Therapeutic agents 713. RU patent 2526055.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein R¹ represents H, fluoro-, chloro- or C_1-2alkoxygroup optionally substituted by one or more fluoro group; A represents O or S; R² and R³ independently represent H or chloro; provided R² and R³ are not positioned in relation to each other; R⁴ and R⁵ independently represent H or C_1-4alkyl group; while X and Y independently represent O or CH₂, provided X and Y are different. The invention also refers to a pharmaceutical composition possessing an antagonist activity in relation to type 1 melanin-concentrating hormone (MCH1) receptor and type 3 histamine receptor (H3) containing the compounds of formula I, a method of treating or preventing and to usage of the compounds of formula I.

EFFECT: compounds of formula I as type 1 melanin-concentrating hormone (MCH1) receptor and type 3 histamine receptor (H3) antagonists.

14 cl, 1 tbl, 2 dwg, 10 ex

THE SCOPE OF THE INVENTION

The present invention relates to certain (3-(4-(1 - or 2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy or phenylthio)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)metanol formula I, to methods of producing such compounds, to intermediate compounds used in these methods and their use in treating diseases or conditions associated with melaninconcentrating hormone, such as obesity, conditions associated with obesity, anxiety and depression, and to pharmaceutical compositions containing these compounds.

PRIOR ART

Consider that the effects melaninconcentrating hormone (sit) is involved in diseases such as anxiety, depression, obesity and disorders associated with obesity. Found that the sit is the main regulator of feeding behavior and energy homeostasis and represents a natural ligand organovo receptor coupled to a G protein having a size of 353 amino acids (GPCR), referred to as the SLC-1 (also known as GPR24). SLC-1 homologous in sequence to the somatostatin receptors, and it is often called "receptor melaninconcentrating hormone" (receptor sit type 1 receptor MSN or MCHR1).

In mice lacking the receptor MSN, there is no increased food reaction to sit and there is a lean phenotype, suggesting that this receptor is responsible for mediating the effects of sit on nutrition. Also it is shown that antagonists of the receptor sit blocking the effect of sit on a diet and reduce weight and obesity in mice in a model of obesity induced by diet. Save the distribution and sequence of the receptor MSN suggests a similar role of this receptor in humans and rodents. Therefore, antagonists of the receptor MSN proposed for the treatment of obesity and other disorders characterized by overeating and overweight.

The findings also suggest that MCHR1 plays a role in the regulation of mood and stress. In the Central nervous system mRNA and protein MCHR1 distributed in various hypothalamic nuclei, including, for example, paraventrikulyarnoe core (VAT) and the medial division of the nucleus accumbens; and limbic structures, including the hippocampus, Sept, amygdala, blue stain and the core of the seam, all of which is reputed to be involved in the regulation of emotions and stress.

Reported that the introduction of sit in the medial praxitelous region is alarming, although it also describes and back, similar to the anxiolytic effect of injection of the sit. Injection sit in the medial division of the nucleus accumbens, abounding MCHR1, reduced mobility of rats in the forced swimming test, suggesting about depressive effect. Also reported that in tests on rodents MCHR1 antagonists exhibit antidepressant and similar anxiolytic effects, which suggests a specific role MCHR1 in depression and anxiety.

Thus, consider that the sit-antagonists are likely to benefit many people have the potential to ease anxiety and depression and may be useful in the treatment of obesity and obesity-related conditions.

At present, the development of new drugs is of interest H3-histamine receptor. The H3 receptor is a presynaptic autoreceptors localized in both the Central and peripheral nervous systems, as well as in the skin and organs such as lungs, intestines, possibly spleen and gastrointestinal tracton data suggest that the H3 receptor has its own constitutive activity in vitro and in vivo (i.e. it is active in the absence of agonist). Compounds that act as inverse agonists can inhibit such activity. It is shown that H3-histamine receptor regulates the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. Some H3-histamine ligands, such as, for example, antagonists or inverse agonists H3-histamine receptor can increase the release of neurotransmitters in the brain, whereas other H3-histamine ligands, such as agonists H3-histamine receptor can inhibit the biosynthesis of histamine, as well as to inhibit the release of neurotransmitters. This suggests that agonists, inverse agonists and antagonists of the H3-histamine receptor could mediate neuronal activity. Therefore, efforts have been made to develop new therapeutics aimed at H3-histamine receptor. Assume that the compounds for modulation of H3-histamine receptors, can be useful in the treatment of cognitive deficit in schizophrenia, narcolepsy, obesity, attention deficit disorder and hyperactivity, pain and Alzheimer's disease.

SUMMARY OF THE INVENTION

In the present invention proposed compounds that are antagonists of the receptor MSN and therefore might be useful in the treatment of anxiety, depression, obesity and obesity-related conditions. The compounds are modulators H3-histamine receptor and may be useful in the treatment of cognitive deficit in schizophrenia, narcolepsy, attention deficit disorder and hyperactivity, pain and Alzheimer's disease. The connection can also be particularly useful in the treatment of disorders that require a dual impact on receptors sit and N3, for example, in the treatment of obesity and obesity-related conditions.

DESCRIPTION OF THE INVENTION

In the present invention proposed a compound of the formula I

or its pharmaceutically acceptable salt, in which

R 1 represents H, fluorescent-, chloro-, bromo-, cyano-, With 1-3 alkyl group, possibly substituted by one or more than one group of fluorescent, or With 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent;

And represents O or S;

R 2 and R 3 independently represent H, fluorescent-, chloro-, bromo-, With 1-4 alkyl group, possibly substituted by one or more than one group of fluorescent, or With 1-4 alkoxygroup, possibly substituted by one or more than one group of fluorescent; provided that R 2 and R 3 are not in metaprogram relative to each other;

R 4 and R 5 independently represent H or With 1-4 alkyl group; and

X and Y independently represent O or CH 2 , provided that X and Y are different.

In another aspect of the present invention proposed a compound of the formula IA

or its pharmaceutically acceptable salt, in which

R 1 represents H, fluorescent-, chloro-, bromo-, cyano-, With 1-3 alkyl group, possibly substituted by one or more than one group of fluorescent, With 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent;

And represents O or S; and

R 2 and R 3 independently represent H, fluorescent-, chloro-, bromo-, C 1-4 alkyl group, possibly substituted by one or more than one group of fluorescent, or With 1-4 alkoxygroup, possibly substituted by one or more than one group of fluorescent; provided that R 2 and R 3 are not in metaprogram relative to each other.

In another aspect of the present invention proposed a compound of the formula IB

or its pharmaceutically acceptable salt, in which

R 1 represents H, chloro - or With 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent;

And represents O or S; and

R 2 represents H or chloro.

In another aspect of the present invention proposed a compound of the formula IC

or its pharmaceutically acceptable salt, in which

R 1 represents H, chloro - or With 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent;

And represents O or S; and

R 3 represents H or chloro.

In another aspect of the present invention proposed a compound of formula ID

or its pharmaceutically acceptable salt, in which

R a and R b independently represent H or With 1-4 alkyl group;

R 1 represents H, chloro - or With 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent;

And represents O or S; and

R 3 represents H or chloro.

Below are private values of the substituents R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , A, X, Y. it Should be understood that such values can be used, when appropriate, in any of the definitions, claims or embodiments described above or below, for example, in appropriate cases, in any of formulas I, IA, IB, IC or ID.

In particular, R a represents H or methyl.

In particular, R b is H or methyl.

In particular, R 1 represents H, chloro, fluorescent, methoxy or deformedarse.

In particular, R 2 represents H or chloro.

In particular, R 3 represents H or chloro.

In particular, R 4 represents N.

In particular, R 5 represents N.

In particular, As it represents O.

In particular, As it represents S.

In particular, X represents O.

In particular, Y is CH 2 .

The term "With 1-4 alkyl" refers to alonovoa the radical with a linear or branched chain containing from 1 to 4 carbon atoms. Typical groups include methyl, ethyl, propyl, isopropyl, 1-methylpropyl, n-butyl, tert-butyl and isobutyl.

The term “C 1-4 alkoxy” refers to groups of the General formula-OR a , where R a is selected from C 1-4 Akilov. Typical alkoxygroup include, without limitation, methoxy, ethoxy-, propoxy-, isopropoxy, butoxy-, tert-butoxy or isobutoxy.

Hereinafter in this application, the term formula I denotes a compound of formula I or formula IA, or formula IB, or formula IC or formula ID, if not specified otherwise.

In another aspect of the present invention is provided with one or more than one of the following compounds:

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-3-chlorophenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon;

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methanon;

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon;

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanon;

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenylthio)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon;

(3-(2-chloro-4-((3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon;

or its pharmaceutically acceptable salt.

Specialists in this field it is obvious that the present invention may include any number of the above compounds 1 to 10 inclusive. Specialists in this field it is obvious that the present invention covers compounds of formula I, in addition to any one or more than one of the above compounds.

Further, the present invention proposed a pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and/or diluent.

In addition, later in this invention, a method for treatment or prevention of a disease or condition in which a positive modulation of receptor MSN, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Also later in this invention it is proposed to use the compounds of formula I, or its pharmaceutically acceptable salts or mixtures thereof for the treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

Also later in this invention it is proposed to use the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof for the manufacture of a medicine for treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

Also later in this invention it is proposed to use the compounds of formula I or its pharmaceutically acceptable salts as a drug.

In another aspect of the present invention proposed a compound of formula I for the treatment of diseases or conditions in which a positive modulation of receptor MSN, in particular obesity.

The term "MCHR" refers to a receptor protein melaninconcentrating hormone type 1 (MCHR1), unless otherwise noted.

The terms "treat", “the act of treating” and "treatment" refers to modulating the disease and/or its attendant symptoms.

The terms "prevent", “warning” and "prevention" refer to the reduction or elimination of the disease and/or its attendant symptoms.

The terms “modulate”, “modulating”, “modulation” and “modulation” in this document include, for example, to activate (for example, the effects of the agonist) or inhibition (e.g., the effects of the antagonist) MCHR.

The term “pharmaceutically acceptable” in this document means that the object identified as “pharmaceutically acceptable”is suitable and physiologically acceptable for administration to a patient/subject. For example, the term “pharmaceutically acceptable salt (salt)” means suitable and physiologically acceptable salt (salt).

The term “prevention" in this document refers to (1) prevent the development of disease and/or condition; and/or (2) to prevent worsening of the disease and/or condition upon the occurrence of the disease and/or condition,

The term "a condition or disease mediated MCHR" in this document refers to the condition or disease that is sensitive to modulation by an agent active against MCHR.

The term "therapeutically effective amount" refers to the amount of the compound sufficient to modulate one or more than one symptom, condition or disease, whose treatment.

