2-aza-bicyclo[3,3,0]octane derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

 

The invention relates to new derivatives of 2-Aza-bicyclo[3.3.0]octane of formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including methods of making the compounds, compositions containing one or more compound of formula (I), and in particular, their use as antagonists of orexin receptor.

Orexin (orexin or OH-and orexin In or OH -) are new neuropeptides, opened in 1998, two research groups. Orexin And is a peptide consisting of 33 amino acids, and orexin is a peptide consisting of 28 amino acids (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexin are produced in separate neurons of the lateral hypothalamus and associated with G-protein-coupled receptors (OX1and OX2receptors). Orexin-1 receptor (OX1is selective in relation to OH -, and orexin-2 receptor (OH2able to connect with OH, AND with OH-Century it Was found that orexin stimulate food intake in rats, which suggests a physiological role of these peptides as mediators in the Central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). On the other hand, it was also noted that orexin regulate States of sleep and waking, and it potentially opens new therapeutic approaches to narcolepsy, as well as insomnia and other sleep disorders (Chemelli R. et al., Cell, 1999, 98, 437-451).

Orexin receptors are in the brain of mammals and, as we know from the literature that may have involvement in numerous pathologies.

The present invention provides derivatives of 2-Aza-bicyclo[3.3.0]octane, which ones are the antagonists orexin receptors person. These compounds, in particular, can potentially be used in the treatment of disorders associated with eating, drinking, sleep disorders, or cognitive disorders in psychiatric and neurological diseases.

Still, there are several low molecular weight compounds exhibiting potential antagonism or specifically in relation to OX1or OX2or in respect of both receptors at the same time. Peptide derivatives that are used as antagonists of orexin receptor disclosed in the publication WO 01/096302.

The present invention first described derivatives of 2-Aza-bicyclo[3.3.0]octane as antagonists of orexin receptor.

i) the First aspect of the present invention relates to the compound of formula (I) with stereogenic centers (1S,3S,5S)-configuration

,

where

And represents aryl or heterocyclyl, and the aryl or heterocyclyl are unsubstituted Il is independently of each other mono - or disubstituted, when the substituents independently of one another selected from the group including1-4alkyl, C3-6cycloalkyl,2-6quinil, C1-4alkoxygroup, NR2R3, halogen and unsubstituted or independently of each other mono - or disubstituted phenyl, where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, fluorine and chlorine;

In represents aryl or heterocyclyl group, where the aryl or heterocyclyl are unsubstituted or independently of each other mono-, di - or tizamidine, while the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, NR2R3, NHC(O)CH3and halogen;

R1represents aryl or heterocyclyl, where the aryl or heterocyclyl are unsubstituted or independently of each other mono-, di - or tizamidine, while the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, halogen, trifluoromethyl and NR2R3; or R1represents a 2,3-dihydrobenzofuranyl or 2,dihydrobenzo[1,4]dioxinlike group, which are unsubstituted or independently of each other mono - or disubstituted With1-4the alkyl, C1-4alkoxygroup and halogen;

R2 represents hydrogen or C1-4alkyl;

R3represents hydrogen or C1-4alkyl.

Also the invention includes compounds of formula (I) and their pharmaceutically acceptable salts.

The term "halogen" means fluorine, chlorine or bromine, preferably fluorine or chlorine.

The term "C1-4alkyl", alone or in combination with other groups, means a linear or branched alkyl group containing from 1 to 4 carbon atoms. Examples1-4alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Preferred are methyl and ethyl. Most preferred is methyl.

The term "C2-6quinil", alone or in combination with other groups, means a linear or branched alkylamino group containing from 2 to 6 carbon atoms. Examples1-4etkinlik groups are ethinyl, 1-PROPYNYL, 1-butynyl, 3-methyl-1-butynyl, 1-pentenyl, 3,3-dimethyl-1-butenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl or 1-hexenyl.

The term "C3-6cycloalkyl", alone or in combination with other groups, means cycloalkyl group containing from 3 to 6 carbon atoms. Examples3-6cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. It is preferable to cyclopropyl.

The term "C1-4alcox the group", alone or in combination with other groups, means a group of the formula C1-4alkyl-O-, in which the term "C1-4alkyl" has the previously described meaning, such as a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan or tert-butoxypropan. Preferred are a methoxy group and ethoxypropan. Most preferred is a methoxy group.

The term "aryl", alone or in combination with other groups, means a phenyl or naftalina group, preferably phenyl group. The aryl group can be unsubstituted or independently mono-, di - or tizamidine, while the substituents independently of one another selected from the group including1-4alkyl, C3-6cycloalkyl,2-6quinil, C1-4alkoxygroup, trifluoromethyl, NR2R3, NHC(O)CH3, halogen and unsubstituted or independently of each other mono - or disubstituted phenyl, where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, fluorine and chlorine.

In the case where "A" represents "aryl"the term preferably means the above-mentioned group which is unsubstituted or independently of each other mono - or disubstituted, the substituents independently of one another selected from the group, Lucaya 1-4alkyl, C3-6cycloalkyl,2-6quinil,1-4alkoxygroup, NR2R3, halogen and unsubstituted or independently of each other mono - or disubstituted phenyl, where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, fluorine and chlorine. The preferred examples, where "a" represents "aryl"are unsubstituted or independently of each other mono - or disubstituted phenyl (preferably monosubstituted phenyl, where the substituents independently of one another selected from the group including1-4alkyl, C3-6cycloalkyl,1-4alkoxygroup and NR2R3. Preferred is phenyl. In addition to the above-mentioned substituents Deputy "A" is also substituted by the Deputy.

In the case where "B" represents "aryl"the term preferably means the above-mentioned group which is unsubstituted or independently of each other mono-, di - or tizamidine, where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, NR2R3, NHC(O)CH3and halogen. Preferred examples of where "B" represents "aryl"includes unsubstituted or independently of each other mono-, di - or tizamidine phenyl (preferably mono - or disame the military phenyl), when the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, NR2R3, NHC(O)CH3and halogen (preferred are:1-4alkyl, NHC(O)CH3, trifluoromethyl and halogen). Examples of aryl groups include phenyl, 3-were, 4-were, 3, 5dimethylphenyl, 2,4-dimetilfenil, 3,4-dimetilfenil, 3-forfinal, 4-forfinal, 3-chlorophenyl, 4-bromophenyl, 3,4-differenl, 3,4-dichlorophenyl, 3-bromo-4-forfinal, 3-acetylaminophenol and 3-triptoreline. In addition to the above-mentioned substituents Deputy "B" attached to the Deputy.

When "a" and "b" both represents "aryl"the combination "a-b" preferably means biphenylene group that is unsubstituted or independently of each other mono - or disubstituted for "A" and unsubstituted or mono-, di - or tizamidine for "In", where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, NR2R3, NHC(O)CH3and halogen. Preferred examples of the "a" and "b" both represents "aryl"are biphenylene groups which are unsubstituted or independently of each other mono - or disubstituted for "A" and unsubstituted or mono-, di - or tizanidine (preferably mono - or disa is exename) for "In", when the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl and halogen.

In the case when R1represents "aryl"the term preferably means the above-mentioned groups which are unsubstituted or independently of each other mono-, di - or tizamidine, while the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, halogen, trifluoromethyl and NR2R3(preferably With1-4alkyl, C1-4alkoxygroup, halogen and trifluoromethyl).

The term "heterocyclyl", alone or in combination with other groups, means a 5-10 membered monocyclic or bicyclic aromatic ring containing one, two or three heteroatoms, each of which is independently selected from oxygen, nitrogen and sulfur, which may be the same or different. Examples of such heterocyclic groups are furanyl, oxazolyl, isooxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolin, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophene, indazole, benzoimidazole, benzoxazole, benzothiazole, benzisothiazole, benzotriazolyl, benzoxazolyl, benzodia azolyl, chinoline, ethenolysis, naphthyridine, cinnoline, hintline, honokalani, phthalazine, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl or imidazo[2,1-b]thiazolyl. The above-mentioned heterocyclyl groups can be unsubstituted or independently of each other mono-, di - or tizamidine, while the substituents independently of one another selected from the group including C1-4alkyl, C3-6cycloalkyl,2-6quinil,1-4alkoxygroup, halogen, trifluoromethyl, NR2R3, NHC(O)CH3and unsubstituted or independently of each other mono - or disubstituted phenyl, where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, fluorine and chlorine.

In the case where "A" represents "heterocyclyl," the term preferably means the above-mentioned groups which are unsubstituted or independently of each other mono - or disubstituted, preferably, unsubstituted or monosubstituted), and the substituents independently of one another selected from the group including C1-4alkyl, C3-6cycloalkyl,2-6quinil,1-4alkoxygroup, NR2R3, halogen and unsubstituted or independently of each other mono - or disubstituted phenyl, where the substituents independently of one another selected from the group including C-4 alkyl, C1-4alkoxygroup, fluorine and chlorine.

