Derivatives with nitrogen-containing six-member aromatic ring and pharmaceutical products containing said derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

 

The technical field to which the invention relates

The present invention relates to anewthe compound and its pharmaceutically acceptable salts, which have the ability to stimulate axonal growth, combined with the ability to stimulate angiogenesis and, thus, are effective in reducing or treating lesions of the Central nervous system such as brain and spinal injuries, ischemic stroke, ischemic heart diseases such as myocardial infarction and angina due to organic lesions, peripheral occlusive artery disease, such as critical limb ischemia, or consequences of these diseases or other diseases, against which the compounds of the present invention are effective.

The level of technology

In the published Japanese patent application number 2005-239711 (patent document 1) set forth the following:

"Advances in the study of regulatory factors of angiogenesis has led to therapeutic application of these factors. Among the factors known as a stimulating angiogenesis, the growth factor vascular endothelial (VEGF), basic fibroblast growth factor (bFGF) and a growth factor for hepatocytes (HGF). These growth factors and their genes are being used for Les is possible diseases, in which you need improvement in circulation (such as the obliteration at the arteriosclerosis and ischemic heart disease).

However, these growth factors are proteins and are therefore difficult to introduce oral. They also lead to other problems associated with anaphylactic reactions caused by repeated introduction, the protection of the viral vectors used in gene therapy, and side effects such as swelling. Therefore, there is a need to develop new ways of treatment.

It is known that some diseases are caused by organic disorder associated with retraction (pulling) the axon and loss of synapses, although their etiology may vary from disease to disease. Such diseases include Alzheimer's disease, multi-infarct dementia, cerebrovascular dementia, senile dementia, disease Taurus Levi's, Parkinson's and Huntington's disease.

Lesions of the Central nervous system such as brain hemorrhage, ischemic stroke, brain tumor, brain damage and spinal injuries can also be caused by organic disorder associated with axon retraction and loss of synapses.

A variety of drugs for these diseases, which are based on protection of the neurons with the participation of different mechanisms.

None of these drugs does not provide a principled treatment of these diseases and is less than satisfactory, although they may to some extent delay the development of the disease. In particular, there is no effective treatment of ischemic stroke, which is currently used worldwide, with the exception of tissue plasminogen activator (tPA, TAP).

Although currently in development of several drugs designed to have a protective effect against neuronal none of them are aimed at actively promoting restoration of the functioning of the nervous system after ischemic stroke.

Great attention was focused on the regeneration of neuronal stem cells, and more research is being conducted in an attempt to implant the cells. With regard to the treatment of ischemic stroke, implanted neural stem cells, however, are not able to work as neurons for the formation of neuronal networks as neural stem cells have a small chance of survival after implantation or may not differentiate into neurons.

Recent studies suggest that vascular remodeling, such as angiogenesis, is essential for the formation and regenera the AI, including subsequent differentiation and maturation of neural stem cells and other cells after ischemic stroke (non-patent document 1: J. Clin. Invest., 114, 2004). Thus, effective treatment of ischemic stroke is required not only to ensure the immediate protection of neurons, to prevent the development of neuronal damage, but also to stimulate axonal growth, regeneration/remodelling of vascular networks, and recreating new neuronal networks in the affected "ischemic penumbra" (the penumbra) (non-patent document 2: Science, 3:272 (5262), pp.664-666 (1996)).

This situation of low molecular weight compounds that can stimulate axonal growth and to stimulate angiogenesis and which can be administered orally, consider potential drugs effective in the reduction or treatment of Central nervous system such as brain and spinal injuries, ischemic stroke, ischemic heart diseases such as myocardial infarction and angina due to organic lesions, peripheral occlusive artery disease, such as critical limb ischemia, and consequences of these diseases, and other diseases, against which the compounds of the present and the gain are considered to be effective. This connection is also seen as a potential drug, effective in reducing or treating symptoms that occur as a result of functional or organic disorders in the brain, including ischemic lesions of the brain, such as the consequences of ischemic stroke, brain hemorrhage and arteriosclerosis of the brain, as well as diseases associated with organic infringement arising from senile dementia, Alzheimer's disease, Parkinson's disease and the consequences of brain injury, spinal cord injury, and surgery on the brain.

I believe that the above compound, which stimulates angiogenesis, can be effective in pathological changes of permeability of vessels detected in peripheral occlusive lesions of the arteries, such as the obliteration at the arteriosclerosis, Buerger's disease and Raynaud's disease. I believe that the connection is particularly effective in the treatment of critical ischemia of the extremities and other severe symptoms, in which traditional medicines are ineffective.

Patent document 1: published Japanese patent application number 2005-239711.

Non-patent document 1: A. Taguchi, et al., J. Clin. Invest., 114:3, pp.330-338 (2004).

Non-patent document 2: M. Barinaga, Science, 3:272 5262), pp.664-666 (1996).

Description of the invention

Problem solved with the help of inventions

In this regard, the present invention is the provision of a therapeutic agent for the treatment or reduction of diseases, including Central nervous system such as brain and spinal injuries, ischemic stroke, ischemic heart diseases such as myocardial infarction and angina due to organic lesions, peripheral occlusive artery disease, such as critical limb ischemia, and consequences of these diseases, where therapeutic agent is a highly secure, has the ability to stimulate axonal growth, combined with the ability to stimulate angiogenesis and is suitable for making in medicine for oral administration, such both pills and powders, medicinal drug for parenteral administration, such as injection drug and medicinal product for external use, such as ointments and cataplasma (poultice).

Means for solving problems

To achieve the above objectives the present invention provides a compound represented by the following formula (I):

(Chemical formula 1)

DG is

the group Nx represents a 6-membered aromatic ring containing 1 or 2 nitrogen atom;

R0, R1and R2each independently represents a hydrogen atom, halogen atom, hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, acetyl group, karbamoilnuyu group, a carboxyl group, an unbranched or branched ester group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched, branched or cyclic alkyl group with 1-5 carbon atoms or the group-NR3R4where R3and R4each independently represents a hydrogen atom, an oxygen atom, unsubstituted or substituted with halogen unbranched, branched or cyclic alkyl group with 1-5 carbon atoms or an unbranched or branched allyloxycarbonyl group with 2-10 carbon atoms;

R5and R6each independently represents a hydrogen atom or an unsubstituted or substituted with halogen unbranched, branched or cyclic alkyl group with 1-5 carbon atoms;

R7represents an unbranched, branched or cyclic alkyl group with 1-5 carbon atoms;

E represents an oxygen atom or the group-NR8(where R8not only is em a hydrogen atom or an unbranched or branched alkyl group with 1-5 carbon atoms);

n is an integer from 0-5;

X and Y each independently represents a connecting bond; an unbranched or branched alkylenes group with 1-5 carbon atoms, either unsubstituted or substituted by 1-4 hydroxy or alkoxy groups; cycloalkenyl group with 3-6 carbon atoms, either unsubstituted or substituted by 1-4 hydroxyl groups, oxygen atoms or alkyl groups; geteroseksualbnogo group, either unsubstituted or substituted by 1-4 hydroxyl groups, oxygen atoms or alkyl groups; alkynylamino group with 2-4 carbon atoms, either unsubstituted or substituted with 1-4 alkyl groups with 1-5 carbon atoms; -NHCO-; -CONH-; -CO - or-SO2and

Q represents a hydrogen atom; a phenyl group either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; tiffaniejoy group, either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched is Oh, alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; fenoxaprop, either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; benzoyloxy group, either unsubstituted or substituted a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; pyridyloxy group, either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, n is substituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; pinolillo group, either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; izohinolinove group, either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 carbon atoms, nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group; or benzimidazolyl group, either unsubstituted or substituted by a halogen atom, a hydroxyl group, an unbranched or branched alkoxy group with 1-5 carbon atoms, unsubstituted or substituted with halogen unbranched or branched alkyl group with 1-5 at the Mami carbon nitrile group, amino group, carboxyl group, carbamoyl group, acetyl group, methylsulfonyl group or phenyl group, provided that when R7represents cyclopropyl group and E represents an oxygen atom, a group Nx is not 3-pyridinoline group;

and its pharmaceutically acceptable salt.

The effects of the invention

Provided by the present invention compounds, which are derived from nitrogen-containing 6-membered aromatic ring represented by the formula (I)are new compounds which have the ability to stimulate axonal growth, combined with the ability to stimulate angiogenesis. It is proved that the compounds are highly effective and safe in various pharmacological tests and can therefore be used as a pharmaceutical product. They are also applicable for the preparation of pharmaceutical preparations.

The best option of carrying out the invention

The present invention further be described here in detail.

In the compounds of the present invention, represented by formula (I), nitrogen-containing 6-membered aromatic ring containing one nitrogen atom, which serves as the group Nx, can be pyridinoline group. Nitrogen-containing 6-membered aromatic the prioritization of the ring, contains two atoms of nitrogen, serving as the group Nx, can be pyrimidinyl group, personilnya group or pyridazinyl group.

Specific examples of such nitrogen-containing 6-membered aromatic rings include 6-membered aromatic ring, which may be either substituted or unsubstituted groups R0, R1, R2and R10including the following placeholders:

(Chemical formula 2)

is the following:

In this formula, R0, R1, R2and R10each independently represents a hydrogen atom, halogen atom, hydroxyl group, alkoxy group, acetyl group, karbamoilnuyu group, carboxyl group, ester group, unsubstituted or substituted with halogen unbranched, branched or cyclic alkyl group with 1-5 carbon atoms, or-NR3R4group (where R3and R4each independently represents a hydrogen atom, an oxygen atom, or an unsubstituted or substituted with halogen unbranched, branched or cyclic alkyl or allyloxycarbonyl group with 1-5 carbon atoms).

With regard to the definition of the substituents R0-R4and R10above, the "halogen atom" includes a fluorine atom, and the om chlorine and bromine atom. "Alkoxy group" includes an unbranched or branched alkoxy group with 1-5 carbon atoms, such as methoxy group, ethoxy group. "Alkyl group" includes an unbranched or branched alkyl group with 1-5 carbon atoms, such as methyl group, ethyl group, through the group and triptorelin group, which may be either unsubstituted or substituted by 1-3 halogen atoms such as fluorine atom, chlorine atom and bromine atom.

"Ester group" includes an unbranched or branched ester group with 1-5 carbon atoms, such as methyl ester, complex with ethyl ether and complex propyl ether.

"Allyloxycarbonyl group" includes an unbranched or branched allyloxycarbonyl group with 2-10 carbon atoms, such as methyloxycarbonyl group, ethoxycarbonyl group, tert-butyloxycarbonyl group and benzyloxycarbonyl group.

R5and R6each independently represents a hydrogen atom or an unsubstituted or substituted with halogen unbranched, branched or cyclic alkyl group with 1-5 carbon atoms. R7represents an alkyl group.

With regard to the definition of the substituents R5and R6above, the "alkyl group" includes an unbranched, branched and cyclic alkyl group with 1-5 carbon atoms, such as methyl group, ethyl group, through the group, cyclopropyl group and triptorelin group, which may be either unsubstituted or substituted by 1-3 halogen atoms such as fluorine atom, chlorine atom and bromine atom.

With regard to the definition of the substituent R7above, the "alkyl group" includes an unbranched, branched or cyclic alkyl group with 1-5 carbon atoms, such as methyl group, ethyl group, through the group and cyclopropyl group.

E represents an oxygen atom or the group-NR8(where R8represents a hydrogen atom or alkyl group).

With regard to the group-NR8, "an alkyl group"represented by R8represents an unbranched or branched alkyl group with 1-5 carbon atoms, such as methyl group, ethyl group, through the group and triptorelin group. The alkyl group may be substituted by 1-3 halogen atoms such as fluorine atom, chlorine atom and bromine atom.

X and Y each independently represents a connecting bond; alkilany group, either unsubstituted or substituted by 1-4 hydroxy or alkoxy groups; cycloalkenyl group, either unsubstituted or substituted by 1-4 hydroxyl groups, oxygen atoms or alkyl groups; geteroseksualbnogo is the Rupp, either unsubstituted or substituted by 1-4 hydroxyl groups, oxygen atoms or alkyl groups; alkynylamino group, either unsubstituted or substituted by 1 or 2 alkyl groups with 1-5 carbon atoms; -NHCO-; -CONH-; -CO - or-SO2-.

Regarding the definition of X and Y above Allenova group includes unbranched or branched alkylenes group with 1-5 carbon atoms such as methylene group, methylmethyldopa group, ethylene group, trimethylene group and tetramethylene group.

Cycloalkenes group includes cycloalkenyl group with 3-6 carbon atoms, such as 1,1-cyclopropylidene group, 1,2-cyclopropylamino group, 1,1-cyclobutene group, 1,2-cyclobutene group, 1,1-cyclopentyloxy group, 1,2-cyclopentyloxy group, 1,1-cyclohexylurea group, 1,2-cyclohexylurea group, 2-hydroxy-1,1-cyclopentyloxy group and 3-hydroxy-1,2-cyclopentyloxy group.

Literoticalolita group includes geteroseksualbnogo group which has 3 to 6 carbon atoms and may contain one or more atoms of oxygen or nitrogen, such as tetrahydro-2H-Pernilla group, piperidinyl group, piperazinilnom group, morpholinyl group, 2-oxopyrrolidin group and azetidinone group.

Alkenylamine group includes alkenylamine g is the SCP with 2-4 carbon atoms, such as venelinova group and butadiene group. An alkyl group with 1-5 carbon atoms, to serve as Deputy alkenylamine group includes unbranched or branched alkyl group such as methyl group, ethyl group, through the group and isopropyl group.

