixture was stirred overnight and concentrated in vacuum. The residue was purified flash chromatography using a gradient of 20-80% ethyl acetate in heptane, to obtain the compound indicated in heading (585 mg, 5%). 1H NMR

(400 MHz, CDCl3) δ (m-1): 0.55 (m, 2H); 0.83 (m, 2H); 2.20 (m, 3H); 2.39 (m, 1H); 3.03 (m, 1H); 3.80 (m, 2H); 5.45 (bs, 1H); 5.87 (bs, 1H); 6.65 (bs, 1H); 7.40 (m, 2H); 7.64 (m, 1H); 7.75 (bs, 1H).

Example 75

Methyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-pyrrolidin-1-carboxymethylate

The suspension methylamide 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-carbothioate (520 mg, of 1.61 mmol) and under the conditions (344 mg, 2,42 mmol) in anhydrous methanol (10 ml) was heated using a single-node microwave irradiation in a tightly closed vessel at 110°C for 15 minutes After cooling the resulting solution was diluted with saturated aqueous sodium bicarbonate (50 ml) and was extracted with dichloromethane (3×70 ml). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of oil (533 mg, 98%).1H NMR (400 MHz, CDCl3) δ (m-1): 2.00 (m, 3H); 2.12 (m, 1H); 2.26 (s, 3H); 3.23 (s, 3H); 3.63 (m, 1H); 3.71 (m, 1H); 5.39 (m, 1H); 6.39 (s, 1H); 7.37 (m, 2H); 7.63 (m, 1H); 7.72 (bs, 1H).

Example 76

a) Methyl ester of 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-cyclopropyl-pyrrolidin-1-carboxymethylate

Suspension of cyclopropylamine 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-carbothioate (546 mg, 1.57 mmol) and under the conditions (335 mg, 2.36 mmol) in anhydrous methanol (10 ml) was heated using a single-MICR is a new exposure in a tightly closed container at 75°C for 2 hours After cooling the resulting solution was diluted with saturated aqueous sodium bicarbonate (40 ml) and was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to obtain the connection specified in the header, in the form of oil (563 mg, 99%).1H NMR (400 MHz, CDCl3) δ (m-1): 0.51 (m, 1H); 0.60 (m, 1H); 0.69 (m, 2H); 1.96 (m, 2H); 2.12 (m, 1H); 2.29 (m, 1H); 2.33 (m, 3H); 3.10 (m, 1H); 3.59 (m, 1H); 3.66 (m, 1H); 5.28 (m, 1H); 6.37 (s, 1H); 7.35 (m, 2H); 7.61 (m, 1H); 7.70 (bs, 1H).

The following compounds were obtained in a similar way:

b) 4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopropyl-4H-[1,2,4]triazole-3-yl)-pyridine-2-yl]-morpholine; yield 24 mg, 23%, white solid;1H NMR CDCl3(500 MHz): 8.54 (d, 1H), 7.92 (dd, 1H), 7.70 (s, 1H). 7.59 (m, 1H), 7.38 (m, 2H), 6.67 (d, 1H), 6.50 (s, 1H), 5.54 (dd, 1H), 4.06 (ddd, 1H), 3.83 (m, 4H), 3.61 (m, 1H), 3.58 (m, 4H), 3.21 (m, 1H), 2.54 (m, 1H), 2.29 (m, 1H), 2.21 (m, 1H), 2.14 (m, 1H), 1.11 (m, 2H), 0.99 (m, 1H), 0.52 (m, 1H).

C) 4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-pyridine-2-yl]-morpholine; yield 41 mg, 34%, light yellow solid;1H NMR CDCl3(500 MHz): 8.38 (d, 1H), 7.81 (dd, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.37 (m, 2H), 6.70 (d, 1H), 6.59 (s, 1H), 5.41 (t, 1H), 3.87 (m, 1H), 3.83 (m, 4H), 3.59 (m, 4H), 3.52 (m, 4H), 2.55 (m, 1H), 2.30 (m, 1H), 2.19 (m, 2H).

