1,2,4-triazole derivatives as sigma receptor inhbitors

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to the use of compounds having pharmacological activity towards the Sigma receptor, and more specifically, some derivatives of 1,2,4-triazole, to methods of producing such compounds and to pharmaceutical compositions that include them.

The LEVEL of TECHNOLOGY

The search for new therapeutic agents in recent years has been a big help a better understanding of the structure of proteins and other biomolecules associated with the target disease. One important class of these proteins is Sigma (σ) receptor, a cell surface receptor of the Central nervous system (CNS), which may be associated with dysphoric, hallucinogenic and cardiotonic effects of opioids. From a study of the biology and function of Sigma receptors were presented proof that the ligands of Sigma receptor may be useful for the treatment of psychosis and movement disorders such as dystonia and late dyskinesia, and impaired motor skills associated with chorea of Huntington's disease or Tourette's syndrome, and Parkinson's disease (Walker J.M. et al.,Pharmacological Reviews, 1990, 42, 355). It was reported that a known ligand of the Sigma receptor rimcazole clinically shows effects in the treatment of psychosis (Snyder S.H., Largent B.L. J. Neuropsychiatry, 1989, 1, 7). Sigma binding sites have site is citicoline affinity for Pervouralsk isomers certain opiate benzomorphans, such as (+) SKF 10047, (+)cyclazocine and (+)pentazocine, and to some narcoleptics, such as haloperidol.

Sigma receptor has at least two subtypes, it is possible to distinguish between isomers by selective data pharmacologically active drugs. SKF 10047 has nanomolar affinity to Sigma 1 (σ-1) site, and has micromolar affinity for Sigma (σ-2) site. Haloperidol has a similar affinity for both subtypes. Endogenous Sigma ligands are not known, although it has been suggested that progesterone is one of them. Possible pharmacological effects mediated by Sigma-plot, include modulation functions glutamate receptor, neurotransmitter response, neurotoxity, behavior, and cognitive abilities. (Quirion R. et al.Trends Pharmacol. Sci.,1992, 13:85-86). Most of the studies meant that the Sigma binding sites (receptors) are plasmalemmal elements of the cascade of signal transduction. Drugs reported that they are selective Sigma ligands were evaluated as antipsychotic drugs (Hanner M. et al.Proc. Natl. Acad. Sci., 1996, 93:8072-8077). The existence of Sigma receptors in the Central nervous system, immune and endocrine systems, talked about the likelihood that it can serve as the link between the three systems.

Taking into attention the potential therapeutic uses of agonists or antagonists of the Sigma receptor, great efforts were aimed at the discovery of selective ligands. Thus, the prior art describes various ligands Sigma receptor.

International patent application no WO 91/09594 describes, in General, a wide class of Sigma ligands of the receptor, some of which are compound 4-phenylpiperidine, tetrahydropyridine or tetrahydropyrazino having optionally substituted aryl or heteroaryl, alkyl, alkanniny, alkynylaryl, CNS or alkoxyalkyl Deputy on the N-atom cycle.

With regard to the chemical structure of the compounds described in this patent application, it should be noted that the cyclic system 1,2,4-triazole has been the object of intensive research, mainly due to the pharmacological properties exhibited by some of its derivatives, and also because of their suitability in synthetic organic chemistry. Recent reports have dealt with derivatives of 1,2,4-triazole as antagonists of oxytocin (WO 2006/092731), as well as MPO inhibitors of the enzyme (WO 2004/096781). 1,2,4-Triazoles have also been described as useful agents for the treatment of psychiatric disorders because of its activity against SW-receptor (WO 2005/039550), for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis (WO 03/092681), and the La prevention of urological disorders, because they act as agonists of GABAb (WO 2005/039569). In addition, some 3-hydroxyalkyl-1,5-diaryl-[1,2,4-triazole] showed significant anti-inflammatory activity (Archiv. Der Pharmazie, 1990, 323(4), 221-223).

However, none of these documents suggests that the impact of these compounds on the Sigma receptor.

There is still a need to find compounds that have pharmacological activity towards the Sigma receptor, being both effective and selective, and having good medicinal properties, i.e. good pharmaceutical properties regarding the introduction, distribution, metabolism and excretion.

The INVENTION

The authors of the present invention it was discovered family of structurally different derivatives of triazole, which are extremely selective inhibitors of the Sigma-1 receptor. Compounds according to the invention are a group of 1,2,4-triazole and are characterized by the substitution in position 3 alkyl chain, which ends with the Deputy amine type.

In one aspect the invention relates to the use of compounds of formula (I):

where R1, R2and R3independently selected from hydrogen, halogen, hydroxyl, alkoxyl, substituted or unsubstituted C1-C6of alkyl, cyano, NRaRb , NHCONRc, NHSO2Rd, COOH, COORewhere Rarepresents hydrogen or C1-C6alkyl, and Rb, Rc, Rdand Reindependently represents a C1-C6alkyl;

R4selected from hydrogen, C1-C6of alkyl, cycloalkyl, heterocyclyl and heteroaryl;

R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group,

X is selected from-S-, -SO-, -SO2and O; and

n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8,

or its pharmaceutically acceptable salt, stereoisomer, prodrug or MES, upon receipt of a medicinal product for the treatment or prevention of a disease or condition mediated by the Sigma-1 receptor.

In a specific embodiment, the compound of formula (I) are used for getting medicines for diarrhoea treatment of lipoprotein disorders, hyperlipidemia, hyperglyceridemia, hypercholesterolemia, obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma, impaired learning, memory and attention disorders cognitive, neurodegenerative diseases, demyelinating diseases, addiction to drugs or chemical substances the TV, including cocaine, amphetamine, ethanol and nicotine; tardive dyskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychotic conditions, in particular depression, anxiety or schizophrenia; inflammation, or autoimmune diseases.

In a more preferred embodiment, a drug used for the treatment of pain, particularly neuropathic pain, inflammatory pain or other pain conditions, including allodynia and/or increased sensitivity to pain.

In another specific embodiment, the compound of formula (I) are used as pharmacological tools, as tranquilizer or as an immunosuppressant.

Another aspect of the invention relates to the compound of formula (I)described above for use in the treatment of diseases or conditions mediated by Sigma-1 receptor.

In the second aspect of the invention relates to the compound of formula (I):

where R1, R2and R3independently selected from hydrogen, halogen, hydroxyl, C1-C6alkoxyl, substituted or unsubstituted C1-C6of alkyl, cyano, NRaRb, NHCONRc, NHSO2Rd, COOH, COORewhere Rarepresents hydrogen or C1-C6alkyl, and Rb, Rc , Rdand Reindependently represents a C1-C6alkyl;

R4selected from hydrogen, C1-C6of alkyl, cycloalkyl, heteroaryl and heterocyclyl;

R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group,

X is selected from-S-, -SO-, -SO2and O; and

n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8,

or its pharmaceutically acceptable salt, stereoisomer, prodrug or MES,

provided that

R4is not cyclopropyl; and

when R4is hydrogen, at least one of R1, R2and R3is not hydrogen.

In a preferred embodiment, at least one of R1-R3represents hydrogen. In another preferred embodiment, two of R1-R3represent hydrogen or halogen, with the latter preferably is chloride.

In another embodiment, R4preferably represents C1-C6alkyl, more preferably methyl.

In one embodiment, R5and R6independently represents a C1-C6alkyl, more preferably ethyl or from Roper.

In another embodiment, R5and R6form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group, preferably selected from pyrrolidine, piperidine, azepane and research.

Further, in the preferred embodiment, n is 1, 2, 3, 4 or 5.

In the third aspect of the invention relates to a method for obtaining compounds of formula (I)or its salt, isomer, prodrug or MES, which includes alkylation of the corresponding 5-alkyl-1-aryl-1H-1,2,4-triazole-3-thiol/ol of formula (II) alkylating agent.

In another aspect, the invention relates to a method for obtaining compounds of formula (I)or its salt, isomer, prodrug or MES, which includes the interaction of the compounds of formula (V) with an amine other5R6where R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group.

In another aspect the invention relates to an intermediate compound of formula (V).

And finally, in another aspect the invention relates to a pharmaceutical composition that includes a compound described above, or its pharmaceutically acceptable salt, isomer, prodrug or MES, and farmacevtichesky acceptable carrier, adjuvant or diluent.

The above advantages and embodiments of you can join, receiving additional preferred connection or application.

DETAILED description of the INVENTION

Typical compounds of the present invention effectively and selectively inhibit the Sigma-1 receptor.

In the present description, the following terms shall have the indicated meanings:

"C1-C6alkyl" refers to hydrocarbon radical with unbranched or branched chain consisting of carbon atoms and hydrogen, containing no unsaturated bonds, having from one to six carbon atoms, and which is attached to the remainder of the molecule by a simple relationship, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, etc.

"C1-C6alkoxyl" refers to a radical of the formula OR, where R represents a C1-C6alkyl radical, as defined above, for example, methoxy, ethoxy, propoxy, etc.

"Cycloalkyl" refers to a stable 3 to 10 membered monocyclic or bicyclic the radical, which is fully saturated and which is composed solely of carbon atoms and hydrogen, for example, cyclopentyl, cyclohexyl, etc. Unless specifically stated otherwise in the description mean that the term "cycloalkyl" who engages cycloalkyl radicals, which optionally substituted by one or more substituents such as alkyl, halogen, hydroxyl, amino, cyano, nitro, alkoxyl, carboxyl, alkoxycarbonyl etc.

"Heteroaryl" refers to substituted or unsubstituted stable 3-8 membered cyclic radical, which is partially unsaturated or aromatic, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably, to a 4-7 membered cycle with one or more heteroatoms, more preferably, to 5, 6 or 7-membered cycle with one or more heteroatoms, provided that at least one of the heteroatoms is a nitrogen. In addition, heteroaryl also may be a monocyclic, bicyclic, and tricyclic ring system, which may include a condensed cyclic system. Examples of such heteroaryl include, but are not limited to, benzimidazole, benzothiazole, isothiazol, imidazole, indole, purine, quinoline, thiadiazole, pyrrole, pyrazole, oxazole, isoxazol, triazole, imidazole, etc.