Used here is the "connecting link" means a direct connection. In particular, if X and Y each represents a connecting bond, two neighboring substituent at "X" and "Y" are directly linked to each other: neither "X"nor "Y" does not exist as a group.

Deputy "Q" is the same as defined above. Preferably the substituents of the phenyl group, tofanelli group, phenoxy group, bentilee group, peredelnoj group, chinoline group, isohynolines group or benzimidazolyl group include a halogen atom such as fluorine atom, chlorine atom and bromine atom; a hydroxyl group; an unbranched or branched alkoxy group with 1-5 carbon atoms, such as methoxy group, ethoxy group; an unbranched or branched alkyl group with 1-5 carbon atoms substituted by 1 to 3 halogen atoms; a nitrile group; amino group; carboxyl group; karbamoilnuyu group; acetyl group and methylsulfonyl group.

The halogen atom in substituted with halogen ner is Svetlanas or branched alkyl group with 1-5 carbon atoms include a fluorine atom, the chlorine atom and a bromine atom.

Although the compounds of the present invention are new compounds, compounds having somewhat similar skeleton described, for example, in published Japanese translation of international application number 2003-507456, WO 01/79170 and WO 00/23076. In contrast to the compounds described in published Japanese translation of international application number 2003-507456 that act as modulators of the activity of a chemokine receptor, the compounds described in the examples 65, 85, 91, 102, 109, 130 and 135 of the present invention detect the affinity to the chemokine receptor CCR3 0,0, 2,4, 18, 0,0, 16, 3,5 and 22% at a concentration of 10 μm, respectively, do not show affinity to the chemokine receptor CCR3. This suggests that the compounds of the present invention do not cause possible side effects that may be associated with the chemokine receptor.

Compounds of the present invention represented by the General formula (I)can exist as isomers such as tautomers, enantiomers, geometrical isomers or diastereoisomers). Therefore, the present invention includes all such isomers and mixtures containing these isomers in any proportion.

Compounds of the present invention represented by the General formula (I)can be obtained by using a known method or any suitable to the munali known methods.

In particular, the compounds can be obtained by the following reaction processes (a), (b), (c) or (d).

(a) Compounds can be obtained by reacting compounds of the following General formula (IV-b):

(Chemical formula 3)

with a compound of the following General formula (V)

(Chemical formula 4)

or its salt.

(b) Or the compound can be obtained by reacting compounds of the following General formula (II-b)

(Chemical formula 5)

with a compound of the following General formula (VI)

(Chemical formula 6)

or its salt.

(C) Or the compound can be obtained by reacting compounds of the following General formula (VII)

(Chemical formula 7)

with a compound of the following General formula (VIII)

(Chemical formula 8)

or its salt.

(d) Or compound can be obtained by reacting compounds of the following General formula (II-a)

(Chemical formula 9)

with a compound of the following General formula (IX)

(Chemical formula 10)

Each of the compounds of formulas (IIa)to(IX), presents the th above is commercially available or can be easily obtained by a known method.

Specialists in the art should understand that functional groups such as hydroxyl groups and amino groups, the initial reagents or intermediates of the process according to the present invention can be protected by a protective group, and obtaining compounds of formula (I) comprises the addition of one or more of these protective groups at the appropriate time and removing the protective group at the right time of any subsequent process.

Methods of introduction of protection and removal to protect functional groups are described, for example, in "Protective Groups in Organic Chemistry", J. W. F. McOmie ed., Plenum Press (1973), "Protective Groups in Organic Synthesis", 2ndEdition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991), and "Greene's Protective Groups in Organic Synthesis", 4th.Edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (2006).

A protective group for the hydroxyl functional group may be any protective group commonly used for the protection of hydroxyl groups. Examples of protective groups include alkoxycarbonyl group, such as benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, isobutylacetate, diphenylmethoxy ronil, 2,2,2-trichlorocyanuric, 2-(trimethylsilyl)etoxycarbonyl, vinyloxycarbonyl and allyloxycarbonyl; acyl group such as acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; lower alkyl group such as methyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylmethyl; group aryl(lower alkyl), such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, trityl; lower alkenylphenol group, such as allyl; lower alkylamino group, such as propargyl; containing nitrogen or sulfur heterocyclic ring group, such as tetrahydrofuryl, tetrahydropyranyl and tetrathiophene; lower alkoxy or alkylthiomethyl group, such as methoxymethyl, methylthiomethyl, benzoyloxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl and 1-(methyl)methoxyethyl; lower alkyl or arylsulfonyl group, such as methanesulfonyl and p-toluensulfonyl; and substituted silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl.

The protective group for the amino group may be a protective group commonly used to protect the amino group. Examples of such groups include alkoxycarbonyl group, such as benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxybenzo jocstarbunny, methoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropanolamine, 2,2,2-trichlorocyanuric, 2-(trimethylsilyl)etoxycarbonyl, 9-fluorenylmethoxycarbonyl, vinyloxycarbonyl and allyloxycarbonyl; acyl group such as acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, phenylacetyl, phthaloyl, succinyl, alanyl, leucyl and benzoyl; a group of the aryl(lower alkyl), such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl; killigrew, such as 2-nitrophenylthio and 2,4-dinitrophenyl; lower alkyl or arylsulfonyl group, such as methanesulfonyl and p-toluensulfonyl; group di(lower alkylamino)lower alkylidene, such as N,N-dimethylaminomethylene; group aryl(lower alkylidene), such as benzylidene, 2-hydroxybenzylidene and 2-hydroxy-5-chlorobenzylidene; nitrogen-containing heterocyclic alkylidene group, such as 3-hydroxy-4-pyridylmethylene; cycloalkylcarbonyl group, such as cyclohexylidene, 2-ethoxycarbonylmethylene and 2-ethoxycarbonylmethylene; phosphoryl group, such as diphenylphosphoryl; and substituted silyl group such as trimethylsilyl.

Compounds and intermediate compounds of the present invention can be isolated from the reaction mixture using conventional methods and, if necessary, can be advanced about ishani.

Each reaction process will be described hereinafter in detail.

[Reaction process (a)]

This reaction process is presented in detail in the following reaction scheme:

(Chemical formula 11)

In the reaction scheme above, R0-R7, E, Nx, n, X, Y and Q are as described above.

Deputy R9represents an alkyl group such as methyl group, ethyl group, tert-butoxy group and benzyl group. The substituents L1and L2each represents a leaving group which can easily be replaced by the amino group or hydroxyl group. Their specific examples include a halogen atom such as chlorine atom, bromine atom and iodine atom; the group alkylsulfonate, such as band methansulfonate and group tripterocalyx; and group arylsulfonate, such as the group of p-toluensulfonate and group 3-nitrobenzenesulfonate.

This process, in General, involves the interaction of compound (II-a) with ester derivative (III-a) to obtain the compound (IV-a), which in turn hydrolyzing to obtain the carboxylic compound (IV-b). Then, the obtained compound (IV-b) is subjected to the condensation reaction with amine derivatives (V) to give the desired compounds (I), which is one aspect of us is Vashego of the invention.

Alternatively, the compound (IV-a) can be obtained by transformation of a compound (II-a) in the compound (II-b), with its subsequent interaction with the ester derivative (III-b).

In those cases where it is necessary to protect functional groups such as hydroxyl group and amino group, in this reaction process, the process may include the process of introducing one or more of these protective groups at an appropriate stage and the procedure for removal of the protective group at a later stage.

For example, when R0in compound (I) represents-NR3R4with R3or R4which methyloxycarbonyl group, ethoxycarbonyl group, tert-butyloxycarbonyl group, benzyloxycarbonyloxy group, benzyl group or each oxygen atom to serve as a protective group of a nitrogen atom, a protective group may be removed or converted into other functional groups to give the desired compounds (I)in which R3and/or R4converted into a hydrogen atom. This reaction process can be provided in these reaction processes.

Corresponding processes are described in more detail below.

Process 1:

The compounds of formula (II-a) and ester derivatives of the formula (III-a), which serve as the source of vases is in the present process, are commercially available, or they can be obtained using known methods.

The compound (II-a) can be obtained in accordance with the method or combination of methods, or using the methods described, for example, in "Heterocyclic compound New Edition, Introduction", Hiroshi Yamanaka, Sakamoto Norio et al., Kodansha Scientific (2004) and "Heterocyclic compound New Edition, Application, Hiroshi Yamanaka, Sakamoto Norio et al., Kodansha Scientific (2004).

Examples of the ester derivative (III-a) include ethylbromoacetate, ethyl-2-bromopropionate and ethyl-2-bromo-2-methylpropionate.

In this process, as the first stage, the compound (II-a) enter into interaction with the ester derivative (III-a) to obtain the compound (IV-a).

The reaction can be carried out by mixing the compound (II-a) with 1.0 to 1.5 equivalents of the ester derivative (III-a) at -20°C to 150°C, and preferably at 0°C - 100°C, in an inert solvent, such as benzene, toluene, tetrahydrofuran, dioxane, dimethylformaldehyde, dimethyl sulfoxide, acetonitrile, acetone, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, diethyl ether, ethylene glycol, methylene chloride or chloroform, and if necessary, in the presence of organic bases such as triethylamine, diisopropylethylamine or pyridine, or inorganic bases, such as sodium, sodium hydride, potassium, potassium hydride, sodium ethylate, tert-butyl potassium, carb is NAT sodium, potassium carbonate, cesium carbonate, cesium fluoride, sodium bicarbonate or potassium bicarbonate.

If necessary, the reaction may use a combination of organic bases or inorganic bases. Alternatively, it may be added sodium iodide, potassium iodide, tetrabutylammonium iodide or crownether.

Processes 2 and 3

These processes are used as an alternative process for the synthesis of the compound (IV-a). In particular, the compound (II-b) first turn of the compound (II-a), and the resulting product is injected into the interaction with the ester derivative (III-b) to obtain the compound (IV-a).

The conversion of compound (II-a) (process 2) may be conducted by various methods depending on the type of substituent L2the compound (II-b). For example, when L2represents a halogen atom such as chlorine atom and bromine atom, the compound (II-a) enter into interaction in the presence of phosphorus oxychloride (POCl3)and petaluridae phosphorus (PCl5), or in the presence of one of phosphorus oxychloride, petaluridae phosphorus, brookie phosphorus (POBr3), pyatibratova phosphorus (PBr5), and the like. If necessary, the reaction can be carried out in an inert solvent, such as benzene, toluene, ethyl acetate, dioxane, chloroform or methylene chloride.

When the leaving group L2is with the battle group alkylsulfonate, such as band methansulfonate or group tripterocalyx; or a group of arylsulfonate, such as the group of p-toluensulfonate or group 3 nitrobenzenesulfonate, the reaction is carried out by mixing the compound (II-a) with 1.0 to 1.5 equivalents. methanesulfonanilide (MsCl), p-toluensulfonate (TsCl) or anhydride triftormetilfullerenov acid (Tf20) at -20°C to 150°C, and preferably at 0°C-100°C, in an inert solvent, such as toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform or acetonitrile, and if necessary, in the presence of organic bases such as triethylamine, diisopropylethylamine or pyridine, or inorganic bases, such as sodium, sodium hydride, potassium, potassium hydride, sodium ethylate, tert-butyl potassium, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium bicarbonate or potassium bicarbonate.

Since the compound obtained can be directly used in the subsequent process, it can be purified, if desired, using known purification method such as recrystallization and column chromatography, to the subsequent process.

The compound (II-b), obtained as described above, then enter into interaction with the ester derivative (III-b)to obtain the compound (IV-a) (process 3).

The reaction can be carried out by mixing the cation of compound (II-b) with 1.0 to 1.5 equivalents. ester derivative (III-b) at -20°C to 150°C, and preferably at 0°C-100°C, in an inert solvent, such as benzene, toluene, tetrahydrofuran, dioxane, dimethylformaldehyde, dimethyl sulfoxide, acetonitrile, acetone, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, diethyl ether, ethylene glycol, methylene chloride or chloroform, and if necessary, in the presence of organic bases such as triethylamine, diisopropylethylamine or pyridine, or inorganic bases, such as sodium, sodium hydride, potassium, the potassium hydride, sodium ethylate, tert-butyl potassium, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium bicarbonate or potassium bicarbonate.

If necessary, the reaction may be added sodium iodide, potassium iodide, tetrabutylammonium iodide or crownether.

The compound (III-b)used in the reaction, may be a commercial product or a known compound or, alternatively, can be easily synthesized by known methods.

Specific examples of such compounds (III-b) include glycolic acid, methylglycol, ethylglycol, tert-butylglycol, benzylglycine, lactic acid, mutilated, ethyllactate, tert-butylacetate, benzylated, 2-hydroxyisobutyryl acid, methyl-2-hydroxyisobutyrate, ethyl-2-hydroxyisobutyrate, tert-butyl-2-hydroxyisobutyrate, glitzy is, methyl ester of glycine, ethyl ester of glycine tert-butyl ester of glycine, benzyl ester of glycine, sarcosine, methyl ether of sarcosine, ethyl ester sarcosine, methyl ether of sarcosine, alanine, methyl ester of alanine, ethyl ester of alanine, tert-butyl ester of alanine, benzyl ester of alanine, N-methylalanine, 2-aminoadamantane acid, methyl-2-aminoisobutyrate, ethyl-2-aminoisobutyrate, tert-butyl-2-aminoisobutyrate, benzyl-2-aminoisobutyrate and 2-(methylamino)somalina acid.

Processes 4 and 5

The compound (IV-a)obtained as described above, hydrolyzing known methods (process 4) for conversion into the carboxylic acid (IV-b), which, in turn, is subjected to condensation with amino derivatives (V) to obtain the amide (I).