In another embodiment of the present invention in the case where "A" represents "heterocyclyl", the term means the above-mentioned groups which are unsubstituted or monosubstituted, where the Deputy is chosen from the group comprising From1-4alkyl, C3-6cycloalkyl and NR2R3. The preferred examples, where "a" represents "heterocyclyl are unsubstituted or monosubstituted thiazolyl, oxazolyl, pyrimidyl and pyrazinyl (preferably thiazolyl), the Deputy select from1-4of alkyl, C3-6cycloalkyl or NR2R3. In addition to the above-mentioned substituents Deputy "A" is also substituted by the Deputy.

Examples, where "a" represents "heterocyclyl" and one of the substituents represents a "In"are the following:

When "In" is a "heterocyclyl," the term preferably means the above-mentioned groups which are unsubstituted or independently of each other mono-, di - or tizanidine (preferably mono - or disubstituted), and the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, NR2R3and halogen (preferably With1-4alkyl, trifluoromethyl and halogen). In addition to the above-mentioned substituents Deputy "B" attached to the Deputy.

In the case when R1is a "heterocyclyl," the term preferably means the above-mentioned groups which are unsubstituted or independently of each other mono-, di - or tizanidine (preferably unsubstituted or independently of each other mono - or disubstituted), and the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, halogen, trifluoromethyl and NR2R3. In another preferred embodiment of the present invention in the case where R1is a "heterocyclyl", the term means the above-mentioned groups which are unsubstituted or independently of each other mono -, di - or tizamidine, when the substituents independently of one another selected from the group including1-4alkyl, trifluoromethyl and halogen. In another preferred embodiment of the present invention, in the case when R1is a "heterocyclyl", the term means the above-mentioned groups which are unsubstituted or independently of each other mono - or disubstituted where the Deputy is methyl.

Preferably an example, where R1is a "heterocyclyl"is:

As a preferred example, where R1is a "heterocyclyl"is:

The term "NR2R3" means, for example, NH2and N(CH3)2.

The term "pharmaceutically acceptable salts" refers to non-toxic additive salts of inorganic or organic acids and/or bases. Reference may be made to: "Salt selection for basic drugs", Int. J. Pharm., (1986), 33, 201-217.

ii) Following the preferred implementation of the present invention includes compounds of formula (I) according to option (i), where

But heterocyclyl, which is unsubstituted or monosubstituted, while the Deputy is chosen from the group comprising From1-4alkyl, C3-6cycloalkyl or NR2R3.

iii) After the ith variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(ii), where

In represents aryl, which is unsubstituted or independently of each other mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup, trifluoromethyl, NHC(O)CH3and halogen.

iv) the Following variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(iii), where

R1represents aryl or heterocyclyl, and the aryl or heterocyclyl are unsubstituted or independently of each other mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, C1-4alkoxygroup and halogen; or R1represents a 2,3-dihydrobenzofuranyl - or 2,3-dihydrobenzo[1,4]dioxines group.

v) the Following variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(iv), where

But oxazolidinyl, thiazolidine or pyramidalnou group, with the named groups are unsubstituted or monosubstituted, where the Deputy is chosen from the group comprising C1-4alkyl, C3-6cycloalkyl or NH2.

vi) the Following variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(v), where

In p establet a phenyl, which is unsubstituted or independently of each other mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, trifluoromethyl and halogen.

vii) the Following variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(vi), where

R1represents imidazo[2,1-b]thiazolidine or benzisoxazole group, which are unsubstituted or monosubstituted, while the Deputy is chosen from the group comprising C1-4alkyl, trifluoromethyl and halogen; or R1represents a 2,3-dihydrobenzofuranyl group.

viii) the Following variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(vii), where

But thiazolidine group, which is unsubstituted or monosubstituted, where the Deputy is chosen from the group comprising From1-4alkyl, C3-6cycloalkyl or NH2.

ix) the Following variant of implementation of the present invention includes compounds of formula (I) according to one of the options (i)-(viii), where

R2and R3both represent hydrogen.

Examples of preferred compounds are selected from the group including:

[(1S,3S,5S)-2-(2-methyl-5-p-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]AMI is 6 methylimidazo[2,1-b]thiazole-5-carboxylic acid;

[(1S,3S,5S)-2-(2-amino-5-p-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;

{(1S,3S,5S)-2-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;

{(1S,3S,5S)-2-[2-cyclopropyl-5-(4-forfinal)thiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;

{(1S,3S,5S)-2-[2-cyclopropyl-5-(3-trifluoromethyl-phenyl)thiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;

[(1S,3S,5S)-2-(2-methyl-5-p-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide benzo[d]isoxazol-3-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide benzo[d]isoxazol-3-carboxylic acid;

[(1S,3S,5S)-2-(2-cyclopropyl-5-phenylthiazol-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid is you;

{(1S,3S,5S)-2-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

[(1S,3S,5S)-2-(2-methyl-5-m-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[2-methyl-5-(3-triptoreline)thiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(4-bromophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(3, 5dimethylphenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-bromo-4-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(3,4-differenl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(2,4-dimetilfenil)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic key is lots;

{(1S,3S,5S)-2-[5-(3,4-dichlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

{(1S,3S,5S)-2-[5-(3-acetamidophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;

[(1S,3S,5S)-2-(2-methyl-5-phenylthiazol-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid and

[(1S,3S,5S)-2-(2-cyclopropyl-5-phenylthiazol-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid.

Compounds according to formula (I) can be used to produce medicinal compounds, which are suitable for the prevention or treatment of diseases selected from the group comprising: estimatesa diseases, including major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional the Parana, adjustable disease and all groups of personality disorders; schizoaffective disease; anxiety, including generalized anxiety, obsessive compulsive condition, the condition of post-traumatic stress is a, panic attacks, all types of phobic anxiety and cancellation; separate anxiety; all types of use, abuse, psychotropic drugs, attracted to him and relapse; all types of psychological or physical addiction, dissociative disorders, including diverse personality syndromes and psychogenic amnesia, sexual and reproductive dysfunction; psychosexual dysfunction and addiction; tolerance to narcotics or withdrawal; increased anaesthesia risk, lack of response to anesthesia; hypothalamic-adrenal dysfunction; distributed biological and circadian rhythms; sleep disturbances associated with such diseases as neurological disorders including neuropathic pain and syndrome "restless legs"; stop breathing during sleep (apnea; narcolepsy; chronic fatigue syndrome; insomnia related to psychiatric disorders; all types of idiopathic insomnia and parasomnias; disorders associated with disturbance of sleep, including sleep disorder associated with moves between time zones; all types of dementia and cognitive dysfunctions in the healthy population and in psychiatric and neurological disorders; mental age-related dysfunction, all types of amnesia, some mental retardation; dyskinesia and muscle disease; muscular Spa is tecnost, tremor, motion sickness; spontaneous and caused by medication dyskinesia; neurodegerative diseases, including Huntington's disease, Creutzfeldt-Jakob disease, Alzheimer's disease and Tourette syndrome; amyotrophic lateral sclerosis; Parkinson's disease; Cushing's syndrome; traumatic injury; spinal cord injury; head trauma; perinatal hypoxia; hearing loss; a feeling of buzzing in ears; demyelinating diseases; spinal and cranial nerve diseases; eye damage; retinopathy; epilepsy; seizures; seizures transient loss of consciousness (absence), complex partial and generalized seizures; the syndrome of Lennox; migraine and headache; pain disorders; anesthesia and analgesia; enhanced or exacerbated sensitivity to pain such as hyperalgesia, causalgia and allotype; acute pain; pain during burn; atypical facial pain; neuropathic pain; spinal pain syndromes I and II complex regional pain; arthritis pain; pain due to sports injuries; dental pain; pain related to infection e.g. by HIV; pain after chemotherapy; pain after stroke; postoperative pain; neuralgia; osteoarthritis; conditions associated with visceral pain such as the syndrome of the irritable intestine; disorders associated with the adoption of food; diabetes; toxic and dismetabolic the ski disorder, including cerebral anoxia, diabetic neuropathology and alcoholism, disorders of appetite, taste, eating, or drinking; somatic disorders, including hypochondria; vomiting/nausea; vomiting; dyskinesia gastrointestinal tract; stomach ulcers; kallman syndrome (anosmia); decreased glucose tolerance; dyskinesia motility of the stomach; diseases of the hypothalamus; disease of the pituitary gland; hyperthermia syndromes such as fever, febrile seizures; idiopathic deficit growth; dwarfism; gigantism; acromegaly; basophilic adenoma; prolactinoma; hyperprolactinemia; brain tumor, adenoma; benign prostatic hypertrophy, prostate cancer; endometrial cancer, breast cancer, colon; all types of testicular dysfunction, fertility control; pathology of reproductive hormones; hot flushes; hypothalamic hypogonadism, functional or psychogenic amenorrhea; incontinence; asthma; allergies; all types of dermatitis, acne and cysts, dysfunction of the sebaceous gland; cardiovascular disease; heart disease and lung, acute and congestive heart failure; hypotension; hypertension; dyslipidemia, hyperlipidemia, insulin resistance; urinary retention; osteoporosis; angina pectoris; myocardial infarction; arrhythmia, vascular disease, left ventricular hypertrophy; ischemia is or hemorrhagic stroke; all types of cerebrovascular diseases, including subarachnoid hemorrhage, ischemic or hemorrhagic stroke and vascular dementia; chronic renal failure and other kidney diseases; gout; kidney cancer; urinary incontinence; and other diseases related to General dysfunction Aracinovo system.

The compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group that includes all types of diseases associated with sleep disorder caused by stress syndromes, the use and abuse of psychotropic drugs, including cravings and re-entry to the application, of cognitive dysfunctions in the healthy population and in psychiatric and neurological disorders, diseases associated with eating disorder or drinking behavior.

Eating disorders include metabolic disorders; misaligned appetite control; compulsive obesity; emetic bulemia or neuro-psychic anerexia. Consumption of pathologically modified food may be a consequence of disturbed appetite (attraction or aversion of food); the modified energy balance (consumption against restrictions); disturbed perception of the amount of food (high fat or high carbohydrate, especially PR is pleasant to the taste; disrupt the availability of food (unlimited consumption or restriction) or disturbed water balance. Diseases associated with the consumption of liquids, include polydipsia with psychiatric disorders and all other types of excessive fluid intake. Sleep disorders include all types of parasomnias, insomnia, narcolepsy and other disorders of sleep deprivation associated with sleep dystonia; syndrome restless legs"; respiratory disorders during sleep; syndrome associated with moving between time zones; violation of the sleep mode, the delay syndrome or earlier onset of sleep or insomnia associated with psychiatric disorders. Insomnia includes sleep disorders, age-related; intermittent treatment of chronic insomnia; situational short-term insomnia (new environment, noise) or short-term insomnia caused by stress, grief, pain or disease. Isomnia also includes stress-related syndromes such as post-traumatic disorders, as well as other types and subtypes of anxiety such as generalized anxiety, obsessive-compulsive disease, panic attacks and all types of phobic anxiety and cancellation; the use and abuse of psychotropic drugs, the desire to use, return to the original status is e, apply to all types of psychological or physical addiction and related components of tolerance and dependence. Cognitive disorders include all types of attention deficit, learning and memory functions, short-term or chronically occurs in normal, healthy, young, Mature or senile population, and short-term or chronically encountered in psychiatric, neurological, cardiovascular and immune diseases.

In the following a preferred embodiment of the present invention the compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group including sleep disorders, which include all types of insomnia, narcolepsy and other disorders caused by insomnia associated with sleep dystonia syndrome caused by moving between time zones; respiratory disorders during sleep; syndrome restless legs"; the violation of the sleep mode, the delay syndrome or earlier onset of sleep or insomnia associated with psychiatric disorders.

In another preferred embodiment of the present invention the compounds of formula (I) are particularly suitable and/or may be applied in the treatment of diseases or disorders selected from the group vkluchaya the cognitive disorders, which include all types of attention deficit, learning and memory functions, short-term or chronically occurs in normal, healthy, young, Mature or senile population, and short-term or chronically encountered in psychiatric, neurological, cardiovascular and immune diseases.

In another preferred embodiment of the present invention the compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group including disorders associated with eating behavior, which include metabolic disorders; misaligned appetite control; compulsive obesity; emetic bulemia or neuro-psychic anerexia.

In another preferred embodiment of the present invention the compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group that includes the use and abuse of psychotropic drugs, which include all types of psychological or physical addiction and related components of tolerance and dependency.

Obtaining pharmaceutical compositions is performed using methods well known to the expert of the art (see, for example, Remington, The Science and Practice of Pharmacy, 1st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by making the above compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically relevant substances in dosage form for administration together with the corresponding, non-toxic, inert, therapeutically compatible solid or liquid carriers and, optionally, conventional pharmaceutical additives.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical compositions for enteral or parenteral administration.

Another aspect of the invention concerns a method for obtaining compounds of formula (I). The compounds of formula (I) of the present invention can be obtained according to the General sequence of reactions shown below in schemes where a, b and R1have the meanings given in the description of formula (I). The compounds obtained can be converted into pharmaceutically acceptable salts are well-known method.

In General, all chemical transformations can be carried out according to well known standard techniques in accordance with literature data or according to the methods described below.

Obtaining compounds of formula (I):

Scheme 1: Synthesis of compounds of formula (I), where a, b and R1have the meanings given above

The first stage of synthesis of derivatives of 2-Aza-bicyclo[3.3.0]octane of formula (I) is the introduction of the protective group for the nitrogen atom in the (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate using Side2O and connection (2), which is reduced to the alcohol (3) by treatment with DIBAL at low temperatures. The alcohol (3) then oxidizes to the corresponding aldehyde (4) with the use of an oxidizing agent type, for example, periodinane dessa-Martin. After reductive amination of compound (4) benzylamine in the presence of a reducing agent, such triacetoxyborohydride sodium, benzyl group of the intermediate compound (5) is removed by hydrogenolysis to obtain the primary amine (6). The acylation of the compound (6) with carboxylic acid R1COOH in the presence of a condensing agent, such TBTU, leads to the formation of amides (7), which after removal of the BOC-group into the compounds of formula (I) by amide condensation (for example,-COOH, TBTU).

Derived thiazole-4-carboxylic acid of the formula B-A-COOH can be synthesized, for example, according to scheme 2.

Scheme 2: Synthesis of derivatives of thiazole-4-carboxylic acid, where a has the meaning indicated above, and R is oznachaet C 1-4alkyl, C3-6cycloalkyl or NR2R3where R2and R3each represent independently from each other hydrogen or C1-4alkyl.

The reaction methyldichlorosilane (9; commercially available) with an aldehyde in the presence of a base, such tert-piperonyl potassium receive α-oxepin derivatives (10), which turn through reaction with thioamides (R represents C1-4alkyl or C3-6cycloalkyl) 2-alkyl - or 2-cycloalkylation derivatives of thiazole (11), or by reaction with thiourea (R denotes NR2R3in 2-aminotoluene derivatives of thiazole (11). Saponification hard-essential functions using, for example, an aqueous solution of sodium hydroxide in a solvent-type methanol, allows to obtain the desired carboxylic acid (12, R represents C1-4alkyl, C3-6cycloalkyl or NR2R3). Derivatives of 2-bromothiazole (13) are obtained, for example, by reaction of the corresponding derivative of 2-aminothiazole (11, R stands for NH2with italianitalian in the presence of copper bromide(II). Hard-ester derivatives of (13) turn catalyzed by palladium reactions with derivatives cyclopropylamine (commercially available) connections (14), which, after saponification converted into carboxylic acid (15). The derived 2-bromothiazole (13) may be more the tion of amylene to the corresponding carboxylic acid (16), as described above, or converted into 2-methoxyphenyl the analogue of (17) by reaction with sodium methoxide and subsequent saponification with sodium hydroxide. In addition, compound (19), which are not substituted at the 2-position can be synthesized by hydrogenation of the compound (13) with hydrogen in the presence of palladium on coal and subsequent saponification of ester intermediate (18). With3-6cycloalkylation thioamides (11)used in the synthesis are commercially available, or can be obtained by reaction of the carboxamide with reagent Lawesson (see also experimental part A). Aldehydes-SNO are commercially available or can be synthesized using any of the methods known from the literature, as, for example, the recovery of the corresponding carboxylic acid or its various derivatives using the recovery agent, recovering the corresponding nitrile or oxidation of benzyl alcohols and their heterocyclic analogues by reaction with oxidizing agents (see, for example: J.March, Advanced Organic Chemistry, 4thedition, John Wiley & Sons, p.447-449, 919-920 and 1167-1171).

Derivative imidazo[2,1-b]thiazolecarboxamide acid of formula R1-COOH, if they are not commercially available, can be synthesized according to one of the paths shown in the diagram .