"Heterocyclyl" refers to substituted or unsubstituted stable 3-8 membered cyclic radical, which is fully saturated and which consists of carbon atoms and from one to three hetero the volume, selected from the group consisting of nitrogen, oxygen and sulfur, preferably, to a 4-7 membered cycle with one or more heteroatoms, more preferably, to 5, 6 or 7-membered cycle with one or more heteroatoms, provided that at least one of the heteroatoms is nitrogen. In addition, a heterocycle may be a monocyclic, bicyclic, and tricyclic ring system, which may include a condensed cyclic system, and atoms of nitrogen, carbon or sulfur in heterocyclyl radical may be optionally oxidized; the nitrogen atom may not necessarily be stereoselectivity. Examples of such heterocycles include, but are not limited to, azepin, piperidine, piperazine, morpholine, etc.

Heterocyclyl and heteroaryl groups can be substituted in one or more available positions by one or more suitable groups, for example, halogen, such as fluorine, chlorine, bromine and iodine; cyano; hydroxyl; nitro; alkyl groups including those groups having from 1 to about 12 carbon atoms, or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; a carbocyclic aryl having 6 or more carbon atoms, in particular phenyl or naphthyl, or aralkyl, such as benzyl. Unless specified otherwise, neobythites is but substituted group may contain a substituent in each capable of substitution position of the group, and each substitution is independent of the other.

"Halogen" refers to bromine, chlorine, iodine and fluorine.

Derivatives of 1,2,4-triazole used in the present invention, are characterized by a wide range of positive effects, at the same time, showing a relatively small side effects, i.e. effects that do not positively contribute or even prevent, in the presence of the patient.

Thus, one aspect of the present invention relates to a method of treatment or prevention of diseases mediated by the Sigma-1 receptor, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or pharmaceutical compositions. Among the diseases mediated by the Sigma-1 receptor, which can be treated or prevented are diarrhoea, lipoprotein disorders, hyperlipidemia, hyperglyceridemia, hypercholesterolemia, obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma, impaired learning, memory and attention disorders cognitive, neurodegenerative diseases, demyelinating diseases, dependence on drugs or chemical substances including cocaine, amphetamine, ethanol and nicotine; later diskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychotic state in particular, depression, anxiety disorder, or schizophrenia; inflammation, autoimmune diseases, neuropathic pain, inflammatory pain or other pain conditions, including allodynia and/or increased sensitivity to pain. Compounds according to the invention can also be used as pharmacological tools or as a tranquilizer or immunosuppressant.

In one embodiment of the invention, preferably, the compound of formula (I)used in the present invention, at least one of R1-R3represented the hydrogen. In another embodiment, preferably, two of R1-R3represent hydrogen or halogen, with the latter preferably is a chloride.

In another embodiment, R4represent lower alkyl, preferably methyl.

In one embodiment, R5and R6independently represent a lower alkyl, more preferably ethyl or isopropyl.

In another embodiment, R5and R6form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group, preferably selected from pyrrolidine, piperidine, azepane and research.

Further, in the preferred embodiment, n t is made by a 1, 2, 3, 4 or 5.

Preferred compounds of formula I are the following compounds:

-4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine;

-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}piperidine;

-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}pyrrolidin;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diisopropylethylamine;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine;

-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]azepin;

-4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine;

-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-pyrrolidin;

-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-phenylpiperidine;

-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]-4-phenylpiperidine;

-4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]morpholine;

-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]piperidine;

-4-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]morpholine;

-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]pyrrolidin;

-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidin;

-4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]morpholine;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diisopropylethylamine;

-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)butyl]-4-phenylpiperidine;

-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]ethyl}pyrrolidin;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diethylethanamine;

-4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)butyl]morpholine;

-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]ethyl}piperidine;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]-N,N-diethylethanamine;

-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]pyrrolidin;

-4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine;

-2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)-N,N-diethylethanamine;

-1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]pyrrolidin;

-4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine;

-1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]piperidine;

-4-[4-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)butyl]morpholine;

-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-4-methylpiperidin;

-4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;

-4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;

-N-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-N,N-diisopropylamino-2-amine;

-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]piperidine;

-4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;

-4-[2-(1-(3-harfe who yl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]pyrrolidin;

-2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine;

-4-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylbutyl-1-amine;

-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]piperidine;

-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]pyrrolidin;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diethylethanamine;

-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidin;

-4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]morpholine;

-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diethylamine;

-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidin;

-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-Diisopropylamine;

-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diethylamine;

or its pharmaceutically acceptable salt, isomer, prodrug or MES.

In addition, in another preferred embodiment of the invention the compound of formula I is its oxalic salt.

Preferred salts of the compounds of formula I are the following salts:

-4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine oxalate;

-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}piperidine oxalate;

-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]the Teal}pyrrolidin oxalate;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diisopropylethylamine oxalate;

-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine oxalate;

-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]azepin oxalate;

-4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine oxalate;

-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-pyrrolidin oxalate;

-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-phenylpiperidine oxalate;

-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]-4-phenylpiperidine oxalate;

-4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]morpholine oxalate;

-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]piperidine oxalate;

-4-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]morpholine oxalate;

-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]pyrrolidine oxalate;

-4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine oxalate;

-4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine hydrochloride;

- oxalate 1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-4-methylpiperidine;

- oxalate 4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;

- oxalate 4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;

the oxalate of N-[2-(1-(3-chlorophenyl)-5-methyl-1 is -1,2,4-triazole-3-ylthio)ethyl]-N,N-diisopropylamino-2-amine;

- oxalate 1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]piperidine;

- oxalate 4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;

- oxalate 4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]pyrrolidine;

- oxalate 2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine.

Unless stated otherwise, also meant that the compounds according to the invention include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure, except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon-carbon enriched13C or14C, or nitrogen enriched15N are within the scope of the patent protection of the present invention.

The term "pharmaceutically acceptable salt, isomer, solvate, prodrug" refers to any pharmaceutically acceptable salt, isomer, MES, prodrug, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) the compound described in this invention. However, it will be clear that not pharmaceutically acceptable salts also fall within the scope of the invention as they may be applicable for the preparation of pharmaceutically acceptable salts. Preparation of Sol is th, isomer, solvate, prodrugs and derivatives can be accomplished by methods known from the prior art.

For example, here pharmaceutically acceptable salts of the compounds are synthesized from the parent compound, which contains the main part, traditional chemical methods. Generally, such salts are, for example, is prepared by the interaction of these compounds in the form of the free base with a stoichiometric amount of the appropriate acid in water or in an organic solvent or a mixture of these two components. Usually, it is preferable non-aqueous medium, for example, ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the additive salts of the acid include an additive salts of mineral acids, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and additive salts of organic acids, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluensulfonate.

Especially preferred derivatives or prodrugs are compounds that increase the bioavailability of the compounds according to this invention when such compounds are administered to a patient (for example, by oral input connection is more easily absorbed into the blood)or which enhance delivery ishodnoj the connection to the biological section (for example, the brain or lymphatic system) relative to the parent compounds.

Any compound that is a prodrug of compounds of formula I, is within the scope of the invention. The term "prodrug" is used in its broadest sense and covers such derivatives, which are converted in vivo into compounds according to the invention. Such derivatives can easily come to mind to a person skilled in the art and include, depending on the functional groups present in the molecule, and without limitation, the following derivatives of these compounds: esters, esters of amino acids, complex phosphate esters, metal salts and sulfate esters, carbamates and amides.

Compounds according to the invention may be in crystalline form or in the form of the free compounds or in the form of a solvate, and we mean that both forms fall within the scope of the present invention. Methods of solvation, generally known from the prior art. Suitable solvate represent a pharmaceutically acceptable solvate. In a specific embodiment, the MES is a hydrate.

The compounds of formula I, their salts, isomers, prodrugs, or a solvate, are preferably in pharmaceutically acceptable or substantially pure form. Under a pharmaceutically acceptable form p is NIMA, among other things, that it is pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and carriers, and does not include a substance is considered toxic at normal dosage levels. The purity levels for medicinal substance, preferably, comprise more than 50%, more preferably above 70%, most preferably above 90%. In the preferred embodiment, it is more than 95% of the compounds of formula I, or its salts, isomers, solvate or prodrugs.

Compounds of the present invention represented by the above formula I, may include enantiomers depending on the presence of chiral centers. Single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

The compounds of formula (I), described above, can be obtained using existing synthetic procedures. For example, the compounds of formula (I) can be prepared by alkylation of the corresponding 5-alkyl-1-aryl-1H-1,2,4-triazole-3-thiol/ol of formula (II):

alkylating agent

where R1, R2and R3independently selected from hydrogen, halogen, hydroxyl, alkoxyl, substituted or unsubstituted C1-C6of alkyl, cyano, NRaRb, NHCONRc, NHSO2Rd, COO, COORewhere Rarepresents hydrogen or C1-C6alkyl, and Rb, Rc, Rdand Reindependently represents a C1-C6alkyl;

R4selected from hydrogen, C1-C6of alkyl, cycloalkyl, heterocyclyl and heteroaryl; and

X represents O or S,

provided that:

R4is not cyclopropyl; and

when R4represents hydrogen, at least one of R1, R2and R3is not hydrogen.

The alkylation reaction preferably occurs in the presence of a base, such as, for example, carbonate, and using proton solvent such as a lower alcohol, e.g. methanol.

Connection 5-alkyl-1-aryl-1H-1,2,4-triazole-3-thiol/ol of formula (II) can be obtained by cyclopentadienes of semicarbazides according to the procedure published inArch. Pharm.(1990), 323, 221-223.

In a specific embodiment of the invention, the alkylating agent is a compound of formula (III):

where Z represents halogen,

R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group, and

n is selected from 1, 2, 3, 4, 5, 6, 7 and 8.

In another prepact the positive variant of the invention, the alkylating agent is a compound of formula (IV):

in which Z and n are as defined above.

In this latter case requires an additional step to obtain the compound of formula (I), in which the compound obtained after the alkylation reaction, interacts with other amine5R6where R5and R6are as defined above.