The compound (V), which can be used in the condensation reaction with compound (IV-b)may be a known compound or, alternatively, can be easily synthesized by known methods.

Conditions the amidation reaction can be based on the methods described in the "Compendium for Organic Synthesis" (Wiley-5 Interscience: Division of John Wiley & Sons).

For example, the carboxylic acid derivative (IV-b) is treated with diethylphosphoramidite (DEPC), diphenylphosphoryl (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-iodine-1-methylpyridinium, anhydride propants the new acid, 2-chloro-l,3-dimethylimidazolidine, 2-chloro-1,3-dimethylimidazolidine or (benzotriazol-1 yloxy)Tris(dimethylamino)phosphodiesterase (BOP reagent). When necessary, the reaction may be conducted in the presence of organic or inorganic bases. Amino derivatives (V) is added either after or prior to the reaction to produce the amide (I). Alternatively, the carboxylic acid derivative (IV-b) can be transformed into an activated ester compound, such as an acid halide, symmetric acid anhydride or mixed acid anhydride, which, in turn, is introduced in the interaction with the amino derivatives (V) to obtain the amide derivative (I).

When R0in the target amide derivative (I) represents-NR3R4and R3or R4is methyloxycarbonyl group, ethoxycarbonyl group, tert-butyloxycarbonyl group, benzyloxycarbonyloxy group, benzyl group or each oxygen atom to serve as a protective group of a nitrogen atom, a protective group may be removed or converted into other functional groups, to obtain the desired compound (I)in which R3and/or R4converted into a hydrogen atom. This may be an alternative reaction process.

The reaction can prosodics the various methods depending on the type of protective groups at the nitrogen atom of the compound (I). For example, the compound (I)in which R0is a group-NR3R4with R3or R4that represents a benzyl group, a 4-methoxybenzyloxy group or benzyloxycarbonyl group, or R3and R4each represents an oxygen atom, together form the nitrogroup, can gidrirovaniya in the presence of a catalyst such as palladium on charcoal, palladium hydroxide on charcoal, platinum or platinum oxide, in an inert solvent, such as methanol, ethanol, isopropyl alcohol, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform or acetic acid. Alternatively, the compound (I) can be recovered in the acidic conditions using zinc or chloride of tin.

The compound (I), in which the protective group R3or R4represents a tert-butoxycarbonyl group, ethoxycarbonyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, acetyl group or formyl group, may be subjected to removal of protection by treatment with acid, such as triperoxonane acid, chloromethane acid, Hydrobromic acid or sulfuric acid, in an inert solvent, such as methanol, ethanol, isopropyl alcohol, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform or acetonitrile.

If necessary, obtained in accordance with the ATA connection (I) can be purified by a known method of purification, such as recrystallization or column chromatography.

[Reaction process (b)]

This process is presented in detail in the following chemical reaction scheme:

(Chemical formula 12)

In the reaction scheme above, R0-R2, R5-R7, E, Nx, n, X, Y, L2and Q are as described above. Deputy R9represents a hydrogen atom and P is a protective group.

Examples of the protective group include benzyl group, p-methoxybenzyloxy group, tert-butoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group and p-methoxybenzylideneamino group.

In particular, the compound (V) enter into interaction with the ester derivative (III-b)to obtain the compound (VI).

In an alternative process for obtaining the compounds (VI), the compound (V) enter into interaction with the ester derivative (III-c) to obtain compound (X), which, in turn, converted into the compound (VI). Then the resulting compound (VI) enter into interaction with the compound (II-b) to obtain the desired compound (I), which is one aspect of the present invention.

When R0in the resulting amide derivative (I) represents-NR3R4with R3or R4 representing methyloxycarbonyl group, ethoxycarbonyl group, tert-butyloxycarbonyl group, benzyloxycarbonyloxy group or benzyl group, or each is an oxygen atom to serve as a protective group of a nitrogen atom, a protective group may be removed or converted into other functional groups to give the desired compounds (I)in which R3and/or R4converted into a hydrogen atom. This may be an alternative reaction process.

Corresponding processes are described in more detail below.

Processes 6 and 7:

The compound (III-b) or (III-c), which serve as the starting material for this process are commercially available substances, or they can be obtained using known methods.

In this process, as its first stage, the carboxylic acid (III-b) or (III-c) is subjected to amide condensation with amino derivatives (V) to obtain the amide (VI) or (X), respectively.

Conditions for the amidation reaction can be based on the methods described in the "Compendium for Organic Synthesis" (Wiley-Interscience: Division of John Wiley & Sons).

For example, the carboxylic acid derivative (III-b) or (III-c) is treated with diethylphosphoramidite (DEPC), diphenylphosphorylacetate (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydra is chloride, 2-iodine-1-methylpyridinium, anhydride papapostolou acid, 2-chloro-1,3-dimethylimidazolidine, 2-chloro-1,3-dimethylimidazolidine or (benzotriazol-1 yloxy)Tris(dimethylamino)phosphodiesterase (BOP reagent). When necessary, the reaction may be conducted in the presence of organic or inorganic bases. Amino derivatives of (III) is added either after or prior to the reaction to produce the amide (VI) or (X).

Alternatively, the carboxylic acid derivative (III-b) or (III-c) can be transformed into an activated ester compound, such as an acid halide, symmetric acid anhydride or mixed acid anhydride, which in turn is introduced in the interaction with the amino derivatives (V) to obtain the amide (VI) or (X).

Process 8:

When the resulting product is a compound (X), it is subjected to removal of the protective group into the compound (VI).

Remove protection can be achieved by different methods depending on the type of the protective group P of compound (X).

For example, when P is a benzyl group, a 4-methoxybenzyloxy group or benzyloxycarbonyl group, the compound (X) hydronaut in the presence of a catalyst such as palladium on charcoal, palladium hydroxide on charcoal, platinum or platinum oxide, in an inert solvent, such to the to methanol, ethanol, isopropyl alcohol, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform or acetic acid. When the protective group P is a tert-butoxycarbonyl group, ethoxycarbonyl group, 4-methoxybenzyloxy group or 3,4-dimethoxybenzyl group, the compounds (X) removing the protective group by treatment with an acid, such as triperoxonane acid, chloromethane acid, Hydrobromic acid or sulfuric acid, in an inert solvent, such as methanol, ethanol, isopropyl alcohol, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform or acetonitrile.

Because the resulting connection can be used directly in the subsequent process, it can optionally be purified by known purification method to the subsequent process.

Process 9:

The compound (VI)obtained as described above, is injected into interaction with the compound (II-b) to obtain a compound represented by the formula (I), which is a compound of the present invention.

The compound (II-b)used in the present process is the same as described in process 2. In this reaction, the compound (I) can be synthesized in the same way as in process 3.

If necessary, the protective group on the nitrogen atom, the resulting amide derivative (I)can butadlene or converted into a functional group, so amide derivative (I) can be converted into a compound represented by the formula (I), which is a compound of the present invention.

In this reaction, the compound (I) can be synthesized as in the reaction process (a).

If necessary, the compound obtained in the above-described reactions can be purified by known purification method such as recrystallization and column chromatography.

[Reaction process (c)]

This process is presented in detail in the following chemical reaction scheme:

(Chemical formula 13)

In the reaction scheme above, R0-R2, R5-R7, E, Nx, n, X, Y and Q are as described above, and P represents a protective group.

Examples of the protective group include benzyl group, p-methoxybenzyloxy group, tert-butoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group and p-methoxybenzylideneamino group.

Deputy L3is a leaving group, which can be easily replaced by the amino group. Specific examples of the groups include a halogen atom such as chlorine atom, bromine atom and iodine atom; the group alkylsulfonate, such as band methansulfonate and group tripterocalyx; and group arylsulfonyl and, such as the group of p-toluensulfonate and group 3-nitrobenzenesulfonate.

This process, in particular, covers the condensation of the carboxylic derivative (IV-b)described in process (4) above, with the compound (XI) to obtain the amide compound (XII). Then the amide compound (XII) remove the protection to obtain compound (VII). The resulting compound (VII) is then injected into interaction with the compound (VIII) to obtain the desired compound (I).

These processes are described in more detail later.

Process 10:

The compound (XI), which serves as the starting material of the present process, may be a commercially available product may be known from the literature (J. Med. Chem., 36:3707(1993) [R.H. Mach et al.], EP 0184257-Al [R. A. Stokbroekx et al.]) or can be obtained by a known method.

The amidation to obtain compound (XII) can be carried out in the same conditions as in process 5.

Process 11:

The compound (XII)obtained above is subjected to removal of the protective group to obtain the compound (VII).

This reaction can be conducted in the same manner as in process 8, to obtain the compound (VII).

Process 12:

The compound (VII)obtained in process 11, above, is introduced in the interaction with the compound (VIII) to obtain the compound represented by formula (I), which is soedinenie the present invention.

In particular, in the present process, the compound (VII) enter into interaction with 1.0 to 1.5 equivalents. compounds (VIII) at approximately -50°C to about 120°C and preferably at approximately -20°C to about 80°C, in an inert solvent, such as benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, diethyl ether, methylene chloride, chloroform or carbon tetrachloride, in the presence of organic bases such as triethylamine, diisopropylethylamine or pyridine, or inorganic bases, such as sodium, sodium hydride, potassium, potassium hydride, sodium ethylate, tert-butyl sodium, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium bicarbonate or potassium bicarbonate.

If necessary, the reaction may be added sodium iodide, potassium iodide, tetrabutylammonium iodide or crownether.

When necessary, the protective group at the nitrogen atom, the resulting amide derivative (I)may be removed or converted into other functional groups, so that the amide derivative (I) can give compound represented by formula (I), which is a compound of the present invention.

The reaction may be conducted in the same manner as described in the reaction process (a), to obtain the compound (I).

When necessary, connect the tion, obtained in the above-described reactions can be purified by known purification method such as recrystallization and column chromatography.

[Reaction process (d)]

This process is presented in detail in the following chemical reaction scheme:

(Chemical formula 14)

In the reaction scheme above, R0-R2, R5-R7, E, Nx, n, X, Y, L3and Q are as described above, and the substituent R9is a hydrogen atom.

This process, in particular, covers the condensation of compound (V) with compound (III-a) to obtain the amide compound (IX). The obtained compound (IX) is then injected into interaction with the compound (II-a) to obtain the desired compound (I).

These processes are described below in more detail.

Process 13:

In this process, as a first stage, the carboxylic acid (III-a) is subjected to amide condensation with amino derivatives (V) to obtain the amide (IX).

The amidation reaction can be conducted in the same manner as in the process 5 to obtain compound (IX).

Process 14:

In this process 14, the compound (IX)obtained above in the process of 13, you enter into interaction with the compound (II-a) to obtain a compound represented by the formula (I) is the desired connection on the present image is ateneu.

The reaction may be conducted in the same manner as in process 1, to obtain the compound (I).

When necessary, the protective group at the nitrogen atom, the resulting amide derivative (I)may be removed or converted into other functional groups, so that the amide derivative (I) can give compound represented by formula (I), which is a compound of the present invention.

The reaction may be conducted in the same manner as described in the reaction process (a), to obtain the compound (I).

When necessary, the compound obtained in the above reaction, can be purified by a known method of cleaning, such as recrystallization and column chromatography.

The isomers present in the compound of the present invention represented by the General formula (I)may be separated using known method such as recrystallization, column chromatography, thin layer chromatography and high performance liquid chromatography, or similar method using optically active reagents.

Compounds of the present invention represented by the General formula (I)can be converted into the corresponding salt by dissolving in a suitable organic solvent, such as water, methanol, ethanol, isopropanol, diethyl ether, diisopropylethylamine ether, tetrahydrofuran, methylene chloride, chloroform, benzene or toluene, and processing of organic or inorganic acid.

The inorganic acid used for this purpose include chloroethanol acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and periodic acid. Organic acids include formic acid, acetic acid, butyric acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, benzoic acid, benzosulfimide acid, p-toluensulfonate acid, methanesulfonate acid and econsultancy acid.

Compounds of the present invention represented by the General formula (I)and their salts exhibit reduced toxicity. In the experiment, which repeatedly orally was administered to rats the compound of Example 65 of the present invention once a day during the week, the connection showed no toxicity at a dose of 150 mg/kg/day.

While the compounds of the present invention represented by the General formula (I)and their salts can be used by themselves, they can be prepared, optionally with other pharmaceutically acceptable, widely used by the media in the pharmaceutical prep the rata which are designed to reduce or treat diseases, including Central nervous system such as brain and spinal injuries, ischemic stroke, ischemic heart diseases such as myocardial infarction and angina due to organic lesions, peripheral occlusive artery disease, such as critical limb ischemia, and consequences of these diseases by stimulating axonal growth stimulation of angiogenesis. The drug can be obtained by applying the filler, baking powder, binder, humectant, agent, contributing raspadaemosti, surfactants, lubricants and other traditionally used diluents and excipients. The pharmaceutical preparations can be provided in various forms depending on the goals of treatment, including tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (such as liquids and suspensions), ointments, poultices, inhalers and other acceptable forms.

Tablets can be formed by using excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicon KIS the PTA; binder, such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; contributing raspadaemosti agent, such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene esters of sorbitol and fatty acids, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose; preventing raspadaemosti agent, such as sucrose, stearin, cacao butter and gidrirovannoe oil; accelerating the absorption agent such as Quaternary ammonium base and sodium lauryl sulfate; wetting agents such as glycerin and starch; a humectant, such as glycerin and starch; adsorbent, such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearate, powdered boric acid and polyethylene glycol; and other media.

When necessary, the tablets may be formed by applying a well-known coating such as sugar coating, gelatin coating, intersolubility coating, film coating, or alternatively, tablets can be formed in two-layer pilul is or multilayer pills.