g) 3-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-pyridine; yield 72 mg, 64%, Belov the second solid; 1H NMR CDCl3(500 MHz): 8.84 (d, 1H), 8.68 (dd, 1H), 8.01 (dt, 1H), 7.71 (m, 1H), 7.61 (m, 1H), 7.42 (dd, 1H), 7.37 (m, 2H), 6.54 (s, 1H), 5.42 (dd, 1H), 3.90 (dt, 1H), 3.57 (s, 3H), 3.54 (ddd, 1H), 2.56 (dddd, 1H), 2.24 (m, 3H).

d) 4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopropyl-4H-[1,2,4]triazole-3-yl)-pyridine; yield 75 mg, 68%, white solid;1H NMR CDCl3(500 MHz): 8.69 (dd, 2H), 7.70 (m, 3H), 7.59 (m, 1H), 7.36 (m, 2H), 6.52 (s, 1H), 5.58 (dd, 1H), 4.11 (dt, 1H), 3.66 (m, 1H), 3.32 (m, 1H), 2.57 (m, 1H), 2.26 (m, 3H), 2.16 (m, 1H), 1.15 (m, 2H), 1.00 (m, 1H), 0.47 (m, 1H).

Example 77

4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)-pyridine

A suspension of methyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-pyrrolidin-1-carboxymethylate (61 mg, 0.18 mmol), the hydrazide of isonicotinic acid (to 43.2 mg, 0.32 mmol) and pyridine (18 mg, 0.23 mmol) in ethanol (3 ml) was heated using a single-node microwave irradiation in a tightly closed container at 130°C. After cooling, the solvent evaporated and the residue was purified preparative HPLC with reversed phase, using a linear gradient of acetonitrile in 0.15% aqueous triperoxonane acid. In the second purification preparative HPLC with reversed phase, using a linear gradient of acetonitrile in 0.1 M aqueous ammonium acetate, received the connection specified in the header (18.5 mg, 25%), in the form of a white solid after lyophilization.1H NMR CDCl3(500 MHz) δ (m-1

Example 78

3-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-cyclopropyl-4H-1,2,4-triazole-3-yl)pyridine

A suspension of methyl ester 2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-cyclopropyl-pyrrolidin-1-carboxymethylate (76 mg, 0.21 mmol), nicotinic acid hydrazide (to 43.2 mg, 0.32 mmol) and pyridine (18 mg, 0.23 mmol) in 2.5 ml of 2-propanol was heated using a single-node microwave irradiation in a tightly closed vessel at 150°C. After cooling, the solvent evaporated and the residue was purified preparative HPLC with reversed phase, using a linear gradient of acetonitrile in 0.1 M aqueous the ammonium acetate, to obtain the compound indicated in heading (50,3 mg, 55%), in the form of a whitish solid after lyophilization.1H NMR CDCl3(500 MHz) δ (m-1): 9.00 (d, 1H), 8.65 (dd, 1H), 8.13 (dt, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.38 (m, 3H), 6.53 (s, 1H), 5.58 (dd, 1H), 4.11 (dt, 1H), 3.65 (ddd, 1H), 3.31 (m, 1H), 2.56 (m, 1H), 2.26 (m, 2H), 2.16 (m, 1H), 1.14 (m, 2H), 0.98 (m, 1H), 0.44 (m, 1H).

Example 79

a) 3-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-yl)morpholine

The isonicotinic acid hydrazide (155,5 mg, 1.13 mmol) was added to methyl 3-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-N-methylmorpholin-4-carbamodithioato (200 mg, 0,567 mmol) in isopropanol (4 ml). This mixture was stirred at 85-95°C overnight, and then diluted the dichloromethane (8 ml). The organic phase is then washed with water and brine, dried, filtered and concentrated in vacuum. In the trituration with diethyl ether got the connection specified in the header (white solid, 212 mg, 88%).1H NMR (CDCl3) δ (m-1): 8.76 (d, 2H), 8.1 (s, 1H), 7.99 (m, 1H), 7.62 (m, 2H), 7.48 (m, 2H), 5.2 (dd, 1H), 4.32 (dd, 1H), 4.12 (m, 2H), 4.03 (m, 1H), 3.77 (s, 3H), 3.6 (m, 1H), 3.42 (m, 1H).