Accordingly, the compounds of formula (I) can also be prepared by a method which involves reacting the compounds of formula (V):

where R1, R2and R3independently selected from hydrogen, halogen, hydroxyl, alkoxyl, substituted or unsubstituted C1-C6of alkyl, cyano, NRaRb, NHCONRc, NHSO2Rd, COOH, COORewhere Rarepresents hydrogen or C1-C6alkyl, and Rb, Rc, Rdand Reindependently represents a C1-C6alkyl;

R4selected from hydrogen, C1-C6of alkyl, cycloalkyl, heterocyclyl and heteroaryl;

X represents O or S;

Z represents halogen;

n is selected from 1, 2, 3, 4, 5, 6, 7 and 8,

provided that

R4is not cyclopropyl; and

when R4is hydrogen, at least one of R1, R2and R3is not hydrogen,

with other amine5R where R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group.

The compounds of formula (I)in which X represents-SO - or-SO2-, can be obtained by oxidation of the corresponding 3-(alkylthio)-1H-1,2,4-triazole prepared according to any of the reactions described above, by methods known to the person skilled in the art. For example, the oxidation reaction can be carried out using Oxone® as oxidant.

In another embodiment, the invention relates to an intermediate compound of formula (V):

where R1, R2and R3independently selected from hydrogen, halogen, hydroxyl, alkoxyl, substituted or unsubstituted C1-C6of alkyl, cyano, NRaRb, NHCONRc, NHSO2Rd, COOH, COORewhere Rarepresents hydrogen or C1-C6alkyl, and Rb, Rc, Rdand Reindependently represents a C1-C6alkyl;

R4selected from hydrogen, C1-C6of alkyl, cycloalkyl, heterocyclyl and heteroaryl;

X represents O or S;

Z represents halogen;

n is selected from 1, 2, 3, 4, 5, 6, 7 and 8,

provided that

R4not a cycle is a propylene; and

when R4is hydrogen, at least one of R1, R2and R3is not hydrogen.

The resulting reaction products can, if desired, to purify by conventional methods such as crystallization, chromatography and rubbing. When the above-described methods for producing compounds according to the invention lead to a mixture of stereoisomers, these isomers can be divided by traditional methods such as preparative chromatography. If there are chiral centers, the compounds can be prepared in racemic form, or you can make individual enantiomers enantiospecific synthesis or by separation.

Another preferred pharmaceutically acceptable form is a crystalline form, including a form of the pharmaceutical composition. In the case of salt or solvate additional ion and solvent groups should also be non-toxic. Compounds according to the invention can be in various polymorphic forms, it is understood that the invention encompasses all such forms.

Further, the present invention provides pharmaceutical compositions comprising a compound according to this invention, or its pharmaceutically acceptable salt, isomer, prodrug or MES, together with a pharmaceutically acceptable carrier, adjuvant or diluent, DL is the introduction of the patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) a composition for oral, topical or parenteral administration.

In a preferred embodiment, the pharmaceutical compositions are in oral form, solid or liquid. Suitable dosage forms for oral administration may be tablets, capsules, syrups or solutions and may contain conventional excipients known in the prior art, such as binders, such as syrup, gum Arabic, gelatin, sorbitol, tragacanth gum or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; sliding substances for the production of tablets, for example, magnesium stearate; substances that contribute raspadaemosti dosage forms, for example, starch, polyvinylpyrrolidone, sodium starch glycolate, or microcrystalline cellulose; or pharmaceutically acceptable moisturizing agents, such as sodium lauryl sulfate.

Solid oral compositions can be prepared by traditional methods of blending, filling or tableting. You can use recurring transactions mixing to distribute the active agent in the compositions, using the considerable amount of fillers. Such operations are common in the prior art. Tablets, for example, it is possible to prepare a wet or dry granulation, and, optionally, cover in accordance with methods well known in normal pharmaceutical practice, in particular, intersolubility the floor.

Pharmaceutical compositions also can be adapted for parenteral administration, for example, in the form of sterile solutions, suspensions or lyophilized products in the relevant standard dosage form. You can use appropriate tools such as fillers, buffering agents or surfactants.

These formulations are prepared using standard methods such as described or referenced in Pharmacopoeias Spain and the United States and similar reference texts.

Introduction compounds or compositions of the present invention can be accomplished by any suitable method, such as intravenous infusion, oral medications, intraperitoneal and intravenous. Oral introduction is preferred because of the convenience for the patient and chronic nature of the diseases that should be treated.

Typically, the effective input the number of compounds according to the invention will depend on the relative efficiency of the selected connection,the severity of the disease, should be treated, and weight of the patient. However, the active compounds will typically be prompted to enter one or more times per day, for example, 1, 2, 3 or 4 times a day with a typical total daily dose in the range from 0.1 to 1000 mg/kg/day.

The compounds and compositions according to this invention can be used with other drugs, providing a combination therapy. Other medicines may form a part of the same composition, or be provided as a separate composition for administration at the same time or at another time.

The following examples are given only as an illustration of the invention and should not be taken as a definition of the scope of the invention.

EXAMPLES

Example 1. Synthesis of 4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine oxalate (compound 1)

A. Synthesis of 3,4-dichlorophenylisocyanate

A mixture of 3,4-dichloropyridazine (18,8 mmol) and potassium thiocyanate (55,7 mmol) was dissolved in water (1 l) and heated for 17 hours. After cooling, the product solid was filtered and dried under vacuum, obtaining 3,4-dichlorophenylisocyanate (4,20 g, yield=95%). N1NMR (300 MHz, DMSO, 25°C) δ: 9,37 (s, 1H); 8.30 to (s, 1H); to 7.84 (s, 1H); of 7.60 (s, 1H); 7,40 (d, J=8.7 Hz, 1H); 6,37 (d, J=2,52 Hz, 1H); 6,60 (DD, J=8,67 Hz, J=2.5 Hz, 1H) ppm EAT (ES+) m/z=236 (100%) [M+H]+.

C. Synthesis of 1-a is ethyl-3,4-(dichlorophenyl)thiosemicarbazide

3,4-Dichlorophenylisocyanate (2.1 mmol) was dissolved in ethyl acetate (200 ml) under nitrogen atmosphere and was heated under reflux. After cooling to room temperature was added dropwise acetylchloride (0,23 ml, 3.2 mmol). The reaction mixture was left to mix for 16 hours. The solvent is then evaporated under vacuum and the obtained pale-pink solid was dried under vacuum, obtaining 1-acetyl-3,4-(dichlorophenyl)thiosemicarbazide (0,369 g, yield=63%). N1NMR (300 MHz, DMSO, 25°C) δ: 10,42 (s, 1H); 8,39 (s, 1H); 8,02 (s, 1H); 7,81 (d, J=2.1 Hz, 1H); to 7.68 (d, J=8.7 Hz, 1H); 7,42 (d, J=8,4 Hz); 2,48 (S, 3H) ppm EAT (ES+) m/z=279 (100%) [M+H]+.

C.Synthesis of 1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-thiol

1-Acetyl-3,4-(dichlorophenyl)thiosemicarbazide (36 mmol) was dissolved in methanol (2 l). Was added dropwise 0,5M sodium hydroxide solution with 25% methanol to pH 9. After 45 min stirring at room temperature was added dropwise 1M solution of hydrochloric acid to pH 2. The obtained mixture in a pale orange solid was filtered and dried under vacuum, obtaining 1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-thiol (of 5.99 g, yield = 60%). H1NMR (300 MHz, DMSO, 25°C) δ: 13,99 (s, 1H); 7,94 (d, J=2.4 Hz, 1H); 7,87 (d, J=8.6 Hz, 1H); 7,63 (DD, J=8.7 Hz, J=2.4 Hz, 1H); 2.49 USD (s, 3H) ppm EM (ES+) m/z=260 (100%) [M+H]+.

D.Synthesis of 4-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yl is ioutil]morpholine oxalate

1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-thiol (0.4 mmol) was dissolved in methanol (100 ml) at room temperature. Was added dropwise a solution of potassium carbonate in water to pH 9. After 15 min stirring solution was added 4-(2-chloroethyl)morpholine hydrochloride (0.4 mmol) in water (20 ml). The reaction mixture was allowed to mix at room temperature over night. The methanol is evaporated and after extraction CH2Cl2the organic layer was dried over magnesium sulfate, then evaporated and finally purified on a chromatographic column, getting dark orange oily substance. The purified product was dissolved in ether (20 ml) and mixed with a solution of oxalic acid (0.31 mmol) in ethyl acetate (5 ml)to give 4-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-indiatel]morpholine oxalate (0,147 g, yield=84%) as a white precipitate, which was filtered and dried under vacuum. N1NMR (300 MHz, DMSO, 25°C) δ: to 7.93 (d, J=2.4 Hz, 1H); of 7.82 (d, J=8.7 Hz, 1H); to 7.61 (DD, J=2.4 Hz, J=8.6 Hz, 1H); 3,66 (t, J=4.6 Hz, 4H); of 3.32 (t, J=6,8 Hz, 2H); 2,983 (t, J=5 7,0 Hz, 2H); 2,78 (users, 4H); 2,47 (s, 3H) ppm EAT (ES+) m/z=373 (100%) [M+H]+. C17H20Cl2N4O5S (463,0) calculated 44,07%; N Of 4.35%; N 12,09%; S=6,92%; found 43,79%; N 4,60%; N, 11.87 per cent; S=6,75%

Examples 2-6 were prepared as described in example 1, using in part D of the corresponding 2-hloretilaminam.

Example 2

1-{2-[1-(3,4-dichlorophenyl)-5-m is Teal-1H-1,2,4-triazole-3-ylthio]ethyl}piperidine oxalate (compound 2)

N1NMR (300 MHz, DMSO, 25°C) δ: 7,79 (d, J=2.4 Hz, 1H); to 7.67 (d, J=8.6 Hz, 1H); of 7.48 (DD, J=2.4 Hz, J=8.6 Hz, 1H); of 3.25 (m, 2H); 3,14 (m, 2H); 2.95 and (m, 4H); 2,31 (s, 3H); and 1.54 (m, 4H); of 1.33 (m, 2H). EAT (ES+) m/z=371 (100%) [M+H]+. C18H22Cl2N4O4S (461) calculated 46,86%; N To 4.81%; N 12,41%; S 6,95%; found 46,38%; N 4,73%; N 11,78%; S 6.69 per cent.