Pills can be formed with the use of auxiliary substances, such as glucose, lactose, starch, cacao butter, gidrirovannoe vegetable oil, kaolin and talc; binders such as powdered gum Arabic, powdered tragakant, gelatin and ethanol; contributing raspadaemosti agent, such as laminaran and agar-agar and other media.

Suppositories can be formed using polyethylene glycol, cacao butter, higher alcohol, a complex ester of higher alcohol, gelatin, semisynthetic glycerides and other media.

Capsules can be traditionally obtained by mixing the compounds of the present invention with various carriers described above, and the conclusion of the mixture in hard gelatin capsule, soft gelatin capsule or other capsules, using known techniques.

When the compound of the present invention receive the injectable form such as solution, emulsion or suspension, injectable form is preferably sterile and is isotonic with blood. Injectable form can be formed with the use of a diluent, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polycyanoacrylates alcohol and polyoxyethylene ether of sorbitol and fatty key is lots.

The injectable form may contain salt, glucose or glycerin in sufficient quantities for the formation of isotonic solutions, also known solubilizers agent, buffer or soothing agent.

When necessary, the pharmaceutical preparation may contain a dye, a preservative, a flavoring substance, a flavoring agent, sweetener or other acceptable pharmaceutical products.

Pastes, creams and gels can be formed with the use of a diluent, such as white petrolatum, paraffin, glycerin derived cellulose, polyethylene glycol, silicone and bentonite.

The above-described pharmaceutical preparation can be administered by any means determined by the form of the drug, age, sex and other conditions of patients, and severity of disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are introduced orally. Injectable forms are administered intravenously alone or in a mixture with known restorer of the lost fluid, such as glucose and amino acids. When necessary, injectable forms are entered one or intramuscularly, intracutaneously, subcutaneously or administered intraperitoneally. Suppositories are inserted rectally. Ointments and poultices are entered transdermal. Forms for inhalation is administered through the mucosa of the nasal cavity or lungs.

With what sposobnostey to stimulate axonal growth and to stimulate angiogenesis and aimed at the reduction or treatment of diseases, including lesions of the Central nervous system such as brain and spinal injuries, ischemic stroke, ischemic heart diseases such as myocardial infarction and angina due to organic lesions, peripheral occlusive artery disease, such as critical limb ischemia, and consequences of these diseases, the compounds of the present invention are introduced in a variable dose, determined by symptoms, disease severity or age of the patients, and whether the patient complications. The dose may also vary from the route of administration, dosage form and frequency of the dose. In the case of oral administration the dose is usually from 0.1 to 1000 mg/day/patient, and preferably from 1 to 500 mg/day/patient that is determined by the amount of the active component. In the case of parenteral administration, the dose can range from one hundredth to one-half the dose for oral administration. However, the preferred dose may vary depending on age, symptoms and other conditions of the patients.

EXAMPLES

The present invention is described hereinafter with reference to Examples, which are not intended to limit the scope of the invention.

The sequence number assigned to the compounds in the following Examples, with testout ordinal compounds presented in the tables.

Example 1

Getting 4,6-dimethyl-5-nitropyrimidin-2-ol (compound 1)

4,6-Dimethylpyrimidin-2-ol hydrochloride (20,0 g) was added to concentrated sulfuric acid (94,2 g), at the same time cooling with ice. To this mixture was added under stirring and ice cooling at 5°C or below fuming nitric acid (15.7 g: d=1,52). The resulting mixture was allowed to slowly warm to room temperature (20-30°C) and then continued to stir at room temperature (20-30°C) during the night. The reaction mixture was poured into ice (340 g) and neutralized 10 N. aqueous solution of sodium hydroxide to a pH of approximately 2.5 (at 20°C or below). Then the mixture was extracted twice with isopropanol (225 ml) and the organic layer was concentrated under reduced pressure to obtain 33.1 g of residue. To the obtained residue was added 660 ml of chloroform and 66 ml of methanol and the mixture is boiled for 30 min, followed by stirring at 50°C for 30 minutes and Then separating the insoluble substance by filtration. The filtrate was concentrated under reduced pressure to 210 g, and then adding 100 ml of chloroform and concentration to 133, the resulting residue was stirred at room temperature (20-30°C) for 30 min and then cooled with ice for 2 hours. Separated crystals were collected by filtration, washed with cold chloroform easily with the receipt of 13.1 g of the desired product.

When necessary, a certain amount of product was purified column chromatography on silica gel (methylene chloride:methanol=50:1) and recrystallized from methylene chloride to obtain the pure product.

Example 2

Getting 2-chloro-4,6-dimethyl-5-nitropyrimidine (compound 2)

A mixture of compound 1 (500 mg) and phosphorus oxychloride (to 3.89 g) was stirred for 3 hours at the boil. After completion of the reaction the mixture was concentrated under reduced pressure. To the obtained residue were added chloroform and water and the mixture was cooled and neutralized 2 N. aqueous solution of sodium hydroxide to a pH of 5-7. Then the mixture was extracted with chloroform and the organic layer was concentrated under reduced pressure to obtain 411 mg of the desired product. When necessary, a certain amount of product was purified column chromatography on silica gel (ethyl acetate:hexane=1:1) to give the pure product.

Example 3

Obtaining 5-amino-4,6-dimethylpyrimidin-2-ol (compound 3)

Compound 1 (1.0 g), 5% Pd-C (131 mg) suspended in methanol (60 ml). Repeated pumping and replacement with hydrogen three times. Then the suspension was intensively stirred at room temperature (20-30°C) for 8 hours in an atmosphere of hydrogen. After completion of the reaction the mixture was filtered through celite and the filtered product was washed with methanol. Fil the rat was evaporated under reduced pressure to obtain 853 mg of the crude desired product compound 3 as a yellow solid.

Example 4

Getting 4,6-diisopropylamide-2-ol (compound 4)

Tert-butyl-4,6-diisopropylamide-2-ylcarbamate (42 mg) was dissolved in methylene chloride (4 ml). As cooling the solution with ice to the solution was added triperoxonane acid (1 ml). Then the mixture was stirred at room temperature (20-30°C) for 1 hour. After completion of the reaction the mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (methylene chloride:methanol=10:1) to give 8.5 mg (30%yield) of the desired product in the form of amorphous material, brown color.

Example 5

Getting 4,6-aminobutiramida 5-nitropyrimidin-2-ol (compound 5)

Compound 4 (20 mg) suspended in a mixture of concentrated sulfuric acid (1 ml) and chloroform (1 ml). To the resulting mixture was added fuming nitric acid (166 μl: d=1,50) under stirring and ice cooling to 5°C or below. The resulting mixture was allowed to slowly warm to room temperature (20-30°C) and then continued to stir at room temperature (20-30°C) during the night. The reaction mixture was poured on ice and neutralized 10 N. aqueous solution of sodium hydroxide to a pH of about 5 (at 20°C or below). The mixture was extracted twice with chloroform, and the organic layer was concentrated under reduced pressure, the NII. The resulting residue was purified column chromatography on silica gel (methylene chloride:methanol=50:1 to 10:1) obtaining of 17.8 mg (yield 49%) of the desired product in the form of amorphous material, brown color.

Example 6

Getting ethyl-2-(4,6-dimethyl-5-nitropyrimidin-2-yloxy)acetate (compound 6)

Connection 1 (111,86 g) and potassium carbonate (274,21 g: 3 EQ.) suspended in acetone (2 l) was added ethylbromoacetate (165,67 g: 1.5 EQ.) at room temperature (20-30°C). The device used to add ethylbromoacetate, thoroughly washed with acetone (237 ml) and stirred at 50°C for 8 hours. The mixture is then cooled to 35°C. and concentrated under reduced pressure. To the obtained residue was added toluene (1120 ml) and the mixture was stirred at room temperature overnight. The mixture is then filtered on a vacuum and the filtered product was washed with toluene (560 ml). The filtered product was pressed and again washed with toluene (450 ml). The filtrate was evaporated under reduced pressure and the resulting crude product was purified column chromatography on silica gel (hexane:ethyl acetate=1:0 to 4:1) to obtain the 75,98 g (yield 45%) of the desired product as a yellow solid.

Example 7

Getting ethyl-2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)acetate (compound 7)

Compound 6 (75,98 g) and 5% Pd-C (7,598 g, N. E. CHEMCAT, STD Type) suspended in ethanol (760 ml). Repeated pumping and replacement with hydrogen three times. Then the suspension was intensively stirred at room temperature (20-30°C) for 4.5 hours in an atmosphere of hydrogen. After completion of the reaction the mixture was subjected to fine filtration under pressure (0.2 μm, PTFE) and the filtered product was washed with ethanol (474 ml). The filtrate was evaporated under reduced pressure to get 66,99 g (yield of 99.9%) of the desired product as a pale yellow solid.

Example 8

Getting ethyl-2-(5-tert-butoxycarbonylamino)-4,6-dimethylpyrimidin-2-yloxy)acetate (compound 8)

Compound 7 (designed to be 75,98 g as the compound 6 obtained in the previous process) and di-tert-BUTYLCARBAMATE (77,97 g) suspended in ethyl acetate (250 ml). The mixture was stirred at 70°C during the night. To this reaction mixture portions was added hexane (576 ml), followed by the addition of a small amount of compound 8 for starters, and portions of hexane (288 ml). Then the mixture was left to cool and was stirred overnight. Next, the mixture was stirred and cooled with ice for 2 hours and then filtered using vacuum. The resulting solid was washed with hexane (288 ml) and dried with getting 92,41 g (yield 95% over 2 stages) of the desired product as a white solid in the society.

Example 9

Getting 2-(5-(tert-butoxycarbonylamino)-4,6-dimethylpyrimidin-2-yloxy)acetic acid (compound 9)

Compound 8 (92,4 g) suspended in ethanol (127 ml) was added to a suspension of 2 N. aqueous sodium hydroxide solution (284 ml) at room temperature (20-30°C). The mixture was stirred for 2 hours at room temperature (20-30°C) was added in portions to the reaction mixture 2 N. aqueous solution of HCl (148 ml) while cooling the mixture. For starters crystallization was added a small amount of compound (9), further portions 2 N. aqueous solution of HCl (119 ml) (internal temperature = 10°C or below). The mixture was stirred at room temperature (20-30°C) during the night. Then the mixture was stirred and cooled on ice for 3 hours and then filtered using vacuum. The resulting solid was washed with cold water (193 ml) and dried with getting 74,8 g (yield 89%) of the desired product as a white solid.

Example 10

Getting ethyl-2-(4,6-dimethyl-5-nitropyrimidin-2-ylamino)acetate (compound 10)

A solution of compound 2 (69 mg), complex ethyl ester of glycine hydrochloride (102 mg) and triethylamine (103 μl) in ethanol was stirred for 3 hours at the boil under reflux. After completion of the reaction the mixture was concentrated under reduced pressure. Obtained in accordance with the ATA, the residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:3) to give 82 mg (yield 86%) of the desired product as a pale yellow amorphous substance.

Example 11

Getting 2-(4,6-dimethyl-5-nitropyrimidin-2-ylamino)acetic acid (compound 11)

Compound 10 (80 mg) suspended in 1,4-dioxane (1.5 ml) was added 2 N. aqueous sodium hydroxide solution (1.5 ml) at room temperature (20-30°C). The mixture was stirred at room temperature (20-30°C) for 8 hours. The mixture is then washed with diethyl ether. Upon cooling the reaction mixture portions was added 2 N. aqueous HCl solution to neutralize the mixture to pH 3. The mixture was extracted twice with chloroform, and the organic layer was concentrated under reduced pressure to obtain 52 mg (yield 75%) of the desired product as a pale yellow amorphous substance.

Example 12

Getting 2-(5-(tert-butoxycarbonylamino)-4,6-dimethylpyrimidin-2-yloxy)propanoic acid (compound 12)

A mixture of Compound 3 (653 mg) and di-tert-BUTYLCARBAMATE (1,02 g) in N,N-dimethylformamide (25 ml) was stirred at 50°C during the night. Then the reaction mixture was cooled to room temperature (20-30°C). Sequentially added potassium carbonate (972 mg) and ethyl-2-bromopropionate (609 μl) and the mixture was stirred at room temperature (20-30°C) during the night. Then to the reaction mixture were added water and the mixture was extracted twice with ethyl ether. The organic layer was concentrated under reduced pressure. To the resulting OS is ATCU was added 1,4-dioxane (15 ml) was added 2 N. aqueous sodium-containing solution (15 ml) at room temperature (20-30°C). The mixture was stirred at room temperature (20-30°C) for 2 hours. Then the reaction mixture was washed with diethyl ether. Upon cooling the reaction mixture portions was added 2 N. aqueous HCl solution to neutralize the mixture to pH 3. The mixture was extracted twice with chloroform, and the organic layer was concentrated under reduced pressure to obtain 708 mg (yield 48%, for stage 3 of example 3) of the desired product as a pale yellow amorphous substance.

Example 13

Getting ethyl-2-(5-amino-4,6-diisopropylamide-2-yloxy)acetate (compound 13)

Compound 5 (6,7 mg) and 5% Pd-C (1 mg, N. E. CHEMCAT, STD Type) suspended in methanol (1 ml). Repeated pumping and replacement with hydrogen three times. Next, the suspension was intensively stirred at room temperature (20-30°C) for 1 hour in a hydrogen atmosphere. After completion of the reaction the mixture was filtered through celite and the filtered product was washed with methanol. The filtrate was concentrated under reduced pressure. To the resulting residue were added potassium carbonate (6.2 mg) and dimethylformamide (1 ml). To the mixture was added ethylbromoacetate (3,3 μl) at room temperature (20-30°C). Next, the mixture was stirred at room temperature (20-30°C) during the night. Then the reaction mixture was concentrated PR is the reduced pressure and the resulting residue was purified by the method of column chromatography on silica gel (ethyl acetate:hexane=1:1) to give 0.7 mg (yield 8%) of the desired product as a pale yellow amorphous substance.

