Ethinyl derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

 

The present invention relates to a derivative of ethinyl formula

where

X represents N or C-R1;

Y represents N or C-R2;

Z represents CH or N;

R4represents a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom, possibly substituted by 1-3 groups selected from halogen, lower alkyl, lower alkoxy or NRR';

R1represents hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, low cycloalkyl or is heteroseksualci, possibly substituted by hydroxy or alkoxy;

R2represents hydrogen, CN, lower alkyl or heteroseksualci;

R and R' independently from each other represent hydrogen or lower alkyl;

or their pharmaceutically acceptable salts or acid-additive salt, to a racemic mixtures, or her corresponding enantiomer and/or optical isomer and/or stereoisomer.

It was unexpectedly discovered that compounds of the General formula I are positive allosteric modulators (PAM, positive allosteric modulators) of metabotropic glutamate receptor subtype 5 (mGIuR5, metabotropic glutamate receptor subtype 5).

In the Central nervous system (CNS) the transmission of stimuli takes place through the interaction of the neurotransmitter, polylimonene, with neuroreceptors.

Glutamate is the main excitatory neurotransmitter in the brain and plays a crucial role in several functions of the Central nervous system (CNS). The receptor-dependent glutamate stimuli, divided into two main groups. The first main group, namely the group of ionotropic receptors that form ligand-controlled ion channels. Metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of receptors associated with G-proteins.

Currently there are eight different types of these receptors mGluR, and some of them are still divided into subtypes. Based on the homology of their sequences and mechanisms of signal transmission and selectivity for agonists, these eight receptors can be subdivided into three subgroups:

mGIuR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group, can be used to treat or prevent acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory disorders, tuberous sclerosis, and chronic and acute pain.

Other conditions that can be treated PR� this, are restricted brain function caused by bypass operations or transplants, inadequate cerebral circulation, spinal cord trauma, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. In addition, conditions that can be treated are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS, on issues related to amyotrophic lateral sclerosis), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or Parkinson's disease drug, and the state, which lead to glutamate-deficient functions, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.

Diseases that are completely or partially mediated by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents(2002), 12(12), 1845-1852 doi: 10.1517/13543776.12.12.1845/

A new way to develop selective modulators is to define the connections that action�t through an allosteric mechanism modulate the receptor by binding to a site different from the highly conservative orthostereoscopic of the binding site. Recently there are positive allosteric modulators of mGluR5 as a new pharmaceutical facilities offering this attractive alternative. Positive allosteric modulators are described, for example in WO 008/151184, WO 2006/048771, WO 2006/129199 and WO 2005/044797 and Molecular Pharmacology (1991), 40, 333-336; The Journal of Pharmacology and Experimental Therapeutics(2005) 313(1), 199-206.

Positive allosteric modulators are compounds that directly activate the receptors, and significantly enhance agonist-stimulated responses, increased activity and high efficiency. The binding of these compounds increases the affinity of glutamate-site agonist at its extracellular N-terminal section of binding. Thus, the positive allosteric modulation is an attractive mechanism for increasing the physiological activation of the corresponding receptor. There is a shortage of selective positive allosteric modulators of the receptor mGIuR5. Traditional receptor modulators mGIuR5 usually do not have sufficient solubility in water and show a low bioavailability when administered orally. Therefore, there remains a need for compounds which overcome these drawbacks and which� essentially constitute a selective positive allosteric modulators of the receptor mGIuR5.

Compounds of formula I differ a valuable therapeutic properties. They can be used in the treatment or prevention of disorders associated with positive allosteric modulators of the receptor mGIuR5.

The most preferred indications for compounds which are positive allosteric modulators, are schizophrenia and impaired cognitive functioning.

The present invention relates to compounds of formula I and their pharmaceutically acceptable salts, of these compounds as pharmaceutically active agents, to methods for their manufacture and use in the treatment or prevention of diseases associated with positive allosteric modulators of the receptor mGIuR5, such as schizophrenia and impaired cognitive activity, and to pharmaceutical compositions containing compounds of formula I.

The following definitions of General terms used in the present description apply irrespective of whether consider the terms separately or in combination.

As used here, the term "lower alkyl" denotes saturated, i.e. aliphatic hydrocarbon group comprising a straight or branched carbon chain of 1-4 carbon atoms. Examples of "alkyl" are methyl, ethyl, n-propyl, isopropyl and tert-b�Teal.

The term "alkoxy" denotes the group-O-R', where R' is a lower alkyl as defined above.

The term "etinil" denotes the group-C≡C-.

The term "low hydroxyalkyl" refers to lower alkyl groups as defined above where at least one hydrogen atom is substituted with hydroxy.

The term "low cycloalkyl" denotes a saturated carbon ring containing from 3 to 7 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "heterocyclyl" denotes a saturated carbon ring, where one or more than one carbon atom is replaced by oxygen or nitrogen heteroatom preferably represents O. Examples of such rings are tetrahydropyran-2, 3 or 4-yl, pyrrolidinyl, imidazolidinyl ureido, pyrazolidine, piperidinyl, piperazinyl or morpholinyl.

The term "6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom" includes the following aromatic ring: phenyl, 2, 3 - or 4-pyridinyl or pyrimidinyl.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable acid-additive salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric sour�and, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluensulfonate acid and the like.

The embodiment of the invention are compounds of formula I where X represents C-R1and Y represents C-R2and Z is N

where

R4represents a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom, possibly substituted by 1-3 groups selected from halogen, lower alkyl, lower alkoxy or NRR';

R1represents hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, low zakouril or is heteroseksualci, possibly substituted by hydroxy or alkoxy;

R2represents hydrogen, CN, lower alkyl or heteroseksualci;

R and R' independently from each other represent hydrogen or lower alkyl;

or their pharmaceutically acceptable acid-additive salt, racemic mixture, or a corresponding enantiomer and/or optical isomer and/or stereoisomer.

The following compounds are these compounds of formula IA:

6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine,

2-Methyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,

6-(2-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,

6-(3-Fluoro-phenylethynyl)-2-methyl-Pires�lo[1,5-a]pyrimidine,

6-(4-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,

2-Methyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine,

2-Methyl-6-p-tolylidene-pyrazolo[1,5-a]pyrimidine,

6-(4-Chloro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(2-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(3-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(4-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(4-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-m-tolylidene-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(3-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-p-tolylidene-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(4-chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine,

5-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-pyridin-2-ylamine,

2-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-pyrimidine-5-ylethynyl-pyrazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(3,4-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,

6-Phenylethynyl-2-(tetrahydro-Piran-4-yl)-pyrazol�[1,5-a]pyrimidine,

4-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine,

2-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-yl)-propan-2-ol,

2-tert-Butyl-6-(5-fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine,

6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,

3-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine,

2-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine,

2-tert-Butyl-6-(2,5-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine or

2-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine.

An additional preferred embodiment of the invention are compounds of formula 1B, where X represents C-R1, Y represents N and Z represents CH,

where

R4represents a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom, possibly substituted by 1-3 groups selected from halogen, lower alkyl, lower alkoxy or NRR';

R1represents hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, low cycloalkyl or is heteroseksualci, possibly substituted by hydroxy or alkoxy;

R and R' independently from each other represent hydrogen or lower alkyl;

or their pharmaceutically acceptable acid-additive salt, racemic mixture, or her appropriate enantio�EP and/or optical isomer and/or stereoisomer.

The following link covers the formula IB:

6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine,

2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine or

2-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol.

An additional preferred embodiment of the invention are compounds of formula I where X represents C-R1and Y and Z represent N,

where

R4represents a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom, possibly substituted by 1-3 groups selected from halogen, lower alkyl, lower alkoxy or NRR';

R1represents hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, low cycloalkyl or is heteroseksualci, possibly substituted by hydroxy or alkoxy;

R and R' independently from each other represent hydrogen or lower alkyl;

or their pharmaceutically acceptable acid-additive salt, racemic mixture, or a corresponding enantiomer and/or optical isomer and/or stereoisomer.