Example 3

1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}pyrrolidine oxalate (compound 3)

N1NMR (300 MHz, DMSO, 25°C) δ: 7,98 (d, J=2.4 Hz, 1H); 7,86 (d, J=8.6 Hz, 1H); 7,63 (DD, J=2.4 Hz, J=8.7 Hz, 1H); 3,44 (users, 4H); 3,29 (users, 4H); of 2.51 (s, 3H); 1,92 (users, 4H). EAT (ES+) m/z=357 (100%) [M+H]+. C17H20Cl2N4O4S (447) calculated 45,64%; N 4,51%; N To 12.52%; S 7,17%; found 45,23%; N 4,48%; N Of $ 11.97%; S is 6.78%.

Example 4

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diisopropylethylamine oxalate (compound 4)

N1NMR (300 MHz, DMSO, 25°C) δ: 7,98 (d, J=2.4 Hz, 1H); 7,86 (d, J=8,4 Hz, 1H); the 7.65 (DD, J=2.4 Hz, 1H); 3,68 (m, 2H); 3.40 in (m, 4H); 2.50 each (s, 3H); 1,31 (m, N); of 2.50 (s, 3H) ppm EAT (ES+) m/z=387 (100%) [M+H+]. 2 [C19H26Cl2N4O4S].3CO4H2(1044,85) calculated 45,98%; N To 5.21%; N Of 10.72%; From 6.14%found S 45,89%; N Of 5.05%; N 10,79%; S 6,05%.

Example 5

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine oxalate (compound 5)

N1NMR (300 MHz, DMSO, 25°C) δ: 7,98 (d, J=2.4 Hz, 1H); 7,86 (d, J=8.6 Hz, 1H); 7,66 (DD, J=2.4 Hz, J=8.6 Hz, 1H); 3,38 (kV, J=6,9 Hz, 4H); 3,13 (kV, J=7,0 Hz, 2H); of 2.51 (s, 3H); 1,21 m, 2H); of 1.09 (t, J=6,9 Hz 6N) ppm EAT (ES+) m/z=359 (100%) [M+H]+. C17H22Cl2N4O4S (449,35), calculated With 45,44%; H 4.93 per cent; N 12,47%; 7,14%found 45,08%; N 4,85%; N 12,42%; From 7.01%.

Example 6

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]azepin oxalate (compound 6)

N1NMR (300 MHz, DMSO, 25°C) δ: of 7.96 (d, J=2.3 Hz, 1H); to 7.84 (d, J=8.6 Hz, 1H); to 7.64 (DD, J=2.4 Hz, J=8.6 Hz, 1H); to 3.38 (m, 4H); is 3.21 (t, J=4.8 Hz, 4H); 2,49 (s, 3H); 1,76 (users, 4H); 1,58 (users, 4H) ppm EM (ES+) m/z=385 (100%) [M+H]+. C19H24Cl2N4O4S (475,39) calculated 48,00%; H 5,09%; N To 11.79%; S 6,74%found 47,77%; H 5,19%; N To 11.61%; S 6.58 percent.

Example 7

4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine oxalate (compound 7)

A.Synthesis of 1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-thiol

This product is prepared by following the stages A-C of example 1.

B.Synthesis of 3-(3-bromopropyl)-1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole

1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-thiol (5.7 mmol) was dissolved in methanol (1 l)by heating under stirring. Was added dropwise a solution of potassium carbonate in water (30 ml) to pH 9. After 15 minutes under stirring was added 1,3-dibromopropane (2,94 ml, 28 mmol). The reaction mixture was stirred at room temperature for 40 minutes Then the solvent is evaporated and the product was purified through column chromatography using e is racette, getting 3-(3-bromopropyl)-1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole (1,58 g, yield=72%). H1NMR (300 MHz, CDCl3, 25°C) δ: to 7.59 (d, J=2.4 Hz, 1H); 7,56 (d, J=8.6 Hz, 1H); 7,30 (DD, J=2.4 Hz, J=8.6 Hz, 1H); of 3.54 (t, J=6.5 Hz, 2H); of 3.25 (t, J=6,7 Hz, 2H); 2,5 (s, 3H); 2,32 (m, 2H) 10 ppm

C.Synthesis of 4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine oxalate

Morpholine (1.3 mmol, to 0.011 ml) was dissolved in methanol (20 ml) at room temperature. Was added dropwise a solution of potassium carbonate in water (20 ml) to pH 9. The mixture was stirred for 15 minutes and Then was added a solution of 3-(3-bromopropyl)-1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole (1,31 mmol) in methanol (300 ml) and the mixture is boiled under reflux during the night. The methanol is evaporated and the aqueous solution was extracted with CH2Cl2. The organic layer was dried over MgSO4, then evaporated and finally purified by chromatography on silica gel using a mixture of 10% methanol/ethyl acetate, getting 3-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine as a yellow oily substance. The purified product was dissolved in ether (30 ml) and mixed with a solution of oxalic acid (0.05 g) in ethyl acetate (5 ml)to give 4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine oxalate (0,23 g, yield 37%) as a white precipitate, which was filtered and dried under vacuum. H1NMR (300 MHz, DM is About, 25°C) δ: to 7.93 (d, J=2.2 Hz, 1H); of 7.82 (d, J=8.6 Hz, 1H); 7,613 (DD, J=2.2 Hz, J=8.6 Hz, 1H); 3,71 (users, 4H); 3,133 (t, J=6.9 Hz, 2H); 2,92 (users, 6H); 2,48 (s, 3H); 2,02 (m, 2H) ppm EM (ES+) m/z=387 (100%) [M+H]+. C18H22Cl2N4O5S (477,36) calculated With 45,29%; H 4,65%; N 11,74%; S 6,72%found 45,31%; N Br4.61%; N 11,93%; S 6,59%.

Examples 8-14 were prepared as described in example 7, using in part B of the relevant dibromodecane and in part C of the corresponding amines.

Example 8

1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-pyrrolidine oxalate (compound 8)

N1NMR (300 MHz, DMSO, 25°C) δ: to 7.93 (d, J=2.3 Hz, 1H); of 7.82 (d, J=8.6 Hz, 1H); a 7.62 (DD, J=2.4 Hz, J=8.6 Hz, 1H); 3,17 (m, 8H); 2,48 (s, 3H); 2,07 (m, 2H); 1,89 (users, 4H) ppm EAT (ES+) m/z=372 (100%) [M+H]+. C18H22Cl2N4O4S (461,36) calculated 46,86%; N To 4.81%; N 12,14%; S 6,95%found 46,96%; N 4,70%; N 12,31%; S 6,85%.

Example 9

1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-phenylpiperidine oxalate (compound 9)

N1NMR (300 MHz, DMSO, 25°C) δ: 7,94 (d, J=2.3 Hz, 1H); 7,83 (d, J=8.6 Hz, 1H); a 7.62 (DD, J=2.3 Hz, J=8.6 Hz, 1H); 3,19 (m, 4H); 2,19 (m, 2H); 2,72 (m, 1H); 2,11 (m, 2H); to 1.83 (m, 4H) ppm EAT (ES+) m/z=461 (100%) [M+H]+. C25H28Cl2N4O4S (551,49) calculated 54,40%; N 5,12%; N 10,16%; S 5,81%found 54,31%; N 5,03%; N 10,24%; S 5,72%.

Example 10

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]-4-phenylpiperidine oxalate (compound 10)

N1NMR (300 is Hz, DMSO, 25°C) δ: a 7.62 (d, J=2.4 Hz, 1H); EUR 7.57 (d, J=8.6 Hz, 1H); 7,28 (m, 4H); 3,18 (t, J=6.9 Hz, 2H); 3,07 (users, 1H); 3,03 (users, 1H); 2,52 (s, 3H); 2,48 (m, 1H); to 2.41 (t, J=7,3 Hz, 2H); 2,03 (users, 1H); 2,02 (users, 1H); to 1.79 (m, 8H) ppm EAT (ES+) m/z=475 (100%) [M+H]+. With26H30CL2N4O4S (565,51) calculated 55,22%; H 5,35%; N To 9.91%; S 5,67%found 55,03%; H 5,50%; N 9,85%; S 5,63%.

Example 11

4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]morpholine oxalate (compound 11)

H1NMR (300 MHz, DMSO, 25°C) δ: a 7.92 (d, J=2.4 Hz, 1H); of 7.82 (d, J=8.6 Hz, 1H); 7,41 (DD, J=2.4 Hz, J=8.6 Hz, 1H); 3.72 points users, 4H); 3,11 (users, 2H); 2.95 and (users, 4H); 2,87 (users, 2H) 2,48 (s, 3H); 1,71 (users, 4H) ppm.EM (ES+) m/z=401 (100%) [M+H]+. C19H24Cl2N4O5S (491,39) calculated With 46,44%; H 4,92%; N 11,40%; S 6,53%found 49,25%; H are 5.36%; N 10,78%; S 5.45 per cent.

Example 12

1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]piperidine oxalate (compound 12)

H1NMR (300 MHz, DMSO, 25°C) δ: of 7.95 (d, J=2.4 Hz, 1H); 7,83 (d, J=8,4 Hz, 1H); of 7.60 (DD, J=2.4 Hz, J=8.6 Hz, 1H); to 3.09 (m, 6H), of 2.93 (m, 2H); to 2.46 (s, 3H); 1,68 (users, 8H); 1,43 (users, 2H); 1.39 in (users, 2H).EM (ES+) m/z=413 (100%) [M+H]+. C21H28Cl2N4O4S (503,44) calculated 50,10%; H 5,61%; N 11,13%; S 6,37%found 49,89%; H 5,56%; N 10,97%; S 6,09%.

Example 13

4-[5-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]morpholine oxalate (compound 13)

H1NMR (300 MHz, DMSO, 25°C) δ: 7.2V (d, J=2.1 Hz, 1H); to 7.84 (d, 8.6 Hz, 1H); of 7.60 (DD, J=2.1 Hz, J=8.6 Hz, 1H); 3,70 (t, J=4.6 Hz, 4H); of 3.13 (t, J=7.2 Hz, 2H); of 2.51 (s, 3H); to 2.42 (t, J=4,2 Hz, 4H); 2,33 (t, J=7.5 Hz, 2H); 1.77 in (p, J=7.5 Hz, 2H); for 1.49 (m, 4H 20). EAT (ES+) m/z=416 (100%) [M+H]+. C20H26Cl2N4O5S (505,42) calculated 47,53%; N 5,19%; N 11,09%; S 6,34%found 47,27%; N 5,09%; N 10,98%; S 6,07%.