Path As:

Path B:

The way In:

Path G:

Path D:

Path E:

Scheme 3: Synthesis of derivatives of imidazo[2,1-b]thiazolecarboxamide acid, where R denotes methyl or ethyl, Radenotes hydrogen or methyl, Rbdenotes hydrogen or methyl, X denotes chlorine or bromine, and Y denotes chlorine or deformity.

Follow through And derived imidazo[2,1-b]thiazolecarboxamide acid synthesized from methyl ester 2-chloro-3-oxomalonate acid (20; commercially available) by reaction with thiourea (commercially available) in a solvent such as ethanol, at elevated temperatures. The resulting aminothiazol (21) in turn derived imidazo[2,1-b]thiazole (22) by alkylation and subsequent cyclization with diethylacetal of bromoacetaldehyde in the presence of acid type of concentrated hydrochloric acid. The saponification of the compound (22), for example, using sodium hydroxide, in solvents of the type of THF and the Meon get the required acid (23).

An alternative method (path B) proceeds from the reaction of the ester of 2-bromo-3-oxomalonate acid (24; commercially available) with 2-amino-5-methylthiazole (commercial access is) in solvent type acetone to obtain derived imidazo[2,1-b]thiazole (25), which in turn the desired acid (26) by saponification, for example, using sodium hydroxide in the solvent as THF and Meon.

By hydrogenation of the ester 2-hydroxyimino-3-oxomalonate acid (27; commercially available) in the presence of palladium on coal in acidic conditions (for example, HCl in EtOH) and subsequent reaction with potassium thiocyanate get imidazole derivative (28), which was transferred to a mixture of the two possible isomers (29) and (30) by reaction with an appropriate α-halogenated propanol (commercially available) or a derivative of butanone (; commercially available). After separation of the isomers (29) and (30) using chromatography required derivative imidazo[2,1-b]thiazolecarboxamide acid (31) and (32) are obtained by saponification, for example, sodium hydroxide in solvents like THF and Meon.

Alternative (path D) imidazole derivative (28) can be converted into the acetal (33) by alkylation with diethylacetal of bromoacetaldehyde (commercially available) in the presence of a base such as sodium hydroxide. Cyclization under acidic conditions (for example, aqueous hydrochloric acid and the dehydration of the intermediate compound (34), for example, with phosphorus oxychloride, lead to complex ether (35), which is transformed into the desired acid (36) by saponification, for example, the R, sodium hydroxide, in solvents like THF and Meon.

In yet another alternative method (path D) corresponding aminothiazol (37; commercially available) in turn derived formamidine (38) by heating the compound (37) with dimethylacetal N,N-dimethylformamide (commercially available) in solvent type toluene. After alkylation with ethylbromoacetate (commercially available) suitable bromide thiazole (39) is injected into the cyclization reaction with DBU, receiving ester (40), which amyraut in the desired acid (41), for example, sodium hydroxide in solvents like THF and Meon.

The final path F start with the alkylation of 2-aminothiazole (commercially available) 3-bromo-1,1,1-triptoreline (commercially available) to obtain deformatsionnogo derived imidazo[2,1-b]thiazole (42), which formuliruut to aldehyde (43) by reaction with phosphorus oxychloride in a solvent like DMF. By oxidation of the aldehyde (43) sodium chlorite get the desired imidazo[2,1-b]diazocarbonyl acid (44, Y=CF3). Similarly, commercially available chlorinated aldehyde (43, Y=Cl) are oxidized to the acid (44, Y=Cl).

Experimental part

Abbreviations used in this description:

AC is acetyl in SLA: acetate, Side - tert-butoxycarbonyl, BSA - bovine serum albumin, Bu is n-butyl, SNO - CL the weave of the ovary of the Chinese hamster, DBU is 1,8-diazabicyclo[5.4.0]Indes-7-ene, DHM - dichloromethane, DIBAL - diisobutylaluminium, DIPEA - diisopropylethylamine, DMAP - 4-dimethylaminopyridine, DMF is N,N-dimethylformamide, EQ. equivalent(s), ES - electrospray ionization, Et is ethyl, ether - diethyl ether, EtOH - ethanol, FCS - fetal calf serum, FLTP fluorescence tomographic tablet reader, h for hour(s), HBSS - balanced salt Hanks solution, HEPES is 4-(2-hydroxyethyl)piperazine-1-econsultancy acid, HPLC - high performance liquid chromatography, KOtBu - tert-piperonyl potassium, LC - liquid chromatography, Me is methyl, MeCN is acetonitrile, Meon - methanol, min - minute(s)MS mass spectroscopy, Ph is phenyl, Rev.- preparative, tR- retention time, TBTU - tetrafluoroborate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea, TPA - triperoxonane acid, THF is tetrahydrofuran.

I - Chemistry

The following examples illustrate the obtaining of the pharmacologically active compounds according to the invention, without limiting, however, its volume.

All of the temperature is given in °C.

Compounds were characterized by using:

1H-NMR: 300 MHz Varian Oxford or 400 MHz Bruker Avance; chemical shifts are given in memorial plaques for the used solvents; multipletness: s = single, d = doublet, t = triplet, q = Quartet, m = multiplet, b = advanced, constants mates are given in the C;

LC-MS: Agilent 1100 series with DAD and MS detection (MS: Finnigan single quadrupole: speakers: (a 4.6×50 mm, 5 μm): Bond SB-AQ, Bond Extend From the 18th or Water 18 XBridge; conditions:

main: eluent A: MeCN, eluent B: conc. NH3in water (1.0 ml/l), 5% to 95% CH3CN;

acid: eluent A: MeCN, eluent B: TFA in water (0.4 ml/l), 5% to 95% CH3CN, the expiry time of 4.5 ml/min; tRgiven in minutes

Compounds purified by column chromatography on silica gel or by using preparative HPLC using a RP-C18column with MeCN/water gradients and additives in the form of formic acid or ammonia.

A. Obtaining initial and intermediate connections:

A.1 Synthesis of derivatives of thiazole-4-carboxylic acid

A.1.1 the Synthesis of derivatives of 3-chloro-2-oxopropionate of the ester (General method)

The solution of the corresponding aldehyde (338 mmol, 1.0 EQ.) and methyldichlorosilane (338 mmol, 1.0 EQ.) in THF (100 ml) is added dropwise to a cooled to -60°C. a suspension of KOtBu (335 mmol, 1.0 EQ.) in THF (420 ml). After 4 h, the mixture is left to spontaneously warm to room temperature, then stirred overnight and concentrated in vacuo. Then add DHM and chilled with ice water, the layers separated, and the aqueous layer was twice extracted with DHM. The combined organic layers washed with ice water and brine, vysushivaya MgSO 4and concentrated in vacuo, obtaining the desired α-oxoethyl, which is used without further purification.

Methyl ether 3-chloro-2-oxo-3-p-tolylpropan acid get through the reaction of 4-methylbenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-3-(3-forfinal)-2-oxopropanoic acid get through the reaction of 3-forventelige with methyldichlorosilane.

Methyl ether 3-chloro-3-(4-forfinal)-2-oxopropanoic acid get through the reaction of 4-forventelige with methyldichlorosilane.

Methyl ether 3-chloro-3-(3-chlorophenyl)-2-oxopropanoic acid get through the reaction of 3-chlorobenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-2-oxo-3-m-tolylpropan acid get through the reaction of 3-methylbenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-2-oxo-3-(3-triptoreline)propionic acid get through the reaction of 3-triftormetilfullerenov with methyldichlorosilane.

Methyl ester of 3-(4-bromophenyl)-3-chloro-2-oxopropanoic acid get through the reaction of 4-bromobenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-3-(3, 5dimethylphenyl)-2-oxopropanoic acid get through the reaction of 3,5-dimethylbenzaldehyde with methyldichlorosilane.

Methyl ester 3-(3-bromo-4-forfinal)-3-chloro-2-oxopropanoic acid p is to obtain, by reaction of 3-bromo-4-forventelige with methyldichlorosilane.

Methyl ether 3-chloro-3-(3,4-differenl)-2-oxopropanoic acid get through the reaction of 3,4-diferentialglea with methyldichlorosilane.

Methyl ether 3-chloro-3-(2,4-dimetilfenil)-2-oxopropanoic acid get through the reaction of 2,4-dimethylbenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-3-(3,4-dichlorophenyl)-2-oxopropanoic acid get through the reaction of 3,4-dichlorobenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-3-(3,4-dimetilfenil)-2-oxopropanoic acid get through the reaction of 3,4-dimethylbenzaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-2-oxo-3-phenylpropionic acid get through reaction of bezaldehyde with methyldichlorosilane.

Methyl ether 3-chloro-3-(3-nitrophenyl)-2-oxopropanoic acid get through the reaction of 3-nitrobenzaldehyde with methyldichlorosilane.