The following link covers the formula IB:

6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(2,5-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(3-fluoro-FeNi�ethinyl)-[1,2,4]triazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(3,4-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,

2-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,

2-Morpholine-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine,

2-Morpholine-4-yl-6-m-tolylidene-[1,2,4]triazolo[1,5-a]pyrimidine,

6-(3-Fluoro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine,

6-(3-Chloro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine or

6-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine.

An additional preferred embodiment of the invention are compounds of formula I where X represents C-R1, Y represents C-R2and Z represents CH,

where

R4represents a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom, possibly substituted by 1-3 groups selected from halogen, lower alkyl, lower alkoxy or NRR';

R1represents hydrogen, lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, low zakouril or is heteroseksualci, possibly substituted by hydroxy or alkoxy;

R2represents hydrogen, CN, lower alkyl or heteroseksualci;

R and R' independently from each other represent hydrogen or lower alkyl;

or their pharmaceutically acceptable acid-additive with�ü, racemic mixture, or a corresponding enantiomer and/or optical isomer and/or stereoisomer.

The following link covers the formula 1G:

6-Phenylethynyl-pyrazolo[1,5-a]pyridine or

2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridine.

An additional preferred embodiment of the invention are compounds of formula I, where X represents N, Y represents C-R2and Z represents CH,

where

R4represents a 6-membered aromatic substituent containing 0, 1 or 2 nitrogen atom, possibly substituted by 1-3 groups selected from halogen, lower alkyl, lower alkoxy or NRR';

R2represents hydrogen, CN, lower alkyl or heteroseksualci;

R and R' independently from each other represent hydrogen or lower alkyl;

or their pharmaceutically acceptable acid-additive salt, racemic mixture, or a corresponding enantiomer and/or optical isomer and/or stereoisomer.

The following connection formula covers D:

6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridine.

Obtaining compounds of formula I of the present invention can perform sequential or convergent synthetic processes. Syntheses of compounds of the invention are illustrated in the following schemes 1-6. Skills required for p�of Ogadenia reactions and purification of the resulting products known qualified specialist in this field. The substituents and indices used in the following description of methods, have the meanings given above.

Compounds of formula 1 can be manufactured by the methods given below, by methods described in the examples or similar methods. Appropriate reaction conditions for the individual stages of the reactions known to a qualified specialist in this field. The reaction sequence is not limited to that shown in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction can be changed easily. The source materials are either commercially available or can be obtained by methods similar to the methods described below or by methods described in references cited in the description or in the examples or by methods known in this field.

These compounds of formula 1 and their pharmaceutically acceptable salts can be obtained by methods known in this field, for example embodiments of the methods described below, according to which

(a) is subjected to interaction of the compound of formula 2

with a suitable aryl-acetylene of formula 3

to the compound of formula 1

where the substituents described above, or

b) the exposed�t the interaction of the compound of formula 4

with a compound of formula 5

what gives compound of formula I

where the substituents described above, and Gal represents a halogen selected from Cl, Br or I,

b) is subjected to interaction of the compound of formula 6

with a suitable aryl-acetylene of formula 3

to the compound of formula 1

where the substituents described above, and

if desired, transfer the compounds obtained into pharmaceutically acceptable acid-additive salts.

In addition, obtaining compounds of formula 1 are described in more detail in schemes 1-10 and in examples 1-51.

Scheme 1

6-Ethinyl-pyrazolo[1,5-a]pyrimidine of the formula IA can be obtained by the condensation of appropriately substituted 2H-pyrazol-3-ylamine 7 and bremelanotide aldehyde 8 with a monohydrate para-toluensulfonate acid in a solvent like n-butanol, which gives the corresponding derivative 6-bromo-pyrazolo[1,5-a]pyrimidine 9. The combination Sonogashira derivative 6-bromo-pyrazolo[1,5-a]pyrimidine 9 with an appropriately substituted aryl-acetylene 3 gives the desired 6-ethinyl-pyrazolo[1,5-a]pyrimidine of the formula IA (scheme 1).

Scheme 2

Alternatives�about, intermediate compound 9 can engage in the combination Sonogashira with trimethylsilyl-acetylene 10, which gives the derived 6-trimethylsilylethynyl-pyrazolo[1,5-a]pyrimidine 11. The deprotonation silyl groups with fluoride tetrabutylammonium (1.5 mmol silica gel) in a solvent such dichloromethane, gives the corresponding derivative etinil 12. The combination Sonogashira 12 with an appropriately substituted aryl-halide gives the desired 6-ethinyl-pyrazolo[1,5-a]pyrimidine of the formula IA (scheme 2). This reaction sequence alternative can be applied, coupling derived trimethylsilane 11 with an appropriately substituted aryl-halide under the reaction conditions Sonogashira with simultaneous addition of fluoride tetrabutylammonium, who is responsible for the deprotonation silila in the reaction mixture.

Figure 3

6-Ethinyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB can be obtained by a combination of Sonogashira aryl-acetylene 3 with 2-amino-5-iteration 13, which gives the corresponding derived 5-ethinyl-pyridine-2-ylamine 14. The reaction of 14 with (1,1-dimethoxy-alkyl)-dimethyl-amine 15 in the presence of acid catalyst, such trifluoroacetic acid, and solvent, such as ethanol, gives the corresponding amidine 16, which is treated with hydroxylamine hydrochloride in a solvent such as i-rOH : THF (5:1 V/V), which gives the desired N-hydroxyamides 17. Carry out the cyclization of this compound with trifluoroacetic anhydride in a solvent such as THF, gives the desired 6-ethinyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB (scheme 3).

Scheme 4

6-Ethinyl-[1,2,4]triazolo[1,5-a]pyrimidine of the formula IB can be obtained in a similar manner during the interaction of 2-amino-5-bromopyrimidine 18 (1,1-dimethoxy-alkyl)-dimethyl-amine 15 in the presence of acid catalyst, such trifluoroacetic acid, and solvent, such as ethanol, gives the corresponding amidine 19, which is treated with hydroxylamine hydrochloride in a solvent such as i-PrOH : THF (5:1 V/V), which gives N-hydroxyamides 20. Carry out the cyclization of this compound with trifluoroacetic anhydride in a solvent such as THF, gives the desired 6-ethinyl-[1,2,4]triazolo[1,5-a]pyrimidine of the formula IB (scheme 4).

Scheme 5

6-Ethinyl-pyrazolo[1,5-a]pyridine of formula 1G can be obtained in the decarboxylation of suitable substituted ether 6-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid 22 with Hydrobromic acid gives the corresponding derivative pyrazolo[1,5-a]pyridin-6-ol 23, which is in turn derived triflate 25, using triftormetilfullerenov anhydride 24 and base, such as triethyl�Jn, in a solvent such as dichloro methane. The combination Sonogashira 25 with an aryl-acetylene of formula 3 to give the desired 6-ethinyl-pyrazolo[1,5-a]pyridine of formula V (scheme 5).

Scheme 6

6-Ethinyl-[1,2,3]triazolo[1,5-a]pyridine of formula D can be obtained during the interaction of the appropriately substituted 5-aloperidin-aldehyde or ketone 26 with hydrazine in a solvent such as methanol, followed by oxidation with an oxidizing agent such as manganese dioxide, which gives the corresponding derivative 6-bromo-[1,2,3]triazolo[1,5-a]pyridine 27. The combination Sonogashira 27, aryl-acetylene 3 gives the desired 6-ethinyl-[1,2,3]triazolo[1,5-a]pyridine of formula D (scheme 6).

Scheme 7

6-Ethinyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB can be obtained by the reaction of 2-amino-5-yodellin 13 with a suitably substituted acid chloride 28 in the presence of base, such as Et3N, in a solvent such dichloromethane, which gives the corresponding N-(5-iodo-pyridin-2-yl)-amide 29. The reaction of 29 with a reagent of Losone in the solvent like toluene gives the corresponding thioamide 30. Interaction 30 with hydroxylamine hydrochloride and a base such as Et3N, in a solvent such tOH, gives the corresponding hydroxyamides 31, which is treated with p-TsCl and pyridine in a solvent like toluene, which gives t�bwamy 6-iodo-[1,2,4]triazolo[1,5-a]pyridine 32. The combination Sonogashira 27 with appropriately substituted aryl-acetylene 3 gives the desired 6-ethinyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB (scheme 7).