The following embodiment is described in this document connections, where one or more than one atom represents a radioisotope of the same element, such as deuterium, With 13 or 14 C. In the private embodiment of the connection observed by tritium. Such labeled with a radioisotope compounds are synthesized using either labeled by an isotope of the original substance, or, in the case of tritium, with the substitution of hydrogen with tritium well-known ways. Known methods include (1) electrophilic halogenoalkane with subsequent recovery of the halogen in the presence of a source of tritium, for example, hydrogenation with gaseous tritium in the presence of palladium catalyst or (2) the substitution of hydrogen with tritium performed in the presence of gaseous tritium and a suitable ORGANOMETALLIC (e.g., palladium) catalyst.

Labeled with tritium compound may be useful in the identification of new drug compounds which are able to bind to the receptor MSN and modulate its activity by agonism, partial agonism or antagonism. Such labeled with tritium compounds may be used in experiments to measure the substitution of these compounds to assess the binding of ligands that bind to receptors MSN.

Obviously, if the compounds of the present invention contain one or more than one chiral center, the compounds according to the invention can exist and can be isolated in enantiomerically or diastereomeric forms or as racemic mixtures. The present invention includes any possible enantiomers, the diastereomers, the racemates of compounds of the formula I or mixtures thereof. Optically active forms of the compounds according to the invention can be obtained, for example, chiral chromatographic separation of a racemate, by synthesis from optically active starting compounds or by asymmetric synthesis based on the following methods.

Compounds of the present invention can be purified using methods well known to specialists in this field. Such methods can be selected from, for example, crystallization, suspension or chromatography. Chromatographic methods can be selected from the ways in which, for example, using methods reversed or normal phase. Eluting solvent or mixture of solvents can be selected from solvents that are suitable for this method.

Also it should be understood that the present invention encompasses tautomers of the compounds of formula I.

Obviously, certain compounds according to the invention, including their pharmaceutically acceptable salts can exist in solvated, for example hydrated, and resolutional forms. It should be understood that the present invention encompasses all such solvated forms of the compounds of formula I.

The compounds of formula I can also form a salt. Therefore, when referred to in this document, the compounds of formula I such reference, unless otherwise indicated, includes salts thereof. In one embodiments of the compounds of formula I form pharmaceutically acceptable salts. In another embodiment of the compounds of formula I form salts, which can be, for example, is used for isolating and/or purifying compounds of formula I.

Generally, pharmaceutically acceptable salts of the compounds of formula I can be obtained using well-known in the field of standard methods. These standard methods include, without limitation, for example, the reaction is very alkaline compounds, such as, for example, alkylamine, with a suitable acid, such as, for example, Hcl or acetic acid, to obtain a physiologically acceptable anion.

In one of the embodiments of the compound of the formula I can be converted into a pharmaceutically acceptable salt or MES, in particular in salt accession acid, such as, for example, hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate and Lara toluensulfonate.

As a rule, the compounds of formula I can be obtained in accordance with the following Schemes and on the basis of well-known experts in the field of information, and/or in accordance with the methods proposed below in the Examples. Solvents, temperatures, pressures and other reaction conditions can be readily selected by the person skilled in the art. Source materials are commercially available or can be easily obtained by a person skilled in the art. Upon receipt of the compounds can be used combinatorial methods, for example, if the intermediate compounds have groups that are suitable for these methods.

The term “protective group of the amine” refers to well-known in this field groups are able to join the amino group in such a way as to prevent the involvement of the amino group in the reactions taking place elsewhere in the molecule containing this group. Suitable protective group of the amine, for example, include, without limitation, the protective group of the amine described in “Protective Groups in Organic Synthesis”, 2nd edition, John Wiley & Sons, 1991. The protective group of the amine may represent, for example, the protective group of the urethane type (often referred to as a urethane protective group), including, without limitation, for example, arylalkylamine groups, such as, for example, benzyloxycarbonyl, and alkoxycarbonyl groups, such as, for example, methoxycarbonyl and tert-butoxycarbonyl. Usually aminosidine group represents a tert-butoxycarbonyl.

The compounds of formula I can be obtained

a) interaction of the compounds of formula II

where A, X, Y, R 2 , R 3 , R 4 and R 5 are as defined above, with a compound formula III

where R 1 is as defined above, and L1 represents a leaving group, for example With 1-4 alkoxy group, possibly in the presence of a solvent, for example ethanol, at a temperature in the range from 0 to 150°C., in particular in the range from 50 to 120°C.; or

b) interaction of the compounds of formula IV

where A, X, Y, R 2 , R 3 , R 4 and R 5 are as defined above, with a compound of formula V

where R 1 is as defined above, and L 2 represents a leaving group, for example, mesilate or tosyloxy, in the presence of alkaline compounds, such as Cs 2 CO 3 possibly in the presence of a solvent, for example DMF or preferably DMA, and at a temperature in the range from 0 to 150°C., in particular in the range from 50 to 120°C.; or

c) the interaction of the compounds of formula VI

where X, Y, R 4 and R 5 are as defined above, with a compound of formula VII

where R 1 , R 2 , R 3 and a are as defined above, and L 3 represents a leaving group, for example halogen, in particular chlorine or bromine; possibly in the presence of a solvent, for example DMF, and possibly in the presence of alkaline compounds, such as amine, for example N-ethyl-N-isopropylparaben-2-amine, at a temperature in the range from 0 to 150°C., in particular in the range from 5 to 50°C; or

d) the interaction of the compounds of formula VI

where X, Y, R 4 and R 5 are as defined above, with a compound of formula XII

where R 1 , R 2 , R 3 and a are as defined above, in the presence of a reducing agent, such as triacetoxyborohydride sodium in a suitable solvent, for example dichloromethane, and possibly in the presence of alkaline compounds, such as amine, such as N-ethyl-N-isopropylparaben-2-amine.

If the compound of formula III represents an ester, a compound of the formula I can be obtained by the reaction of a compound of formula II and an ether of formula III, possibly in the presence of a solvent, for example ethanol, and possibly in the presence of a catalyst, such as sodium cyanide, and at a temperature in the range from 0 to 150°C., in particular in the range from 50 to 120°C. When using a catalyst, such as sodium cyanide, the temperature is preferably approximately equal to the ambient temperature, for example from 10 to 30°C.

Compounds of formulas II and IV can be obtained, as shown in the following scheme 1 and in a manner similar to those described in the examples.

The compound of formula IV can be obtained by the coupling of compounds of formula VI in which R 4 and R 5 are as defined above, with a derivative of benzaldehyde of the formula VIII, in which A, R 2 and R 3 are as defined above, and a reducing agent, such as triacetoxyborohydride sodium in a suitable solvent, for example dichloromethane.

The compound of formula IX can be obtained by the coupling of compounds of formula IV with a compound of azetidine formula X,

where PG is aminosidine group, for example, tert-butoxycarbonyl, and L 4 is a leaving group, for example, mesilate or tosyloxy, in the presence of a base, for example, Cs 2 CO 3 , in the presence of a suitable solvent, for example DMF.

The compound of formula II can be obtained by treating compounds of formula IX agent for the removal of protection, such as HCl or TFU, in a suitable solvent, for example dichloromethane.

The compounds of formula III can be obtained by known methods, for example by the methods described in Journal fuer Praktische Chemie, 327, 109-116 (1985), using compounds benzhydrazide formula XI,

where R 1 is as defined above.

The compounds of formula V can be obtained as shown below in scheme 2, and by methods similar to those described in the examples.

Compound of formula VII can be obtained by the coupling of compounds of formula III in which R 1 is as defined above, with 3-hydroxyazetidine or its salt in the presence of alkaline compounds, such as triethylamine, possibly in the presence of a catalyst, such as sodium cyanide, in a suitable solvent, for example methanol.

The compound of formula V can be obtained by treating compounds of formula VII agent that activates an alcohol group, such as methanesulfonamido, in the presence of a base, such as triethylamine, in a suitable solvent such as dichloromethane.

The compounds of formula VI can be obtained by well-known methods such as described in Angew. Chem. Int. Ed., 47, 4512-4515 (2008) and WO 2008/131103.

Compounds of formulas VIII, X and XI are either available commercially or can be easily obtained by methods well known to specialists in this field.

The compounds of formula XII can be obtained by the coupling of compounds of formula V in which R 1 and L 2 are as defined above, with a compound of formula VIII, in which R 2 , R 3 and a are as defined above, in the presence of a base, such as Cs 2 CO 3 , possibly in the presence of a solvent, for example DMF, at temperatures in the range from 0 to 150°C., in particular in the range from 50 to 120°C.

Suppose that the compounds of formulas II, IV, V, VII and XII are novel and are claimed in this document as the next aspect of the present invention. In a preferred aspect of the invention, these compounds are essentially pure, for example, have a purity of more than 50%, in particular more than 95% and in particular more than 99%.

The following embodiment of the invention relates to a method of treatment or prevention of a disease or condition in which a positive modulation of receptor MSN, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

A more specific embodiment relates to a method of treatment or prevention of a disease or condition in which a positive modulation of receptor MSN, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I.

The following embodiment of the invention relates to the use of compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof for the treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

A more specific embodiment of the invention relates to the use of antagonistic compounds of the formula I, or their pharmaceutically acceptable salts, or mixtures thereof for the treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

The following embodiment of the invention relates to the use of compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof for the manufacture of a medicine for treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

The following embodiment of the invention relates to the use of compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof as a medicinal product.

Another embodiment of the invention relates to pharmaceutical compositions containing a compound of formula I, or its pharmaceutically acceptable salt, or a mixture thereof and a pharmaceutically acceptable carrier and/or diluent.

The following embodiment of the invention relates to pharmaceutical compositions useful for the treatment or prevention described in this invention, the disease or condition caused by the dysfunction of receptors MSN in warm-blooded animal, containing a therapeutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof, effective to treat or prevent such disease or condition and a pharmaceutically acceptable carrier and/or diluent.

In one of the embodiments, a warm-blooded animal represents a mammal, including, without limitation, for example, humans and domestic animals, such as dogs, cats and horses.

In the following embodiment of a warm-blooded animal represents a person.

In one of the embodiments of the invention the disease and/or condition, to treat, cure or prevention of which the compound of the formula I can be used include, without limitation, for example, mood disorders, anxiety disorders and eating disorders.

Typical mood disorders include, without limitation, for example, depressive disorders, such as major depressive disorder(a) and delimitable disorder(a); bipolar depression and/or bipolar mania, such as, for example, bipolar disorder type 1, including, without limitation, disorder with manic, depressive and mixed episodes, and bipolar II disorder; cyclothymic disorder(a); anxiety, depression; mood disorders associated with General health.