Example 14

Getting ethyl-2-(2-chloro-5-methylpyrimidin-4-ylamino)acetate (compound 14)

Ethyl ester of glycine hydrochloride (157 mg) was added to a solution of 2,4-dichloro-5-methylpyrimidine (184 mg) and diisopropylethylamine (486 μl) in acetonitrile (3 ml) while cooling the solution with ice. The mixture was stirred at 40°C during the night. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) to give 205 mg (yield 81%) of the desired product as a white amorphous substance.

Example 15

Getting ethyl-2-(2-chloro-5-methylpyrimidin-4-yloxy)-2-methylpropionate (compound 15)

Sodium hydride (52 mg, 60%) was suspended in tetrahydrofuran (3 ml). Cooling the slurry with ice, was added ethyl-alpha-hydroxyisobutyrate (145 μl). The mixture was stirred at room temperature (20-30°C) for 30 minutes While cooling the mixture with ice was added to portions of 2,4-dichloro-5-methylpyrimidine (176 mg) and the mixture was stirred at room temperature (20-30°C) for 4 days. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:49 - 1:4.5) to obtain 78 mg (30%yield) of the desired product as an oily substance.

Example 16

Obtaining 2-(2-chloro-5-methylpyrimidin-4-yloxy)-2-methylpropanoic acid (compound 16)

Named in the title compound was synthesized from compound 15 in the same manner as in example 11.

Example 17

Getting ethyl-2-(2-amino-4,6-dimethylpyrimidin-5-yloxy)acetate (compound 17)

Named in the title compound was synthesized from 2-amino-4,6-dimethylpyrimidin-5-ol in the same manner as in example 6.

Example 18

Getting ethyl-2-(4-amino-5-fluoro-2-oxopyrimidine-1(2H)-yl)acetate (compound 18)

5-Ferritin (500 mg) and potassium carbonate (803 mg) suspended in N,N-dimethylformamide (5 ml) and was added to the suspension ethylbromoacetate (430 μl). The mixture was stirred at 100°C during the night. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (methylene chloride:methanol=99:1 to 92:9) to give 329 mg (yield 39%) of the desired product as a white amorphous substance.

Example 19

Getting ethyl-2-(3-methyl-5-nitropyridine-2-yloxy)acetate (compound 19)

Sodium hydride (116 mg, 60%) was suspended in tetrahydrofuran (4 ml). Added ethylglycol (273 ml) while cooling the slurry with ice. The mixture was stirred at room temperature (20-30°C) for 30 minutes. C is added to the mixture in portions of 2-chloro-3-methyl-5-nitropyridine (200 mg) at room temperature (20-30°C) and the mixture was stirred at room temperature (20-30°C) for 3 hours. Then to the reaction mixture were added water and the mixture was twice extracted with chloroform. The organic layer was concentrated under reduced pressure to provide 310 mg of the crude desired product compound 19 in the form of amorphous material, brown color.

Example 20

Getting ethyl-2-(5-(tert-butoxycarbonylamino)-3-methylpyridin-2-yloxy)acetate (compound 20)

Compound 19 (319 mg) and 5% Pd-C (5mg, N. E. CHENCAT, STD Type) suspended in methanol. Repeated pumping and replacement with hydrogen three times. Then the suspension was intensively stirred at room temperature (20-30°C) for 1 hour in a hydrogen atmosphere. After completion of the reaction the mixture was filtered through celite and the filtered product was washed with methanol. The filtrate was concentrated under reduced pressure. To the resulting residue were added dimethylformamide, and to the mixture was added di-tert-BUTYLCARBAMATE (253 mg) at room temperature. Next, the mixture was stirred at 50°C during the night. Then to the reaction mixture were added water and the mixture was twice extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 368 mg of the crude desired product compound 20 as a yellow oily substance.

Example 21

Getting 2-(5-(tert-butoxycarbonylamino)-3-methylpyridin-2-yloxy)acetic acid the (compound 21)

Named in the title compound was synthesized from compound 20 in the same manner as in example 11 (yield 70%, for stage 3 from example 19).

Example 22

Getting ethyl-2-(3-chloropyrazine-2-ylamino)acetate (compound 22)

To an ethanol solution (10 ml) of 2,3-dichloropyrazine (1.0 g) was added ethyl ester of glycine hydrochloride (940 mg) and triethylamine (1.9 ml) and the mixture was subjected to microwave irradiation (150°C, min). The reaction mixture was concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium bicarbonate solution and the product was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by the method of column chromatography on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; NH-DM1020) (hexane:ethyl acetate=10:1) to give 212 mg (yield 15%) of the desired product.

Example 23

Getting 2-(3-chloropyrazine-2-ylamino)acetic acid (compound 23)

2 N. Aqueous sodium hydroxide solution (0.6 ml) was added to an ethanol solution (0.3 ml) of compound 22 (194 mg) and the mixture was stirred at room temperature for 1 hour. Then added to the reaction mixture 2 N. chloroethanol acid under ice cooling and the mixture was neutralized. The product was extracted with chloroform (5 times). The PR is anceschi layer was dried over sodium sulfate, was filtered and concentrated under reduced pressure to obtain 38 mg (yield 23%) of the desired product.

Example 24

Getting ethyl-2-(3-chloropyrazine-2-yloxy)acetate (compound 24)

Named in the title compound was synthesized from 2,3-dichloropyrazine and ethyl-2-hydroxyacetate in the same manner as in example 19.

Example 25

Getting ethyl-2-(6-chloropyrazine-2-yloxy)acetate (compound 25)

Named in the title compound was synthesized from 2,6-dichloropyrazine and ethyl ester of glycine hydrochloride in the same manner as in example 19.

Example 26

Getting 2-(3-chloropyrazine-2-yloxy)acetic acid (compound 26)

Named in the title compound was synthesized from compound 24 in the same manner as in example 23.

Example 27

Getting 2-(6-chloropyrazine-2-yloxy)acetic acid (compound 27)

Named in the title compound was synthesized from compound 25 in the same manner as in example 23.

Example 28

Getting ethyl-2-(5,6-dichloropyridazin-4-ylamino)acetate (compound 28)

A solution of 3,4,5-trichloropyridine (300 mg), ethyl ester of glycine hydrochloride (228 mg) and diisopropylethylamine (844 μl) in ethanol was stirred for 3 hours at the boil. After completion of the reaction the mixture was concentrated under reduced pressure and the residue was purified colonoscopy because it allows the Noah chromatography on silica gel (ethyl acetate:hexane=1:9-1:1) to give 126 mg (yield 31%) indicated in the title compounds as a pale pink amorphous substance.

Example 29

Getting ethyl-2-(3,5-dichloropyridazin-4-ylamino)acetate (compound 29)

In the synthesis of example 28 was also received 78 mg (yield 19%) indicated in the title compounds as a pale pink amorphous substance.

Example 30

Obtain tert-butyl 2-(2-((1-benzylpiperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 30)

Compound 9 (74,74 g), 1-benzyl-N-methylpiperidin-4-amine (up 66,78 g: 1.3 EQ.) and triethylamine (127,20 g: 5 EQ.) suspended in acetonitrile (800 ml). Was added in portions to 50% of an ethyl acetate solution of the anhydride papapostolou acid (191,99 g) cooling the slurry with ice. A device used to add 50% of an ethyl acetate solution of the anhydride papapostolou acid, thoroughly washed with acetonitrile (192 ml) and was carried out by stirring at room temperature (20-30°C) during the night. The mixture is then concentrated under reduced pressure. To the resulting residue was sequentially added chloroform (250 ml) and saturated aqueous sodium bicarbonate solution (140 ml) and the mixture transferred to a separating funnel. The reaction vessel was thoroughly washed with chloroform (175 ml) and was carried out by the division. After separation of the organic layer to the water layer was added chloroform (175 ml) and again was carried out by the division. The combined organic layer is sewed over magnesium sulfate and filtered using vacuum. The filtrate was evaporated under reduced pressure to get 183,27 g of the crude desired product Compound 30 as a yellow amorphous substance.

Example 31

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 31)

To a solution of compound 30 (3.7 g) in methanol (111 ml) was added Pd-C (371 mg) and then carried out the hydrogenation under stirring of the mixture at atmospheric pressure and room temperature over night. Then the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to obtain 2.9 g (yield 96%) specified in the connection header.

Example 32

Obtain tert-butyl 2-(2-((1-(cyclohexylmethyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 32)

Bromeilles (25 μl) and diisopropylethylamine (63 μl) was added to a solution of compound 31 (71 mg) in dimethylformamide (1 ml) and the mixture was stirred at 120°C for 8 hours. Then to the reaction mixture were added saturated aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by the method of column chromatography (hexane:this is laatat=1:1) on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; NH-DM1020) to obtain 40 mg (yield 46%) of the desired product.

Example 33

Obtain tert-butyl 2-(2-((1-(4-Chlorobenzyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 33)

Named in the title compound was synthesized from compound 31 and 4-chlorobenzylamino in the same manner as in example 32.

Example 34

Obtain tert-butyl 2-(2-((1-isobutylpyrazine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 34)

Named in the title compound was synthesized from compound 31 and isobutyramide in the same manner as in example 32.

Example 35

Obtain tert-butyl 2-(2-((1-benzoylpiperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 35)

Named in the title compound was synthesized from compound 31 and benzoyl chloride in the same manner as in example 32.

Example 36

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-finetipped-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 36)

Named in the title compound was synthesized from compound 31 and geneticbased in the same manner as in example 32.

Example 37

Obtain tert-butyl 2-(2-((1-(cyclohexanecarbonyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 37)

On the bath in the title compound was synthesized from compound 31 and cyclohexanecarbonitrile in the same way, as in example 32.

Example 38

Obtain tert-butyl 2-(2-((1-acetylpiperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 38)

Named in the title compound was synthesized from compound 31 and acetylchloride in the same manner as in example 32.

Example 39

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-(phenylsulfonyl)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 39)

Named in the title compound was synthesized from compound 31 and benzosulfimide in the same manner as in example 32.

Example 40

Obtain tert-butyl 2-(2-((1-cyclohexylpiperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 40)

Named in the title compound was synthesized from compound 31, cyclohexanone and triacetoxyborohydride sodium in the same manner as in example 32.

Example 41

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-(piperidine-1-carbonyl)piperidine-4-yl)amino)-2-oksidoksi)-pyrimidine-5-ylcarbamate (compound 41)

Named in the title compound was synthesized from compound 31 and 1-piperidinecarbonitrile in the same manner as in example 32.

Example 42

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-(2-methylbenzyl)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (Conn is out of 42)

Named in the title compound was synthesized from compound 31 and 2-methylbenzylamine in the same manner as in example 32.

Example 43

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-phenylpiperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 43)

Named in the title compound was synthesized from compound 31, phenylboric acid, copper acetate(II) and pyridine in the same manner as in example 32.

Example 44

Obtain tert-butyl 2-(2-((1-(2-methoxyethyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 44)

Named in the title compound was synthesized from compound 31 and pomatoleios ether in the same manner as in example 32.

Example 45

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-(pyridine-3-ylmethyl)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 45)

Named in the title compound was synthesized from compound 31 and 3-(methyl bromide)pyridine hydrobromide in the same manner as in example 32.

Example 46

Obtain tert-butyl 2-(2-((1-(4-terbisil)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 46)

Named in the title compound was synthesized from compound 31 and 4-ftorangidridy in the same manner as in example 32.

Example 47

P is the receiving tert-butyl-4,6-dimethyl-2-(2-(methyl(1-((tetrahydrofuran-2-yl)methyl)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 47)

Named in the title compound was synthesized from compound 31 and tetrahydrofurfurylamine in the same manner as in example 32.

Example 48

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-(pyridin-3-yl)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 48)

Named in the title compound was synthesized from compound 31, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, copper acetate(II) and pyridine in the same manner as in example 32.

Example 49

Obtain tert-butyl 2-(2-((1-(cyclopropylmethyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 49)

Compound 9 (100 mg), 1-(cyclopropylmethyl)-N-methylpiperidin-4-amine (56.6 mg) and triethylamine (234 μl) suspended in acetonitrile (2 ml). Was added in portions to 50% of an ethyl acetate solution of the anhydride papapostolou acid (273 mg) while cooling the slurry with ice. A device used to add 50% of an ethyl acetate solution of the anhydride papapostolou acid, thoroughly washed with acetonitrile (0.5 ml) and was carried out by stirring at room temperature (20-30°C) during the night. Then the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by the method of column chromatography (methylene chloride:methanol=30:1) on silica gel with grafted amine (Fuji Sylysia Chemcal Ltd.; NH-DM1020) to give 79 mg (yield 52%) of the desired product as a pale yellow amorphous substance.

Example 50

Obtain tert-butyl 2-(2-((1-(3-methoxybenzyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 50)

Named in the title compound was synthesized from compound 31 and 1-(methyl bromide)-3-methoxybenzoyl in the same manner as in example 32.

Example 51

Obtain tert-butyl 2-(2-((1-(4-cyanobenzyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 51)

Named in the title compound was synthesized from compound 31 and 4-(methyl bromide)benzonitrile in the same manner as in example 32.

Example 52

Obtain tert-butyl-4,6-dimethyl-2-(2-methyl(1-(3-(trifluoromethyl)benzyl)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 52)

Named in the title compound was synthesized from compound 31 and 1-(methyl bromide)-3-(trifluoromethyl)benzene in the same manner as in example 32.