Scheme 8

6-Ethinyl-pyrazolo[1,5-a]pyridine of formula 1G can be obtained during the formation of 1-amino-3-bromo-pyridinium 2,4-dinitro-phenolate 35 from 3-bromopyridine 33 and 0-(2,4-dinitro-phenyl)-hydroxylamine 34 in a solvent like acetonitrile. Interaction derived pyridinium 35 with a suitably substituted methyl ether propionovoi acid 36 and a base, such as K2CO3in a solvent like DMF gives the corresponding ester 6-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid 37, which decarboxylases with Hydrobromic acid, yielding the corresponding derivative 6-bromo-pyrazolo[1,5-a]pyridine 38. The combination Sonogashira 38 with appropriately substituted aryl-acetylene 3 gives the desired 6-ethinyl-pyrazolo[1,5-a]pyridine of formula V (scheme 8).

Scheme 9

6-Ethinyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula 1 can be obtained during the condensation of the appropriately substituted 1H-1,2,4-triazole-5-amine 39 with 2-bromomalonate the aldehyde 40 in AcOH, gives the corresponding 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine 21. The combination Sonogashira 21 with appropriately substituted aryl-acetylene 3 gives the desired 6-ethinyl-[1,2,4]triazole�[1,5-a]pyrimidine of formula 1 (scheme 9).

Scheme 10

6-Ethinyl-[1,2,4]triazolo[1,5-a]pyrimidine of the formula IB can also be obtained during the condensation of appropriately substituted O-1,2,4-triazole-5-amine 39 with 2-bromomalonate the aldehyde 40 in AcOH, gives the corresponding 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine 21. The combination Sonogashira 21 with trimethylsilyl-acetylene 10 gives the corresponding 6-trimethylsilylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine 41. The combination Sonogashira to the cleavage in the reaction mixture of the silyl group with 41 suitably substituted aryl-halide 5 gives the desired 6-ethinyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula 1 (scheme 10).

Preferably, the compound of formula I as described herein, as well as its pharmaceutically acceptable salt used in the treatment or prevention of psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory disorders, chronic and acute pain, restricted brain function caused by bypass operations or transplants, inadequate cerebral circulation, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or drug parkinsonism, spasm mouse�, convulsions, migraine, urinary incontinence, gastroesophageal reflux disease, liver damage or liver failure, caused either by drugs or by disease, syndrome fragile X-chromosome, down syndrome, autism, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, eating disorders, namely bulimia or anorexia nervosa, and depression, especially in the treatment and prevention of acute and/or chronic neurological disorders, anxiety, chronic and acute pain, urinary incontinence and obesity.

Preferred indications are schizophrenia and cognitive disorders.

In addition, the present invention relates to the use of a compound of formula I as described herein, as well as its pharmaceutically acceptable salt for the manufacture of medicines, preferably for the treatment and prevention of the aforementioned disorders.

Biological analysis and data:

Analysis of the mobilization of intracellular Ca2+

Received line of monoclonal cells HEK-293, stably transfected with cDNA encoding the receptor mGlu5a man; for positive allosteric mGlu5 modulators selected cell line with low expression levels of receptors and low constitutive receptor activity, which allowed to differentiate agonist�economic activity in comparison with the AMP. Cells were cultured according to standard protocols (Freshney, 2000) modified by the method of Dulbecco medium Needle with a high content of glucose with the addition of 1 mm glutamine, 10% (V/V) thermoinactivation bovine calf serum, penicillin / streptomycin, 50 µg/ml of hygromycin and 15 μg/ml of blasticidin (all cell culture reagents and antibiotics were obtained from Invitrogen, Basel, Switzerland).

Approximately 24 hours before the experiment, 5×104cells/well were sown in covered with poly-D-lysine black / clear bottom 96-well plates. Cells were loaded with 2.5 μm Fluo - 4M into the loading buffer (1×HBSS, 20 mm HEPES) for 1 hour at 37°C and washed five times with a loading buffer. Cells was transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris, France) and added 11 logarithmically serially diluted solutions of the investigated compounds at 37°C, and cells were incubated for 10-30 minutes with the registration of fluorescence in real-time. After this pre-incubation stage, the agonist L-glutamate was added to the cells at a concentration corresponding to EC20(usually about 80 μm), with the registration of fluorescence in real-time to account for diurnal variations in reactivity of the cells, EC20glutamate was determined immediately before each experi�COP during the recording of the complete dose response curve - the effect of glutamate.

Responses were measured as the increase in fluorescence peak at minus primary (i.e. fluorescence without the addition of L-glutamate), normalized to the maximal stimulatory effect obtained with saturated concentrations of L-glutamate. Graphics built with % of the maximum stimulatory effect using XLfit, a program for drawing curves that iteration gets the data using the algorithm of loewenberg-Marquardt. The equation used analysis of competition single sites was represented by y=A+((B-A)/(1+((x/C)D))), where y represents the % of the maximum stimulatory effect, And represents the minimum y value, b is the maximum y value, C is the EC50, x is the log 10 of the concentration of the competing compound and D is the slope of the curve (the hill coefficient). From these curves was calculated EC50(concentration at which was achieved premaxilla stimulation), the hill coefficient, and the maximum response in % of the maximum stimulatory effect obtained with saturated concentrations of L-glutamate.

Positive signals obtained during pre-incubation with the test compounds PYRIDOXAMINE (i.e. before application of the EC20the concentration of L-glutamate), testified about the agonistic activity of the�, the absence of such signals showed a lack of agonistic activity. The decrease in signal was observed after adding EC20the concentration of L-glutamate, indicating that the inhibitory activity of the test compounds.

In the list of examples below shows the corresponding results for compounds that all have with EC50<500 nm.

PR.StructureNameEC50(nm) mGlu5 PAMEff. (%)
170116
22-Methyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine4999
36-(2-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine4781
4-(3-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine 4277
56-(4-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine7874

62-Methyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine49882
72-Methyl-6-p-tolylidene-pyrazolo[1,5-a]pyrimidine13273
86-(4-Chloro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine14869
92-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine575
10 2-tert-Butyl-6-(2-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine1980
112-tert-Butyl-6-(3-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine586
122-tert-Butyl-6-(4-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine775

132-tert-Butyl-6-pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine3388
142-tert-Butyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine437
152-tert-Butyl-6-(4-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine6853
162-tert-Butyl-6-m-tolylidene-pyrazolo[1,5-a]pyrimidine10050
172-tert-Butyl-6-(3-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine10441
182-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine182102

192-tert-Butyl-6-p-tolylidene-pyrazolo[1,5-a]pyrimidine10068
202-tert-Butyl-6-(4-chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine40089
212-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5 a]pyrimidine 18377
225-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-pyridin-2-ylamine25598
232-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine3459
242-tert-Butyl-6-pyrimidine-5-ylethynyl-pyrazolo[1,5-a]pyrimidine18168

252-tert-Butyl-6-(3,4-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine4593
266-Phenylethynyl-2-(tetrahydro-Piran-4-yl)-pyrazolo[1,5-a]pyrimidine472124
27 4-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine4199
282-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-yl)-propan-2-ol15259
292-tert-Butyl-6-(5-fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine16161
306-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile31063
316-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin274123

326-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine210 100
336-Phenylethynyl-pyrazolo[1,5-a]pyridin13688
346-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridin5077
353-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine3769
362-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine15588
372-tert-Butyl-6-(2,5-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine3965
382-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine18 53

392-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin3054
402-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol6688
412-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridin32122
422-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine973
432-tert-Butyl-6-(2,5-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine1437
442-tert-BU�Il-6-(3-fluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine 985

452-tert-Butyl-6-(3,4-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine2854
462-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine4749
472-Morpholine-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine69119
482-Morpholine-4-yl-6-m-tolylidene-[1,2,4]triazolo[1,5-a]pyrimidine5884
496-(3-Fluoro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine50101
50 6-(3-Chloro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine3988

516-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine56141

Compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of pills, tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However effective also may be rectal administration, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

Compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used, for example, as �such carriers for tablets, of tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols, etc.; however, depending on the nature of the active substance carriers are usually not required for soft gelatin capsules. Suitable carriers for the receiving of solutions and syrups are e.g. water, polyols, sucrose, invert sugar, glucose etc. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils, etc., can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but, as a rule, are not necessary. Suitable carriers for suppositories are e.g. natural or solidified oils, waxes, fats, semi-liquid or liquid polyols etc.