A Synthesis of methyl ester derivatives of the thiazole-4-carboxylic acid (General method)

A solution of thioacetamide (132 mmol, 1.0 EQ.) in MeCN (250 ml) was added to a mixture of the corresponding α-atsoever (132 mmol, 1.0 EQ.) and molecular sieves (4Å, 12 g) in MeCN (60 ml). After stirring for 5 h the mixture is cooled in a bath with ice and the precipitate is filtered off. The residue was washed with cold MeCN, dried, dissolved in Meon (280 ml) and displaced the more at 50°C for 6 hours Then the solvent is removed in vacuum, obtaining the desired thiazole derivative as a white solid.

Methyl ester of 2-methyl-5-p-tolyltriazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-2-oxo-3-p-tolylpropan acid with thioacetamide.

LC-MS: tR=to 0.92 min; [M+H]+=248,2.

Methyl ester 5-(3-forfinal)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3-forfinal)-2-oxopropanoic acid with thioacetamide.

LC-MS: tr=of 0.91 min; [M+H]+=252,1.

Methyl ester 5-(4-forfinal)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(4-forfinal)-2-oxopropanoic acid with thioacetamide.

1H-NMR (CDCl3): δ=2,75 (s, 3H); of 3.84 (s, 3H); 7,10 (m, 2H); 7,47 (m, 2H).

Methyl ester 5-(3-chlorophenyl)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3-chloro-phenyl)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=of 0.95 min; [M+H]+=268,0.

Methyl ester of 2-methyl-5-m-tolyltriazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-2-oxo-3-m-tolylpropan acid with thioacetamide.

LC-MS: tR=0,98 min; [M+H]+=248,5.

Methyl ester of 2-methyl-5-(3-triptoreline)thiazole-4-carboxylic acid get through the reaction of methyl ether 3-chloro-2-oxo-3-(3-triptoreline)propionic acid with thioacetamide.

LC-MS: tR=0,98 min; [M+H]+=302,2.

Methyl ester 5-(4-bromophenyl)-2-methylthiazole-4-carboxylic acid get through the reaction of methyl ester of 3-(4-bromophenyl)-3-chloro-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=of 0.95 min; [M+H]+=312,2.

Methyl ester 5-(3, 5dimethylphenyl)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3, 5dimethylphenyl)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=0,97 min; [M+H]+=262,3.

Methyl ester 5-(3-bromo-4-forfinal)-2-methylthiazole-4-carboxylic acid get through the reaction of methyl ester 3-(3-bromo-4-forfinal)-3-chloro-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=of 0.95 min; [M+H]+=330,2.

Methyl ester 5-(3,4-differenl)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3,4-differenl)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=to 0.92 min; [M+H]+=270,3.

Methyl ester 5-(2,4-dimetilfenil)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(2,4-dimetilfenil)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=to 0.96 min; [M+H]+=262,3.

Methyl ester 5-(3,4-dichlorophenyl)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3,4-dichlo is phenyl)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=0,99 min; [M+H]+=302,2.

Methyl ester 5-(3,4-dimetilfenil)-2-methylthiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3,4-dimetilfenil)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=to 0.96 min; [M+H]+=262,3.

Methyl ester of 2-methyl-5-phenylthiazol-4-carboxylic acid get through reaction of methyl ether 3-chloro-2-oxo-3-phenylpropionic acid with thioacetamide.

LC-MS: tR=to 0.89 min; [M+H]+=234,0.

Methyl ester of 2-methyl-5-(3-nitrophenyl)thiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(3-nitrophenyl)-2-oxopropanoic acid with thioacetamide.

LC-MS: tR=0,94 min; [M+H]+=279,3.

A the Synthesis of derivatives of methyl ester 2-aminothiazol-4-carboxylic acid (General method)

A solution of the appropriate α-atsoever (22.1 mmol, 1.0 EQ.) in acetone (25 ml) are added to a suspension of thiourea (22.1 mmol, 1.0 EQ.) in acetone (45 ml). The mixture is heated to a temperature of 57°C (bath temperature), stirred for 24 h and concentrated to half volume. The resulting suspension is filtered, and the residue is washed with acetone. After drying receive the required derived aminothiazole in the form of solids.

Methyl ester 2-amino-5-p-tolyltriazole-4-carboxylic acid get what exploits the reaction of methyl ester of 3-chloro-2-oxo-3-p-tolylpropan acid with thiourea.

LC-MS: tR=of 0.77 min; [M+H]+=249,3.

Methyl ester 2-amino-5-(4-(forfinal)thiazole-4-carboxylic acid get through reaction of methyl ether 3-chloro-3-(4-forfinal)-2-oxopropanoic acid with thiourea.

LC-MS: tR=0,75 min; [M+H]+=253,2.

Methyl ester 2-amino-5-(3-triptoreline)thiazole-4-carboxylic acid

receive by reaction of methyl ether 3-chloro-3-(3-triptoreline)-2-oxopropanoic acid with thiourea.

LC-MS: tR=0,86 min; [M+H]+=303,3.

A the Synthesis of derivatives of methyl ester 2-bromothiazole-4-carboxylic acid (General method)

In an inert atmosphere bromide copper(II) (69,6 mmol, 1.0 EQ.) suspended in acetonitrile (300 ml) and cooled to a temperature of 5-10°C., then add 3-methylbutyronitrile (104 mmol, 1.45 equiv.) within 15 minutes Then to this reaction mixture in parts add derived 2-aminothiazole (70.0 mmol, 1 EQ., free amine) for 20 min at 5-10°C. the Reaction mixture is then gently heated to a temperature of 65°C, and stirring is continued for 2 hours Volatile fractions are removed under reduced pressure and the residue purified by column chromatography (silica gel; heptane/EtOAc or DHM/methanol, in the form of a corresponding mixture)to give the desired product.

Methyl ester of 2-bromo-5-(4-f is arvanil)thiazole-4-carboxylic acid get through the reaction of methyl ester 2-amino-5-(4-forfinal)thiazole-4-carboxylic acid.

LC-MS: tR=0,97 min; [M+H]+=316,1.

Methyl ester of 2-bromo-5-(3-triptoreline)thiazole-4-carboxylic acid

get through the reaction of methyl ester 2-amino-5-(3-triptoreline)thiazole-4-carboxylic acid.

LC-MS: tR=1,04 min; [M+H]+=366,2.

A. 1.5 Synthesis of derivatives of methyl esters of 2-cyclopropylethanol-4-carboxylic acid methyl (General method I)

In an inert atmosphere a solution of the corresponding derivative of 2-bromothiazole (9.0 mmol, 1.0 EQ.) and tributyltinchloride (9.9 mmol, 1.1 EQ.) in 1,2-dichloroethane (90 ml) is stirred for 5 min, and then treated with chloride bis(triphenylphosphine)palladium(II) (0.45 mmol, of 0.05 EQ.). The mixture is heated to a temperature of 80°C., stirred for 3 days, after which leave unexpectedly to warm to room temperature. Then add DHM and water, the layers separated, the aqueous layer was extracted with DHM. The combined organic layers dried over MgSO4and concentrated in vacuo. The residue is purified by column chromatography (silica gel; heptane/EtOAc, in the form of an appropriate mixture)to give the desired product.

Methyl ester 2-cyclopropyl-5-(4-forfinal)thiazole-4-carboxylic acid

get through cyclopropylamine methyl ester of 2-bromo-5-(4-forfinal)thiazole-4-carboxylic acid.

LC-MS: R=0,97 min; [M+H]+=278,3.

Methyl ester 2-cyclopropyl-5-(3-triptoreline)thiazole-4-carboxylic acid get through cyclopropylamine methyl ester of 2-bromo-5-(3-triptoreline)thiazole-4-carboxylic acid.

LC-MS: tR=1,03 min; [M+H]+=328,2.

A the Synthesis of derivatives of methyl esters of 2-cyclopropylethanol-4-carboxylic acid (General method II)

Synthesis of amide cyclopropanecarboxylic acid

2,4-Bis-(4-methoxyphenyl)-[1,3,2,4]dithiadiphosphetane-2,4-disulfide (reagent Lawesson, 115 mmol) was added to the mixture cyclopropanecarboxamide (115 mmol) and sodium carbonate (115 mmol) in THF (500 ml). The mixture is heated under reflux for 2 h, then the solvents are removed in vacuo and the residue diluted with ether (500 ml) and water (500 ml). The layers separated, and the aqueous layer was extracted with ether (250 ml). The combined organic layers washed with brine (100 ml), dried over MgSO4and concentrated in vacuo, obtaining the required thioamide, which is used without further purification.

LC-MS: tR=0,39 min; [M+H+CH3CN]+=143,2.