Typical anxiety disorders include, without limitation, for example, panic disorder(without agoraphobia; panic disorder with agoraphobia; agoraphobia without panic disorder(s) in history; specific phobia; social phobia; obsessive-compulsive disorder(a), disorder(s)associated with stress; post-traumatic stress disorder(a), sharp(s) reaction(s) to stress, generalized anxiety disorder(a); and generalized anxiety disorder(s)associated with General health.

Typical of eating disorders include, without limitation, for example, obesity.

Many of the above-mentioned conditions and disorders are defined, for example, in the leadership of the American Psychiatric Association: Diagnostic and Statistical Manual of Mental disorders, Fourth Edition, Text Revision, Washington, DC, American Psychiatric Association, 2000.

Another embodiment relates to a method of treating or preventing mood disorders, anxiety disorders, or eating disorders, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof.

Another embodiment relates to a method of treatment or prophylaxis of mood disorders, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof.

Another embodiment relates to a method of treatment or prevention of anxiety disorders, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof.

Another embodiment relates to a method of treatment or prevention of eating disorders, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof.

In another embodiment, a method for treatment or prevention of a disease or condition selected from anxiety, depression, and obesity in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I.

In another embodiment, a method for treating or preventing anxiety in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I.

In another embodiment, a method for treatment or prevention of generalized anxiety disorder in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I.

In another embodiment, a method for treatment or prevention of depression in warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I.

In another embodiment, a method of treating or preventing obesity in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I.

A more specific embodiment relates to a method of treatment or prevention of a disease or condition in which a positive modulation of receptor MSN, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of antagonist compounds of formula I.

The following embodiment of the invention relates to a method of treatment or prevention of a disease or condition selected from anxiety, depression, and obesity in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

The following embodiment of the invention relates to a method of treating or preventing anxiety in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

The following embodiment of the invention relates to a method of treatment or prevention of generalized anxiety disorder in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

The following embodiment of the invention relates to a method of treatment or prevention of depression in warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

The following embodiment of the invention relates to a method of treating or preventing obesity in a warm-blooded animal, including the introduction of a specified animal in need of such treatment or prevention, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

A more specific embodiment of the invention relates to the use of antagonistic compounds of the formula I or their pharmaceutically acceptable salts for the treatment or prevention of a disease or condition in which a positive modulation of receptor MSN.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of a disease or condition selected from mood disorders, anxiety disorders and eating disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of mood disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of anxiety disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of eating disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of a disease or condition selected from anxiety, depression, and obesity.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of anxiety.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of generalized anxiety disorder.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of depression.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts for the treatment or prevention of obesity.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of a disease or condition selected from mood disorders, anxiety disorders and eating disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of mood disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of anxiety disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of eating disorders.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of a disease or condition selected from anxiety, depression, and obesity.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of anxiety.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of generalized anxiety disorder.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of depression.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of obesity.

The following embodiment relates to the use of compounds of formula 1 or its pharmaceutically acceptable salts for the treatment or prevention of insulin resistance, fatty liver (including non-alcoholic steatohepatitis (Nash)), fatty infiltration of the liver or seizures sleep apnea.

The following embodiment of the invention relates to the use of compounds of formula I or its pharmaceutically acceptable salts as a drug.

Further, in this invention the application of the compounds of formula I, or diastereomers or enantiomers, or pharmaceutically acceptable salts of formula I, or diastereomers or enantiomers, or mixtures thereof for the manufacture of a medicinal product for the treatment of a disorder selected from cognitive deficit in schizophrenia, narcolepsy, obesity, attention deficit disorder and hyperactivity, pain and Alzheimer's disease.

Further, in this invention the application of the compounds of formula IC, or diastereomers or enantiomers, or pharmaceutically acceptable salts of the compounds of formula IC, or diastereomers or enantiomers, or mixtures thereof for the manufacture of a medicinal product for the treatment of a disorder selected from cognitive deficit in schizophrenia, narcolepsy, obesity, attention deficit disorder and hyperactivity, pain and Alzheimer's disease.

Further, the present invention proposed a pharmaceutical composition comprising a compound of formula I or IC, or diastereomers or enantiomers, or pharmaceutically acceptable salts of compounds of formula I or IC, or diastereomers or enantiomers, or mixtures thereof, and a pharmaceutically acceptable carrier and/or diluent.

Further, in this invention, a method of treatment of a disorder selected from cognitive deficit in schizophrenia, narcolepsy, obesity, attention deficit disorder and hyperactivity, pain and Alzheimer's disease in a warm-blooded animal, including the introduction of a specified animal in need of such treatment, a therapeutically effective amount of the compounds of formula I or IC, or diastereomers, enantiomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds of formula I or IC, or diastereomers, enantiomers or mixtures.

Further, in this invention, a method for treatment of disorders, in which positive modulation of H3-histamine receptor, including the introduction of a warm-blooded animal in need of such treatment, a therapeutically effective amount of the compounds of formula I or IC, or diastereomers, enantiomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds of formula I or IC, or diastereomers, enantiomers or mixtures.

Another embodiment of the invention relates to pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and/or diluent.

The following embodiment of the invention relates to pharmaceutical compositions useful for the treatment or prevention described in this invention, the disease or condition caused by the dysfunction of the receptor MSN in warm-blooded animal, containing a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, is effective for treatment or prevention of such disease or condition and a pharmaceutically acceptable carrier and/or diluent.

In one of the embodiments of the warm-blooded animal represents a mammal, including, without limitation, for example, humans and domestic animals, such as dogs, cats and horses.

In the following embodiment of a warm-blooded animal represents a person.

In another embodiment of the invention, a method for obtaining compounds of formula I.

In another embodiment of the invention the compound of formula I, or its pharmaceutically acceptable salt, and/or pharmaceutical composition or pharmaceutical preparation containing a compound of formula I or its pharmaceutically acceptable salt, can be introduced at the same time, together, sequentially or separately with another pharmaceutically active compound selected from the following:

(1) antidepressants, including, without limitation, for example, agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, DULOXETINE, eltasone, ESCITALOPRAM, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, minisoccer, tranilcipromin, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomers and metabolites;

(2) atypical neuroleptics, including, without limitation, for example, quetiapine and pharmaceutically active isomers and metabolites;

(3) neuroleptics, including, without limitation, for example, amisulpride, aripiprazole, asenapine, benzisoxazol, bifeprunox, carbamazepine, clozapine, chlorpromazine, dibenzepin, divalproex, DULOXETINE, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapi, perphenazine, phenothiazines, privatelyoperated, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, supraglan, suriclone, thioridazine, trifluoperazine, trimeton, valproate, valproate acid, zopiclone, zotepine, ziprasidone, and equivalents and pharmaceutically active isomers and metabolites;

(4) anxiolytics, including, without limitation, for example, alnespirone, azaperone, benzodiazepines, barbiturates, such as adinazolam, alprazolam, balasan, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, lprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, postepu, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, kwazepam, reclusiam, tracazolate, crepidam, temazepam, triazolam, medazepam, zolazepam and equivalents and pharmaceutically active isomers and metabolites;

(5) anticonvulsants, including, without limitation, for example, carbamazepine, valproate, lamotrigine, gabapentin, and equivalents and pharmaceutically active isomers and metabolites;

(6) medicines for the treatment of Alzheimer's disease, including, without limitation, for example, donepezil, memantine, taken and equivalents and pharmaceutically active isomers and metabolites;

(7) medicines for the treatment of Parkinson's disease, including, without limitation, for example, deprenyl, L-DOPA, requip, mirapex, inhibitors of monoamine oxidase B (MAO-B), such as selegiline and rasagiline, inhibitors of OMRS, such as tasmar inhibitors a-2, inhibitors of reuptake of dopamine antagonists N-methyl-D-aspartate (NMDA)agonist nicotine, dopamine agonists, inhibitors synthase neuronal nitric oxide and equivalents and pharmaceutically active isomers and metabolites;

(8) medicines for the treatment of migraine, including, without limitation, for example, almotriptan, amantadine, parlodel, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolid, pramipexol, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zolmitriptan and equivalents and pharmaceutically active isomers and metabolites;

(9) medicines for the treatment of stroke, including, without limitation, for example, abciximab, activase, NXY-059, citicoline, kabinetten, desmoteplase, repinotan, traxoprodil and equivalents and pharmaceutically active isomers and metabolites;

(10) medicines for the treatment of urinary incontinence, including, without limitation, for example, darifenacin, flavoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and equivalents and their pharmaceutically active isomers and metabolites;

(11) medicines for the treatment of neuropathic pain, including, without limitation, for example, gabapentin, LIDODERM, pregablin and equivalents and pharmaceutically active isomers and metabolites;

(13) medicines for the treatment of insomnia including, without limitation, for example, agomelatine, allobarbital, econimic, amobarbital, benzoctamine, butabarbital, capured, chloral, claparede, clarett, exclama, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midfloor, Nizamabad, pentobarbital, phenobarbital, propofol, ramelteon, related, triclofos, secobarbital, zaleplon, zolpidem and equivalents and pharmaceutically active isomers and metabolites;

(14), mood stabilizers, including, without limitation, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproate acid, verapamil, and equivalents and pharmaceutically active isomers and metabolites;

(15) insulin and insulin analogues;

(16) means increasing the secretion of insulin, including sulfonylureas (eg, glyburide, glipizide), prandialno regulators of glucose (for example, meglitinide, such as Repaglinide and nateglinide);

(17) inhibitors dipeptidylpeptidase-IV (e.g., saxagliptin, sitagliptin, alogliptin, vildagliptin);

(18) means that increase sensitivity to insulin, including agonists receptors that activate peroxisome proliferation gamma (PPAR-gamma) (eg, pioglitazone and rosiglitazone), and agents with combined PPAR-alpha and gamma activity;

(19) agents modulating the balance of glucose in the liver (e.g., biguanides, such as Metformin, fructose 1, 6 inhibitors-bisphosphatase, glycogen phosphorylase inhibitors, inhibitors of kinases glikogensintetazy);

(20) agents designed to reduce glucose absorption in the intestine (for example, alpha-glucosidase inhibitors such as acarbose);

(21) agents that prevent reabsorption of glucose by the kidney (e.g., inhibitors of SGLT-2, such chandapillai);

(22) agents designed to treat the complications of prolonged hyperglycaemia (for example, inhibitors alsoreported);

(23) compounds against obesity, for example, orlistat (EP 129748) or sibutramine (GB 2184122 and US 4929629);