In addition, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

As mentioned earlier, medication, containing the compound of formula (I) or its pharmaceutically acceptable salt and a therapeutically inert excipio�t, also are the subject of the present invention, as the method of obtaining these drugs, wherein one or more compounds of formula 1 or their pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances turn into a galenical dosage form together with one or more than one therapeutically inert carrier.

As mentioned earlier, the use of compounds of formula (I) to obtain drugs that are useful for the prevention and/or treatment of the above diseases is also an object of the present invention.

The dosage may vary within wide limits and, of course, must be matched according to the individual requirements in each particular case. In General, an effective dosage for oral or parenteral administration is in the range of 0.01-20 mg/kg/day, at a dose of 0.1-10 mg/kg/day being preferred for all of the described indications. The daily dosage for an adult person weighing 70 kg, respectively, is in the range of 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

Obtaining pharmaceutical compositions containing the compounds of the invention are:

Tablets of the following composition is prepared in the usual way:

�g/tablet
Active ingredient100
Powdered lactose95
White corn starch35
Polyvinylpyrrolidone8
Na carboxymethylcel10
Magnesium stearate2
Tablet weight250

Experimental section:

Example 1

6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine

Bis-(triphenylphosphine)-palladium (II) dichloride (27 mg, 0.04 mmol) was dissolved in 1 ml THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg, 0,76 mmol) and phenylacetylene (130 µl, 1.21 mmol) was added at room temperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg, is 0.023 mmol) and copper iodide (I) (4 mg, is 0.023 mmol) was added and the mixture stirred for 2 hours at 65°C. the Reaction mixture was cooled and extracted with saturated solution of NaHCO3and two times a small volume of dichloromethane. The crude product was purified using flash chromatography by directly loading dichloromethane layers in a column with silica gel and elwira heptane : atilas�tat 100:0→50:50. The desired compound was obtained as a yellow solid (150 mg, 90%), MS: m/e=RUB 220.3 (M+H+).

Example 2

2-Methyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, white solid, MS: m/e=234,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and phenylacetylene.

Example 3

6-(2-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=252,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethinyl-2-fluoro-benzene.

Example 4

6-(3-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=252,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethinyl-3-fluoro-benzene.

Example 5

6-(4-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=252,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-�tinil-4-fluoro-benzene.

Example 6

2-Methyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=amount of 235.1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethenylpyridine.

Example 7

2-Methyl-6-p-tolylidene-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, brown solid, MS: m/e=248,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-atenolol.

Example 8

6-(4-Chloro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, brown solid, MS: m/e=268,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-chloro-4-ethynylbenzene.

Example 9

2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine

3-tert-Butyl-1H-pyrazol-5-amine (9 g, or 64.7 mmol) was dissolved in BuOH (100 ml). 2-Bromley aldehyde (9,76 g, or 64.7 mmol) and p-TsOH*H2O (615 mg, 3.23 mmol) was added at room temperature. The mixture was stirred in tech�of 16 hours at 100°C. The reaction mixture was evaporated to dryness and the residue was purified using flash chromatography on silica gel (120 g, 0% to 40% EtOAc in heptane) and crystallization with a small amount of diisopropyl ether. The crystals were washed with diisopropyl ether and dried for 1 hour at 50°C and <20 mbar. The desired compound was obtained as a light yellow solid (9.5 g, yield 58%), MS: m/e=256,1/254,1 (M+H+).

Stage 2: 2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=276,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and phenylacetylene.

Example 10

2-tert-Butyl-6-(2-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=294,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethinyl-2-fluoro-benzene.

Example 11

2-tert-Butyl-6-(3-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=294,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazol�[1,5-a]pyrimidine (example 9, stage 1) and 1-ethinyl-3-fluoro-benzene.

Example 12

2-tert-Butyl-6-(4-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=294,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethinyl-4-fluoro-benzene.

Example 13

2-tert-Butyl-6-pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, white solid, MS: m/e=277,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 3-ethynylpyridine.

Example 14

2-tert-Butyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, white solid, MS: m/e=277,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 4-ethenylpyridine.

Example 15

2-tert-Butyl-6-(4-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, yellow solid, MS: m/e=306,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butylpyrazine[1,5-a]pyrimidine (example 9, stage 1) and 1-ethinyl-4-methoxybenzene.

Example 16

2-tert-Butyl-6-m-tolylidene-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, yellow solid, MS: m/e=290,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethinyl-3-methylbenzol.

Example 17

2-tert-Butyl-6-(3-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, yellow solid, MS: m/e=306,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethinyl-3-methoxybenzene.

Example 18

2-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-2-cyclobutyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, yellow solid, MS: m/e=254,0/252,1 (M+H+), can be obtained in accordance with the General method of example 9, step 1 from 5-cyclobutyl-1H-pyrazol-3-ylamine and 2-bromoanisole aldehyde.

Stage 2: 2-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=274,3 (M+H+), can be obtained in accordance� with the General method of example 1 from 6-bromo-2-cyclobutyl-pyrazolo[1,5-a]pyrimidine (example 18, stage 1) and phenylacetylene.

Example 19

2-tert-Butyl-6-p-tolylidene-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=290,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethinyl-4-methylbenzol.

Example 20

2-tert-Butyl-6-(4-chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=310,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethinyl-4-chlorobenzene.

Example 21

2-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

Stage 1: 2-tert-Butyl-6-trimethylsilylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, brown solid, MS: m/e=272,3 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and trimethylsilylacetamide.

Stage 2: 2-tert-Butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine

2-tert-Butyl-6-trimethylsilylethynyl-pyrazolo[1,5-a]p�rimidine (example 21, stage 1) (2.4 g, of 8.85 mmol) was dissolved in dichloromethane (10 ml) and the fluoride of tetrabutylammonium on silica gel (7.1 g, 10.6 mmol, 1.5 mmol/g) was added at room temperature. The mixture was stirred for 2 hours at room temperature and was purified using flash chromatography by directly loading the mixture in a 70 g silica column and elwira heptane: ethyl acetate 100:0→40:60. The desired compound was obtained as a light yellow solid (1.45 g, yield 83%), MS: m/e=of 200.2 (M+H+).

Stage 3: 2-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=311,3 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 2-chloro-5-yodellin.

Example 22

5-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-pyridin-2-ylamine

Specified in the title compound, solid white, MS: m/e=292,1 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 5-yodellin-2-amine.

Example 23

2-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid �emesto, MS: m/e=311,2 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 3-bromo-5-chloropyridine.

Example 24

2-tert-Butyl-6-pyrimidine-5-ylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=278,2 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 3-bromopyrimidine.

Example 25

2-tert-Butyl-6-(3,4-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=312,2 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 1,2-debtor-4-yogashala.

Example 26

6-Phenylethynyl-2-(tetrahydro-Piran-4-yl)-pyrazolo[1,5-a]pyrimidine

Stage 1: 5-(Tetrahydro-Piran-4-yl)-2H-pyrazol-3-ylamine

Specified in the title compound can be obtained in accordance with the General method described in patent application WO 2008001070 (example 114).

Stage 2: 6-Bromo-2-(tetrahydro-Piran-4-yl)-pyrazolo[1,5-a]pyrimidine

Specified in �agolove connection light brown solid, MS: m/e=284,0 (M+H+), can be obtained in accordance with the General method of example 9, step 1 from 5-(tetrahydro-Piran-4-yl)-2H-pyrazol-3-ylamine (example 26, step 1) and 2-bromoanisole aldehyde.