The following compounds were obtained in a similar way:

b) 3-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazole-3-yl)morpholine; output 89,3 mg, 87,4%, white solid;1H NMR (CDCl3) δ (m-1): 8.89 (s, 1H), 8.73 (d, 1H), 8.11 (m, 1H), 8.03 (m, 2H), 7.47 (m, 3H), 5.2 (dd, 1H), 4.33 (dd, 1H), 4.12 (m, 2H), 4.04 (m, 1H), 3.74 (s, 3H), 3.59 (m, 1H), 3.46 (m, 1H).

C) 3-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-4-[5-(3,5-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]morpholine; output 78,9 mg, 71,4%, white solid;1H NMR (CDCl3) δ (m-1): 8.1 (s, 1H), 7.99 (m, 1H), 7.48 (m, 2H), 7.23 (m, 2H), 6.94 (tm, 1H), 5.18 (dd, 1H), 4.32 (dd, 1H), 4.11 (m, 2H), 4.02 (m, 1H), 3.73 (s, 3H), 3.57 (dm, 1H), 3.41 (m, 1H).

Pharmacology

Pharmacological properties of the compounds according to the invention can be tested using standard tests for functional activity. Examples of analyses of glutamate receptors are well known in the art, as described, for example, Aramori et al., Neuron 8:757 (1992), Tanabe et al., Neuron 8:169 (1992), Miller et al., J. Neuroscience 15: 6103 (1995), Balazs et al., J. Nerochemistry 69:151 (1997). The methodology described in these publications included in this description by reference. For convenience, the compounds according to the invention can be explored through analysis, which measures the mobilization of intracellular calcium [CA2+]iin cells expressing mGluR5.

For FLIPR analysis of cells expressing human mGluR5d, as described in WO 97/05252, were sown on coated collagen 96-well tablets with a transparent bottom with black walls and the analysis of the mobilization of [CA2+]iconducted 24 h after seeding.

FLIPR experiments were performed using a laser installation 0.800 to W and the speed of the breaker beam CCD camera 0.4 seconds. Each FLIPR experiment initiated 160 μl of buffer present in each well of the tablet for cell cultures. After each addition of the compounds were taken the sample fluorescence signal 50 times in 1 second intervals, and then 3 of the sample in 5-second intervals. Responses were measured as peak height response for the period of the sample. Definition EC50and IC50conducted on the basis of data obtained from the 8-point curves of the concentration-response (CRC, concentration response curve), obtained in two iterations. Agonistic CRC built by matching all the responses with the maximum response observed for the tablet. Antagonistic blockade of agonist stimulation of normalizable average response to stimulation by the agonist in 14 control wells on the same pad.

The inventors have confirmed the reliability of the secondary functional analysis for mGluR5d, as described in WO 97/05252, based on the exchange of insiststhat

(IP3). Accumulation IP3measured as index of receptor-mediated exchange of phospholipase C. Cell GHEK, stably expressing human receptors mGluR5d, incubated with [3H]-myo-Inositol overnight, washed three times in saline solution, buffered HEPES, and pre-incubated for 10 min with 10 mm LiCl. Added compounds (agonists) and incubated for 30 min at 37°C. Antagonistic activity was determined by pre-incubation of test compounds for 15 min, then incubation in the presence of glutamate (80 μm) or DHPG (30 μm) for 30 minutes the Reaction was stopped by adding perchloric acid (5%). Samples were collected and neutralized and insafety was isolated using ion-exchange columns which can be operated by gravity.

A detailed Protocol of the test compounds according to the invention presents the following analysis.

Analysis of antagonistic activity against receptors of group 1

For FLIPR analysis of cells expressing human mGluR5d, as described in WO 97/05252, were sown on coated collagen 96-well tablets with a transparent bottom and black walls and conducted analysis of the mobile is ment [CA 2+]i24 h after seeding. These 96-well tablets with cell cultures have made 4 μm solution of fluorescent calcium indicator fluo-3 (Molecular Probes, Eugene, Oregon) in the form acetoxymethyl ether 0.01% Pluronic. All analyses were performed in buffer containing 127 mm NaCl, 5 mm KCl, 2 mm MgCl2,

0.7 mm NaH2PO4, 2 mm CaCl2, 0,422 mg/ml NaHCO3, 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml BSA fraction IV (pH 7.4).