(24) agents against dyslipidemia, such as inhibitors of HMG COA reductase (3-hydroxy-3-methylglutaryl-coenzyme A) (for example, statins such as rosuvastatin), PPARα agonists (fibrates, such as fenofibrate, clofibrate, and gemfibrozil), biliary acids (cholestyramine), inhibitors of cholesterol intake (vegetable stanely, synthetic inhibitors), inhibitors of absorption of bile acids (IBATi) and nicotinic acid and analogues (Niacin and dosage form slow release);

(25) antihypertensive agents such as β-blockers (eg atenolol, inderal); angiotensin converting enzyme inhibitors (ACE) (eg, lisinopril); calcium antagonists (e.g. nifedipine); antagonists of angiotensin receptor (eg candesartan), α antagonists and diuretics (eg, furosemide, benzthiazide);

(26) modulators of hemostasis, such as antithrombotic agents, activators of fibrinolysis, antagonists of thrombin inhibitors factor XA inhibitors, factor VIIa, antiplatelet tools (e.g., aspirin, clopidogrel), anticoagulants (heparin and low molecular weight analogues, hirudin) and warfarin;

(27) agents, which have antagonistic effects effects of glucagon;

(28) anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (e.g. aspirin) and steroidal anti-inflammatory drugs (such as cortisone);

(29) antihypertensive compounds, for example an inhibitor of angiotensin-converting enzyme (ACE)receptor antagonist angiotensin II blocker, alpha-blocker, beta-blocker, a combined alpha/beta-blocker, adrenostimulator, calcium channel blocker, blocker at-1 receptors, saluretic, diuretic or vasodilator;

(30) PDK inhibitor;

(31) phytosteroles connection;

(32) an inhibitor of 11β-HSD-1 (hydroxysteroiddehydrogenase);

(33) activator UCP-1, 2 or 3;

(34) cannabinoid modulator (SW) receptor, for example, inverse agonist or antagonist such as rimonabant or taranabant;

(35) receptor modulator of neuropeptide Y (NPY), for example, agonist NPY, or NPY2 agonist, or NPY5 antagonist;

(36) modulator receptor melanocortin MSG, for example, agonist MSG;

(37) modulator MSG, for example, agonist MSG;

(38) receptor modulator of orexin, for example, antagonist;

(39) modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ, δ and RORalpha;

(40) inhibitor diglycidylethers 1 (DGAT-1);

(41) an inhibitor of DGAT-2;

(42) of antisense oligonucleotide DGAT-2;

(43) an inhibitor of fatty acid synthase;

(44) inhibitor SETR (transport protein cholesterol esters);

(45) antagonist cholesterol intake;

(46) inhibitor MTP (microsomal transport protein);

(47) probucol;

(48) agonists glucagon-like peptide 1 (GLP-1);

(49) glucokinase modulator;

50) antibodies to ghrelin;

51) of ghrelin antagonist;

52) agonist gastrin-releasing peptide 119 (GPR119) and

53) other modulators melaninconcentrating hormone (sit), for example, an antagonist of the sit-1;

For applications of the methods, medicaments and compositions mentioned in this izobretenii, the amount of compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof and enter the dose may vary depending on the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof, and/or the desired method of administration, and/or treatment. However, in General, satisfactory results are achieved, if the compound of formula I, or its pharmaceutically acceptable salt, or a mixture thereof is administered in a daily dosage from about 0.1 mg to about 20 mg/kg animal body weight. Such doses may be entered as separate doses 1 to 4 times per day or as dosage forms continuous release. For a human, the total daily dose may, for example, be from about 5 mg to about 1400 mg, in a more particular case, from about 10 mg to about 100 mg Standard dosage form suitable for oral administration includes, for example, from about 2 mg to about 1400 mg of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof, in a mixture with solid and/or liquid pharmaceutical carrier, the lubricant and/or diluent.

However, the specific dose level and frequency of injection for each individual entity can vary and usually depend on a number of factors, including, without limitation, for example, the bioavailability of specific compounds of formula I, or their pharmaceutically acceptable salts, or mixtures thereof in the input form, the metabolic stability and length of action of specific compounds of formula I, or their pharmaceutically acceptable salts, or mixtures thereof, species, age, body weight, General health, sex and diet of the subject, the mode and time of administration, excretion rate, combination of drugs and the severity of the particular condition.

The compounds of formula I, or their pharmaceutically acceptable salts, or mixtures thereof may be introduced by any means suitable for the condition, the treatment is carried out, and the number of compounds of the formula I, or their pharmaceutically acceptable salts, or mixtures thereof.

The compounds of formula I, or their pharmaceutically acceptable salts, or mixtures thereof can be introduced in the form of conventional pharmaceutical compositions by any method, including, without limitation, for example, oral, intramuscular, subcutaneous, local, intranasal, epidural, intraperitoneal, intrathoracic, intravenous, intrathecal, intracerebroventricular introduction and injection into the joints.

In one of the embodiments of the invention, the method of administration is oral, intravenous or intramuscular.

The compound of formula I, or its pharmaceutically acceptable salt, or a mixture thereof can be used in its original form or in the form of a suitable pharmaceutical preparation for enteral or parenteral administration.

Suitable solid pharmaceutical compositions include, without limitation, for example, powders, tablets, dispersible granules, capsules, pills and suppositories.

In the solid pharmaceutical compositions of pharmaceutically acceptable carriers include, without limitation, for example, solids, liquids and their mixtures. Solid media can also be a diluent, Corrigendum, solubilizer, lubricant, suspenders agent, a binder encapsulating substance and/or baking powder tablets. Suitable carrier materials include, without limitation, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and mixtures thereof.

The powder can be manufactured, for example, by mixing finely ground solids with micronized compound of formula I, or its pharmaceutically acceptable salts, or mixtures thereof.

The tablet can be manufactured, for example, by mixing the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof in suitable proportions with a pharmaceutically acceptable carrier having the necessary binding properties, and pressing the desired shape and size.

The suppository can be produced, for example, by mixing the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof with suitable non-irritating by excipients, which is liquid at rectal temperature but solid at temperatures below rectal, while non-irritating excipient first melted and dispersed compound of formula I. the molten homogeneous mixture is then poured into a matrix suitable form and is allowed to cool and harden. Typical non-irritating excipients include, without limitation, for example, cocoa butter, gelatin, glycerol, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and esters of fatty acids and polyethylene glycol.

Suitable liquid pharmaceutical compositions include, without limitation, for example, solutions, suspensions and emulsions.

Typical liquid pharmaceutical compositions suitable for parenteral administration include, without limitation, for example, solutions of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof in sterile water or aqueous propylene glycol and the solution formula I, or its pharmaceutically acceptable salts, or mixtures thereof in aqueous polyethylene glycol.

Aqueous solutions for oral administration can be produced by dissolving the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof in water and adding, if necessary, suitable dye, corrigentov, stabilizers and/or thickeners.

Aqueous suspensions for oral administration can be produced by dispersing micronized compound of formula I, or its pharmaceutically acceptable salts, or mixtures thereof in water together with a viscous substance, such as, for example, synthetic natural gum, resin, methyl cellulose and sodium carboxymethylcellulose.

In one of the embodiments of the invention the pharmaceutical composition contains from about 0.05% to about 99% (by weight) of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof. In all cases, the mass percentage calculated with respect to the total weight of the composition.

In another embodiment of the invention the pharmaceutical composition contains from about 0.10% up to about 50% (by weight) of the compounds of formula I, or its pharmaceutically acceptable salts, or mixtures thereof. In all cases, the mass percentage calculated with respect to the total weight of the composition.

Also in this invention, a method for manufacturing a pharmaceutical composition, including mixing or combining the ingredients and forming the mixed ingredients in tablets or suppositories, encapsulating ingredients in capsules or dissolution of the ingredients to obtain injection solutions.

Analytical techniques.

Analysis of the binding of the sit.

Linking melaninconcentrating hormone (sit) can be measured by analyzing radioligand binding using [ 125 I]sit and membranes expressing human receptors melaninconcentrating hormone type 1 (MCHR1). The ligands that bind with MCHR1, can be identified by their ability to compete with the binding of [ 125 I]sit.

[ 125 I]sit can be purchased from Perkin Elmer (NEK373050UC 25 µci). Membrane (2.20 mg/ml) can be obtained from cells SNACK expressing human receptors sit type 1, these cells can be purchased from EuroScreen. Trizma, bovine serum albumin (BSA), NaCl and MgCl 2 6H 2 O can be purchased from Sigma. Human sit can be purchased from Bachem (0.5 mg, cat no.N-1482).

Analysis of saturation binding can be carried out in 50 mm Tris, pH of 7.4, containing 3 mm MgCl 2, and 0.05% BSA. For the analysis, 100 μl of twofold serially diluted radioligand [ 125 I]sit added to the wells shallow 96-well plate. This is followed by the addition of 100 ál of analytical buffer containing membrane with a final protein concentration of 20 μg/ml of the Mixture incubated at room temperature for 1 h, and then filtered through a filter Wallac A-filter, treated with 0.1% PEI using collector cells (Skatron). The collected membrane is washed 3 times with wash buffer (50 mm Tris, pH of 7.4, containing 5 mm MgCl 2, 50 mm NaCl) at 300 μl per well and then dried in air overnight or at 60°C. 125 I measure the scintillation method.

Analysis of binding of [ 125 I]MCH conducted in the presence of the compounds under study, either at a fixed concentration or series of concentrations can be used in the analysis of competitive binding of ligands. When investigating the relationship between dose and response connections can be three-fold serially diluted in analytical tablet to obtain concentration range. In single point analysis [ 125 I]MCH membrane may be pre-mixed and then transferred to the analytical tablets with final concentrations of membrane protein and radioligand 20 μg/ml and 0.04 nm, respectively.

For data analysis of saturation binding number of pulses per minute is converted into the number of disintegrations per minute, and the concentration of radioligand in nm calculated from the specified manufacturer specific radioactivity.

Data saturation binding can be analyzed using equation (1):

where is the concentration of bound ligand, B max is the maximum concentration of the bound ligand, and K d is the dissociation constant of the ligand.

The level of inhibition (% Inh) can be calculated from equation (2):

The values of IC 50 can be calculated by using common methods using non-linear least squares method.