Stage 3: 6-Phenylethynyl-2-(tetrahydro-Piran-4-yl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, grey solid, MS: m/e=304,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-(tetrahydro-Piran-4-yl)-pyrazolo[1,5-a]pyrimidine (example 26, step 2) and phenylacetylene.

Example 27

4-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine

Specified in the title compound, brown solid, MS: m/e=291,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 4-itinerancia.

Example 28

2-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-yl)-propan-2-ol

Stage 1: Methyl ester of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

Specified in the title compound, brown solid, MS: m/e=256,0/254,1 (M+H+), can be obtained in accordance with the General method of example 9, step 1, from methyl 5-amino-1H-pyrazole-3-carboxylate and 2-bromoanisole aldehyde./p>

Stage 2: Methyl ester of 6-phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

Specified in the title compound, grey solid, MS: m/e=278,2 (M+H+), can be obtained in accordance with the General method of example 1 from methyl ester of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (example 28, step 1) and phenylacetylene.

Stage 3: 2-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-yl)-propan-2-ol

Methyl ester of 6-phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (example 28, step 2) (60 mg, 0,22 mmol) was dissolved in 5 ml of THF and cooled to 0-5°C. a Solution of Metalmania chloride (150 μl, 0.45 mmol, 3 n in THF) was added dropwise at 0-5°C. the Reaction mixture was stirred for 30 minutes at 0-5°C. was Added water and the mixture was extracted with twice with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatography on silica gel (heptane : EtOAc 100:0→70:30) and was suspended in Et2O. the Desired compound was obtained as a light brown solid (7 mg, yield 12%), MS: m/e=278,1 (M+H+).

Example 29

2-tert-Butyl-6-(5-fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=295,3 (M+H+), can be�ü obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2.) and 3-bromo-5-fervently.

Example 30

6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Specified in the title compound, yellow solid, MS: m/e=245,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-pyrazolo[1,5-a]pyrimidine-3-carbonitrile and phenylacetylene.

Example 31

6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin

Stage 1: 5-Phenylethynyl-pyridin-2-ylamine

Specified in the title compound, light yellow solid, MS: m/e=195,2 (M+H+), can be obtained in accordance with the General method of example 1 from 2-amino-5-yodellin and phenylacetylene.

Stage 2: 6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin

Specified in the title compound, white solid, MS: m/e=RUB 220.3 (M+H+), can be obtained in accordance with the General method described in patent application WO 2007059257 (page 109, step A, b and C), based on 5-phenylethynyl-pyridine-2-ylamine (example 31, step 1).

Example 32

6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, white solid, MS: m/e=201,0/199,2 (M+H+), can be obtained in accordance with the General method�m, described in the patent application WO 2007059257 (page 109, step A, b and C) on the basis of 2-amino-5-bromopyrimidine.

Stage 2: 6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=of 221.2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (example 32, step 1) and phenylacetylene.

Example 33

6-Phenylethynyl-pyrazolo[1,5-a]pyridin

Stage 1: Pyrazolo[1,5-a]pyridin-6-ol

Specified in the title compound, white solid, MS: m/e=135,1 (M+H+), can be obtained in accordance with the General method described in EP 1972628.

Stage 2: Pyrazolo[1,5-a]pyridine-6-silt ether of trifter-methanesulfonic acid

Pyrazolo[1,5-a]pyridin-6-ol (example 22, step 1) (200 mg, 1,49 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (200 μl, 1.49 mmol) and the anhydride triftormetilfullerenov acid (250 μl, 1.49 mmol) was added at 0-5°C. the Mixture was stirred for 1 hour at room temperature and then was extracted with a saturated solution of NaHCO3and twice with dichloromethane. The organic layers were extracted with brine, dried over Na2SO4, filtered and evaporated to dryness. The desired compound was obtained in the form�e white solid (400 mg, quantitative), MS: m/e=267,0 (M+H+).

Stage 3: 6-Phenylethynyl-pyrazolo[1,5-a]pyridin

Specified in the title compound, light yellow solid, MS: m/e=219,2 (M+H+), can be obtained in accordance with the General method of example 1 from pyrazolo[1,5-a]pyridine-6-silt ether of trifter-methanesulfonic acid (example 33, step 2) and phenylacetylene.

Example 34

6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridin

Stage 1: 6-Bromo-[1,2,3] triazolo[1,5-a]pyridin

Specified in the title compound, light brown solid, MS: m/e=200,1/198,0 (M+H+), can be obtained in accordance with the General method described in B. Abarca et al. / Tetrahedron 64 (2008) 3794-3801.

Stage 2: 6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridin

Specified in the title compound, light brown solid, MS: m/e=RUB 220.3 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-[1,2,3]triazolo[1,5-a]pyridine (example 34, step 1) and phenylacetylene.

Example 35

3-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine

Specified in the title compound, light yellow solid, MS: m/e=291,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 3-Atin�of lanoline.

Example 36

2-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine

Specified in the title compound, light yellow solid, MS: m/e=291,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 2-itinerancia.

Example 37

2-tert-Butyl-6-(2,5-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, white solid, MS: m/e=312,2 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-ethinyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 1,4-debtor-2-yogashala.

Example 38

2-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-2-isopropyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=240,2/of 242.2 (M+H+), can be obtained in accordance with the General method of example 1, step 1, from 5-isopropyl-2H-pyrazol-3-ylamine.

Stage 2: 2-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Specified in the title compound, brown solid, MS: m/e=245,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-isopropyl-pyrazolo[1,5-a]pyrim�Dean (example 38, stage 1) and phenylacetylene.

Example 39

2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin

Stage 1: N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamide

5-Yodellin-2-amine (5 g, 22,7 mmol) was dissolved in 50 ml of dichloromethane and Et3N (6,3 ml, 45.5 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5°C and pualeilani (3,4 ml, 27.3 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was stirred for 1 hour at 0-5°C. was Added a saturated solution of NaHCO3and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The desired N-(5-yodellin-2-yl)pivalate (7,34 g, a yield of 99.8%) was obtained as brown oil, MS: m/e=305,0 (M+H+).

Stage 2: N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionic

N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (example 39, step 1) (5.8 g, 19,1 mmol) was dissolved in 30 ml of toluene and reagent Losson (7.7 g, 19,1 mmol, 1 equiv.) was added at room temperature. The reaction mixture was stirred for 48 hours at 110°C. the Crude product was purified using flash chromatography by directly loading the cooled toluene the reaction mixture into 300 g of silica-gel column and elwira heptane : ethyl acetate 100:0→80:20. Required�desired N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionic was obtained as yellow oil (5.1 g, the 75% yield), MS: m/e=321,0 (M+H+).

Stage 3: N-Hydroxy-N'-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamide

.

N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionic (example 39, step 2) (5.1 g, 15,9 mmol) was dissolved in 50 ml of EtOH and Et3N (2,9 ml, of 20.7 mmol, 1.3 equiv.) and hydroxylamine hydrochloride (1.3 g, 19,1 mmol, 1.2 equiv.) was added at room temperature. The mixture was stirred for 2 hours at room temperature. The suspension was diluted with 100 ml of water and filtered. The crystals were washed with water and dried for 2 hours at 50°C and <10 mbar. The desired N-hydroxy-N'-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (4.35 g, yield 86%) was obtained as white solid, MS: m/e=319,9 (M+H+).

Stage 4: 2-tert-Butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridin

N-Hydroxy-N'-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (example 39, step 3) (2.8 g, 8,77 mmol) was suspended in 15 ml of toluene and pyridine (2.8 ml, or 35.1 mmol, 4 equiv.). The mixture was cooled to 0-5°C and added n-toluensulfonate (6.7 g, 35.1 per mmol, 4 equiv.). The reaction mixture was stirred for 1 hour at 0-5°C and 4 hours at room temperature. The reaction mixture was extracted with saturated solution of NaHCO3and two times a small volume of dichloromethane. The crude product was purified using flash chromatography by directly loading dichlormethane� layers in a 20 g silica column and elwira heptane: ethyl acetate 100:0→0:100. The desired 2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (2 g, yield 76%) was obtained as a light yellow oil, MS: m/e=302,1 (M+H+).