Example 53

Obtain tert-butyl-4,6-dimethyl-2-(2-(methyl(1-(3,4,5-triptorelin)piperidine-4-yl)amino)-2-oksidoksi)pyrimidine-5-ylcarbamate (compound 53)

Named in the title compound was synthesized from compound 31 and 5-(methyl bromide)-1,2,3-triterpenols in the same manner as in example 32.

Example 54

Obtain tert-b is Teal-2-(2-((1-(cyclopropanecarbonyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 54)

Named in the title compound was synthesized from compound 31 and cyclopropanecarbonitrile in the same manner as in example 32.

Example 55

Obtain tert-butyl 2-(2-((1-(biphenyl-4-yl)(methyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 55)

Named in the title compound was synthesized from compound 31 and 4-(methyl bromide)biphenyl in the same manner as in example 32.

Example 56

Obtain tert-butyl-2-(1-((1-benzylpiperidine-4-yl)(methyl)amino)-1-oxoprop-2-yloxy)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 56)

Named in the title compound was synthesized from compound 12 and 1-benzyl-N-methylpiperidin-4-amine in the same manner as in example 49.

Example 57

Obtain tert-butyl-4,6-dimethyl-2-(2-oxo-2-(piperidine-4-ylamino)ethoxy)pyrimidine-5-ylcarbamate (compound 57)

Tert-butyl 2-(2-(1-benzylpiperidine-4-ylamino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate synthesized from compound (9) and 4-amino-1-benzylpiperidine in the same manner as in example 49. Then specify in the title compound was synthesized from tert-butyl 2-(2-(1-benzylpiperidine-4-ylamino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate in the same manner as in example 31.

Example 58

Obtain tert-butyl 2-(2-(1-(cyclopropylmethyl)piperidine-4-ylamino)-2-oksidoksi)-,6-dimethylpyrimidin-5-ylcarbamate (compound 58)

Named in the title compound was synthesized from compound 57 and bromelicola in the same manner as in example 32.

Example 59

Obtain tert-butyl 2-(2-(1-(4-perbenzoic)piperidine-4-ylamino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 59)

Named in the title compound was synthesized from compound 57 and 4-tormentilla in the same manner as in example 32.

Example 60

Obtain tert-butyl 2-(2-((1-benzylpiperidine-4-yl)(cyclopropyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate (compound 60)

Named in the title compound was synthesized from compound (9) and 1-benzyl-N-cyclopropylidene-4-amine in the same manner as in example 49.

Example 61

Obtain tert-butyl-6-(2-((1-benzylpiperidine-4-yl)(methyl)amino)-2-oksidoksi)-5-methylpyridin-3-ylcarbamate (compound 61)

Named in the title compound was synthesized from compound 21 and 1-benzyl-N-methylpiperidin-4-amine in the same manner as in example 49.

Example 62

Obtaining N-(1-benzylpiperidine-4-yl)-2-(4,6-dimethyl-5-nitropyrimidin-2-ylamino)-N-methylacetamide (compound 62)

Named in the title compound was synthesized from the compound (11) and 1-benzyl-N-methylpiperidin-4-amine in the same manner as in example 49.

Example 63

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-the laminitis)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide (compound 63)

Compound 62 (93 mg) and zinc (147 mg) suspended in acetic acid (2 ml) and the suspension was stirred at room temperature (20-30°C) for 3 hours. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by the method of column chromatography on silica gel (ethyl acetate:hexane=5:1-3:1) obtaining of 25.4 mg (yield 29%) of the desired product as a pale yellow amorphous substance.

Example 64

Getting 4-((4-(2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methylacetamide)piperidine-1-yl)methyl)benzamide (compound 64)

Tert-butyl 2-(2-((1-(4-carbamoylmethyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate synthesized from compound (9) and 4-((4-(methylamino)piperidine-1-yl)methyl)benzamide in the same manner as in example 49. Then tert-butyl 2-(2-((1-(4-carbamoylmethyl)piperidine-4-yl)(methyl)amino)-2-oksidoksi)-4,6-dimethylpyrimidin-5-ylcarbamate was dissolved in methylene chloride (4 ml). While cooling the solution with ice was added triperoxonane acid (1 ml). The mixture was stirred at room temperature (20-30°C) for 4-5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; NH-DM1020) method column of chromatogra the AI (methylene chloride:methanol=10:1) obtaining of 28.1 mg (yield 36%over 2 stages) of the desired product as a white solid.

Example 65

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide (compound 65)

Compound 30 (calculated, assuming that the connection 9 in the previous process was 74,74 g and the output of amidation was 80%) was dissolved in chloroform (140 ml). The solution was added to 6 N. aqueous solution of HCl (530 ml) at room temperature (20-30°C). A device used to add connections 30, thoroughly washed with chloroform (240 ml) and then was carried out by stirring at room temperature (20-30°C) for 2.5 hours. After separation of the chloroform layer to the water layer was added chloroform (300 ml). Added portions 4 N. aqueous sodium hydroxide solution (805 ml), adding as needed ice (just 740,7 g). Added additional number 4 N. aqueous sodium hydroxide solution (25 ml for pH adjustment of the aqueous layer to 8.5), followed by the addition of chloroform (80 ml), and was carried out by the division. After separation of the chloroform layer to the water layer was added chloroform (200 ml) and again was carried out by the division. The chloroform layer is collected in two processes of extraction, dried over magnesium sulfate and filtered by suction. Then, the filtrate was evaporated under reduced pressure to get 100,15 g (yield 103,9%over 2 stages) of the crude desired product as a pale yellow solid is th substance.

To the resulting solid substance was added isopropanol (1020 ml), and the mixture was heated at 85°C to dissolve the solid. The mixture was stirred, allowing it to cool. When the temperature of the heating bath was reached 67°C, was carried out by the introduction of the seed and the mixture continued to stir overnight. Then the mixture was stirred for 2 hours under ice cooling and then filtered by suction. The resulting solid was washed with cold isopropanol (150 ml) and dried with getting 89,60 g (yield of 92.9%, for stage 2) of the desired compound (recrystallized from isopropanol) as colorless crystals.

To recrystallized from isopropanol the product (50,00 g) was added ethanol (220 ml) and the mixture was heated to 85°C to dissolve the product. The mixture was stirred, allowing it to cool. When the temperature of the heating bath was reached 65°C, was carried out by the introduction of the seed and the mixture continued to stir overnight. Then the mixture was stirred for 2 hours while cooling with ice and then filtered by suction. The resulting solid was washed with cold isopropanol (100 ml) and dried with getting 48,18 (yield 96%) of the desired product as white crystals.

Example 66

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopropyl the Teal)piperidine-4-yl)-N-methylacetamide dihydrochloride (compound 66)

To a chloroform solution (1 ml) of compound 49 (78 mg) was added 6 N. HCl (1 ml)and the mixture was stirred at room temperature for 1 hour. Added 4 n sodium hydroxide solution, while cooling the reaction mixture with ice, to neutralize the mixture. The resulting product was extracted with chloroform and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; NH-DM1020) using column chromatography (ethyl acetate) to obtain 37.5 mg (yield 62%) of 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide. Then a methanol solution of 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide was added 2 EQ. 4 n HCl/1,4-dioxane and the mixture was concentrated under reduced pressure. The desired product was provided by recrystallization from methanol/ethyl acetate as white crystals.

Example 67

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopentyl)piperidine-4-yl)-N-methylacetamide (compound 67)

Named in the title compound was synthesized from compound 9 and 1-cyclopentyl-N-methylpiperidin-4-amine in the same manner as in example 64.

Example 68

Receiving the s 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(2-cyclohexylethyl)piperidine-4-yl)-N-methylacetamide dihydrochloride (compound 68)

2-(5-Amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(2-cyclohexylethyl)piperidine-4-yl)-N-methylacetamide synthesized from compound (9) and N-methyl-1-(2-cyclohexylethyl)piperidine-4-amine in the same manner as in example 64. Then a methanol solution of 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(2-cyclohexylethyl)-piperidine-4-yl)-N-methylacetamide was added 2 equivalents of 4 n HCl/1,4-dioxane and the mixture was concentrated under reduced pressure. The desired product was provided by recrystallization from methanol/diethyl ether as white crystals.

Example 69

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidine-4-yl)ndimethylacetamide (compound 69)

Named in the title compound was synthesized from compound 9 and N-methyl-1-(4-(trifluoromethyl)benzyl)-piperidine-4-amine in the same manner as in example 64, and recrystallized from methylene chloride.

Example 70

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclobutanecarbonyl)piperidine-4-yl)-N-methylacetamide (compound 70)

Named in the title compound was synthesized from compound 9 and cyclobutyl(4-(methylamino)piperidine-1-yl)methanone in the same manner as in example 64.

Example 71

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-methylacetamide (compounds is their 71)

To a chloroform solution (0.5 ml) of compound 32 (39 mg) was added 6 N. HCl (0.7 ml) and the mixture was stirred at room temperature for 1 hour. Added 4 N. aqueous sodium hydroxide solution, while cooling the reaction mixture with ice, to neutralize the mixture. The resulting product was extracted with chloroform and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd., NH-DM1020) using column chromatography (ethyl acetate) to give 23 mg (yield 76%) specified in the connection header.

Example 72

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(4-Chlorobenzyl)piperidine-4-yl)-N-methylacetamide (compound 72)

Named in the title compound was synthesized from compound 33 in the same manner as in example 71.

Example 73

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-isobutylpyrazine-4-yl)-N-methylacetamide (compound 73)

Named in the title compound was synthesized from compound 34 in the same manner as in example 71.

Example 74

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzoylpiperidine-4-yl)-N-methylacetamide (compound 74)

Named in the title compound was synthesized from compound 35 t is Kim the same way as in example 71.

Example 75

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-finetipped-4-yl)ndimethylacetamide (compound 75)

Named in the title compound was synthesized from compound 36 in the same manner as in example 71.

Example 76

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclohexanecarbonyl)piperidine-4-yl)-N-methylacetamide hydrochloride (compound 76)

2-(5-Amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-cyclohexanecarbonyl)piperidine-4-yl)-N-methylacetamide synthesized from compound 37 in the same manner as in example 71. Then a methanol solution of 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-cyclohexanecarbonyl)piperidine-4-yl)-N-methylacetamide was added 1 EQ. 4 n HCl/1,4-dioxane and the mixture was concentrated under reduced pressure. The desired product was provided by recrystallization from methanol/diethyl ether as a pale yellow solid.

Example 77

Obtaining N-(1-acetylpiperidine-4-yl)-2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methylacetamide hydrochloride (compound 77)

Named in the title compound was synthesized from compound 38 in the same manner as in example 76.

Example 78

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(phenylsulfonyl)piperidine-4-yl)ndimethylacetamide (compound 78)

Nazvanov the title compound was synthesized from compound 39 in the same way, as in example 71.

Example 79

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-cyclohexylpiperidine-4-yl)-N-methylacetamide (compound 79)

Named in the title compound was synthesized from compound 40 in the same manner as in example 71.

Example 80

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(piperidine-1-carbonyl)piperidine-4-yl)ndimethylacetamide (compound 80)

Named in the title compound was synthesized from compound 41 in the same manner as in example 71.

Example 81

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(2-methylbenzyl)piperidine-4-yl)ndimethylacetamide (compound 81)

Named in the title compound was synthesized from compound 42 in the same manner as in example 71.

Example 82

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-phenylpiperidine-4-yl)ndimethylacetamide (compound 82)

Named in the title compound was synthesized from compound 43 in the same manner as in example 71.

Example 83

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(2-methoxyethyl)piperidine-4-yl)-N-methylacetamide hydrochloride (compound 83)

Named in the title compound was synthesized from compound 44 in the same manner as in example 76.

Example 84

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(p is ridin-3-ylmethyl)piperidine-4-yl)ndimethylacetamide hydrochloride (compound 84)

Named in the title compound was synthesized from compound 45 in the same manner as in example 76.

Example 85

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(4-terbisil)piperidine-4-yl)-N-methylacetamide (compound 85)

Named in the title compound was synthesized from compound 46 in the same manner as in example 71.

Example 86

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-((tetrahydrofuran-2-yl)methyl)piperidine-4-yl)ndimethylacetamide (compound 86)

Named in the title compound was synthesized from compound 47 in the same manner as in example 71.

Example 87

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(pyridin-3-yl)piperidine-4-yl)ndimethylacetamide hydrochloride (compound 87)

Named in the title compound was synthesized from compound 48 in the same manner as in example 76.

Example 88

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(3-methoxybenzyl)piperidine-4-yl)-N-methylacetamide hydrochloride (compound 88)

Named in the title compound was synthesized from compound 50 in the same manner as in example 76.

Example 89

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(4-cyanobenzyl)piperidine-4-yl)-N-methylacetamide hydrochloride (compound 89)

Named in the title compound was synthesized from the organisations 51 in the same manner as in example 76.

Example 90

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(3-(trifluoromethyl)benzyl)piperidine-4-yl)ndimethylacetamide (compound 90)

Named in the title compound was synthesized from compound 52 in the same manner as in example 71.

Example 91

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(3,4,5-triptorelin)piperidine-4-yl)ndimethylacetamide (compound 91)

Named in the title compound was synthesized from compound 53 in the same manner as in example 71.

Example 92

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopropanecarbonyl)piperidine-4-yl)-N-methylacetamide (compound 92)

Named in the title compound was synthesized from compound 54 in the same manner as in example 71.

Example 93

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(biphenyl-4-ylmethyl)piperidine-4-yl)-N-methylacetamide hydrochloride (compound 93)

Named in the title compound was synthesized from compound 55 in the same manner as in example 76.