Example 14

1-[5-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]pyrrolidine oxalate (compound 14)

N1NMR (300 MHz, DMSO, 25°C) δ: a 7.92 (d, J=2.4 Hz, 1H); 7,83 (d, J=8.7 Hz, 1H); of 7.60 (DD, J=2.4 Hz, J=8.7 Hz, 1H); of 3.12 (m, 4H); 1,89 (m, 2H); 1.69 in (m, 4H); of 1.41 (m, 2H) ppm EAT (ES+) m/z=399 (100%) [M+H]+. C20H26Cl2N4O4S (489,42) calculated 49,08%; N 5,35%; N, 11.45 per cent; S 6,55%found 48, 97mm%; N 5,20%; N 11,25%; S 6.80 per cent.

Example 15

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidine (compound 15)

A mixture of oxalate of 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl}pyrrolidine (0.7 mmol) and ohope® (0.67 mmol) was dissolved in water (250 ml) at room temperature under stirring for 3 hours. Then was added dropwise 1M solution of potassium hydroxide to a pH of 7. After extraction of CH2CL2the organic layer was dried over MgSO4, then evaporated and finally purified by chromatography on silica gel using a mixture of 0-10% methanol/ethyl acetate, obtaining 4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl)pyrrolidin (0,082 g, yield 33%) in the ideal colorless oily substance.

N1NMR (300 MHz, CDCl3, 25°C) δ: to 7.64 (d, J=2.5 Hz, 1H); a 7.62 (d, J=8.7 Hz, 1H); to 7.35 (DD, J=2.4 Hz, J=8.7 Hz, 1H); 3.46 in (m, 1H); of 3.32 (m, 1H); and 3.31 (m, 1H); of 2.86 (m, 1H) 2,60 (users, 7H) 1,78 (users, 4H) ppm EAT (ES+) m/z=373 (100%) [M+H]+. C15H18Cl2N4OS (372) calculated 48,26%; N 4,86%; N 15,01%; S 8,59%; found 48,30%; N 4,70%; N 14,81%; S 8,45%.

Examples 16-18 were prepared by following the procedure described in example 15 using the appropriate 3-thio-1H-1,2,4-triazole.

Example 16

4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]morpholine (compound 16)

N1NMR (300 MHz, Dl3, 25°C) δ: to 7.64 (d, 2.2 Hz, 1H); a 7.62 (d, J=8,3 Hz, 1H); to 7.35 (DD, J=2.3 Hz, J=8,4 Hz, 1H); 3,68 (t, J=4.5 Hz, 4H); 3.40 in (m, 1H); to 3.34 (m, 1H); to 3.02 (m, 1H); 2,77 (m, 1H); 2,60 (s, 3H); 2.57 m (m, 4H) ppm EAT (ES+) m/z=389 (100%) [M+H]+. C15H18Cl2N4O2S (389,30) calculated 46,28%; N 4,66%; N 14,39%; S 8,24%found 46,03%; N Of 4.77%; N 14,13%; S of 7.65%.

Example 17

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diisopropylethylamine (compound 17)

N1NMR (300 MHz, CDCl3, 25°C) δ: to 7.64 (d, J=2.4 Hz, 1H); a 7.62 (d, J=8.7 Hz, 1H); 7,34 (DD, J=2.4 Hz, J=8.7 Hz, 1H); to 3.33 (m, 1H); with 3.27 (m, 1H); of 3.07 (m, 3H); 2,92 (m, 1H); at 2.59 (s, 3H); 1.04 million (d, J=6,6 Hz, 6N); and 1.00 (d, J=6,5 Hz, 6N) ppm EAT (ES+) m/z=403 (100%) [M+H]+. C17H24Cl2N4OS (403,37) calculated 50,62%; N 6,00%; N At 13.84%; S 7,95%found 50,66%; N 5,77%; N 19,83%; S 7,45%.

Example 18

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-insul inil)butyl]-4-phenylpiperidine (compound 18)

N1NMR (300 MHz, Dl3, 25°C) δ: 7,60 (d, J=2.4 Hz, 1H); EUR 7.57 (d, J=8.7 Hz, 1H); 7,30 (m, 6N); 3,40 (m, 2H); and 3.31 (m, 2H); 3,10 (m, 4H) 2,61 (m, 4H); 2,49 (s, 3H); of 2.09 (m, 2H); 1,71 (m, 5H) ppm EAT (ES+) m/z=491 (100%) [M+H]+. 2[C24H28Cl2N4OS]. 3H2On (1037,00) calculated 53,93%; N 5,85%; N 10,48%; S 6,00%found 53,82%; N, 5.96 per cent; N 10,24%; S ceiling of 5.60%.

Example 19

1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]ethyl}pyrrolidine (compound 19)

Example 19 was prepared following the procedure described in example 15, interacting 4-(2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl)pyrrolidine oxalate (0.67 mmol) with ohope® (1,34 mmol). N1NMR (300 MHz, CDCl3, 25°C) δ: the 7.65 (d, J=2.3 Hz, 1H); 7,63 (d, J=8.6 Hz, 1H); to 7.35 (DD, J=2.3 Hz, J=8.7 Hz, 1H); of 3.60 (t, J=7.2 Hz, 2H); 3,03 (t, J=7,6, 2H); 2,61 (s, 3H); 2.50 each (users, 4H); 1.70 to (users, 4H) ppm EAT (ES+) m/z=389 (100%) [M+H]+. C15H18Cl2N4O2S (389,30) calculated 46,28%; N 4,66%; N 14,34%; S 8,24%found 46,40%; N 4,74%; N Of 14.28%; S 7,41%.

Examples 20 and 21 were prepared by following the procedure described in example 19.

Example 20

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diethylethanamine (compound 20)

N1NMR (300 MHz, CDCl3, 25°C) δ: 7,63 (d, J=2.4 Hz, 1H); 7,63 (J=8,5 Hz, 1H); 7,34 (DD, J=2.4 Hz, J=8.7 Hz, 1H); 3,51 (m, 2H); of 3.07 (m, 2H); 2,61 (s, 3H); 2.49 USD (kV, J=7,l Hz, 4H); to 0.97 (t, J=7,1 Hz, 6N) ppm EAT (ES+) m/z=391 (100%) [M+H]+. C15H20Cl2N4O2S (391,32) Vice the Leno With 46,04%; N 5,15%; N 14,32%; S 8,19%found 46,09%; N 5,25%; N, 14.24 From%S to 8.20%.

Example 21

4-[4-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)butyl]morpholine (compound 21)

N1NMR (300 MHz, CDCl3, 25°C) δ: the 7.65 (d, J=2.4 Hz, 1H); TO 7.61 (D, J=8.6 Hz, 1H); 7,34 (DD, J=2.4 Hz, J=8.6 Hz, 1H); however, 4.40 (m, 2H); and 3.72 (m, 2H); of 3.32 (m, 6N); to 3.09 (m, 2H); 2,8 (m, 4H); of 2.58 (s, 3H); of 2.16 (m, 2H); 1,92 (m, 2H) ppm EAT (ES+) m/z=433 (100%) [M+H]+. With17H22CL2N4O3S. 2H2O (469,38) calculated 42,68%; N 5,69%; N 11,71%; S 6,70%found 42,94%; N 5,44%; N 11,70%; S 6,18%.

Example 22

1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]ethyl}piperidine (compound 22)

A. Synthesis of 1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ol

This product was prepared by following the stages a-C of example 1 using potassium cyanate in stage a and using ethanol as a solvent under an atmosphere of Na at 60°C in stage C.

Century {2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]ethyl}piperidine

1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ol (0.41 mmol) was dissolved in methanol (150 ml) at room temperature. Was added dropwise a solution of potassium carbonate in water (30 ml) to pH 9. After 15 minutes under stirring solution was added 1-(2-chloroethyl)piperidine hydrochloride (0,62 mmol) in water (100 ml). The reaction mixture was stirred at room temperature overnight. The methanol is evaporated and after extraction CH2Cl2the organic layer is dried over MgSO 4, then evaporated and finally purified by chromatography on silica gel, receiving 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]ethyl}piperidine (0.03 g, yield=20%) as a dark orange oily substance. N1NMR (300 MHz, Dl3, 25°C) δ: 7,53 (d, J=2.4 Hz, 1H); of 7.48 (d, J=8.6 Hz, 1H); 7.23 percent (DD, J=2.4 Hz, 1H); to 4.33 (t, J=5,9 Hz, 2H); a 2.71 (t, J=5,9 Hz, 2H); 2,44 (t, J=4.9 Hz, 4H); 2.40 a (s, 3H); 1,51 (kV, J=5.5 Hz, 4H); 1,34 (m, 2H) ppm EAT (ES+) m/z=355 (100%) [M+H]+. C16H20Cl2N4O (355,26) calculated 54,09%; N 5,67%; N 15,77%; found 53,80%; N 5,72%; N 15,48%.

Examples 23-30 were prepared as described in example 22, using in part Into the corresponding 2-hloretilaminam. Example 30 was prepared by following the procedure described for preparation of example 7, starting from 5-methyl-1-phenyl-1H-1,2,4-triazole-3-ol with the appropriate dibromethane (part b) and the amine (part C).

Example 23

2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]-N,N-diethylethanamine (compound 23)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,53 (d, J=2.3 Hz, 1H); 7,47 (d, J=8.6 Hz, 1H); 7.23 percent (DD, J=2.3 Hz, J=8.6 Hz, 1H); to 4.28 (t, J=6.6 Hz, 2H); and 2.83 (t, J=6.3 Hz, 2H); 2,56 (kV, J=7,1 Hz, 4H); 2.40 a (s, 3H); 0,99 (t, 7,1 Hz, 6H) ppm EM (ES+) m/z=343 (100%) [M+H]+. 3[C15H20Cl2N4O].2H2O (1065,79) calculated With 50,71%; H 6,05%; N 15,81%; found 50,70%; H of 5.82%; N 16,12%.