Stage 5: 2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin

Specified in the title compound, yellow solid, MS: m/e=276,2 (M+H+), can be obtained in accordance with the General method of example 1 from 2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (example 39. stage 4) and phenylacetylene.

Example 40

2-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol

Stage 1: 3-Acetoxy-2,2-dimethyl-propionic acid;

A solution of 3-hydroxy-2,2-dimethyl-propionic acid (1.5 g, 12,69 mmol) in 5 ml of acetyl chloride was heated at 80°C in a nitrogen atmosphere for 2 hours. The excess acetyl chloride was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried and evaporated to obtain the desired 3-acetoxy-2,2-dimethyl-propionic acid (1.65 g, yield 81%) as colorless liquid.

Stage 2: 2-Chlorocarbonyl-2-methyl-propyl ester of acetic acid

To a solution of 3-acetoxy-2,2-dimethyl-propionic acid (example 40, step 1) (2.2 g, to 13.75 mmol) in CH2Cl2(25 ml) was added� oxaliplatin (2,62 ml Of 27.50 mmol) and 2-4 drops of DMF and stirred at 25°C for 3 hours. The solvent was evaporated and the resulting 2-chlorocarbonyl-2-methyl-propyl ester of acetic acid (2.4 g) used directly in the next stage without purification.

Stage 3: 2-(5-iodo-pyridin-2-ylcarbonyl)-2-methyl-propyl ester of acetic acid

Specified in the title compound, white solid, MS: m/e=363,2 (M+H+), can be obtained in accordance with the General method of example 39, step 1, from 2-amino-5-yodellin and 2-chlorocarbonyl-2-methyl-propyl ester acetic acid (example 40, step 2).

Stage 4: 2-(5-iodo-pyridin-2-illiotibial)-2-methyl-propyl ester of acetic acid

Specified in the title compound, MS: m/e=379,4 (M+H+), can be obtained in accordance with the General method of example 39, step 2, from 2-(5-iodo-pyridin-2-ylcarbonyl)-2-methyl-propyl ester acetic acid (example 40, step 3).

Stage 5: 2-[N-hydroxy-N'-(5-iodo-pyridin-2-yl)-carbamimidoyl]-2-methyl-propyl ester of acetic acid

Specified in the title compound, MS: m/e=378,0 (M+H+), can be obtained in accordance with the General method of example 39, step 3 from 2-(5-iodo-pyridin-2-illiotibial)-2-methyl-propyl ester acetic acid (example 40, step 4).

Stage 6: 2-(6-Iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propyl ester of acetic acid

Specified in the title compound, white solid, MS: m/e=360,0 (M+H+), can be obtained in accordance with the General method of example 39, step 4, from 2-[N-hydroxy-N'-(5-iodo-pyridin-2-yl)-carbamimidoyl]-2-methyl-propyl ester acetic acid (example 40, step 5).

Step 7: 2-(6-Iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propane-1-ol

A solution of 2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propyl ester acetic acid (example 40, step 6) (750 mg, of 2.09 mmol) and K2CO3(576 mg, 4,18 mmol, 2 equiv.) in MeOH (8 ml) was stirred at 25°C for 2 hours. The solvent was evaporated and the resulting crude product was purified by column chromatography. The desired 2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propane-1-ol (662 mg, yield 91%) was obtained as white solid, MS: m/e=318,0 (M+H+).

Stage 8: 2-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol

Specified in the title compound, brown solid, MS: m/e=292,0 (M+H+), can be obtained in accordance with the General method of example 1 from 2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propane-1-ol (example 40, step 7) and phenylacetylene.

p> Example 41

2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridin

Stage 1: 1-Amino-3-bromo-pyridinium 2,4-dinitro-phenolate

To a solution of 3-bromopyridine (2.3 g, 15.0 mmol) in acetonitrile (4 ml) was added O-(2,4-dinitro-phenyl)-hydroxylamine (3.0 g, 15.0 mmol, 1 equiv.) and the reaction mixture was stirred at 40°C for 16 hours. Then the solvent was evaporated, the resulting residue was triturated with ether, and dried to obtain the desired 1-amino-3-bromo-pyridinium 2,4-dinitro-phenolate (4.5 g, yield 85%) as brown solid substance.

Stage 2: Methyl ester of 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid

To a solution of 1-amino-3-bromo-pyridinium 2,4-dinitro-phenolate (example 41, step 1) (1.98 g, 14,16 mmol) in DMF (20 ml) was added methyl ester of 4,4-desmethyl-pent-2-invoi acid (CAS 20607-85-6) (5 g, 14,16 mmol, 1 equiv.) and K2CO3(3.9 g, is 28.3 mmol, 2 equiv.) and stirred at 25°C by blowing air. DMF was completely evaporated, the residue was dissolved in ethyl acetate and washed with water (100 ml). The organic extract was dried with sodium sulfate, filtered and evaporated to dryness. The resulting crude product together with undesirable regioisomer methyl ether 4-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carbon�th acid was purified by column chromatography. The desired methyl ester 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (1.04 g, yield 24%) was obtained as white solid, MS: m/e=312,2 (M+H+).

Stage 3: 6-Bromo-2-tert-butyl-pyrazolo[1,5-a]pyridin

A solution of methyl ester of 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (example 41, step 2) (1.1 g, of 3.53 mmol) in H2SO4(5 ml) and H2O (5 ml) was heated at 80°C for 36 hours. The reaction mixture was neutralized with 2 n sodium hydroxide and was extracted with ethyl acetate (4×60 ml). The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified using flash chromatography (heptane: EtOAc 95:5→90:10). The desired 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (370 mg, yield 38%) was obtained as white solid, MS: m/e=254,2 (M+H+).

Stage 4: 2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridin

Specified in the title compound, white solid, MS: m/e=275,4 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (example 41, step 3) and phenylacetylene.

Example 42

2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine

3-tert-Butyl-1H-1,2,4-triazole-5-amine (CAS 202403-45-0) (35%, 13 g, 32.5 mmol) was dissolved in acetic acid (50 ml) was added 2-Bromley aldehyde (7,35 g of 48.7 mmol, 1.5 equiv.). The reaction mixture was stirred for 3 hours at 60°C. the Reaction mixture was evaporated, neutralized with saturated 2 n solution of NaHCO3and extracted twice with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified using flash chromatography on 70 g of silica gel (heptane: EtOAc 100:0→50:50). The desired 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (6,83 g, yield 83%) was obtained as white solid, MS: m/e=255,0/257,1 (M+H+).

Stage 2: 2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, yellow solid, MS: m/e=277,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and phenylacetylene.

Example 43

2-tert-Butyl-6-(2,5-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Stage 1: 2-tert-Butyl-6-trimethylsilylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=273,3 (M+1H+), can be obtainedfrom in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, stage 1) and ethinyl-trimethyl-silane.

Stage 2: 2-tert-Butyl-6-(2,5-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

2-tert-Butyl-6-trimethylsilylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) (100 mg, of 0.37 mmol) was dissolved in DMF (1 ml). 1,4-Debtor-2-iadanza (176 mg, 0,73 mmol, 2 equiv.), Et3N (150 μl, 1.1 mmol, 3 equiv.), bis-(triphenylphosphine)-palladium (II) dichloride (13 mg, 0.02 mmol, 0.05 equiv.), triphenylphosphine (3 mg, is 0.011 mmol, of 0.03 equiv.) and copper iodide (I) (2 mg, is 0.011 mmol, of 0.03 equiv.) was added in a nitrogen atmosphere and the mixture was heated to 80°C. 1 M TBAF in THF (440 μl, 0.44 mmol, 1.2 equiv.) was added dropwise within 20 minutes at 80°C. the Reaction mixture was stirred for 5 minutes at 80°C. the Reaction mixture was evaporated and extracted with saturated solution of NaHCO3and two times a small volume of dichloromethane. The crude product was purified using flash chromatography by directly loading dichloromethane layers in a 20 g silica column and elwira heptane : ethyl acetate 100:0→50:50. The desired 2-tert-butyl-6-(2,5-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine (73 mg, yield 64%) was obtained as a light yellow solid, MS: m/e=313,1 (M+N+).