Example 94

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(piperidine-4-yl)ndimethylacetamide (compound 94)

Named in the title compound was synthesized from compound 31 in the same manner as in example 71.

Example 95

Obtaining N-(1-benzylpiperidine-4-yl)-2-(4,6-dimethyl rimidine-2-yloxy)-N-methylacetamide hydrochloride (compound 95)

N-(1-benzylpiperidine-4-yl)-2-(4,6-dimethylpyrimidin-2-yloxy)-N-methylacetamide (147 mg, yield 62%) was synthesized from 2-(4,6-dimethylpyrimidin-2-yl)exucuse acid (117 mg) and 1-benzyl-N-methylpiperidin-4-amine (131 mg) in the same manner as in example 49. Then a methanol solution of N-(1-benzylpiperidine-4-yl)-2-(4,6-dimethylpyrimidin-2-yloxy)-N-methylacetamide was added 1 EQ. 4 n HCl/ethyl acetate. The mixture is then concentrated under reduced pressure to give the desired product as a white amorphous substance.

Example 96

Getting 2-(4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidine-4-yl)ndimethylacetamide maleate (compound 96)

2-(4,6-Dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidine-4-yl)ndimethylacetamide was synthesized from 2-(4,6-dimethylpyrimidin-2-yl)exucuse acid and N-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-4-amine in the same manner as in example 49. Then a methanol solution of 2-(4,6-dimethyl-pyrimidine-2-yloxy)-N-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidine-4-yl)ndimethylacetamide was added 1 equivalent of maleic acid and the mixture was concentrated under reduced pressure. The desired product was provided by recrystallization from 2-propanol/isopropyl ether as a white solid.

Example 97

Getting 2-(5-amino-4,6-dimethyl-2-oxopyrimidine-1(2H)-yl)-N-(1-gasoline is piperidine-4-yl)-N-methylacetamide (compound 97)

Ethyl-2-(4,6-dimethyl-5-nitro-2-oxopyrimidine-1(2H)-yl)acetate (500 mg)obtained in example 6 by-product, and 5% Pd-C (40 mg) suspended in methanol (20 ml). Repeated pumping and replacement with hydrogen three times. Then the suspension was intensively stirred at room temperature (20-30°C) for 1 hour in a hydrogen atmosphere. After completion of the reaction the mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The resulting residue and di-tert-BUTYLCARBAMATE (427 mg) was dissolved in dimethylformamide (15 ml) and the solution was stirred at 50°C during the night. The reaction mixture was distributed between ethyl acetate and water. The aqueous layer was concentrated under reduced pressure. To the resulting residue were added 2 N. aqueous sodium hydroxide solution (4 ml) and the mixture was stirred at room temperature (20-30°C) for 6 hours. Then portions were added 2 N. aqueous solution of HCl (4 ml) while cooling the reaction mixture and the mixture was concentrated under reduced pressure. Next was added methanol and the insoluble products were removed by filtration. The filtrate was concentrated under reduced pressure. 9.5 mg (yield of 1.3%, on 5 stages) named in the title compound was synthesized from the resulting residue and 1-benzyl-N-methylpiperidin-4-amine in the same manner as in example 64.

Example 98

Getting 2-5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylpropanamide (compound 98)

Named in the title compound was synthesized from compound 12 and 1-(cyclopropylmethyl)-N-methylpiperidin-4-amine in the same manner as in example 64.

Example 99

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylpropanamide (compound 99)

Named in the title compound was synthesized from compound 56 in the same manner as in example 71.

Example 100

Obtaining N-(1-benzylpiperidine-4-yl)-2-(4,6-dimethyl-5-(methylamino)pyrimidine-2-yloxy)-N-methylpropanamide (compound 100)

To a solution in tetrahydrofuran (1 ml) of compound 56 (72 mg) was added bis(trimethylsilyl)amide and potassium (0,5M solution in toluene: 273 μl) at -78°C. the Mixture was stirred at -78°C for 30 min was added in portions methyliodide (9 µl). Then the mixture was stirred overnight, allowing to slowly warm to room temperature (20-30°C). Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and the mixture was twice extracted with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; NH-DM1020) using column chromatography (ethyl acetate:hexane=1:19-1:1) to give 7.7 mg (yield 10%) of tert-butyl 2-(1-((1-benzylpiperidine-4-yl)(methyl)amino)-1-oxoprop-2-yloxy)-4,6-dimethylpyrimidin-5-yl(METI is)carbamate. 2.6 mg (yield 42%) indicated in the title compound was synthesized from tert-butyl 2-(1-((1-benzylpiperidine-4-yl)(methyl)amino)-1-oxoprop-2-yloxy)-4,6-dimethylpyrimidin-5-yl(methyl)carbamate in the same manner as in example 71.

Example 101

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)ndimethylacetamide (compound 101)

Named in the title compound was synthesized from compound 58 in the same manner as in example 71.

Example 102

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(4-perbenzoic)piperidine-4-yl)ndimethylacetamide (compound 102)

Named in the title compound was synthesized from compound 59 in the same manner as in example 71.

Example 103

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-cyclopropylacetylene (compound 103)

Named in the title compound was synthesized from compound 60 in the same manner as in example 71.

Example 104

Getting 2-(5-amino-4,6-diisopropylamide-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide (compound 104)

In the same way as in example 11, carboxyl derivative was synthesized from compound 13. Then synthesised named in the title compound from the resulting carboxyl derivative and 1-benzyl-N-methylpiperidin-4-amine in the same manner as in example 9.

Example 105

Getting 2-(5-amino-4,6-diisopropylamide-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide (compound 105)

In the same way as in example 11, carboxyl derivative was synthesized from compound 13. Then synthesised named in the title compound from the resulting carboxyl derivative and 1-(cyclopropylmethyl)-N-methylpiperidin-4-amine in the same manner as in example 49.

Example 106

Obtaining 2-(2-chloro-5-methylpyrimidin-4-ylamino)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide (compound 106)

Named in the title compound was synthesized from compound 14 in the same manner as in example 105.

Example 107

Obtaining N-(1-(cyclopropylmethyl)piperidine-4-yl)-2-(2-(4-methoxybenzylamine)-5-methylpyrimidin-4-ylamino)-N-methylacetamide (compound 107)

A solution of compound 106 (93 mg), 4-methoxybenzylamine (345 μl) and diisopropylethylamine (45,5 μl) in n-butanol (1.5 ml) was stirred overnight while heating to a boil. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel (methylene chloride:methanol=50:1 to 4:1) to give 43 mg (yield 36%) of the desired product as a white amorphous substance.

Example 108

Obtaining 2-(2-amino-5-methylpyrimidin-4-ylamino)-N-(-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide (compound 108)

Compound 107 (24,9 mg) was dissolved in methylene chloride (1 ml). Added triperoxonane acid (3 ml) while cooling the solution with ice. The reaction mixture was stirred at room temperature (20-30°C) during the night. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (methylene chloride:methanol=10:1-4:1) to give 12.6 mg (yield 68%) of the desired product as a white amorphous substance.

Example 109

Obtaining N-(1-benzylpiperidine-4-yl)-2-(2-chloro-5-methylpyrimidin-4-ylamino)-N-methylacetamide (compound 109)

Named in the title compound was synthesized from compound 14 in the same manner as in example 104.

Example 110

Obtaining N-(1-benzylpiperidine-4-yl)-2-(2-(4-methoxybenzylamine)-5-methylpyrimidin-4-ylamino)-N-methylacetamide (compound 110)

Named in the title compound was synthesized from compound 109 in the same manner as in example 107.

Example 111

Obtaining 2-(2-amino-5-methylpyrimidin-4-ylamino)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide maleate (compound 111)

2-(2-Amino-5-methylpyrimidin-4-ylamino)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide synthesized from compound 110 in the same manner as in example 108. Then a methanol solution of 2-(2-amino-5-methylpyrimidin-4 and the amino)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide was added 1 equivalent of maleic acid and the mixture was concentrated under reduced pressure to obtain specified in the connection header.

Example 112

Obtaining N-(1-benzylpiperidine-4-yl)-2-(2-chloro-5-methylpyrimidin-4-yloxy)-N,2-dimethylpropanamide maleate (compound 112)

Named in the title compound was synthesized from compound 16 and 1-benzyl-N-methylpiperidin-4-amine in the same manner as in example 96.

Example 113

Obtaining 2-(2-amino-4,6-dimethylpyrimidin-5-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide (compound 113)

Named in the title compound was synthesized from compound 17 in the same manner as in example 104.

Example 114

Obtaining 2-(4-amino-5-fluoro-2-oxopyrimidine-1(2H)-yl)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide (compound 114)

Named in the title compound was synthesized from compound 18 in the same manner as in example 104.

Example 115

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide hydrobromide (compound 115)

Compound 65 (198 mg) suspended in methanol (1 ml) was added to a suspension of Hydrobromic acid (89 mg, 47% aqueous solution) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. To the resulting residue were added ethanol (3 ml) and the mixture is stirred at boiling. Then portions were added water (0.6 ml). When the precipitate had dissolved, the mixture was stirred for the eyes, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with ethanol and dried to obtain 189 mg (yield 78%) of the desired product as white crystals.

Example 116

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide hydrochloride (compound 116)

Compound 65 (200 mg) suspended in methanol (1 ml) and to the suspension was added 4 n HCl/1,4-dioxane (130 ml) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue was added isopropanol (2.0 ml) and the mixture is stirred at boiling. Then portions were added water (0.2 ml). When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with isopropanol and dried to obtain 162 mg (yield 74%) of the desired product as pale yellow crystals.

Example 117

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide maleate (compound 117)

Compound 65 (1.0 g) is suspended in methanol (5.0 ml) and to the suspension was added m Lanovoy acid (307 mg) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue was added isopropanol (5.0 ml) and the mixture is stirred at boiling. Then portions were added water (0.4 ml). When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with isopropanol and dried to obtain 1.1 g (yield 86%) of the desired product as white crystals.

Example 118

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide methanesulfonate (compound 118)

Compound 65 (202 mg) suspended in methanol (1 ml) and to the suspension was added methanesulfonyl acid (50,6 mg) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue was added isopropanol (1.0 ml) and the mixture is stirred at boiling. When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with isopropanol and dried to obtain 232 mg (yield 92%) of the desired product as white to the of itallow.

Example 119

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide nitrate (compound 119)

Compound 65 (186 mg) suspended in methanol (1 ml) and added to a suspension of nitric acid (44,3 mg: d=1,42) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue was added isopropanol (2.0 ml) and the mixture is stirred at boiling. Then portions were added water (240 μl). When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with isopropanol and dried to obtain 116 mg (yield 54%) of the desired product as white crystals.

Example 120

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide tosylate (compound 120)

Compound 65 (201 mg) suspended in methanol (1 ml) and to the suspension was added n-toluensulfonate acid monohydrate (99,3 mg) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue was added isopropanol (2.0 ml) and the mixture is stirred at boiling. Then since the s was added water (150 ml). When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with isopropanol and dried to obtain 247 mg (yield 84%) of the desired product as white crystals.

Example 121

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide econsultant (compound 121)

Compound 65 (202 mg) suspended in methanol (1 ml) and was added to the suspension econsultancy acid (58,8 mg) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue were added ethanol (2.0 ml) and the mixture is stirred at boiling. Then portions were added water (100 ml). When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with ethanol and dried with getting 181 mg (yield 70%) of the desired product as white crystals.

Example 122

Getting 2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide bansilalpet (compound 122)

Compound 65 (200 is g) suspended in methanol (1 ml) and to the suspension was added benzosulfimide acid monohydrate (of 83.4 mg) at room temperature (20-30°C). After dissolution of the connection and the mixture was concentrated under reduced pressure. Then to the resulting residue was added isopropanol (2.0 ml) and the mixture is stirred at boiling. Then portions were added water (230 ml). When the precipitate had dissolved, the mixture was stirred overnight, allowing it to cool. Then the mixture was stirred and cooled in ice for 1 hour and filtered by suction. The resulting solid was washed with isopropanol and dried to obtain 194 mg (yield 69%) of the desired product as white crystals.

Example 123

Obtaining N-(1-benzylpiperidine-4-yl)-N-methyl-2-(3-methyl-5-nitropyridine-2-ylamino)ndimethylacetamide (compound 123)

Named in the title compound was synthesized from 2-chloro-3-methyl-5-nitropyridine and 2-amino-N-(1-benzylpiperidine-4-yl)-N-methylacetamide in the same manner as in example 10.

Example 124

Getting 2-(5-amino-3-methylpyridin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide hydrochloride (compound 124)

Named in the title compound was synthesized from compound 61 in the same manner as in example 76.

Example 125

Obtaining N-(1-benzylpiperidine-4-yl)-2-(5-chloropyridin-3-yloxy)-N-methylacetamide hydrochloride (compound 125)

Named in the title compound was synthesized from 2-(5-chloropyridin-3-yloxy)acetic acid this is th way as in example 95.

Example 126

Getting 2-(5-chloropyridin-3-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide hydrochloride (compound 126)

Named in the title compound was synthesized from 2-(5-chloropyridin-3-yloxy)acetic acid and 1-(cyclopropylmethyl)-N-methylpiperidin-4-amine in the same manner as in example 95.

Example 127

Obtaining N-(1-benzylpiperidine-4-yl)-2-(3-chloropyrazine-2-ylamino)-N-methylacetamide hydrochloride (compound 127)

Named in the title compound was synthesized from compound 23 in the same manner as in example 95.

Example 128

Obtaining N-(1-benzylpiperidine-4-yl)-2-(3-chloropyrazine-2-yloxy)-N-methylacetamide hydrochloride (compound 128)

Named in the title compound was synthesized from compound 26 in the same manner as in example 95.