Synthesis of derivatives of methyl esters of 2-cyclopropylethanol-4-carboxylic acid (General method II)

A solution of amide cyclopropanecarboxylic acid (44.5 mmol, 1.0 EQ.) in MeCN (40 ml) is added to a mixture of the corresponding α-atsoever (44,5 mole is, 1.0 EQ.) and NaHCO3(134 mmol, 3.0 EQ.) in MeCN (80 ml). After stirring for 16 h the mixture was concentrated in vacuo, and the residue diluted with ethyl acetate (200 ml) and water (200 ml). The layers separated, and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers washed with brine (100 ml), dried over MgSO4and concentrated in vacuo. The crude product is dissolved in Meon (90 ml) and treated with conc. H2SO4(0.25 ml). The mixture was then heated at 60°C for 16 h and concentrated in vacuo, obtaining the corresponding thiazole derivative.

Methyl ester 2-cyclopropyl-5-phenylthiazol-4-carboxylic acid get through reaction of methyl ether 3-chloro-2-oxo-3-phenylpropionic acid with Amida cyclopropanecarboxylic acid.

LC-MS: tR=0,99 min; [M+H]+=260,5.

A.1.7 Synthesis of methyl ester of 5-(3-acetamidophenyl)-2-methylthiazole-4-carboxylic acid

A Synthesis of methyl ester of 5-(3-AMINOPHENYL)-2-methylthiazole-4-carboxylic acid

A suspension of methyl ester of 2-methyl-5-(3-nitrophenyl)thiazole-4-carboxylic acid (44.1 mmol) and ammonium chloride (220 mmol) in ethanol (100 ml) and water (50 ml) is treated with powdered iron (53.0 mmol) and heated to 80°C. After 4 h, add additional portion of iron powder (53.0 mmol), the mixture was stirred at ambient temperature the re 80°C for 3 h, again add iron powder (26.5 mmol) and the mixture is again stirred at 80°C for 3.5 hours and Then the mixture is left to cool spontaneously to room temperature, diluted with DHM and filtered through celite. The filtrate was concentrated in vacuo and diluted with DHM and saturated aqueous NaHCO3. The layers separated, and the organic layer washed with water, dried over MgSO4and concentrated in vacuo, obtaining the desired aniline derivative.

LC-MS: tR=0,67 min; [M+H]+=249,4.

A Synthesis of methyl ester of 5-(3-acetamidophenyl)-2-methylthiazole-4-carboxylic acid

The triethylamine (14.2 mmol) and DMAP (4.00 mmol) was added to a solution of methyl ester 5-(3-AMINOPHENYL)-2-methylthiazole-4-carboxylic acid (4.00 mmol) in acetic anhydride (25 ml). After 30 minutes add EtOAc and water, the layers separated, and the aqueous layer was once extracted with EtOAc. The combined organic layers washed twice with a saturated aqueous solution of ammonium chloride, once with an aqueous solution NaHCO3once with water, after which the solvent is removed in vacuum. The residue was diluted with EtOAc and extracted three times with a saturated aqueous solution of NaHCO3. The organic layer is dried over MgSO4and concentrated in vacuo give crude solid, which was diluted with ether. The resulting suspension is filtered, ostatok washed with ether, getting required ndimethylacetamide.

LC-MS: tR=0,81 min; [M+H]+=291,3.

A Synthesis of derivatives of thiazole-4-carboxylic acid (General method)

The appropriate solution of ester (96,2 mmol) in a mixture of THF (150 ml) and Meon (or isopropanol, 50 ml) is treated with an aqueous solution of NaOH (1-molar, 192 ml). After stirring for 3 h formed white suspension, after which the volatile organic fraction is removed in vacuum. The remaining mixture is diluted with water (100 ml), cooled in a bath with ice and acidified (pH 3-4) the addition of an aqueous HCl solution (1-molar). In the case of precipitation, the suspension is filtered, and the residue is washed with cold water and dried in vacuum, obtaining the desired acid. In other cases, the mixture is twice extracted with EtOAc, and the organic layers combined dried over MgSO4and concentrated in vacuo getting the corresponding acid.

2-Methyl-5-p-tolyltriazole-4-carboxylic acid

receive by saponification of methyl ester of 2-methyl-5-p-tolyltriazole-4-carboxylic acid.

LC-MS: tR=0,83 min; [M+H]+=234,0.

5-(3-Forfinal)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3-forfinal)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,82 min; [M+H]+=238,1.

5-(4-Forfinal)-2-methylthiazole-4-carboxylic key is lot

receive by saponification of methyl ester 5-(4-forfinal)-2-methylthiazole-4-carboxylic acid.

1H-NMR (DMSO-d6): δ=to 2.67 (s, 3H); 7,27 (m, 2H); 7,53 (m, 2H); 12,89 (advanced s, 1H).

5-(3-Chlorophenyl)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3-chlorophenyl)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,84 min; [M+H]+=254,0.

2-Methyl-5-m-tolyltriazole-4-carboxylic acid

receive by saponification of methyl ester of 2-methyl-5-m-tolyltriazole-4-carboxylic acid.

LC-MS: tR=of 0.87 min; [M+H]+=234,4.

2-Methyl-5-(3-triptoreline)thiazole-4-carboxylic acid

receive by saponification of methyl ester of 2-methyl-5-(3-triptoreline)thiazole-4-carboxylic acid.

LC-MS: tR=0,88 min; [M+H]+=288,0.

5-(4-Bromophenyl)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(4-bromophenyl)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,85 min; [M+H]+=298,2.

5-(3, 5dimethylphenyl)-2-methylthiazole-4-carboxylic acid

receive by saponification of 5-(3, 5dimethylphenyl)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,86 min; [M+H]+=248,3.

5-(3-Bromo-4-forfinal)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3-bromo-4-forfinal)-2-methylthiazole-4-carbon is th acid.

LC-MS: tR=0,86 min; [M+H]+=316,2.

5-(3,4-Differenl)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3,4-differenl)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,82 min; [M+H]+=256,3.

5-(2,4-Dimetilfenil)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(2,4-dimetilfenil)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,85 min; [M+H]+=248,3.

5-(3,4-Dichlorophenyl)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3,4-dichlorophenyl)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,88 min; [M+H]+=288,2.

5-(3,4-Dimetilfenil)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3,4-dimetilfenil)-2-methylthiazole-4-carboxylic acid.

LC-MS: tr=0,86 min; [M+H]+=248,3.

2-Methyl-5-phenylthiazol-4-carboxylic acid

receive by saponification of methyl ester of 2-methyl-5-phenylthiazol-4-carboxylic acid.

LC-MS: tR=of 0.77 min; [M+H]+=220,0.

5-(3-Acetamidophenyl)-2-methylthiazole-4-carboxylic acid

receive by saponification of methyl ester 5-(3-acetamidophenyl)-2-methylthiazole-4-carboxylic acid.

LC-MS: tR=0,73 min; [M+H]+=277.2 M..

2-Amino-5-p-tolyltriazole-4-carboxylic acid

get the exploits of saponification of methyl ester 2-amino-5-p-tolyltriazole-4-carboxylic acid.

LC-MS: tR=0,64 min; [M+H]+=235,2.

2-Cyclopropyl-5-(4-forfinal)thiazole-4-carboxylic acid

receive by saponification of methyl ester 2-cyclopropyl-5-(4-forfinal)thiazole-4-carboxylic acid.

LC-MS: tR=of 0.87 min; [M+H]+=AZN 264.2.

2-Cyclopropyl-5-(3-triptoreline)thiazole-4-carboxylic acid

receive by saponification of methyl ester 2-cyclopropyl-5-(3-triptoreline)thiazole-4-carboxylic acid.

LC-MS: tR=0,94 min; [M+H]+=314,2.

2-Cyclopropyl-5-phenylthiazol-4-carboxylic acid

receive by saponification of methyl ester 2-cyclopropyl-5-phenylthiazol-4-carboxylic acid.

LC-MS: tR=of 0.91 min; [M+H]+=246,4.

A.2 Synthesis of 2,3-dihydrobenzofuran-4-carboxylic acid

Benzofuran-4-carboxylic acid (30.8 mmol, M.A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105) was added to a suspension of Pd/C (10%, 2.00 g) in EtOH (25 ml). Then add additional EtOH (75 ml) and the mixture is stirred at room temperature under hydrogen pressure (4 bar) for 16 h After filtration through celite and removal of the solvents to obtain the desired product which is used without further purification.

1H-NMR (DMSO-d6): δ=of 3.45 (t, J=8,79 Hz, 2H); 4,55 (t, J=8,79 Hz, 2H); 6,99 (d, J=7,78 Hz, 1H); 7,21 (t, J=7.91 Hz, 1H); 7,39 (d, J=7,78 Hz, 1H); 12,9 (advanced s, 1H).