Analysis of the activation of the MCHR1 receptor:

Receptor melaninconcentrating hormone type 1 (MCHR1) is paired with G-protein receptor that interacts with the heterotrimeric G protein containing Gα i/o subunit. Linking sit MCHR1 receptor leads to the replacement of GDF for GTP on the Gα i/o proteins, coupled with the activated receptor. This activation can be measured by determining the amount of an analog of GTP, γ 35 S associated with membraneassociated receptors. γ 35 S not hydrolyzed in the characteristic of G-protein GTPase activity, but instead forms a stable complextion way, activation of receptors MSN can be measured by determining the amount γ 35 S associated with membranes derived from cells expressing such receptors. The membrane can be separated by filtration or may be bound to the SPA beads (Amersham). Then associated γ 35 S can be measured by determining the amount present 35 S. Thus, inhibition of binding of the sit competing ligand can be determined to reduce γ 35 S associated with membranes in the presence of such competing ligand.

H3-histamine SPA analysis with [ 3 H]-N-α-methylhistamine as radioligand-agonist

Analysis of the binding of H3 can be/has been used to assess the ability of compounds according to the invention to inhibit the binding of [ 3 H]-N-α-methylhistamine with Cho-K1 membranes expressing human H3-histamine receptors (full-H3, the most common brain isoform 445). To determine the effect in percent relative to the total (1% DMSO) and nonspecific binding (10 µm emetica) human H3 membrane (12.5 µg protein per well) and 1.4 nm [ 3 H]-N-α-methylhistamine can be/were incubated with the compound according to the invention in 200 ál 96-hole tablet SPA format for 1.5 hours reproducibility of the analysis allows to construct curves IC 50 according to the results of one measurement. Single-point analysis can be performed in three replications.

Membranes derived from Cho-K1 cells stably expressing human H3-histamine receptors, can be purchased from ACS.

The test compounds of formulas I, IA and/or IB can be a/was a sample dissolved in pure DMSO. Serial dilutions can be used/used DMSO.

Tablets can be a /was a 96-well tablets Unifilter GF/B (Perkin Elmer, 6005177). Measurements on tablets can be conducted/carried out on Perkin Elmer TopCount. For analysis can be used/used data pulses per minute, unless not required/required obtained from the curves of attenuation data disintegrations per minute.

Preparatory work:

1. 1 mg/ml BSA can be added/added to the analytical buffer (AB) on the day of analysis.

2. Number of batteries required for a pool of beads and membranes, can be calculated/counted as “R” - required for 17.1 ml analytical tablet plus 10 ml of excess on PlateMate. So before adding the beads to homogenize the membrane using a transmitter station, the buffer volume can be split/shared between the beads and membranes.

a) PVT-WGA SPA beads: beads (R×9,83 mg/ml) can be resuspendable/resuspendable in the final number 1750 µg per well. Membranes can be added/added no earlier than 15 minutes (see below .b.).

b) Membrane (HH HH3 membranes from Cho cells containing recombinant human H3 receptors, to 11.7 mg/ml): membrane stored/stored at -80°C, can be extracted/removed and defrosted/thawed in a water bath at room temperature; (0,0702 mg/ml×P) mg membranes can be resuspendable/resuspendable in the remaining, not previously used for the beads volume in the final number of 12.5 µg per well and briefly homogenized/homogenized using a transmitter station at a speed of 5.0. The mixture is homogenised membranes can be combined/combined with beads and not earlier than 30 minutes caused/inflicted on the tablet.

3. Compounds of formulas I, IA and/or IB: for single point analysis, 2 μl of 1 mm of the compounds of formula I, IA and/or IB can be caused/inflicted on tablets Optiplate (in triplicate) with a final concentration of 10 μm. (0,909 mm SMA inflicted 2.2 µl). For IC 50 6 μl of the compounds of formula I, IA and/or IB can be placed/put in DMSO in column 1 of the 96-well 500 μl polypropylene plate with U-shaped wells with a maximum final concentration of 10 μm. The control can be used/used emetic (see below).

4. Emetic (for NSS (nonspecific binding) and control): can be cooked/prepared 100 mm solution in DMSO with a final concentration in the analysis of 1 μm (NSS) or 100 nm (IC 50 ).

5. [ 3 H]-N-α-methylhistamine ( 3 H]-NAMH): can be cooked/prepared solution in AB concentration of 14 nm, with a 10-fold dilution to a final concentration of 1.4 nm. Measurements can be conducted/carried out on β-counter at the 5 μl in four replications. If the concentration is/was 12-14,5 nm, the amendments are not required/not required. (IC 50 is used, the final concentration on the Calculation tab of the template ABase.)

Analysis:

4. 20 μl of [ 3 H]-NAMH can be added/added by using Rapid Plate. Analytical tablet can be hermetically closed/sealed closed and incubated/were incubated for 1.5 h at RT shaker at a speed of ~6,5.

5. After this analytical tablet can be spin-on/centrifuged at 1000 rpm./min for 10 minutes.

6. Measurement of radioactivity can be executed/performed by using a TopCount using one of the programs 3H SPA H3 Quench.

Data disintegrations per minute can be parsed/analyzed, if the value of tSIS was less than the value corresponding to 70% of the full interval of the curve of attenuation (tSIS<25%). Otherwise, it can be used/used data pulses per minute. A typical window is/was $ 800-1200 imp./min, 45-70 imp./min for NSS (Z' 0,70-0,90).

Data can be analyzed by calculating the effect in% {average [1 - (sample - NSS tablet)/(Total tablet - NSS tablet)]×100%}, and IC 50 and Ki using the following equation Cheng-Prusoff and template ActivityBase or XLfit.

where Kd represents a value for [ 3 H] ligand (to 0.67 nm).

In this assay, the ligand concentration can be adjusted to 1.4 nm, which is approximately two times greater than average Kd (of 0.67 nm).

IC 50 and mo can be determined by approximation of the data model 205 in XLfit:

y=A+((B-A)/(1+((C/x) ∧ D)).

Analysis of the binding of guanosine-5'-O-(3-[ 35 S]thio)triphosphate [γS]

The analysis of binding γS can be used to study the antagonistic properties of the compounds in Cho cells (cells of the Chinese hamster ovary), transfected with the human H3-histamine receptor (hH3R). The membranes of Cho cells expressing the hH3R (10 μg per well), diluted in analytical buffer γS (20 mm Hepes, 10 mm MgCl 2 , 100 mm NaCl, pH 7.4) and preincubated with saponin (3 μg/ml), GDF (10 μm) and PVT-WGA SPA beads (125 μg per well) (Amersham) for 30 minuts determine the antagonistic activity of (R)-α-methylhistamine (30 nm) is added to 96-well SPA tablet with [ 35 S]γS (0.2 nm) and various concentrations 3R-antagonists. The analysis of binding γS start with adding a mixture of membranes, saponin and GDF and incubation for 90 minutes at room temperature. The amount of bound [ 35 S]γS determined using counter MicroBeta Trilux (Perkin Elmer). The percentage of bound [ 35 S]γS in each sample was calculated relative to the binding in a control sample incubated in the absence of H3-antagonist. For each concentration measurements are performed twice, and for receiving the IC 50 data analyzed by ExcelFit4.

The values of IC 50

The values of IC 50 for the Examples of the compounds shown below in Table 1.

At least one compound according to the present invention has a value of IC 50 of less than about 100 microns. In the following embodiment of the present invention at least one compound of the present invention have activity in at least one of the above tests, characterized by the value of the IC 50 of about 1 nm to about 100 μm. In the following embodiment, at least one compound of the present invention have activity in at least one of the above tests, characterized by the value of the IC 50 of about 2 nm to about 100 nm. In the following embodiment, at least one compound of the present invention have activity in at least one of the above tests, characterized by the value of the IC 50 of about 2 nm to about 50 nm. In one of the embodiments, at least one compound of the present invention have activity in at least one of the above tests, characterized by the value of the IC 50 of less than about 100 nm. In another embodiment, at least one compound of the present invention have activity in at least one of the above tests, characterized by the value of the IC 50 of less than about 50 nm. In another embodiment, at least one compound of the present invention have activity in at least one of the above tests, characterized by the value of the IC 50 of less than about 20 nm.

Table 1 shows the values of IC 50 , which were obtained according to the described above H3-histamine SPA analyses and/or analyses linking γS.

MSG IC 50 (nm)

H3 IC 50 (μm)

Example No.

Hereinafter the invention is described in the following Examples. It should be understood that the Examples are given only for explanation. Based on the above description and Examples, a person skilled in the art can determine the essential characteristics of the invention and, without departing from the essence and scope, can make various changes and modifications to adapt the invention to various uses and conditions. Thus, the invention is not limited to the illustrative examples below, as defined in the Annex of this document by the claims.

As a rule, the compounds of formula 1 can be derived from well-known experts in the field of information and/or using suggested in the following Examples and/or sections of Intermediate compounds. Solvents, temperatures, pressures and other reaction conditions can be readily selected by the person skilled in the art. Source materials are commercially available and/or can easily be obtained by the person skilled in the art. In obtaining the compounds can be used combinatorial methods, for example, if the intermediate compounds have groups that are suitable for these methods.

This document uses the following abbreviations: head: chemical ionization at atmospheric pressure; aq.: water; DMA: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; DMF: N,N-dimethylformamide; h: hour(s); RP HPLC: reverse phase high-performance liquid chromatography; K 2 CO 3 : potassium carbonate; LC: liquid chromatography; MgSO 4 : magnesium sulfate; min: minutes; MS: mass spectrum; NaCl: sodium chloride; NaHCO 3 : sodium bicarbonate; Na 2 SO 4 : sodium sulfate; Cs 2 CO 3 : cesium carbonate; NH 3 : ammonium; NMR: nuclear magnetic resonance; d: doublet; dd: doublet of doublets; t, triplet; MHz: megahertz; us.: rich; TFU: triperoxonane acid.

Conditions of HPLC/MS: column Acquity UPLC Column Acquity UPLC VEINS C18, 1.7 mm, and 2.1×100 mm (Waters). The gradient of 5-95% acetonitrile in ammonium carbonate buffer at rn (40 mm NH 3 +6.5 mm H 2 CO 3 ) for 5.8 minutes at 60°C. the Flow of 0.8 ml/min

Chemical name according to IUPAC obtained using software company CambridgeSoft Corporation, Cambridge, MA 02140, USA.

Example 1

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-3-chlorophenoxy)-azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

1A. 4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-3-chlorophenol

To a solution of 2-chloro-4-hydroxy-benzaldehyde (0.50 g, 3,19 mmol) in dichloromethane (35 ml) was added hemoccult 2-oxa-6-azaspiro[3.3]heptane, method of production, see, for example, in Angew. Chem. Int. Ed., 47, 4512-4515 (2008), (0.55 g, a 3.83 mmol). After stirring for 20 min was added triacetoxyborohydride sodium (1.01 g, 4,79 mmol) and the reaction mixture primatively during the night. The mixture was diluted with dichloromethane and transferred into a separating funnel. Added water and the separated organic phase. The aqueous phase was saturated K 2 CO 3 and then was extracted three times with dichloromethane. The combined organic layers were dried (phase separator) and concentrated under vacuum. Received 0.65 g (85%) of compound 1A in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 3.51 (s, 4H), 3.62 (s, 2H), 4.74 (s, 4H), 6.55 (d, 1H), 6.71 (d, 1H), 7.09 (d, 1H), MS (head+) m/z 240 [M+H] + .