Example 24

1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]pyrrolidine (connect the tion 24)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,58 (d, J=2.4 Hz, 1H); 7,53 (d, J=8.7 Hz, 1H); 7,28 (DD, J=2.4 Hz, J=8.7 Hz, 1H); however, 4.40 (t, J=5,9 Hz, 2H); 2,90 (t, 5.8 Hz, 2H); 2.63 in (m, 4H); of 2.45 (s, 3H); 1,78 (p, J=3.2 Hz, 4H) ppm.EM (ES+) m/z=341 (100%) [M+H]+. C15H18Cl2N4O (341,24) calculated 52,80%; H 5,32%; N 16,42%; found 51,86%; H 5,26%; N 16,13%.

Example 25

4-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine oxalate (compound 25)

H1NMR (300 MHz, DMSO, 25°C) δ: to $ 7.91 (d, J=2.4 Hz, 1H); 7,82 (J=8,7 Hz, 1H); of 7.60 (DD, J=2.4 Hz, J=8.7 Hz, 1H); of 4.45 (t, J=5,1 Hz, 2H); 3,70 (t, J=4.6 Hz, 4H); of 3.13 (t, J=5,1 Hz, 2H); 2,89 (m, 4H); 2,49 (s, 3H) ppm EM (ES+) m/z=357 (100%) [M+H]+. C17H20Cl2N4O6(447,27) calculated 45,65%; H 4,51%; N 12,53%; found 45,48%; N 4,43%; N 12,27%.

Example 26

2-(5-Methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)-N,N-diethylethanamine (compound 26)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,42 (m, 5H); of 4.35 (t, J=6.2 Hz, 2H); 2,90 (t, J=6.2 Hz, 2H); 2.63 in (kV, t=7,1 Hz, 4H); 2,43 (s, 3H); of 1.05 (t, J=7,1 Hz, 6H) ppm EM (ES+) m/z=275 (100%) [M+H]+. C15H22N4O (274,36) calculated 65,67%; H, 8.08 per cent; N 20,42%; found 65,39%; H 7,92%; N 20,26%.

Example 27

1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]pyrrolidine (compound 27)

H1NMR (300 MHz, CDCl3, 25°C) δ: the 7.43 (m, 5H); to 4.41 (t, J=5,9 Hz, 2H); 2,90 (t, J=5,9 Hz, 2H); of 2.64 (m, 4H); to 2.42 (s, 3H); of 1.78 (m, 4H) ppm EM (ES+) m/z=273 (100%) [M+H]+. C15H20N4O (272,35) calculated 66,15%; H, 7.4 per cent; N 20,57%; found 65,87%; H 7,22%; N 20,39%.

Example 28

4-[2-(5-Methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine (compound 28)

H1NMR (300 MHz, CDCl3, 25°C) δ: the 7.43 (m, 5H); 4,42 (t, 5.6 Hz, 1H); 3,71 (t, J=4.6 Hz, 4H); of 2.81 (t, J=5.5 Hz, 2H); of 2.58 (m, 4H); of 2.44 (s, 3H) ppm EM (ES+) m/z=289 (100%) [M+H]+.

Example 29

1-[2-(5-Methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl] piperidine (compound 29)

N1NMR (300 MHz, Dl3, 25°C) δ: the 7.43 (m, 5H); to 4.41 (t, J=5,9 Hz, 2H); and 2.79 (t, J=5,9 Hz, 2H); of 2.51 (m, 4H); 2,43 (s, 3H); 1.57 in (m, 4H); to 1.42 (m, 2H) ppm EAT (ES+) m/z=287 (100%) [M+H]+. C16H22N4O (286,37) calculated 67,11%; N 7,74%; N 19,56%; found 66,96%; N 7,65%; N 19,37%.

Example 30

4-[4-(5-Methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)butyl]morpholine (compound 30)

N1NMR (300 MHz, Dl3, 25°C) δ: the 7.43 (m, 5H); to 4.28 (t, J=6,1 Hz, 2H); 3,70 (t, J=4.6 Hz, 4H); 2,43 (s, 3H); 2,39 (m, 6N); to 1.83 (m, 2H); of 1.65 (m, 2H) ppm EAT (ES+) m/z=317 (100%) [M+H]+. C17H24N4O2(316,40) calculated 64,53%; N 7,65%; N 17,71%; found 63,56%; N 7,45%; N 17,40%.

Example 31

4-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine hydrochloride (compound 31)

Example 31 was prepared as described in example 1. In part D procedures subjected to chromatography the product was dissolved in ether and this solution was saturated with gaseous hydrogen chloride. The resulting suspension was filtered and dried under Vacu the IOM.

N1NMR (300 MHz, DMSO, 25°C) δ: 11,98 (users, 1H); 9,99 (users, 3H); 8,00 (d, J=2.4 Hz, 1H); to 7.84 (d, J=8.6 Hz, 1H); to 7.68 (DD, J=2.4 Hz, J=8.6 Hz, 1H); to 3.89 (m, 4H); 3.49 points (m, 6N); of 3.12 (m, 2H); 2.50 each (s, 3H) ppm15H19N4CL3S.l, 5H2O (473,25) calculated With 38,07%; N 4,90%; N 11,84%; S is 6.78% found 37,93%; H 4,94%; N 11,64%; S 6,00%.

Examples 32-39 were prepared as described in example 1 using the appropriate hydrazine in part A.

Example 32

Oxalate of 1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-4-methylpiperidine (compound 32)

H1NMR (300 MHz, DMSO, 25°C) δ: of 7.97 (d, J=2.3 Hz, 1H); to 7.84 (d, J=8.6 Hz, 1H); the 7.65 (DD, J=2.4 Hz, J=8,6, 1H); to 3.45 (m, 4H); to 3.36 (m, 2H); 2,92 (m, 2H); 2,48 (s, 3H); to 1.75 (m, 2H); to 1.59 (m, 1H); to 1.37 (m, 2H,); of 0.90 (d, J=3.8 Hz, 3H) ppm EM (ES+) m/z=385 (100%) [M+H]+. 5[C19H24Cl2N4O4S].3C2H2O4(2647,05) calculated C, 45,83%; H, 4,80%; N, Of 10.58%; S, 6,06%, found C, 45,61%; H, 4,74%; N, 10,61%; S, 6.08%in General.

Example 33

Oxalate of 4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-ylthio) ethyl]morpholine (compound 33)

H1NMR (300 MHz, DMSO, 25°C) δ: 7,51 (m, 5H); 3,68 (t, J=4.5 Hz, 4H); to 3.36 (t, J=6,1 Hz, 2H); 3.04 from (t, J=6.3 Hz, 2H); 2,84 (users, 4H); 2,49 (s, 3H) ppm, 2[C17H22N4O5S]/ C2H2O4(878,93)calculated C, 49,19%; H, 5,28%; N, Was 12.75%; S, 7,30%, found C, 48,86%; H, 5,49%; N, 12,47%; S, 7.45%per.

Example 34

Oxalate of 4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine (compound 34)

<> H1NMR (300 MHz, DMSO, 25°C) δ: 7.62mm (users, 4H); 3,68 (t, J=4.4 Hz, 4H); to 3.33 (t, J=6.9 Hz, 2H); 3.04 from (t, J=7.8 Hz, 2H); 2,84 (users, 4H); of 2.44 (s, 3H) ppm EM (ES+) m/z=339 (100%) [M+H]+. C17H21ClN4O5S (428,89)calculated C, 47,61%; H, 4,94%; N, 13,06%; S, of 7.48%, found C, 47,50%; H, 4,91%; N, 13,12%; S, 7,26%.

Example 35

Oxalate of N-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-N,N-diisopropylamino-2-amine (compound 35)

H1NMR (300 MHz, CDCl3, 25°C) δ: the 7.43 (m, 3H); 7,31 (m, 1H); to 3.73 (m, 2H); of 3.54 (m, 2H); 3.46 in (m, 2H); 2.50 each (s, 3H); 1,43 (d, J=6.0 Hz, 12H) ppm EM (ES+) m/z=353 (100%) [M+H]+.

Example 36

Oxalate of 1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]piperidine (compound 36)

H1NMR (300 MHz, DMSO, 25°C) δ: 7,73 (s, 1H); 7,58 ( users, 3H); 3,44 (m, 2H); to 3.34 (m, 2H); 3.15 in (users, 4H); 2,49 (s, 3H); to 1.70 (m, 4H); 1.50 in (users, 2H) ppm EM (ES+) m/z=337 (100%) [M+H]+. C18H23ClN4O4S.3H2O (504,39)calculated C, 50,64%; H, 5,43%; N, 13,12%; S, 7,51%; Cl, 8,30%, found C, 50,37%; H, 5,42%; N, 12,99%; S, 7,37%; Cl, 8,88%.

Example 37

Oxalate of 4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine (compound 37)

H1NMR (300 MHz, DMSO, 25°C) δ: 7,71 (s, 1H); EUR 7.57 (users, 3H); 3,66 (m, 4H); to 3.34 (m, 2H); 2,96 (m, 2H); 2,77 (users, 4H); to 2.46 (s, 3H) ppm EM (ES+) m/z=339 (100%) [M+H]+. C17H21ClN4O5S (428,89)calculated, 47,61%; H, 4,94%; N, 13,06%; S, Of 7.48%; Cl, 8,27%, found C, 47,54%; H, 4,90%; N, 12,87%; S, 7,35%; Cl, charged 8.52%.

Example 38

Oxalate of 4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]pyrrolidine (compound 38)

H1NMR (300 MHz, DMSO, 25°C) δ: 7,74 (s, 1H); 7,60 (users, 3H); 3,41 (users, 6H); 3,25 (users, 2H); 2.49 USD (s, 3H); 1,84 (users, 4H) ppm EM (ES+) m/z=323 (100%) [M+H]+. C17H21ClN4O4S (412,89)calculated C, 49,45%; H, 5,13%; N, 13,57%; S, to 7.77%, found C, 49,21%; H, 5,08%; N, 13,28%; S, 7.55 per cent.