A.3 Synthesis of tert-butyl methyl ether (1S,3S,5S)-3-aminomethyl-2-asabis the CLO[3.3.0]octane-2-carboxylic acid

A.3.1 Synthesis of benzyl ether (1S,3S,5S)-(2-tert-butoxycarbonyl)-2-azabicyclo[3.3.0]octane-3-carboxylic acid

To a suspension of the hydrochloride benzyl(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate (17.3 mmol, 1.0 EQ.) in DHM (50 ml) added DIPEA (22.5 mmol, 1.3 EQ.), di-tert-BUTYLCARBAMATE (17.3 mmol, 1.0 EQ.) and additional amounts DHM (5 ml). The mixture was then stirred for 1 h and concentrated in vacuo, then add EtOAc and an aqueous solution of citric acid (10%), the layers separated, and the aqueous layer was once extracted with ethyl acetate. The combined organic layers washed, concentrated, dried over MgSO4and concentrated in vacuo. The residue is purified by column chromatography (heptane/EtOAc in a ratio of 3:1)to give the desired product.

LC-MS: tR=1,08 min; [M+H]+=346,3.

A.3.2 Synthesis of tert-butyl methyl ether (1S,3S,5S)-3-hydroxymethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid

Cooled to a temperature of -78°C solution DIBAL in toluene (1,7-molar, 22.5 mmol) is added dropwise to a solution of benzyl ester of (1S,3S,5S)-(2-tert-butoxycarbonyl)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (9.0 mmol) in THF (50 ml). After 40 min, the mixture is left to spontaneously warm to room temperature, optionally stirred for 45 min and transferred into a mixture of aqueous NaOH (1-molar, 250 ml) and ice were Then added EtOAc, the layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers washed with aqueous solution of NaOH (1-molar) and brine, dried over MgSO4and concentrated in vacuo, obtaining the desired alcohol, which is purified by column chromatography (heptane/EtOAc in a ratio of 3:1).

LC-MS: tR=of 0.91 min; [M+H]+=242,4.

A.3.3 Synthesis of tert-butyl methyl ether (1S,3S,5S)-3-formyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid

The solution periodinane dessa-Martin (4.14 mmol, 2.2 EQ.) in DHM (10 ml) is treated with a solution of tert-butyl methyl ether (1S,3S,5S)-3-hydroxymethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid (1.85 mmol, 1.0 EQ.) in DHM (4 ml) and few drops of water. After 5 h was added aqueous NaOH solution (1-molar) and the layers separated. The organic layer was washed with aqueous solution of citric acid (10%) and brine, then dried over MgSO4and concentrated in vacuo, obtaining the desired aldehyde, which is used without further purification.

A Synthesis of tert-butyl methyl ether (1S,3S,5S)-3-(benzylamino)-2-azabicyclo[3.3.0]octane-2-carboxylic acid

Benzylamine (2.76 mmol, 2.3 EQ.) added to a solution of tert-butyl methyl ether (1S,3S,5S)-3-formyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid (1.2 mmol, 1.0 EQ.) in chloroform (10 ml). The mixture was then stirred for 5 min, treated with triacetoxyborohydride on the model (4.8 mmol, 4.0 EQ.) and acetic acid (0.05 ml), stirred additionally for 14 h and transferred into a saturated solution of NaHCO3, then add DHM, the layers separated and the aqueous layer was extracted with DHM. The combined organic layers washed with water (100 ml) and concentrated in vacuo. The residue is dissolved in ether and shaken out three times with hydrochloric acid (about 0.1-molar solution). The combined aqueous layers once extracted with ether, alkalinized (pH 9-10) by adding NaOH solution (1.0 in-molar) and thrice extracted with ether. The combined organic layers dried over MgSO4and concentrated in vacuo, obtaining the required benzylamine, which is used without further purification.

LC-MS: tR=to 0.89 min; [M+H]+=331,5.

A.3.5 Synthesis of tert-butyl methyl ether (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid

A solution of tert-butyl methyl ether (1S,3S,5S)-3-(benzylamino)-2-azabicyclo[3.3.0]octane-2-carboxylic acid (9.0 mmol) in ethanol (10 ml) was added to a suspension of Pd/C (1.9 g, 10%) in ethanol (40 ml) and stirred under hydrogen pressure (1 bar) for 16 h After filtration through celite, the mixture is washed with ethanol and remove the solvent, obtaining the desired amine, which is used without further purification.

LC-MS: tR=0,73 min; [M+H]+=241.4 M..

A.4 Synthesis of derivatives of (1S,3S,5S)-(2-azabicyclo[3.3.0]OK the EN-3-ylmethyl)amide

A Synthesis of tert-butyl methyl ether (1S,3S,5S)-3-(aroylamino)-2-azabicyclo[3.3.0]octane-2-carboxylic acid (General method)

TBTU (5.0 mmol, 1.2 EQ.) added to a solution of the appropriate carboxylic acid (4.6 mmol, 1.1 EQ.) in DMF (15 ml). After 30 minutes add DIPEA (12.5 mmol, 3.0 EQ.) and a solution of tert-butyl methyl ether (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid (4.2 mmol, 1.0 EQ.) in DMF (10 ml), after which the mixture is stirred for 60 minutes Then add the water and EtOAc, the layers separated, and the organic layer washed once with water. The combined aqueous layers once extracted with ethyl acetate and the combined organic layers dried over MgSO4. The solvents are removed in vacuo and the residue purified by column chromatography (DHM)to give the corresponding amide.

tert-Butyl ether (1S,3S,5S)-3-{[(6-methylimidazo[2,1-b]thiazole-5-carbonyl)amino]methyl}-2-azabicyclo[3.3.0]octane-2-carboxylic acid

get through the reaction of 6-methylimidazo [2,1-b]thiazole-5-carboxylic acid (A.Andreani et al. Eur. J. Med. Chem 1982, 17, 271-274) with tert-butyl ether (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid.

LC-MS: tR=of 0.91 min; [M+H]+=405,2.

tert-Butyl ether (1S,3S,5S)-3-{[(benzo[d]isoxazol-3-carbonyl)amino]methyl}-2-azabicyclo[3.3.0]octane-2-carboxylic acid

get what exploits the reaction of tert-butyl methyl ether benzo[d]isoxazol-3-carboxylic acid tert-butyl ester (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid.

LC-MS: tR=1,11 min; [M+H]+=386,6.

tert-Butyl ether (1S,3S,5S)-3-{[(2,3-dihydrobenzofuran-4-carbonyl)amino]methyl}-2-azabicyclo[3.3.0]octane-2-carboxylic acid

get through the reaction of 2,3-dihydrobenzofuran-4-carboxylic acid tert-butyl ester (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid.

LC-MS: tR=1,00 min; [M+H]+=387,1.

A.4.2 the Synthesis of derivatives of (1S,3S,5S)-(2-azabicyclo[3.3.0]Octan-3-ylmethyl)amide (General method)

A solution of HCl in dioxane (4.0 to molar, 20 ml) was added to a solution of the appropriate BOC-protected derivative of 2-azabicyclo[3.3.0]octane (3.6 mmol) in dioxane (20 ml). After analysis using LC-MS, indicating completion of the reaction (from 1 to 3 hours), the mixture was concentrated in vacuo, obtaining the corresponding freed from the protective groups of the product, which is used without more purification.

[(1S,3S,5S)-(2-Azabicyclo[3.3.0]Octan-3-yl)methyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid

receive by removal of the protective group with tert-butyl methyl ether (1S,3S,5S)-3-{[(6-methylimidazo[2,1-b]thiazole-5-carbonyl)amino]methyl}-2-azabicyclo[3,3 .0]octane-2-carboxylic acid.

LC-MS: tR=0,56 min; [M+H]+=305,3.

[(1S,3S,5S)-(2-Azabicyclo[3.3.0]Octan-3-yl)methyl]amide benzo[d]isoxazol-3-carboxylic acid

receive by removing C the protective group with tert-butyl methyl ether (1S,3S,5S)-3-{[(benzo[d]isoxazol-3-carbonyl)amino]methyl}-2-azabicyclo[3.3.0]octane-2-carboxylic acid.

LC-MS: tR=to 0.71 min; [M+H]+=286,3.

[(1S,3S,5S)-(2-Azabicyclo[3.3.0]Octan-3-yl)methyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid

receive by removal of the protective group with tert-butyl methyl ether (1S,3S,5S)-3-{[(2,3-dihydrobenzofuran-4-carbonyl)amino]methyl}-2-azabicyclo[3.3.0]octane-2-carboxylic acid.

LC-MS: tR=0,70 min; [M+H]+=287,4.