FLIPR experiments were performed using a laser installation 0.800 to W and the speed of the breaker beam CCD camera 0.4 seconds. Each FLIPR experiment initiated 160 μl of buffer present in each well of the tablet for cell cultures. After adding 40 μl of antagonistic tablet was added 50 μl of agonistic tablet. After each addition took the sample fluorescence signal 50 times in 1 second intervals, and then 3 of the sample in 5-second intervals. Responses were measured as peak height response for the period of the sample. Definition EC50and IC50conducted on the basis of data obtained from the 8-point curves of the concentration-response (CRC), obtained in two iterations. Agonistic CRC built by matching all the responses with the maximum response observed for the tablet. Antagonistic blockade of agonist stimulation were normalized by the average response to stimulation by the agonist 4 control wells on the same pad.

The measurement currency of insiststhat in intact whole cells

GHEK, stably expressing the human receptor mGluR5d, were sown on 24-hole tablets coated with poly-L-lysine, at a concentration of 40×104cells/well in medium containing 1 MCI/well of [3N]-myoinositol. Cells were incubated overnight (16 h), then washed three times and incubated for 1 h at 37°C in saline solution, buffered HEPES (146 mm NaCl, 4.2 mm KCl, 0.5 mm MgCl2, 0.1% glucose, 20 mm HEPES, pH 7,4), with the addition of glutamyltransferase at a concentration of 1 unit/ml and 2 mm pyruvate. Cells were washed once in saline solution, buffered HEPES, and pre-incubated for 10 min in saline solution, buffered HEPES containing 10 mm LiCl. Added compounds (agonists) and incubated at 37°C for 30 minutes Antagonistic activity was determined by pre-incubation of test compounds for 15 min, then incubation in the presence of glutamate (80 μm) or DHPG (30 μm) for 30 minutes the Reaction was stopped by adding 0.5 ml of perchloric acid (5%) on ice with incubation at 4°C for at least 30 minutes, the Samples were collected in 15-ml Falcon tubes and insafety was isolated using Dowex column, as described below.

Analysis insafety using ion-exchange columns, rabotaushi the gravity

Preparation of ion-exchange columns

Ion-exchange resin (Dowex AG1-X8 FORMATA form, 200-400 mesh, BIORAD) were washed three times with distilled water and kept at 4°C. 1.6 ml of resin was added to each column and washed with 3 ml of 2.5 mm HEPES, 0.5 mm EDTA, pH 7.4.

a) Processing sample

Samples were collected in 15-ml Falcon tubes and neutralized 0,375 M HEPES, 0.75 M KOH. Added 4 ml of HEPES/EDTA (2,5/0,5 mm, pH 7.4) for precipitation of potassium perchlorate. The supernatant was added to the prepared Dowex column.

b) isolation of insiststhat

Elution of glycerophosphatides 8 ml of 30 mm ammonium formate.

Elution of total Inozemtsev 8 ml 700 mm ammonium formate/100 mm formic acid and collecting the eluate in scintillation vials. The reading of the eluate mixed with 8 ml of scintillator.

One aspect of the invention relates to a method of inhibiting activation of mGluR5, in which the cell containing the specified receptor, is treated with an effective amount of the compounds of formula I.

Screening for compounds active against VRNPS

Use of adult Labrador retrievers trained standing in the machine Pavlova. Form esophagostomy mucosa-skin, and give dogs a chance to fully recover before conducting any experiments.

Measurement of contractility

Briefly, after fasting for about 17 h Ave the free access to water through esophagostomy enter mnogopolnoe device sleeve/side holes (Dentsleeve, Adelaide, South Australia) for measuring stomach, the lower esophageal sphincter (Les) and esophageal pressure. This device perfusion water, using manometric perfusion pump with a low elastic deformation (Dentsleeve, Adelaide, South Australia). Tube, blown air, placed in the direction of the oral cavity for measurement of swallowing movements and antimony electrode for pH monitoring is placed 3 cm above the NTC. All signals amplify and collect on a personal computer with a 10 Hz.