Example 44

2-tert-Butyl-6-(3-fluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light gelcoated substance MS: m/e=295,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and ethinyl-3-fervently.

Example 45

2-tert-Butyl-6-(3,4-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=313,1 (M+H+), can be obtained in accordance with the General method of example 43, step 2, from 2-tert-butyl-6-trimethylsilylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) and 3,4-debtor-4-yogashala.

Example 46

2-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=312,2/314,1 (M+H+), can be obtained in accordance with the General method of example 43, step 2, from 2-tert-butyl-6-trimethylsilylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) and 3-chloro-5-yodellin.

Example 47

2-Morpholine-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light yellow solid, MS: m/e=284,2/286,1 (M+H+), can be obtained in accordance with the General method of example 42, step 1, from 5-Maur�Olin-4-yl-2H-[1,2,4]triazole-3-ylamine (CAS 51420-46-3) and 2-bromoanisole aldehyde.

Stage 2: 2-Morpholine-4-yl-6-Phenylethynyl[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=306,1 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and phenylacetylene.

Example 48

2-Morpholine-4-yl-6-m-tolylidene-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, brown solid, MS: m/e=320,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethinyl-3-methylbenzol.

Example 49

6-(3-Fluoro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=324,3 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethinyl-3-fervently.

Example 50

6-(3-Chloro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=340,0/342,1 (M+H+), can be obtained in accordance with the General method �reamer 1 of 6-bromo-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, stage 1) and ethinyl-3-chlorobenzene.

Example 51

6-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Stage 1: 6-Bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light red solid, MS: m/e=268,1/RUB 270.1 (M+H+), can be obtained in accordance with the General method of example 42, step 1, from 5-pyrrolidin-1-yl-1H-[1,2,4]triazole-3-ylamine (CAS 154956-89-5) and 2-bromoanisole aldehyde.

Stage 2: 6-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Specified in the title compound, light brown solid, MS: m/e=290,2 (M+H+), can be obtained in accordance with the General method of example 1 from 6-bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 51, step 1) and phenylacetylene.

1. Derivative etinil of the formula I

where
X represents N or C-R1;
Y represents N or C-R2;
Z represents CH or N;
R4represents a 6-membered aromatic ring containing 0, 1 or 2 nitrogen atom, possibly substituted with 1-2 groups selected from halogen, lower alkyl, lower alkoxy or NRR';
R1represents hydrogen, lower alkyl, lower hydroxyalkyl, low cycloalkyl or performance�t a 5-6-membered heteroseksualci, containing 1-2 heteroatom selected from O and N;
R2represents hydrogen, CN;
R and R' independently from each other represent hydrogen;
or their pharmaceutically acceptable salt, or acid-additive salt,
provided that compounds
6-(3-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridine,
6-(3-forgenerating)-[1,2,4]triazolo[1,5-a]pyridine,
6-(3-methylphenylethyl)-[1,2,4]triazolo[1,5-a]pyridine,
6-(4-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridine,
6-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridine,
6-(4-methylphenylethyl)-[1,2,4]triazolo[1,5-a]pyridine,
6-(3,4-differentiating)-[1,2,4]triazolo[1,5-a]pyridine,
6-(2-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridine and
6-(6-methylpyridine-2-ylethynyl)-[1,2,4]triazolo[1,5-a]pyridine;
excluded.

2. Derivative etinil of the formula IA according to claim 1 for compounds of formula I where X represents C-R1and Y represents C-R2and Z represents N,

where
R4represents a 6-membered aromatic ring containing 0, 1 or 2 nitrogen atom, possibly substituted with 1-2 groups selected from halogen, lower alkyl, lower alkoxy or NRR';
R1represents hydrogen, lower alkyl, lower hydroxyalkyl, low cycloalkyl or is a 5-6-membered heteroseksualci containing 1-2 heteroatom selected from O and N;
R2performance�ulation of a hydrogen, CN;
R and R' independently from each other represent hydrogen;
or their pharmaceutically acceptable acid-additive salt.

3. Derivative etinil of the formula IA according to claim 2, which compounds are
6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,
2-methyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,
6-(2-fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,
6-(3-fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,
6-(4-fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,
2-methyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine,
2-methyl-6-p-trilateral-pyrazolo[1,5-a]pyrimidine,
6-(4-chloro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(2-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(3-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(4-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(4-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-m-trilateral-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(3-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-p-trilateral-pyrazolo[1,5-a]pyrimidine
2-tert-butyl-6-(4-chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine,
5-(2-tert-butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-pyridin-2-ylamine,
2-tert-butyl-6-(5-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-pyrimidine-5-ylethynyl-pyrazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(3,4-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine,
6-phenylethynyl-2-(tetrahydro-Piran-4-yl)-pyrazolo[1,5-a]pyrimidine,
4-(2-tert-butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine,
2-(6-phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-yl)-propan-2-ol,
2-tert-butyl-6-(5-fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine,
6-phenylethynyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,
3-(2-tert-butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine,
2-(2-tert-butyl-pyrazolo[1,5-a]pyrimidine-6-ylethynyl)-phenylamine,
2-tert-butyl-6-(2,5-debtor-phenylethynyl)-pyrazolo[1,5-a]pyrimidine or
2-isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine.

4. Derivative ethinyl formula IB according to claim 1 for compounds of formula I where X represents C-R1, Y represents N and Z represents CH,

where
R4represents a 6-membered aromatic ring containing 0, 1 or 2 nitrogen atom, possibly substituted with 1-2 groups selected from Gal�gene lower alkyl, lower alkoxy or NRR';
R1represents hydrogen, lower alkyl, lower hydroxyalkyl, low cycloalkyl or is a 5-6-membered heteroseksualci containing 1-2 heteroatom selected from O and N;
R and R' independently from each other represent hydrogen;
or their pharmaceutically acceptable acid-additive salt,
provided that compounds
6-(3-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridine,
6-(3-forgenerating)-[1,2,4]triazolo[1,5-a]pyridine,
6-(3-methylphenylethyl)-[1,2,4]triazolo[1,5-a]pyridine,
6-(4-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridine,
6-(4-forgenerating)-[1,2,4]triazolo[1,5-a]pyridine,
6-(4-methylphenylethyl)-[1,2,4]triazolo[1,5-a]pyridine,
6-(3,4-differentiating)-[1,2,4]triazolo[1,5-a]pyridine,
6-(2-chlorpheniramine)-[1,2,4]triazolo[1,5-a]pyridine and
6-(6-methylpyridine-2-ylethynyl)-[1,2,4]triazolo[1,5-a]pyridine;
excluded.

5. Derivative ethinyl formula IB according to claim 4 where the compound is a
6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine,
2-tert-butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine or
2-methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol.

6. Derivative ethinyl formula IB according to claim 1 for compounds of formula I where X represents C-R1and Y and Z represent N,

where
R4represents a 6-membered aromatic�algebraic ring, containing 0, 1 or 2 nitrogen atom, possibly substituted with 1-2 groups selected from halogen, lower alkyl, lower alkoxy or NRR';
R1represents hydrogen, lower alkyl, lower hydroxyalkyl, low cycloalkyl or is a 5-6-membered heteroseksualci containing 1-2 heteroatom selected from O and N;
R and R' independently from each other represent hydrogen;
or their pharmaceutically acceptable acid-additive salt.

7. Derivative ethinyl formula IB according to claim 6 where the compound is a
6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine,
2-tert-butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(2,5-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(3-fluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(3,4-debtor-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,
2-tert-butyl-6-(5-chloro-pyridin-3-ylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine,
2-morpholine-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine,
2-morpholine-4-yl-6-m-tolylidene-[1,2,4]triazolo[1,5-a]pyrimidine,
6-(3-fluoro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine,
6-(3-chloro-phenylethynyl)-2-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine or
6-phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine.