Example 39

Oxalate 2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylether-2-amine(compound 39)

H1NMR (300 MHz, DMSO, 25°C) δ: 7,74 (s, 1H); to 7.59 (s, 3H); 3,37 (m, 4H); 3,11 (m, 4H); 2,49 (users, 3H); 1,19 (m, 6H) ppm EM (ES+) m/z=325 (100%) [M+H]+. C17H23ClN4O4S (414,91)calculated C, 49,21%; H, 5,59%; N, 13,50%; S, 7,73%; Cl, 8,54%, found C, 48, 97mm%; H, 5,40%; N, 13,39%; S, 7,65%; Cl, 8,59%.

Examples 40-42 were prepared as described in example 7 using the appropriate 1,4-dibromsalan in part B.

Example 40

4-[1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylbutyl-1-amine(compound 40)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,60 (d, J=2.4 Hz, 1H); 7,53 (d, J=8.6 Hz, 1H); 7,31 (DD, J=2.4 Hz, J=8.6 Hz, 1H); 3.15 in (t, J=7,0 Hz, 2H); 2,59 (kV, J=7,1 Hz, 4H); of 2.51 (m, 5H); 1.69 in (m, 4H); of 1.06 (t, J=7,1 Hz, 6H) ppm EM (ES+) m/z=386 (100%) [M+H]+. C17H24Cl2N4S.H2O (405,39), calculated C, 50,37%; H, 6,46%; N, 13,82%; S, to $ 7.91%, found C, 49,88%; H, for 6.81%; N, 13,55%; S, 8,64%.

Example 41

1-[4-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-is ltio)butyl]piperidine (compound 41)

H1NMR (300 MHz, CDCl3, 25°C) δ: to 7.59 (d, J=2.4 Hz, 1H); 7,56 (d, J=8.6 Hz, 1H); 7,31 (DD, J=2.4 Hz, J=8.6 Hz, 1H); 3,14 (t, J=6.5 Hz, 2H); 2,62 (users, 4H); to 2.55 (m, 2H); 2.50 each (s, 3H); 1.77 in (m, 4H); 1,49 (users, 2H) ppm EM (ES+) m/z=399 (100%) [M+H]+. C18H24Cl2N4S.H2O (417,40), calculated C, 49,65%; H, 6,45%; N, 12,87%; S, of 7.36%, found C, 49,27%; H, 6.58 percent; N, 12,70%; S, 7,51%.

Example 42

1-[4-(1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]pyrrolidine (compound 42)

H1NMR (300 MHz, CDCl3, 25°C) δ: to 7.59 (d, J=2.4 Hz, 1H); 7,56 (d, J=8.6 Hz, 1H); 7,33 (DD, J=2.4 Hz, J=8.6 Hz, 1H); of 3.13 (t, J=6.9 Hz, 2H); 2,96 (users, 4H); and 2.83 (m, 2H); 2.50 each (s, 3H); to 1.98 (m, 4H) ppm EM (ES+) m/z=385 (100%) [M+H]+. C17H22Cl2N4S.3H2O (439,40), calculated C, 46,47%; H, 6.42 per cent; N, Was 12.75%; S, 7,30%, found C, 46,45%; H, of 5.99%; N, 12,55%; S, at 6.84%.

Examples 43-46 were prepared as described in example 15.

Example 43

2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diethylethanamine (compound 43)

N1NMR (300 MHz, Dl3, 25°C) δ: to 7.64 (d, J=2.5 Hz, 1H); a 7.62 (d, J=8.7 Hz, 1H); to 7.35 (DD, J=2.4 Hz, J=8.7 Hz, 1H); to 3.52 (m, 2H); is 3.08 (m, 1H); to 2.85 (m, 1H); of 2.58 (m, 7H); of 1.02 (t, J=7,1 Hz, 6N) ppm EAT (ES+) m/z=374 (100%) [M+H]+. C15H20Cl2N4OS (375,32)calculated. With 48,00%; H, 5.37 Percent; N, 14,93%; S, 8,54%found, 47,71%; N, 5,20%; N, 14,62%; S, 8.34 per cent.

Example 44

1-[2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidine (compound 44)

N NMR (300 MHz, CDCl3, 25°C) δ: 7,50 (users, 1H); 7,47 (users, 1H); 7,46 (users, 1H); of 7.36 (m, 1H); of 3.48 (m, 1H); of 3.32 (m, 1H); 3,13 (m, 1H); 2,80 (m, 1H); 2,56 (users, 7H); 1,76 (users, 4H) ppm EAT (ES+) m/z=339 (100%) [M+H]+. C15H19ClN4OS (338,86)calculated, 53,17%; N, 5,65%; N, 16,53%; S, 9,46%; Cl, 10,46%found, 53,25%; N, 5,80%; N, 16,76%; S, Of 9.21%; Cl, 10,26%.

Example 45

4-[2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]morpholine (compound 45)

N1NMR (300 MHz, CDCl3, 25°C) δ: of 7.48 (m, 3H); of 7.36 (users, 1H); 3,66 (m, 4H); 3.42 points (m, 1H); of 3.32 (m, 1H); 3,01 (m, 1H); 2,77 (m, 1H); of 2.58 (s, 3H); 2.50 each (m, 4H) ppm EAT (ES+) m/z=355 (100%) [M+H]+. C15H19ClN4O2S (354,85)calculated, 50,77%; N, Of 5.40%; N, 15,79%; S, 9,04%found, 50,58%; H, 5.25 Percent; N, 15.62 Wide%; S, 9,31%.

Example 46

1-[2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diethylamine (compound 46)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,50 (users, 1H); 7,47 (m, 2H); of 7.36 (m, 1H); 3.40 in (m, 2H); to 3.06 (m, 1H); 2,87 (m, 1H); of 2.58 (m, 7H); a 1.01 (t, J=7,1 Hz, 6H) ppm EM (ES+) m/z=341 (100%) [M+H]+. C15H21ClN4OS (340,87)calculated C, 52,85%; H, 6,21%; N, 16,44%; S, 9,41%, found C, 52,76%; H, 6,50%; N, 16,22%; S, 9,71%.

Examples 47-49 were prepared as described in example 19.

Example 47

1-[2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidin(compound 47)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,58 (m, 3H); 7,47 (m, 1H); of 3.60 (t, J=7,3 Hz, 2H); 3,03 (t, J=7.2 Hz, 2H); 2,61 (s, 3H); 2.50 each (users, 4); to 1.70 (m, 4H) ppm EM (ES+) m/z=355 (100%) [M+H]+. C15H19ClN4O2S (3548,85)calculated C, 50,77%; H, 5,40%; N, 15,79%; S, 9,04%, found C, 50,48%; H, 5.25 percent; N, 15.62 Wide%; S, 9,31%.

Example 48

1-[2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-Diisopropylamine(compound 48)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,51 (m, 3H); 7,38 (m, 1H); 3,47 (m, 2H); 3,01 (m, 4H); 2,61 (users, 3H); and 0.98 (m, 12H) ppm EM (ES+) m/z=385 (100%) [M+H]+. C17H25ClN4O2S (384,92), calculated C, 53,04%; H, 6,55%; N, 14,56%; S, 8,33%, found C, 53,19%; H, 6,26%; N, 14,42%; S, 8,51%.

Example 49

1-[2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diethylamino(compound 49)

H1NMR (300 MHz, CDCl3, 25°C) δ: 7,49 (m, 3H); 7,37 (m, 1H); 3,63 (t, J=4,8 Hz, 2H); of 3.07 (m, 2H); 2,60 (s, 3H); 2.50 each (m, 4H); to 0.97 (t, J=7.0 Hz, 6H) ppm EM (ES+) m/z=357 (100%) [M+H]+. C15H21C1N4O2S (356,87)calculated C, 50,48%; H, 5,93%; N, 15,70%; S, 8,99%, found C, 50,25%; H, of 5.84%; N, 15,60%; S, 9,20%.

EXAMPLES of BIOLOGICAL ACTIVITY

Connection 1-30 synthesized according to the procedures described above, were tested for their activity as inhibitors of s-1. Used the following Protocol.

Preparation of brain membranes and analysis of binding to σ1-receptor were performed as described (DeHaven-Hudkins et al., 1992) with some modifications. Briefly, the brain of the Guinea pig homogenized in 10 vol.(wt./about.) Tris-HCl 50 mm 0,32M sucrose, pH 7.4 using a Kinematica transmitter station PT 3000 at 15,000 rpm for 30 C. the Homogenate was centrifuged at 1000g for 10 min at 4°C, and supernatant was collected and centrifuged at 48000g for 15 min at 4°C. the Tablet re-suspended in 10 volumes of Tris-HCl buffer (50 mm, pH 7.4), incubated at 37°C for 30 min and centrifuged at 48000g for 20 min at 4°C. After that, the tablet re-suspended in fresh Tris-HCl buffer (50 mm, pH 7.4) and kept in ice until use.

Each test tube contained 10 μl of [3H](+)-pentazocine (final concentration 0.5 nm), 900 μl of the suspension fabric to a final sample volume of 1 ml and a final concentration of tissue about 30 mg net weight of tissue/ml non-specific binding was determined by adding a final concentration of 1 μm haloperidol. All test tubes were incubated at 37°C for 150 min before termination of the reaction by rapid filtration through filters fiberglass Schleicher &Schuell GF 3362 [pre-soaked in a solution of 0.5% polyethylenimine for at least 1 hour]. Then the filters were washed four times with 4 ml of cold Tris-HCl buffer (50 mm, pH 7.4). After adding scintillation cocktail account the samples were allowed to come into equilibrium during the night. The amount of bound radioactivity was determined by liquid scintillation spectroscopy using LM the bone scintillation counter Wallac Winspectral 1414. Protein concentration was determined by the method of Lowry et al. (1951).

Links

DeHaven-Hudkins, D. L., L.C. Fleissner, and F. Y. Ford-Rice, 1992, Characterization of the binding of [3H](+)pentazocine to σ recognition sites in guinea pig brain, Eur. J. Pharmacol. 227, 371-378.

Lowry, O.H., N.J. Rosebrough, A.L. Farr, and R.J. Randall, 1951, Protein measurement with the Folin phenol reagent, J. Biol. Chem, 193, 265.