When the received measurement baseline level of physical activity, phase III of the stomach/PS amid starvation, placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in the vein of the front paw. Ten minutes after i.v. the introduction of the nutrient mixture (10% peptone, 5% D-glucose, 5% intralipid, pH 3.0) infuziruut into the stomach through the Central lumen of the device at a rate of 100 ml/min to a final volume of 30 ml/kg After infusion of the nutrient mixture is conducted infusion of air at a rate of 500 ml/min to obtain intragastric pressure 10±1 mm Hg. Then the pressure is maintained at this level throughout the experiment, using an infusion pump for an additional infusion of air or the escape of air from the stomach. The time of the experiment from the beginning of the infusion of the nutrient mixture before the end of the injection of air is 45 minutes of This meediauurijate as a reliable measurement initiation VRNPS.

VRNPS defined as the reduction of pressure in the lower esophageal sphincter (compared to intragastric pressure) at a rate of >1 mm Hg/sec Relaxation should not precede faringealny signal <2 with before, and in this case, the relaxation qualify as caused by swallowing. The pressure difference between the NTC and the stomach should be less than 2 mm Hg, and the duration of complete relaxation for longer than 1 second

Reduction

BSABovine serum albumin
CCDDevice with an associated charge (Charge Coupled Device)
CRCThe curve of the concentration-response
DHPG3,5-Dihydroxyphenylglycol
EDTAEthylenediaminetetraacetic acid
FLIPRTablet reader for fluorometrically visualization (Fluorometric Imaging Plate reader)
GHEKGLAST-containing embryonic human kidney
GLASTCarrier glutamate/aspartate

HEPES4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (buffer)
IP3Insectivora

Results

Typical values IC50measured in the above analyses is 10 μm or less. In one aspect of the invention IC50below 2 microns. In another aspect of the invention IC50below 0.2 μm. In another aspect of the invention IC50below 0.05 microns.

ConnectionFLIPP IC50
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-{5-[4-(deformedarse)phenyl]-4-methyl-4H-1,2,4-triazole-3-yl}morpholine199 nm
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)pyridine40 nm

1. The compound of the formula I

where R represents phenyl;
R1attached to R through a carbon atom on the ring R and is selected from the group consisting of halogeno, C1-6alkylhalogenide, OC1-6alkylhalogenide, C1-6of alkyl, OC1-6the alkyl and C0-6alkylene;
X1selected from the group consisting of N, NR4and CR4;
X2vibrant group, consisting of C and N;
X3selected from the group consisting of N and O;
X4selected from the group consisting of N and O;
X5selected from the group consisting of ties, CR4R4', NR4, O, S, SO, SO2;
X6represents N;
X7selected from the group consisting of C and N;
R4and R4'independently selected from the group consisting of hydrogen, C1-6of alkyl, C1-4alkylhalogenide, halogeno;
Q represents triazolyl;
R2and R3independently selected from the group consisting of C1-4alkylhalogenide, C1-6of alkyl, C3-6cycloalkyl,0-6alkylphenyl, OS0-6alkylphenyl, (CO)OS1-4of alkyl, O(CO)1-4the alkyl and 6-membered ring containing atoms independently selected from C, N, O and S, and where the specified ring may be substituted by one or more A;
And selected from the group consisting of hydrogen, hydroxy, halogen, oxo, C0-6alkylene, C1-6of alkyl, -OC1-6of alkyl, C1-6alkylhalogenide, OC1-6alkylhalogenide,0-6NR5R6OC2-6aNR5R6and 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
R5and R6independently selected from N and C1-6of alkyl;
m is 1;
n is selected from 1 and 2;
p is selected from 0 and 1; and
its pharmaceutically acceptable salt.

2. The connection is giving according to claim 1, where X7is a C.

3. The compound according to claim 1, where X5selected from the group consisting of CR4R4', NR4, O, S, SO and SO2.

4. The compound according to claim 1, where R1selected from the group consisting of Cl, F, Me, OMe, CF3, OCF3and CN.

5. The compound according to claim 1, where X2is a C.

6. The compound according to claim 5, where X1represents N or CR4.

7. The connection according to claim 6, where, when X3represents O, X4represents N, and when X3represents N, X4represents O.