B. Obtaining compounds of formula (I):

B.1 Synthesis carboxyamide derivatives (General method)

To a mixture of the corresponding carboxylic acid (0.44 mmol, 1.1 EQ.) in acetonitrile (1.0 ml) was added, TBTU (0.48 mmol, 1.2 equiv.) and then, after 30 minutes, DERAA (1.2 mmol, 3.0 EQ.). After 15 minutes, add a solution of the corresponding derivative of 2-azabicyclo[3.3.0]octane (0.40 mmol, 1.0 EQ.) in DHM (1.0 ml). The mixture is stirred overnight and then purified using preparative HPLC, obtaining the corresponding amide derivative.

II. Biological assays

The activity of compounds of the formula (I) as antagonists of orexin receptor was determined in accordance with the following experimental method.

Measurement of intracellular calcium:

Cells Chinese hamster ovary (Cho)expressing the human orexin-1-receptor and orexin-2-receptor, is responsible, grown in culture medium (Ham F-12 with L-glutamine)containing 300 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and 10%inactivated fetal calf serum (FCS). The cells are sown with a density of 20'000 cells/cell in a sterile 384-honeycomb tablet with a darker bottom (Greiner). All reagents obtained from the company Gibco BRL. Cropped tablets incubated over night at 37°C in a 5%atmosphere of CO2.

Human orexin-And as agonist is prepared in the form of 1 mm source of diluent in the mixture Meon/water (ratio 1:1), diluted in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO30.375 g/l and 20 mm HEPES, for use in the analysis at final concentration of 0.3 nm.

Antagonists receive in the form of 10 mm initial reconstitution solution in DMSO, then diluted in 384-honeycomb tablet, using DMSO, with subsequent transition to the dilution in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g/l and 20 mm HEPES. The next day the analysis in each cell add 50 ál of buffer for staining (HBSS containing 1% FCS, 20 mm HEPES, NaHCO3: 0.375 g/l, 5 mm test indicator (Sigma) and 3 μm fluorescent calcium indicator fluo-4 AM (1 mm initial solution in DMSO containing 10% planovoe acid). Then 384-cellular cellular tablet in ubermut for 50 min at 37°C in 5% CO 2followed by equilibration at room temperature for 30-120 min before measurement.

Inside fluorescent tomographic tablet reader (FLIPR2 or FLIPR Tetra, the company Molecular Devices) antagonists add in the amount of 10 μl/cell, incubated for 10 min and at the end add 10 ál of cell agonist. The fluorescence is measured for each cell with a 1-second intervals, and the height of each fluorescent peak is compared with the height of the fluorescence peak induced by 3 nm orexin with buffer instead of the antagonist. For each antagonist define the size of the IC50(the concentration of compound necessary for inhibiting 50% of the agonistic response). Calculated IC50the magnitude of the compounds may vary depending on the daily conduct of cellular analysis. Fluctuations of this kind are known to specialists in the field of technology.

IC50value 26 of the studied compounds lie in the range from 4 to 2438 nm against OX1the receptor. IC50the values of all the studied compounds lie in the range from 11 to 1669 nm against OH2the receptor. Antagonistic activity of some compounds presented in the table.

ExampleIC50(n the) OX 1IC50(nm) OX2
11740
71895
9275283
16111)12l)
19371)32l)
26481)411)

The values given in the table, measured using FLIPR2 or using the1)FLIPR Tetra.

1. The compound of formula (I) with stereogenic centers (1S,3S,5S)-configuration

where a represents thiazolyl, which is unsubstituted or monosubstituted, where Deputy independently from each other selected from the group including1-4alkyl, C3-6cycloalkyl and NH2;
Represents a phenyl, which is unsubstituted or mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, trifluoromethyl, NHC(O)CH3and halogen;
R1is with the battle group imidazo[2,1-b]thiazolyl or benzisoxazole, where these groups are, independently from each other unsubstituted or monosubstituted, where the substituents independently of one another selected from the group including1-4alkyl; or R1is a group of 2,3-dihydrobenzofuranyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where
Represents a phenyl, which is unsubstituted or independently of each other mono - or disubstituted where the substituents independently of one another selected from the group including1-4alkyl, trifluoromethyl and halogen;
or its pharmaceutically acceptable salt.

3. The compound according to claim 1, where
R1represents a

or its pharmaceutically acceptable salt.

4. The compound according to claim 1, selected from the group including:
[(1S,3S,5S)-2-(2-methyl-5-p-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[(1S,3S,5S)-2-(2-amino-5-p-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide of 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{(1S,3S,5S)-2-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-CFT is henyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{(1S,3S,5S)-2-[2-cyclopropyl-5-(4-forfinal)thiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
{(1S,3S,5S)-2-[2-cyclopropyl-5-(3-triptoreline)thiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid;
[(1S,3S,5S)-2-(2-methyl-5-p-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide benzo[d]isoxazol-3-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide benzo[d]isoxazol-3-carboxylic acid;
[(1S,3S,5S)-2-(2-cyclopropyl-5-phenylthiazol-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide benzo[d]isoxazol-3-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-chlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(4-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
[(1S,3S,5S)-2-(2-methyl-5-m-tolyltriazole-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[2-methyl-5-(3-tripto who were)thiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(4-bromophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3, 5dimethylphenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-bromo-4-forfinal)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3,4-differenl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(2,4-dimetilfenil)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3,4-dichlorophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3,4-dimetilfenil)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
{(1S,3S,5S)-2-[5-(3-acetamidophenyl)-2-methylthiazole-4-carbonyl]-2-azabicyclo[3.3.0]Octan-3-ylmethyl}amide 2,3-dihydrobenzofuran-4-carboxylic acid;
[(1S,3S,5S)-2-(2-methyl-5-phenylthiazol-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid and
[(1S,3S,5S)-2-(2-cyclopropyl-5-phenylthiazol-4-carbonyl)-2-azabicyclo[3.3.0]Octan-3-ylmethyl]amide 2,3-dihydrobenzofuran-4-carboxylic acid;
and the and its pharmaceutically acceptable salt.

5. Pharmaceutical composition having activity of the antagonists orexin receptor containing as an active component a compound of the formula (I) according to claim 1 or 4, or its pharmaceutically acceptable salt and at least one therapeutically inert excipient.

6. The compound according to claim 1 or 4, or its pharmaceutically acceptable salt for use as a medicinal product with the activity of the antagonists orexin receptor.

7. The use of compounds according to claim 1 or 4, or its pharmaceutically acceptable salt for a medicinal product for the treatment of sleep disorders.

8. The compound according to claim 1 or 4, or its pharmaceutically acceptable salt for the treatment of sleep disorders.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: method is realised by mixing a compound of formula (B) with p-toluenesulphonic acid or a monohydrate of toluenesulphonic acid in less than 1 molar equivalent with respect to the compound of formula (B), in a solvent while heating. An additional amount of p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid is then added to the mixed solution while cooling in such an amount that their total molar equivalent with p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid at the mixing step is equal to 1 molar equivalent or more with respect to the compound of formula (B). At the last step, the obtained solution is crystallised to separate a compound of formula (A).

EFFECT: obtaining a compound of formula (A) with stable high output.

12 cl, 1 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes the pyrrolo- and thiazolopyridinium compounds and their pharmaceutically acceptable salts covered by general structural formula I: wherein the values A, B, R1, R2, R3, R4, R5, R6, R7 and R8 are those as presented in cl.1, and a pharmaceutical composition based on the given compound for inhibition of hypoxia-inducible factor (HIF) hydroxylase activity.

EFFECT: there are produced and described new compounds able to modulate hypoxia-inducible factor (HIF) stability and/or activity.

29 cl, 178 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

wherein the cycle A represents a carbocyclic group or a heterocyclic group; R1 means (i) lower alkyl optionally substituted by halogen, (ii) lower alkenyl, (iii) lower alkynyl or (iv) a carbocyclic group; each of R3a, R3b, R3c and R3d independently means hydrogen, halogen, lower alkyl optionally substituted by halogen, lower alkenyl, carbocyclyl - lower alkoxy or a carbocyclic group, or R3a and R3b or R3c and R3d can form C3-C10 cycloalkane ring together with an adjoining carbon atoms and can form oxo; a pharmaceutically acceptable salt or solvate of said compound effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

EFFECT: preparing the pharmaceutically acceptable salt or solvate effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

18 cl, 139 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenyl-bipyrrolidine ureas of formula (I) ,

where values of R, R1, R2, R3, R4 and R5 are given in claim 1.

EFFECT: compounds are capable of binding with the H3 receptor, which enables use thereof to prepare a pharmaceutical composition and for diseases associated with the central nervous system.

10 cl, 36 ex

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