1 V. (3-Hydroxyazetidine-1-yl)(5-Phenyl-1.3.4-oxadiazol-2-yl)methanon

To a clear solution of ethyl-5-phenyl-1,3,4-oxadiazol-2-carboxylate (0.40 g, to 1.83 mmol) in anhydrous methanol (5 ml) was added sodium cyanide (18 mg, of 0.37 mmol). A solution of 3-hydroxyazetidine hydrochloride (0.45 g, 2,84 mmol) and triethylamine (and 0.40 ml, 2,84 mmol) in methanol (5 ml) was added at ambient temperature. After stirring for 20 min was added water (20 ml) and dichloromethane (30 ml). The layers were separated, and the aqueous phase was twice extracted with dichloromethane (30 ml). The combined organic layers were evaporated. Then the crude product was treated with toluene (5 ml), was filtered, washed with toluene (5 ml) and dried under vacuum. Received 0.40 g (90%) of compound 1 In the form of a solid substance. 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.84 (dd, 1H), 4.31 (m, 2H), 4.56 (m, 1H), 4.79 (dd, 1H), 5.87 (d, 1H), 7.64 (m, 3H), 8.05 (d, 2H), MS (head+) m/z 246 [M+H] + .

1C. 1-(5-Phenyl-1.3.4-oxadiazol-2-carbonyl)azetidin-3-elmersolver

A suspension of compound 1B (2.00 g, 8.16 mmol) in dichloromethane (200 ml) was cooled in an ice bath. Was added triethylamine(1,58 ml, 11,42 mmol), and then methanesulfonanilide of 0.85 ml, br11.01 mmol). After the reaction mixture was removed from the ice bath. The mixture was stirred overnight and then transferred into a separating funnel. The mixture was washed with water and then aqueous solution of NaHCO 3 . The organic solution was dried (phase separator) and evaporated. Got 2.58 g (98%) of compound 1C in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.64 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.40 (m, 1H), 7.54 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (head+) m/z 324 [M+H] + .

1.(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-3-chlorophenoxy)-azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

Compound 1A (0,30 g, 1.25 mmol) was dissolved in anhydrous DMF (10 ml), was added compound 1C (0,61 g, 1.88 mmol), and then Cs 2 CO 3 (0,82 g of 2.50 mmol). The reaction mixture was stirred at 90°C for 24 hours The mixture was filtered and about half of the volume of the solvent evaporated. Product was purified preparative RP HPLC (gradient: 15-55% acetonitrile for 30 min, and 0.2% ammonium buffer). Pure fractions were combined and concentrated. Added dichloromethane and the solution was dried (phase separator) and concentrated under vacuum. Obtained 0.26 g (44.5%) of compound 1 in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 3.57 (s, 4H), 3.73 (s,2H), 4.33 (d, 1H), 4.65 (dd, 1H), 4.73 (m, 1H), 4.77 (s, 4H), 5.06 (m, 1H), 5.14 (dd, 1H), 6.70 (d, 1H), 6.80 (s, 1H), 7.37 (m, 1H), 7.54 (m, 2H), 7.59 (m, 1H), 8.16 (d, 2H), MC (head+) m/z 467 [M+H] + . The LC purity: 96%.

2A. 4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)Phenol

Hemoccult 2-oxa-6-azaspiro[3.3]heptane, method of production, see, for example, in Angew. Chem. Int. Ed., 47, 4512-4515 (2008), (2.0 g, a 13.9 mmol) and 4-hydroxybenzaldehyde (1.7 g, a 13.9 mmol) was mixed with dichloromethane. The suspension was stirred at room temperature for 30 min and then in small portions was added triacetoxyborohydride sodium (3.8 g, 18.0 mmol). The mixture was stirred at room temperature for 18 h, then was diluted with dichloromethane and transferred into a separating funnel. The mixture was extracted with water and the aqueous phase in small portions was added K 2 CO 3 to saturation. The solution was extracted several times with dichloromethane. The combined organic solutions were dried over Na 2 SO 4 and the solvent is then removed by evaporation. Got 2.2 g (77%) of compound 2A in the form of an oily liquid. 1 H NMR (500 MHz, CDCl 3 ): δ 3.41 (s, 4H), 3.48 (s, 2H), 4.72 (s, 4H), 6.64 (d, 2H), 7.04 (d, 2H), MC (head+) m/z 206 [M+H] + .

2B. (5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)(3-hydroxyazetidine-1-yl)methanon

To a suspension of ethyl-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-carboxylate, method of production, see, for example, WO 97/05131, (0,53 g, 2.10 mmol) in anhydrous methanol (10 ml) was added sodium cyanide (20 mg, 0.42 mmol). A solution of 3-hydroxyazetidine hydrochloride (0,38 g, 2,78 mmol) and triethylamine (of 0.39 ml, 2,78 mmol) in methanol (10 ml) was added at ambient temperature. The mixture was stirred for 2.5 hours was Added water (30 ml)and the mixture was extracted with dichloromethane. The organic layers were combined and evaporated to yield a white solid, which was treated with toluene (5 ml) and then filtered. The product was washed with toluene (5 ml) and then dried under vacuum. Received 0.52 g (90%) of compound 2 In the form of a solid substance. 1 H NMR (400 MHz, CD 3 OD): δ 4.00 (dd, 1H), 4.46 (dd, 2H), 4.70 (m, 1H), 4.93 (dd, 1H), 7.62 (d, 2H), 8.11 (d, 2H), MS (head+) m/z 280 [M+H] + .

2C. 1-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-carbonyl)azetidin-3-elmersolver

A suspension of compound 2B (1,38 g, 2,47 mmol) in dichloromethane (50 ml), which is in the form of impurities contained approximately 50% methyl-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-carboxylate, cooled in an ice bath. Was added triethylamine (0.51 ml, 3,70 mmol), and then methanesulfonanilide (0,27 ml of 3.45 mmol). After the reaction mixture was removed from the ice bath. The mixture was stirred for 7 hours, the Reaction mixture was transferred into a separating funnel and washed with water, and then aqueous solution of NaHCO 3 . The organic solution was dried (phase separator) and evaporated. Added dichloromethane (50 ml) and diethyl ether (200 ml), and the solid product was separated by filtration. The solid is washed twice with diethyl ether and then dried under vacuum. The product was purified using column flash chromatography, first elwira dichloromethane and then a mixture of dichloromethane and methanol containing 2 M NH 3 (20:1). Got to 0.66 g (75%) of compound 2C in the form of solids. 1 H NMR (500 MHz, Dl 3 ): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.65 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.41 (m, 1H), 7.53 (d, 2H), 8.10 (d, 2H), MC (head+) m/z 358 [M+H] + .

2. (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methanon

Specified in the title compound was obtained in a manner analogous to the one described in Example 1, using as starting compounds compounds 2A and 2C. Received 70 mg (12%) of compound 2 in the form of an oily liquid. Upon standing at room temperature oily liquid gradually hardened. 1 H NMR (500 MHz, CDCl 3 ): δ 3.41 (s, 4H), 3.53 (s, 2H), 4.34 (d, 1H), 4.65 (m, 1H), 4.74 (s, 5H), 5.09 (m, 1H), 5.14 (m, 1H), 6.73 (d, 2H), 7.21 (d, 2H), 7.52 (d, 2H), 8.10 (d, 2H), MC (head+) m/z 467 [M+H] + , LC Purity: 92%.

For cultivation of suspension weighed 10.5 mg of the compound of Example 2, was placed in a test tube and was added ethanol (168 μl). The suspension was shaken for 7 days at ambient temperature and then using a small spatula was selected crystals. The crystals were dried in a fume hood for one hour and then analyzed using DSC (differential scanning calorimetry). The sample was weighed in an aluminum dish with a perforated lid and heated from 0°C to 300°C at 5°C/min and a modulation amplitude of ±0,6°C every 45 seconds. The apparatus was purged with a stream of nitrogen at 50 ml/min; melting point 128±5°C and 138±5°C.

Example 3

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

3A. tert-Butyl 3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)-azetidin-1-carboxylate

Compound 2A (0,77 g, 3.75 mmol) was dissolved in anhydrous DMF (20 ml) was added Cs 2 CO 3 (2,44 g, 7,50 mmol). The reaction mixture was stirred at room temperature for 10 min and then was added tert-butyl 3-(methylsulfonylamino)azetidin-1-carboxylate (1.88 g, 7,50 mmol). Then the reaction mixture was stirred at 90°C for 24 hours The mixture was filtered, and the solvent evaporated. The residue was dissolved in DMSO (6 ml) and was purified preparative RP HPLC (gradient: 15-55% acetonitrile for 30 min, and 0.2% ammonium buffer). Pure fractions were combined and concentrated. Added dichloromethane, and the solution was dried (phase separator) and concentrated. Got to 1.00 g (74%) of compound 3A in the form of an oily liquid which hardened on standing at room temperature. 1 H NMR (500 MHz, CDCl 3 ): δ 1.45 (s, 9H), 3.34 (s, 4H), 3.46 (s, 2H), 3.99 (dd, 2H), 4.28 (dd, 2H), 4.73 (s, 4H), 4.84 (m, 1H), 6.68 (d, 2H), 7.15 (d, 2H), MS (head+) m/z 361 [M+H] + .

3V. 6-(4-(Azetidin-3-yloxy)benzyl)-2-oxa-6-azaspiro[3.3]heptane

Compound 3A (0.19 g, 0.52 mmol) was dissolved in dichloromethane (20 ml) and added TFU (1,95 ml, 26 mmol). The reaction mixture was stirred at room temperature for two hours. Added portions K 2 CO 3 (5 g)and the mixture was stirred for 20 minutes was Added a saturated solution of K 2 CO 3 (aq.), and the mixture was transferred into a separating funnel. The layers were separated and then the aqueous layer was extracted several times with dichloromethane. The combined organic solutions were dried (phase separator) and evaporated. Received 128 mg (94%) of compound 3B in the form of an oily liquid. 1 H NMR (500 MHz, CDCl 3 ): δ 3.34 (s, 4H), 3.45 (s, 2H), 3.80 (m, 2H), 3.92 (m, 2H), 4.72 (s, 4H), 4.98 (m, 1H), 6.69 (d, 2H), 7.13 (d, 2H), MS (head+) m/z 261 [M+H] + .