8. The compound according to claim 1, where X2represents N.

9. The connection of claim 8, where X1represents N.

10. The connection according to claim 9, where X3represents N, and X4represents N.

11. The connection according to claim 6, where X5selected from the group consisting of ties, CR4R4', NR4and O.

12. The connection according to claim 7, where X5selected from the group consisting of communication, and NR4.

13. The connection of claim 10, where X5selected from the group consisting of O and CR4R4'.

14. The compound according to claim 1, where R2and R3independently selected from the group consisting of C1-4alkylhalogenide, C1-6the alkyl and C3-6cycloalkyl.

15. The compound according to claim 1, where a is selected from the group consisting of hydrogen, hydroxyl, halogeno,0-6alkylene, C1-6of alkyl, -OC 1-6of alkyl, C1-6alkylhalogenide, OC1-6alkylhalogenide.

16. The compound according to claim 1, chosen from:
4-(5-{2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-pyridine;
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-the research;
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-the research;
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-the research;
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-the research;
tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine-1-carboxylic acid;
2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine;
2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-1-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-piperazine;
tert-butyl ester 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine-1-carboxylic acid;
2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-piperazine;
2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-deformedarse-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-4-methyl-piperazine;
2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-1,2,4-Tria is ol-3-yl}-piperidine;
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)pyridine;
2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-1-[5-(4-methoxyphenyl)-4-methyl-4H-1,2,4-triazole-3-yl]piperidine;
[4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)phenyl]amine;
[4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-benzyl]-dimethyl-amine;
{2-[4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-phenoxy]-ethyl}-dimethyl-amine;
(R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-the research;
(S)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-the research;
(R)-2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-1,2,4-triazole-3-yl}piperidine;
(S)-2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(deformedarse)phenyl]-4-methyl-4H-1,2,4-triazole-3-yl}piperidine;
(R)-4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)pyridine;
(S)-4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)pyridine;
4-[5-(5-{2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopropyl-4H-[1,2,4]triazole-3-yl)-pyridine-2-yl]-the research;
4-[5-(5-{2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H-[1,2,4]triazole-3-yl)-pyridine-2-yl]-the research;
3-(5-{2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-meth is l-4H-[1,2,4]triazole-3-yl)-pyridine;
4-(5-{2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopropyl-4H-[1,2,4]triazole-3-yl)-pyridine;
3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-(5-pyridin-4-yl-4H-[1,2,4]triazole-3-yl)-the research;
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-3-yl-4H-1,2,4-triazole-3-yl)research;
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-yl)research;
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazole-3-yl)research;
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-4-[5-(6-methoxy-pyridin-3-yl)-4-methyl-4H-[1,2,4]triazole-3-yl]-the research;
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methoxypyridine-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]the research;
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]the research;
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(5-herperidin-3-yl)-4-methyl-4H-1,2,4-triazole-3-yl]the research;
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(5-herperidin-3-yl)-4-methyl-4H-1,2,4-triazole-3-yl]the research;
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-2-yl-4H-1,2,4-triazole-3-yl)research;
4-[5-(5-herperidin-3-yl)-4-methyl-4H-1,2,4-triazole-3-yl]-3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]the research;
3-[3-(3-itfinal)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-yl)research;
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]the research;
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-PI is one-3-yl-4H-1,2,4-triazole-3-yl)research;
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-[5-(3,5-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]the research;
3-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-cyclopropyl-4H-1,2,4-triazole-3-yl)pyridine and
4-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-methyl-4H-1,2,4-triazole-3-yl)pyridine.

17. Pharmaceutical composition having the properties of mGluR5 inhibitor containing as an active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 16 in combination with one or more pharmaceutically acceptable diluent, excipients and/or inert carrier.

18. The compound according to any one of claims 1 to 16, having the properties of an inhibitor of mGluR5.

19. The compound according to any one of claims 1 to 16 as an active agent for obtaining a medicinal product having the properties of an inhibitor of mGluR5.

20. The use of compounds according to any one of claims 1 to 16 in the manufacture of a medicinal product for the treatment of disorders mediated by mGluR5.