The results are summarized in the following table I:

6td align="justify"> 17
Table I
Connection # Sigma-1
The percentage of inhibition
(0.1 ám)
Sigma-1
The percentage of inhibition
(0.01 µm)
Sigma-1
Ki (nm)
The display is. 10-7M
(10-8M)
1107,4102,11,1
2109,3105,20,8
3106,4102,71,4
4108,8to 105.31,1
5109,3104,41,1
99,290,6
785,567,88,2
882,557,42,1
98974,29
10at 88.127,3
1166,914,5
1282,852,1
1358,24,3
1452,56
1588,9to 47.27
164228,6
93,962,34
1837,2-39,5
1996,471,82,2
2082,151,216,7
2120,58,3
2294,854,33,1±1,6
238532,2
2491,839,5
25is 83.8to 33.8
2615,27,3
2730,48,1
28-3,4-20,9
2946,15,8
3018,3-15,1

As can be seen from the values given in table I, substituted derivatives of 1,2,4-triazole according to the invention are particularly suitable for inhibiting the Sigma-1 receptor.

1. The use of the compounds of formula (I):

where
R1, R2and R3independently selected from hydrogen and halogen;
R4represents a C1-C6alkyl;
R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocyclic group in which 6-membered heterocyclyl may optionally contain one oxygen atom or one nitrogen atom and may be substituted by acetyl, C1-C6the alkyl or phenyl;
X is selected from-S-, -SO-, -SO2- and About; and
n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8
or its pharmaceutically acceptable salt, stereoisomer or MES, when getting medicines for Les the program, or prevention of disease or condition mediated by the Sigma-1 receptor selected from disorders of learning, memory and attention disorders cognitive, neurodegenerative diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine; stroke, stress, cancer, psychotic conditions, in particular depression, anxiety or schizophrenia; autoimmune diseases.

2. The use according to claim 1, where the disease is a pain, especially neuropathic pain, inflammatory pain or other pain conditions, including allodynia, and/or increased sensitivity to pain.

3. The use of the compounds of formula (I)described in claim 1, as a tranquilizer or immunosuppressant.

4. The method of treatment or prophylaxis of a disease selected from disorders of learning, memory and attention disorders cognitive, neurodegenerative diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine; stroke, stress, cancer, psychotic conditions, in particular depression, anxiety or schizophrenia;
autoimmune diseases, neuropathic pain, inflammatory pain or other pain conditions, including allodynia, and/or increased sensitivity to pain, including the introduction is the patient, in need of such treatment, a therapeutically effective amount of the compounds of formula (I)described in claim 1, or pharmaceutical compositions.

5. The compound of formula (I):

where
R1, R2and R3independently selected from hydrogen and halogen;
R4represents a C1-C6alkyl;
R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocyclic group in which 6-membered heterocyclyl may optionally contain one oxygen atom or one nitrogen atom and may be substituted by acetyl, C1-C6the alkyl or phenyl;
X is selected from-S-, -SO-, -SO2- and About; and
n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8, or its pharmaceutically acceptable salt, stereoisomer or MES.

6. The compound according to claim 5, in which at least one of R1-R3represents hydrogen.

7. The compound according to claim 5, in which two of R1-R3represent hydrogen or chloride.

8. The compound according to claim 5, in which R4represents methyl.

9. The compound according to claim 5, in which R5and R6independently represents a C1-C6alkyl, preferably ethyl or isopropyl.

10. The compound according to claim 5, inwhich R 5and R6form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocyclic group in which 6-membered heterocyclyl may optionally contain one oxygen atom or one nitrogen atom, preferably selected from pyrrolidine, piperidine, azepane and research, in which 6-membered heterocyclyl may be substituted by acetyl, C1-C6the alkyl or phenyl.

11. The compound according to claim 5, in which n represents 1, 2, 3, 4 or 5.

12. The compound according to claim 5, selected from the group formed by:
-4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine;
-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl} - piperidine;
-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}pyrrolidine;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diisopropylethylamine;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine;
-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]azepane;
-4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine;
-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-pyrrolidino;
-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-phenylpiperidine;
-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]-4-phenylpiperidine;
-4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]morpholine;br/> -1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]piperidine;
-4-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]morpholine;
-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]pyrrolidine;
-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidine;
-4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]morpholine;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diisopropylethylamine;
-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)butyl]-4-phenylpiperidine;
-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]ethyl}pyrrolidine;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diethylethanamine;
-4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)butyl]morpholine;
-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]ethyl} - piperidine;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy]-N,N-diethylethanamine;
-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]pyrrolidine;
-4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine;
-2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)-N,N-diethylethanamine;
-1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]pyrrolidine;
-4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine;
-1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-yloxy)ethyl]piperidine;
-4-[4-(5-methyl-1-phenyl-1 is -1,2,4-triazole-3-yloxy)butyl]morpholine;
1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-4-methylpiperidine;
-4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;
-4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;
-N-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-N,N-diisopropylamino-2-amine;
-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]piperidine;
-4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;
-4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]pyrrolidine;
-2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine;
-4-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylbutyl-1-amine;
-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]piperidine;
-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]pyrrolidine;
2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl]-N,N-diethylethanamine;
-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidine;
-4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]morpholine;
-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diethylamino;
-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]pyrrolidine;
-1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diisopropylamino;
1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylsulphonyl)ethyl]-N,N-diethylamino;
or Pharma is efticiency acceptable salt, isomer or MES.

13. The compound according to claim 5, which is its oxalic salt.

14. The compound according to claim 5 selected from:
-4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine oxalate;
-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}piperidine oxalate;
-1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}pyrrolidin oxalate;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diisopropylethylamine oxalate;
-2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine oxalate;
-1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]azepin oxalate;
-4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]morpholine oxalate;
-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-pyrrolidin oxalate;
-1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)propyl]-4-phenylpiperidine oxalate;
-1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]-4-phenylpiperidine oxalate;
-4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)butyl]morpholine oxalate;
-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]piperidine oxalate;
-4-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]morpholine oxalate;
-1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)pentyl]pyrrolidine oxalate;
-4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yloxy)ethyl]morpholine oxalate;
--{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]ethyl}morpholine hydrochloride;
- oxalate 1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-4-methylpiperidine;
- oxalate 4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;
- oxalate 4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;
- oxalate of N-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]-N,N-diisopropylamino-2-amine;
- oxalate 1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]piperidine;
- oxalate 4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]morpholine;
- oxalate 4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl]pyrrolidine;
- oxalate 2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio]-N,N-diethylethanamine.

15. The method of obtaining the compounds of formula (I)described in claim 5, or a salt, stereoisomer or MES, including
a) alkylation of the corresponding 5-alkyl-1-aryl-1H-1,2,4-triazole-3-thiol/ol of formula (II):

where
R1, R2and R3independently selected from hydrogen and halogen;
R4represents a C1-C6alkyl, and
X represents O or S,
alkylating agent of the formula (III):

where
Z represents halogen,
R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a 5-7 membered, heterocycle is a mini-group, in which 6-membered heterocyclyl may optionally contain one oxygen atom or one nitrogen atom and may be substituted by acetyl, C1-C6the alkyl or phenyl; and
n is selected from 1, 2, 3, 4, 5, 6, 7 and 8, and
(b) if necessary, the oxidation of the corresponding obtained 3-(alkylthio)-1H-1,2,4-triazole.

16. The method of obtaining the compounds of formula (I)described in claim 5, or a salt, stereoisomer or MES, including (a) alkylation of the corresponding 5-alkyl-1-aryl-1H-1,2,4-triazole-3-thiol/ol of formula (II), as defined in § 15,
alkylating agent of the formula (IV):

in which Z represents a halogen, and n is selected from 1, 2, 3, 4, 5, 6, 7 and 8
(b) coordination compounds obtained after alkylation reaction with an amine other5R6where R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocyclic group in which 6-membered heterocyclyl may optionally contain one oxygen atom or one nitrogen atom and may be substituted by acetyl, C1-C6the alkyl or phenyl; and
(c) if necessary, the oxidation of the corresponding obtained 3-(alkylthio)-1H-1,2,4-triazole.

17. The method of obtaining the compounds of formula (I)described in claim 5,
or its salts, is of stereoisomer or MES, including
(a) interactions of the compounds of formula (V):

where
R1, R2and R3independently selected from hydrogen and halogen;
R4represents a C1-C6alkyl;
X represents O or S;
Z represents halogen;
n is selected from 1, 2, 3, 4, 5, 6, 7 and 8
with other amine5R6,
where R5and R6independently represents a C1-C6alkyl or form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocyclic group in which 6-membered heterocyclyl may optionally contain one oxygen atom or one nitrogen atom and may be substituted by acetyl, C1-C6the alkyl or phenyl; and
(b) if necessary, the oxidation of the corresponding obtained 3-(alkylthio)-1H-1,2,4-triazole.

18. The compound of formula (V):

where
R1, R2and R3independently selected from hydrogen and halogen;
R4represents a C1-C6alkyl;
X represents O or S;
Z represents halogen;
n is selected from 1, 2, 3, 4, 5, 6, 7 and 8.

19. Pharmaceutical composition having activity against the disease or condition mediated by the Sigma-1 receptor, comprising the compound described in claim 5, or its pharmaceutically acceptable with the ü, stereoisomer or MES, and a pharmaceutically acceptable carrier, adjuvant or diluent.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

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

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

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the chemistry of N,N-disubstituted nicotinamide-(Z)-O-methyloximes with the general formula I where if X denotes a methylene group, then R denotes phenyl, benzyl or 2-furyl, R' denotes methyl or n-chlorophenyl, if X denotes a carbonyl group, then R denotes styryl, n-chlorostyryl or benzyl, R' denotes methyl that is characterized by the fungicidal activity.

EFFECT: new compounds that can be efficient against maleficent fungi.

1 cl, 10 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the compound 5-[3-[(2S)-1-(difluoromethoxy)-propane-2-yl]-oxy-5-[(5-methylpyrazin-2-yl)-carbamoyl]]phenoxy]-N,N-dimethyl-pyrazine-2-carboxamide. The invention also refers to a pharmaceutical composition, and also to application of the compound under cl.1.

EFFECT: making the new biologically active compounds showing GLK (glucokinase) activator activity.

5 cl, 6 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

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