3. (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

Compound 3B (0,30 g, 1.15 mmol) was mixed with ethyl-5-phenyl-1,3,4-oxadiazol-2-carboxylate (0,30 g, 1.38 mmol) in vitro for microwave processing and corked. The solid mixture is melted in a preheated oil bath and stirred at 120°C for 4 h was Added DMSO (2 ml)and the mixture was filtered, and then purified preparative RP HPLC (gradient: 15-55% acetonitrile over 25 min, and 0.2% ammonium buffer). Pure fractions were combined and then evaporated. Added dichloromethane, and the solution was dried (phase separator) and concentrated under vacuum. Got 0,30 g (61%) of compound 3 as a colorless oily liquid. Upon standing at room temperature oily liquid gradually hardened. 1 H NMR (500 MHz, CDCl 3 ): δ 3.38 (s, 4H), 3.49 (s, 2H), 4.31 (d, 1H), 4.65 (m, 1H), 4.73 (s, 5H), 5.06 (m, 1H), 5.11 (m, 1H), 6.72 (d, 2H), 7.19 (d, 2H), 7.47-7.63 (,), 8.14 (d, 2H), MS (head+) m/z 433 [M+H] + . . The LC purity: 97%.

Example 4

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanon

4A. (3-Hydroxyazetidine-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanon

To a suspension of ethyl-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-carboxylate, see, for example, Journal fuer Praktische Chemie, 327, 109-116 (1985), (0.50 g, a 2.01 mmol) in anhydrous methanol (10 ml) was added sodium cyanide (20 mg, 0.40 mmol). Solution was added 3-hydroxyazetidine hydrochloride (0.26 g, 2,42 mmol) in methanol (2 ml)and then triethylamine (0,34 ml, 2,42 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature overnight. Was added water (20 ml) and dichloromethane (30 ml). Some amount of the desired product was precipitated, and was filtered. After filtering, the two layers were separated, and the aqueous phase was twice extracted with dichloromethane (30 ml). The combined organic layers were dried over MgSO 4 , and the solution was evaporated. Just got 0,43 g (77%) of compound 4A in the form of solids. 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.82 (dd, 1H), 3.84 (s, 3H), 4.30 (m, 2H), 4.55 (m, 1H), 4.77 (dd, 1H), 5.85 (d, 1H), 7.16 (d, 2H), 7.98 (d, 2H), MS (head+) m/z 276 [M+H] + .

4B. 1-(5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-carbonyl)azetidin-3-elmersolver

A suspension of compound 4A (of 5.45 g of 19.8 mmol) in dichloromethane (100 ml) was cooled in an ice bath. Was added triethylamine (4.4 ml, and 31.7 mmol), and then methanesulfonanilide (2.3 ml, 29.7 mmol). After the reaction mixture was removed from the ice bath. The mixture was stirred for 7 hours, the Reaction mixture was transferred into a separating funnel and washed with water, and then aqueous solution of NaHCO 3 (us.). The organic solution was dried (phase separator) and evaporated. Added dichloromethane (50 ml) and diethyl ether (200 ml), the solid product was separated by filtration. The product is washed twice with diethyl ether and then dried under vacuum. Got to 5.03 g (72%) of compound 4B in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 3.13 (s, 3H), 3.90 (s, 3H), 4.42 (dd, 1H), 4.64 (dd, 1H), 4.86 (dd, 1H), 5.11 (dd, 1H), 5.40 (m, 1H), 7.02 (d, 2H), 8.09 (d, 2H), MS (head+) m/z 354 [M+H] + .

4. 3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-eocde)-1,3,4-oxadiazol-2-yl)methanon

Compound 2A (0,41 g, 2.00 mmol) was dissolved in anhydrous DMF (10 ml), was added compound 4B (0,92 g, 2,60 mmol), and then Cs 2 CO 3 (of 1.30 g, 4.00 mmol). The reaction mixture was stirred at 90°C for 24 hours The mixture was evaporated almost to dryness and added dimethyl sulfoxide (10 ml). The mixture was filtered and purified preparative RP HPLC (gradient: 15-55% acetonitrile for 30 min, and 0.2% ammonium buffer). Pure fractions were combined and concentrated. Added dichloromethane, the solution was dried (phase separator) and concentrated under vacuum, obtaining 0.26 g of pale yellow solid. Then the product was purified flash chromatography, starting with tO, and then elwira product dichloromethane/methanol containing 2 M NH 3 (20:1), was Obtained 0.20 g (22%) of the desired product as a solid. 1 H NMR (500 MHz, CDCl 3 ): δ 3.35 (s, 4H), 3.47 (s, 2H), 3.87 (s, 3H), 4.30 (d, 1H), 4.62 (dd, 1H), 4.72 (s, 5H), 5.04 (m, 1H), 5.09 (dd, 1H), 6.71 (d, 2H), 7.00 (d, 2H), 7.17 (d, 2H), 8.07 (d, 2H), MC (head+) m/z 463 [M+H] + , LC Purity: 95%.

For cultivation of suspension weighed 15 mg of the compound of Example 4 was placed in a test tube and was added ethanol (2400 ml). The suspension was shaken for 7 days at ambient temperature and then using a small spatula was selected crystals. The crystals were dried in a fume hood for one hour and then analyzed using DSC (differential scanning calorimetry). The sample was weighed in an aluminum dish with a perforated lid and heated from 0°C to 300°C at 5°C/min and a modulation amplitude of ±0,6°C every 45 seconds. The apparatus was purged with a stream of nitrogen at 50 ml/min; melting point 152±5°C.

Example 5

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenylthio)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

(4-Mercaptophenyl)methanol (2.38 g, 17,0 mmol) and compound 1C (5,00 g of 15.5 mmol) were mixed in DMF (80 ml). Added Cs 2 CO 3 (6,05 g, 18,56 mmol). The mixture was stirred at 90°C. overnight and then cooled to room temperature. Added ethyl acetate (150 ml)and the mixture was washed with water (50 ml). The aqueous layer was extracted with ethyl acetate (100 ml). The organic phases were combined, dried (MgSdi) and evaporated to dryness. The residue was purified column chromatography, elwira with ethyl acetate/heptane (20:80, 40:60, and then 60:40). Received 3.5 g (61%) of compound 5A in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 4.19 (m, 2H), 4.64 (m, 2H), 4.69 (s, 2H), 5.10 (m, 1H), 7.34 (m, 4H), 7.53 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MC (head+) m/z 368 [M-H] + .

5V. (3-(4-(Chloromethyl)phenylthio)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

Compound 5A (3,48 g, 9.47 mmol) was dissolved in dichloromethane (150 ml) and the mixture was cooled in an ice bath. Thionyl chloride (0.76 to ml, 10.4 mmol) was added dropwise with stirring. The mixture was removed from the cooling bath for 30 minutes, was stirred for 2.5 h, and then evaporated to dryness. The residue was purified column chromatography, elwira dichloromethane. Received of 2.93 g (80%) of compound 5B in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 4.22 (m, 2H), 4.57 (s, 2H), 4.65 (m, 2H), 5.14 (m, 1H), 7.29 (d, 2H), 7.36 (d, 2H), 7.53 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (head+) m/z 386 [M+H] + .

5. (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenylthio)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

Hemoccult 2-oxa-6-azaspiro[3.3]heptane, method of production, see, for example, in Angew. Chem. Int. Ed., 47, 4512-4515 (2008), (0.18 g, 1,24 mmol) and compound 5B (0.24 g, of 0.62 mmol) were mixed in DMF (5 ml). Was added N-ethyl-N-isopropylparaben-2-amine (0,36 ml, 2.05 mmol). The mixture was stirred at room temperature for 1.5 h and then was added methanol (5 ml). The mixture was stirred for 3 days at room temperature and then was evaporated to dryness. The residue was purified preparative RP HPLC using a gradient 20-95% acetonitrile in water, acetonitrile, ammonium (95/5/0,2) a buffer at 25 minutae product was purified column chromatography, elwira ammonia in methanol (2M)/dichloromethane (0.5 to 2%). Received 59 mg (21%) of the desired product as a solid. 1 H NMR (500 MHz, CDCl 3 ): δ 3.36 (s, 4H), 3.50 (s, 2H), 4.17 (m, 2H), 4.61 (m, 2H), 4.72 (s, 4H), 5.08 (m, 1H), 7.20 (d, 2H), 7.26 (d, 2H), 7.50 (t, 2H), 7.57 (t, 1H), 8.13 (d, 2H), MS (head+) m/z 449 [M+H] + . The LC purity: 93%.

Example 6

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-forfinal)-1,3,4-oxadiazol-2-yl)methanon

To a solution of ethyl-5-(4-forfinal)-1,3,4-oxadiazole-2-carboxylate (55 mg, 0.23 mmol) in MeOH (3 ml) was added a solution of compound 3 (55 mg, 0.21 mmol) in MeOH (3 ml). Was added sodium cyanide (4 mg)and the reaction mixture was stirred at room temperature for 3 hours the Mixture was transferred into a separating funnel and diluted DHM (50 ml). The organic layer was washed with an aqueous solution of Na 2 CO 3 , dried (phase separator) and then evaporated. The crude product was purified column flash chromatography, first elwira with ethyl acetate, and then elwira mixture DHM and MeOH, which contained 2 M NH 3 (20:1). Received 75 mg (79%) of compound 6 in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 3.37 (s, 4H), 3.48 (s, 2H), 4.32 (dd, 1H), 4.64 (dd, 1H), 4.75 (s, 5H), 5.06 (m, 1H), 5.10 (m, 1H), 6.72 (d, 2H), 7.22 (m, 4H), 8.17 (m, 2H), MC (head+) m/z 451 [M+H] + . The LC purity: 92%.

For cultivation of suspension weighed 2.7 mg of the compound of Example 6, was placed in a test tube was added in ethanol (43 ml). The suspension was shaken for 7 days at ambient temperature and then using a small spatula was selected crystals. The crystals were dried in a fume hood for one hour and then analyzed using DSC (differential scanning calorimetry). The sample was weighed in an aluminum dish with a perforated lid and heated from 0°C to 300°C at 5°C/min and a modulation amplitude of ±0,6°C every 45 seconds. The apparatus was purged with a stream of nitrogen at 50 ml/min; melting point 117±5°C.