21. The application of claim 20, where the disorder mediated by mGluR5, is a neurological disorder.

22. The application of claim 20, where the disorder mediated by mGluR5, is a psychiatric disorder.

23. The application of claim 20, where the disorder mediated by mGluR5, is a chronic or acute pain disorder.

24. The application of claim 20, the de disorder, mediated by mGluR5, is a gastrointestinal disorder.

25. Method of inhibiting activation of mGluR5 receptors, including the processing of cells containing the indicated receptor, an effective amount of a compound according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound of the formula (I) , where R1 is a group of the formula and, in which R2, R3, R4, R5, R6, R7 and R8, each one independently represents a hydrogen atom or C1-6alkyl or its salt, to the method of its producing, to the method of antagonist effect on angiotensin II in the mammal, to the application of compounds of formula (I) as well as to methods of diseases prevention or treatment.

EFFECT: there are produced and provided new compounds that can be applied for prevention or treatment of disturbed circulation.

16 cl, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydrochinoline derivatives represented by general formula , where t is equal 0, 1 or 2; each R independently represents H, alkyl, alkenyl or cycloalkyl; n is equal 0; R is selected from group, consisting of H, alkyl, halogenalkyl, cycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5 or group - Racycloalkyl, and where R2 is not substituted with amine or alkylamine; each R4 independently represents halogen; m is equal 0, 1 or 2; each R5 independently represents H, alkyl, alkenyl, alkinyl, cycloalkyl; p is equal 0 or 1; y represents -NR10-, -O-, -S-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, -RaHetRaN(R10)2, -HetRaAy or -HetRaHet; each Ra independently represents alkylene, possibly suibstituted with one or more than one alkyl or hydroxyl, cycloalkylene, possibly substituted with one or more than one alkyl or hydroxyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl or -Ra-cycloalkyl; each Ay independently represents possibly substituted phenyl or naphtyl group; each Het independently represents possibly substituted 3-12-member mono- or polycyclic heterocyclyl group, containing as heteroatoms N, or 5-7-member possibly substituted heteroaryl group, containing as heteroatom N; or its pharmaceutically acceptable salts or ethers. Also described are methods of obtaining compounds of formula (I-G).

EFFECT: obtained are novel compounds, which demonstrate protective against HIV-infection effect on target-cells by means of specific binding with chemokine receptor and which influence binding of natural ligand or chemokine with target-cell receptor, such as CXCR4 and/or CCR5.

54 cl, 2 tbl, 90 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to piperidine-amino-benzidazoles having formula (I) and to addition salts or stereochemically isomeric forms, where Q is C1-6alkyl optionally substituted with one or two substitutes, each independently selected from a group consisting of trifluoromethyl, C3-7cycloalkyl, Ar2, hydroxyl, Ar2 - oxy-, hydroxycarbonyl, aminocarbonyl, C1-4alkylcarbonyl, aminocarbonyloxy, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyloxy, C1-4alkoxycarbonyl-(CH2)noxy, mono- or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono(C1-4alkyl)aminosulfonyl, or heterocycle selected from a group consisting of pyrrolidinyl, dihydropyrrolyl, imidazolyl, triazolyl, homopiperidinyl, pyridyl and tetrahydropyridyl; or where Q is C1-6alkyl substituted with two substitutes, where substitute is an amino group and the other is C1-6alkyloxycarbonyl; G is -CH2-; R1 is pyridyl optionally substituted with two substitutes selected from a group consisting of hydroxyl, C1-6alkyl; each n equals 1; one of R2a and R3a is C1-6alkyl and the other is hydrogen; when R2a is not hydrogen, R2b is C1-6alkyl and R3b is alkyl; and R3a, R2a, R2b all represent hydrogen; or R5 is hydrogen; t equals 2; Ar2 is phenyl or phenyl substituted with one or more, for example 2 substitutes selected from halogen, C1-6alkyloxy, aminosulfonyl and C1-4alkoxycarbonyl. The invention also relates to a pharmaceutical composition based on compound of formula I and use of the said compounds in making medicinal agents.

EFFECT: novel piperadine-amino-benzimidazoles are obtained, having inhibitory effect on respiratory syncytial virus replication.

10 cl, 3 tbl, 5 ex

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