8. Derivative ethinyl formula V according to claim 1 for compounds of formula I, where X ameri� a C-R 1, Y represents C-R2and Z represents CH,

where
R4represents a 6-membered aromatic ring containing 0, 1 or 2 nitrogen atom, possibly substituted with 1-2 groups selected from halogen, lower alkyl, lower alkoxy or NRR';
R1represents hydrogen, lower alkyl, lower hydroxyalkyl, low cycloalkyl or is a 5-6-membered heteroseksualci containing 1-2 heteroatom selected from O and N;
R2represents hydrogen, CN;
R and R' independently from each other represent hydrogen;
or their pharmaceutically acceptable acid-additive salt.

9. Derivative ethinyl formula V according to claim 8, wherein the compound is a
6-phenylethynyl-pyrazolo[1,5-a]pyridine or
2-tert-butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridine.

10. Derivative ethinyl formula D according to claim 1 for compounds of formula I, where X represents N, Y represents C-R2and Z represents CH,

where
R4represents a 6-membered aromatic ring containing 0, 1 or 2 nitrogen atom, possibly substituted with 1-2 groups selected from halogen, lower alkyl, lower alkoxy or NRR';
R2represents hydrogen, CN;
R and R' independently from each other represent hydrogen;
or �x pharmaceutically acceptable acid-additive salt.

11. Derivative ethinyl formula D according to claim 10, wherein the compound is a
6-phenylethynyl-[1,2,3]triazolo[1,5-a]pyridine.

12. The compound according to any one of claims.1-11 for use as a positive allosteric modulator of the mGluR5 receptor.

13. Pharmaceutical composition having the activity of positive allosteric modulator of the mGluR5 receptor, comprising an effective amount of at least one compound according to claims.1-11, as well as its pharmaceutically acceptable salt and a therapeutically inert carrier.

14. Use of a compound according to any one of claims.1-11, as well as its pharmaceutically acceptable salt for the manufacture of drugs for the treatment or prevention of diseases associated with positive allosteric modulators of the mGluR5 receptor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes a method of producing and a method of purifying dialkyl pemetrexed of formula (I) , having antifolate action. The compound can be used to treat non-small-cell cancer and, coupled with cisplatin, to treat malignant pleural mesothelioma of the lungs. The method includes reacting a carboxylic acid of formula (II) with a diester of glutamic acid of formula (III) or an acid-addition salt thereof. The process is carried out in the presence of a substituted triphenyl phosphate of formula (IV) , a base and a solvent. In formulae (I) and (III) each R1 and R2 independently represents alkyl groups. In formula (IV) X, Y and Z assume values given in the claim.

EFFECT: use of safe, mild, cheap, non-oxidising and easy to handle triphenyl phosphate simplifies the process and enables to obtain, for example, diethyl pemetrexed with purity higher than 99%.

14 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to a method of obtaining methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid and benzosulphonate of methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid, which includes the interaction of methyl ether of 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid with an oxidiser and, optionally, processing the reaction product in acidic conditions, as well as to intermediate compounds and .

EFFECT: simplification and reduction of the price of the obtaining method due to the reduction of the number of stages.

13 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.

EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.

12 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chemical compounds of general formula I wherein LA, LB, LC, cycle A, cycle B, RA, RB, RC, RD, RE and RF have the values specified in the patent claim. The compounds of formula (I) are protein kinase inhibitors.

EFFECT: invention refers to pharmaceutical compositions containing the above compounds, as well as to using the above compounds for treating and/or preventing the diseases related to aberrant protein kinase activity, particularly oncological diseases.

10 cl, 14 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives 1-4 having the general structural formula: , where 1 - R=CH3, 2 - R=CH2CH3, 3 - R=CH2CF3, 4 - R=CH(CH3)2, characterised by that 6,7-diethoxy-3,4-dihydro-1-(3,4-diethoxybenzoyl)isoquinoline is mixed with methyl propiolate and methane, or ethanol, or 2,2,2-trifluoroethanol, or isopropanol and stirred at temperature of +50°C, the precipitate obtained at the end of the reaction and after removing reagents, is crystallised in ether.

EFFECT: method of producing derivatives which can be used as intermediate compounds when producing biologically active compounds.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to dihydroazol compounds of formula (I) wherein R1 means a C1-C6alkyl or C1-C6haloalkyl; X means a phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C12alkyls, C3-C10cycloalkyls, C1-C12haloalkyls, C2-C12alkenyls, C2-C12haloalkenyls, C1-C12alkinyls or C1-C12haloalkynyls; A1 means hydrogen, and A2 means CR7R8; G means G-1 or G-2; B1, B2, B3, B4 and B5 independently mean N or C-R9; Y means Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8 or Y-9 (as it is presented in the patent claim); R2, R3 independently mean hydrogen, C1-C12alkyl, C1-C12haloalkyl, thio-C1-C12alkyl, C1-C12alkylthio-C1-C12alkyl, hydroxy-C1-C12alkyl, C1-C12alkoxy-C1-C12alkyl, C2-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl, C3-C10cycloalkyl; R4 independently means hydrogen, C1-C12alkyl, C1-C12haloalkyl, thio-C1-C12alkyl, C1-C12alkylthio-C1-C12alkyl, hydroxy-C1-C12alkyl, C1-C12alkoxy-C1-C12alkyl, C2-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl or C3-C10cycloalkyl; R7 and R8 independently mean hydrogen, C1-C12alkyl or C1-C12haloalkyl; R9 means hydrogen, halogen, C1-C12alkyl, C1-C12haloalkyl, C1-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl or C2-C12haloalkynyl; each R10, R11, R12 and R13 independently means hydrogen, C1-C12alkyl or C1-C12haloalkyl; or R10 together with R11 form =O, =S or =NR2; or R12 together with R13 form =O, =S or =NR2; n=1. The invention also refers to compositions for treating or preventing endoparasitic infections or ectoparasitic invasions in animals and for protecting crops, plants, planting stock or timber against pests, to a method of treating or preventing endoparasitic infections or ectoparasitic invasions in animals, to a method for protecting crops and growing plants against pest attacks or invasions, to a method for preventing or controlling a pest invasion on site, and to using the compounds of formula (I).

EFFECT: compounds of formula (I) applicable for preventing or treating endoparasitic infections or ectoparasitic invasions in animals, and also as pesticides

30 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, including: i) opening of epoxy cycle of Compound 3 by means of methylamine with obtaining compound 4, ii) separation of Compound 4 by means of chiral acid, selected from L-(-)-malic acid and L-(-)-pyroglutamic acid with obtaining Compound 5A or 5B, or iii protection of secondary amine of Compound 5A or 5B with tert-butoxycarbonyl protective group with obtaining compound 6 iv) methylation of free hydroxyl group of Compound 6 with methylating agent, v) removal of protection from amino groups by means of monohydrate of p-toluenesulphonic acid with obtaining Compound 8 and vi) interaction of Compound 8 with compound 10 with the following obtaining (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid.

EFFECT: method improvement.

29 cl, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to new 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivatives, which can be used for modulating histamine receptors in individuals or for treating neurodegenerative diseases. The above derivatives have formula , wherein R1 is specified in an alkyl, substituted alkoxy or phenyl, and aralalkyl; R2 is specified in an alkyl, C6-C14-aryl optionally substituted by 1 to 5 substitutes specified in alkoxy and alkyl; R3 is an alkyl; and R4 is an alkyl.

EFFECT: presented are the new compounds effective as histamine receptor modulators, and a based pharmaceutical composition.

20 cl, 1 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to pharmaceutical composition, possessing GABA-ergic activity, which contains 4[(4'-nicotinoylamino)butyroylamino]butanic acid, nicotinoyl gamma-aminobutyric acid, calcium salt of homopantothenic acid, thiamine chloride (vitamin B1), riboflavin (vitamin B2), pyridoxine (vitamin B6), nicotinic acid (vitamin B3), nicotinamide (vitamin B3*) calcium pantothenate (B5), folic acid (vitamin B9), cyancobalamine (vitamin B12) and as additional substances talc, calcium stearate, magnesium stearate, starch-sugar granulate, or microcrystalline cellulose, or lactose, where vitamin B1 is present in form of double granulate with polyvinylpyrrolidone and starch-sugar paste.

EFFECT: composition improvement.

5 cl, 3 tbl, 10 ex

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