Example 7

(3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-(deformedarse)phenyl)-1,3,4-oxadiazol-2-yl)methanon

7A. Ethyl-5-(4-(deformedarse)phenyl)-1,3,4-oxadiazol-2-carboxylate

Hydrazide 4-diplomatchisinau acid (2.0 g, 9.9 mmol) was mixed with DHM (40 ml) and triethylamine (1.80 g, 17.8 mmol). The mixture was cooled in an ice bath and then added ETHYLACETYLENE (1.42 g, 10.4 mmol) for 10 minutes The reaction mixture was stirred at room temperature for 2 h and then washed with saturated aqueous NaHCO 3 . The organic solution was dried (phase separator) and then concentrated. The residue was dissolved in toluene (40 ml) and then was added pyridine (0.96 g, 12.1 mmol). Thionyl chloride (3.6 g, 30.2 mmol) was added dropwise over 5 min. and the Mixture was boiled under reflux for 2.5 hours the Solvent was removed by evaporation, and the residue was dissolved in DHM (60 ml). The solution was twice washed in an aqueous solution of NaHCO 3 , and then water. The organic phase was dried over MgSO 4 and the solvent was removed by evaporation. Got 2.50 g (73%) of compound 7A in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 1.48 (t, 3H), 4.56 (m, 2H), 6.64 (t, 1H), 7.28 (d, 2H), 8.19(d, 2H).

7. (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-(deformedarse)phenyl)-1,3,4-oxadiazol-2-yl)methanon

Using the method similar to that described in Example 6, but using as starting compounds compound 7A (60 mg, 0.21 mmol) and 3B (50 mg, 0,19 mmol), obtained 65 mg (68%) of compound 7 in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 3.0-4.2 (m, 6H), 4.34 (m, 1H), 4.66 (m, 1H), 4.76 (m, 5H), 5.10 (m, 2H), 6.62 (t, 1H), 6.76 (m, 2H), 7.27 (m, 4H), 8,18 (d, 2H), MS (head+) m/z 499 [M+H] + , LC Purity: 96%.

Example 8

8A. 4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-2-chlorophenol

Using the method similar to that described in Example 2A, but using as starting substances hemoccult 2-oxa-6-azaspiro[3.3]heptane (150 mg, 0.79, which mmol) and 3-chloro-4-hydroxybenzaldehyde (160 mg, of 1.02 mmol), received 160 mg (84%) of compound 8A in the form of an oily liquid. 1 H NMR (500 MHz, CD 3 D): δ 3.43 (s, 4H), 3.48 (s, 2H), 4.72 (s, 4H), 6.86 (d, 1H), 7.03 (d, 1H), 7.22(s, 1H).

8B. 1-(5-Phenyl-1,3,4-oxadiazol-2-carbonyl)azetidin-3-yl-4-methylbenzenesulfonate

Using the method similar to that described in Example 2C, but using as starting compounds, the compound 1B (250 mg, of 1.02 mmol) and 4-methylbenzol-1-sulphonylchloride (250 mg, 1,31 mmol)were 365 mg (90%) of compound 8B in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 2.49 (s, 3H), 4.24 (dd, 1H), 4.47 (dd, 1H), 4.72 (dd, 1H), 4.98 (dd, 1H), 5.22 (m, 1H), 7.41 (d, 2H), 7.53 (t, 2H), 7.59 (t, 1H), 7.82 (d, 2H), 8.14 (d, 2H).

8. 3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-2-chlorophenoxy)-azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

Using the method similar to that described in Example 2, but using as the source substances of compound 8A (130 mg, 0.54 mmol) and 8B (220 mg, 0.55 mmol), was obtained 130 mg (51%) of compound 8 in the form of a resin. 1 H NMR (500 MHz, CD 3 OD): δ 3.38 (s, 4H), 3.48 (s, 2H), 4.25 (dd, 1H), 4.6-4.8 (m, 6H), 5.15 (m, 2H), 6.78 (d, 1H), 7.15 (d, 1H), 7.32 (s, 1H), 7.56 (t, 2H), 7.61 (t, 1H), 8.09 (d, 2H), MS (head+) m/z 467 [M+H] + . The LC purity: 91%.

Example 9

(3-(4-((3,3-Dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanon

9A. 4-(1-(5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-carbonyl)azetidin-3-yloxy)benzaldehyde

4-Hydroxybenzaldehyde (1.10 g, 9,17 mmol), cesium carbonate (3,49 g, 10,70 mmol) and compound 4B (2.70 g, of 7.64 mmol) was mixed with DMF (80 ml). The mixture was stirred at 110°C for 18 h, then cooled to room temperature. The solid was filtered, and the filtrate was evaporated. The residue was treated with methanol, and the formed solid substance was separated by filtration. Drying under vacuum was obtained 1.8 g (62%) of compound 9A in the form of a beige solid. 1 H NMR (500 MHz, DMSO-d 6 ): δ 3.85 (s, 3H), 4.13 (dd, 1H), 4.57 (dd, 1H), 4.65 (dd, 1H), 5.12 (dd, 1H), 5.29 (m, 1H), 7.10 (d, 2H), 7.16 (d, 2H), 7.90 (d, 2H), 8.00 (d, 2H), 9.90 (s, 1H), MS (head+) m/z 380 [M+H] + .

9. (3-(4-((3,3-Dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)phenoxy)-azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanon

To a solution of compound 9A (217 mg, or 0.57 mmol) in DHM (10 ml) added 3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane 2,2,2-triptorelin (179 mg, of 0.74 mmol) and triethylamine (of 0.20 ml, 1.44 mmol). Added triacetoxyborohydride sodium (140 mg, 0.66 mmol)and the reaction mixture was stirred at room temperature for 3 days. The mixture was washed with a saturated aqueous solution of NaHCO 3 . The organic layer was filtered through a phase separator and then was evaporated. The product was purified by preparative chromatography on a column (Kromasil C8, using a mixture of acetonitrile and an aqueous solution of acetic acid (0.2 percent) as the mobile phase. Fractions of product were combined, and most of the acetonitrile was removed by evaporation. The aqueous residue was dried by sublimation. Got 165 mg (59%) of compound (9) in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 1.24 (s, 6N), 3.15 (d, 2H), 3.59 (s, 2H), 3.69 (d, 2H), 3.89 (s, 3H), 4.17 (s, 2H), 4.33 (m, 1H), 4.63 (m, 1H), 4.74 (m, 1H), 5.06-5.12 (m, 2H), 6.73 (d, 2H), 7.23 (d, 2H), 7.27 (d, 2H), 8.10 (d, 2H), MC (head+) m/z 491 [M+H] + . The LC purity: 95%.

Example 10

(3-(2-Chloro-4-((3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

10A. 3-Chloro-4-(1-(5-phenyl-1,3,4-oxadiazol-2-carbonyl)azetidin-3-yloxy)benzaldehyde

Using the method similar to that described in Example 9, but using as starting compounds compound 1C (500 mg, 1.55 mmol) and 3-chloro-4-hydroxybenzaldehyde (250 mg, to 1.60 mmol)were 205 mg (34%) of compound 10A in the form of solids. 1 H NMR (500 MHz, CD 3 OD): δ 4.33 (m, 1H), 4.6-4.9 (m, 2H), 5.23 (m, 1H), 5.36 (m, 1H), 7.07 (d, 1H), 7.5-7.7 (m, 3H), 7.8-9.0 (m, 4H), 9.86 (s, 1H).

10. (3-(2-Chloro-4-((3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanon

Using the method similar to that described in Example 9, but using as starting compounds 3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-2,2,2-triptorelin (125 mg, 0.52 mmol) and compound 10A (100 mg, 0.26 mmol)were 95 mg (74%) of compound 10 in the form of solids. 1 H NMR (500 MHz, CDCl 3 ): δ 1.24 (s, 6H), 3.11 (d, 2H), 3.51 (s, 2H), 3.62 (d, 2H), 4.17 (s, 2H), 4.41 (m, 1H), 4.66 (m, 1H), 4.82 (m, 1H), 5.1-5.2 (m, 2H), 6.60 (d, 1H), 7.13 (d, 1H), 7.35 (s, 1H), 7.4-7.7 (m, 3H), 8.15 (d, 2H), MS (head+) m/z 495 [M+H] + . The LC purity: 97%.

1. The compound of formula I

or its pharmaceutically acceptable salt, where R 1 represents H, fluorescent-, chloro - or C 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent; And a represents O or S; R 2 and R 3 independently represent H or chloro; provided that R 2 and R 3 are not in metaprogram relative to each other; R 4 and R 5 independently represent H or C 1-4 alkyl group; and X and Y independently represent O or CH 2 , provided that X and Y are different.

2. The compound according to claim 1 of formula IA

or its pharmaceutically acceptable salt, where R 1 represents H, fluorescent-, chloro - or C 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent; And a represents O or S; and R 2 and R 3 independently represent H or chloro; provided that R 2 and R 3 are not in metaprogram relative to each other.

4. The compound according to claim 1 of the formula IC

or its pharmaceutically acceptable salt, where R 1 represents H, chloro - or C 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent; And a represents O or S; and R 3 represents H or chloro.

5. The compound according to claim 1 of the formula ID

or its pharmaceutically acceptable salt, where R a and R b independently represent H or C 1-4 alkyl group; R 1 represents H, chloro - or C 1-2 alkoxygroup, possibly substituted by one or more than one group of fluorescent; And represents O or S; and R 3 represents H or chloro.

6. The compound according to claim 1, where a represents O.

7. The compound according to claim 1, where a represents S.

8. The compound according to claim 1, selected from the group consisting of: (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-3-chlorophenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenylthio)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-forfinal)-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-(deformedarse)phenyl)-1,3,4-oxadiazol-2-yl)methanone; (3-(4-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)-2-chlorophenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone; (3-(4-((3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)phenoxy)-azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone; and (3-(2-chloro-4-((3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone; or its pharmaceutically acceptable salt.

9. Pharmaceutical composition having antagonistic activity against receptor melaninconcentrating hormone type 1 (MSN) and histamine receptor type 3 (H3), containing a therapeutically effective amount of a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier and/or diluent.

10. Method for the treatment or prevention of a disease or condition wherein a beneficial receptor antagonism MSN, including the introduction of a warm-blooded animal in need of such treatment or prevention, a therapeutically effective amount of a compound according to any one of claims 1 to 8.

11. The method according to claim 10, where the disease or condition selected from anxiety, obesity and depression.

12. The method according to claim 11, where the disease or condition is a obesity.

13. The use of compounds according to any one of claims 1 to 8 for the treatment or prevention of a disease or condition wherein a beneficial antagonism H3-receptor.

14. The use of compounds according to item 13, where the disease or condition selected from cognitive deficit in schizophrenia, narcolepsy, obesity, attention deficit disorder and hyperactivity, pain and Alzheimer's disease.