Example 129

Obtaining N-(1-benzylpiperidine-4-yl)-2-(6-chloropyrazine-2-yloxy)-N-methylacetamide hydrochloride (compound 129)

Named in the title compound was synthesized from compound 27 in the same manner as in example 95.

Example 130

Obtaining N-(1-benzylpiperidine-4-yl)-N-methyl-2-(3-(methylamino)pyrazin-2-yloxy)ndimethylacetamide hydrochloride (compound 130)

30% Solution of methylamine in ethanol (120 mg) was added to a solution in ethanol (1 ml) of compound 128 (100 mg) and the mixture was subjected to microwave exposed the tion (160°C, 30 min). The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; MH-DM1020) method column chromatography (hexane:ethyl acetate=1:2) and converted into the hydrochloride with getting to 68.1 mg (yield 63%) specified in the connection header.

Example 131

Obtaining N-(1-benzylpiperidine-4-yl)-N-methyl-2-(6-(methylamino)pyrazin-2-yloxy)ndimethylacetamide hydrochloride (compound 131)

Named in the title compound was synthesized from compound 129 in the same manner as in example 130.

Example 132

Obtaining N-(1-benzylpiperidine-4-yl)-2-(3-(dimethylamino)pyrazin-2-yloxy)-N-methylacetamide maleate (compound 132)

Named in the title compound was synthesized from compound 128 and dimethylamine hydrochloride in the same manner as in example 130.

Example 133

Obtaining N-(1-benzylpiperidine-4-yl)-2-(6-(dimethylamino)pyrazin-2-yloxy)-N-methylacetamide hydrochloride (compound 133)

Named in the title compound was synthesized from compound 129 and dimethylamine hydrochloride in the same manner as in example 130.

Example 134

On the doctrine 2-(3-aminopyrazine-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide hydrochloride (compound 134)

(4-Methoxyphenyl)methylamine (40 mg) was added to a solution in ethanol (1 ml) of compound 128 (100 mg) and the mixture was subjected to microwave irradiation (160°C, 100 min). The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; MH-DM1020) method column chromatography (hexane:ethyl acetate=1:1) to obtain colorless oily substance (46,7 mg). Then this product was dissolved in chloroform (1 ml) was added to a solution of triperoxonane acid (1 ml). The mixture was stirred at room temperature overnight. Then the reaction mixture was concentrated under reduced pressure and to the residue was added water. The resulting product was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; MH-DM1020) using column chromatography (ethyl acetate) and was converted into hydrochloride with getting a 21.5 mg (yield 21%) specified in the connection header.

Example 135

Getting 2-(6-chlorine is pyridazin-3-yloxy)-N-(1-(cyclopropanecarbonyl)piperidine-4-yl)-N-methylacetamide (compound 135)

Named in the title compound was synthesized from ethyl-2-(6-chloropyridin-3-yloxy)acetate and cyclopropyl-(4-(methylamino)piperidine-1-yl)methanone in the same manner as in example 105 (yield 63%, stage 2).

Example 136

Obtaining N-(1-(cyclopropanecarbonyl)piperidine-4-yl)-2-(6-(dimethylamino)pyridin-3-yloxy)-N-methylacetamide (compound 136)

A mixture of compound 135 (60 mg), 2M solution of dimethylamine/tetrahydrofuran (766 μl), potassium iodide (2,82 mg), triethylamine (23,7 μl) and n-butanol (1.0 ml) was stirred at 110°C for 2 days in a sealed tube. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel (ethyl acetate:hexane=1:3-99:1) obtaining of 12.1 mg (yield 19%) of the desired product as a pale yellow amorphous substance.

Example 137

Obtaining N-(1-benzylpiperidine-4-yl)-2-(6-chloropyridin-3-yloxy)-N-methylacetamide (compound 137)

Named in the title compound was synthesized from ethyl-2-(6-chloropyridin-3-yloxy)acetate in the same manner as in example 104 (yield 48%, stage 2).

Example 138

Obtaining N-(1-benzylpiperidine-4-yl)-2-(6-chloropyridin-3-yloxy)-N-cyclopropylacetylene (compound 138)

Named in the title compound was synthesized from ethyl-2-(6-chloropyridin-3-yloxy)acetate and 1-benzyl-N-4-amine in the same manner as in example 104.

Example 139

Obtaining N-(1-benzylpiperidine-4-yl)-2-(3,5-dichloropyridazin-4-ylamino)-N-methylacetamide (compound 139)

Named in the title compound was synthesized from compound 29 in the same manner as in example 104.

Example 140

Obtaining N-(1-benzylpiperidine-4-yl)-2-(3-chloro-5-methoxypyridazine-4-ylamino)-N-methylacetamide (compound 140)

A solution of compound 139 (10 mg) and sodium methylate (1.3 mg) in methanol (1 ml) was stirred overnight at boiling. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified on silica gel with grafted amine (Fuji Sylysia Chemical Ltd.; NH-DM1020) using column chromatography (ethyl acetate:hexane=1:9 to 1:1) to obtain 3.0 mg (30%yield) of the desired product as a white amorphous substance.

Example 141

Obtaining N-(1-benzylpiperidine-4-yl)-2-(5,6-dichloropyridazin-4-ylamino)-N-methylacetamide (compound 141)

Named in the title compound was synthesized from compound 28 in the same manner as in example 104.

The physical properties of the compounds obtained in the above example, are presented in tables 1, 25-27.

Derivative of the present invention with a nitrogen-containing six-membered aromatic ring represented by the formula (I), evaluated at different activity in the following tests 1-7.

Test 1: the Ability to stimulate axonal growth.

Test 2: the Ability to stimulate angiogenesis.

Test 3: the Ability to stimulate neurite outgrowth of neurons of the spinal cord.

Test 4: Evaluation of angiogenesis in models of ischemic lower extremity in mouse (critical limb ischemia).

Test 5: the Ability to improve cardiac function in models of myocardial infarction in rats.

Test 6: the Ability to improve the function on the model induced microspheres (microemboli), in rats.

Test 7: the Ability to improve functiona models lesions of the spinal cord in rats.

Specific methods for evaluation are described below.

Test example 1: the Ability to stimulate axonal growth

In accordance with the method R.M. of Mattson [M. P. Mattson, Brain Res. Rev., 13, 179, (1988)] in 18-day-old embryos in female rats, Wistar (Wistar) were isolated region hippocampal and neurons were separated from each other by the system of dissociation with papain. Hippocampal neurons suspended in 5% Nu-serum + B27 supplement + Neurobasal medium at 5×104cells/well/2 ml 2 ml cell suspension were seeded on coated with poly-D-lysine Cup with a diameter of 36 mm and incubated neurons at 37°C in an incubator with 5% CO2.

On the third day of the incubation period, 1 ml of culture medium was replaced with 1 ml of 5% Nu-serum + B27 supplement + Neurobasal medium containing 2 mm AraC. Each test compound was added to the culture on day 3 and day 7 of the incubation period. On day 9, the cells were fixed with 4% solution of paraformaldehyde. Axons of neurons in fixed cells were labeled polyclonal antibody rabbit against protein 43 associated with the growth of neurons, and is labeled cells was quantitatively determined using software Kurabo for counting processes of neurons.

Ability (%) of each test compound to stimulate axonal growth was calculated by the following equation:

The ability to stimulate axonal growth (%)=[(measurement result on the I interest of compound)/(the measurement results to control)]×100

Connection examples shown in table 25, were used as test compounds and each was added at concentrations of 3 μm and 0.3 μm.

The results are presented in table 25. Although the results of the measurements are presented in table 25, are mainly given for the concentration of 3 μm, the measurement results obtained in the case of a concentration of 0.3 μm, presents for compounds that gave the dimensions 120 (value, reflecting a significant effect) or above only at a concentration of 0.3 microns or compounds, which gave significantly higher results of measurements at 0.3 microns than 3 microns.

As bFGF (basic fibroblast growth factor) results in this test to the result of measurement of approximately 120, 120 used as a threshold to determine whether the compound's ability to stimulate axonal growth.

Table 25
No. Conn.Stimulation of axonal growth (%)
(Conc. Connections = 3 μm)
63186
64120 (Conc. Connection = 0.3 μm)
65 134
69172 (Conc. Connection = 0.3 μm)
71140
72141
73131
74159
75125
76123
77135
78130
79123
80129
81115
82154
85140
88142 (Conc. Connection = 0.3 μm)
91150
92127
93143
94122
95 201
97127
98130
100128
101193
102233
104134 (Conc. Connection = 0.3 μm)
108122
109159
111118 (Conc. Connection = 0.3 μm)
112126
113144
114183
123131
125173 (Conc. Connection = 0.3 μm)
126167
128156
129147
130143
135131
136133
138151
139143
140128 (Conc. Connection = 0.3 μm)

As can be seen from table 25, each of the compounds of examples according to the present invention showed the result of approximately 120 (value, reflecting a significant effect) or higher, demonstrating a significant ability to stimulate axonal growth.

Test example 2: the ability to stimulate angiogenesis

Using the test set angiogenesis, containing a mixture of endothelial cells of vessels, and fibroblasts [KZ-1000; Kurabo], evaluated the ability of test compounds to stimulate angiogenesis.

Each test compound was added at 1, 4 and 7 days incubation period. On day 9, the cells were subjected to immune staining with CD31 and photographed. Control cells were cultured in the same conditions, but without addition of the test compounds, and photographed.

The size of the lumen of the blood vessel quantitatively determined from the obtained images using software for quantitative analysis of angiogenesis. Ability (%) of each test compound stimulating the SQL angiogenesis was calculated in the following equation:

The ability to stimulate angiogenesis (%)=[(measurement result for interest compound)/(the measurement results to control)]×100

Connection Examples shown in table 26, were used as test compounds.

The results are shown in table 26. Although the measurement results are presented in table 26, are mainly given for the concentration of 3 μm, the measurement results obtained in the case of a concentration of 0.3 μm, presents for compounds that gave the dimensions 120 (value, reflecting a significant effect) or above only at a concentration of 0.3 microns or compounds, which gave significantly higher results of measurements at 0.3 microns than 3 microns.

Since bFGF results in this Test to the result of measurement of approximately 120, 120 used as a threshold to determine whether this compound's ability to stimulate angiogenesis.

Table 26
No. Conn.Stimulation of angiogenesis (%)
(Conc. Connections = 3 μm)
64177
65170
69161 (Conc. Connection = 0.3 μm)
71126
72142
73139
74136
75150
76149
77149
78144
79133
80116 (Conc. Connection = 0.3 μm)
81126
82130
85123
88122
91124
92153
93138
95133
97134
98129 (Conc. Connection = 0.3 μm)
100116 (Conc. Connection = 0.3 μm)
108114 (Conc. Connection = 0.3 μm)
109124
111121
114125
123132
128115 (Conc. Connection = 0.3 μm)
130118 (Conc. Connection = 0.3 μm)
135140
136110 (Conc. Connection = 0.3 μm)

As can be seen from table 26, each of the compounds of examples according to the present invention showed the result of approximately 120 (value, reflecting a significant effect) or higher, demonstrating a significant ability to stimulate angiogenesis.

Test example 3: the Ability to stimulate neurite outgrowth of neurons of the spinal cord

In accordance with the method of Martin, Hanson Jr [Martin G. Hanson Jr., J. Neurosci., 1998 Sep. 15; 18(18): 7361-71] in 15-day-old embryos in females of Wistar rats Wistar) were isolated region of the spinal cord and the cells were separated from each other by the system of dissociation with papain. Neurons were collected in the density gradient of 6.8% metrizamide and suspended in 2% FBS + medium L-15 (Leibovitz), so that the cell density was 2×103cells/well/200 μl. 200 μl of cell suspension were seeded on coated with poly-D-lysine/laminin 96-well plate and the plate is incubated in the incubator at 37°C. Test compounds were added 1 hour after deposition of cells.

On day 3 of the incubation period, the neurons were stained with Kalayna AM determined length of neurites using the analyzer cell IN (GE Healthcare Bioscience).

Ability (%) of each test compound to stimulate neurite outgrowth was calculated by the following equation:

The ability to stimulate neurite outgrowth (%)=[(measurement result for interest compound)/(the measurement results to control)]×100

Compounds of examples 65, 71, 74, 92, 130, and 135 were used as test compounds and each was added at a concentration of 0.1 ám.

The results are presented in table 27. bFGF results in this test to the result of the measurement is approximately 130. A value of 120 was used as a threshold for determining that the connection detect a significant effect.

Table 27
No. Conn.65135
71139
14125
92120
130128
135121

As can be seen from table 27, each of the compounds of examples according to the present invention showed the result of approximately 120 (value, reflecting a significant effect) or higher, demonstrating a significant ability to stimulate neurite outgrowth of neurons of the spinal cord.

Test example 4: Evaluation of angiogenesis in models of ischemic lower extremity in mouse (critical limb ischemia)(testin vivo)

In accordance with the method of Ichiro Masaki [Ichiro Masaki, Circ Res.90; 966-973 (2002)] in mouse Balb/c mice was dissected left femoral artery to create a model of critical limb ischemia (n=29-30).

Used tested compounds were compounds of example 65, 92, 114, 130, 135 and 136, each of which oral was administered once daily at a dose of 0.1 mg/kg or 1.0 mg/kg for 10 days starting from the day of excision of the femoral arterial observation of necrosis in the lower limbs of the animal monitoring individual stopped and watched the survival of the lower limb over time.

The results are presented in figures 1 to 6, where 1, 2, 3, 4, 5 and 6 presents the results for the compounds of examples 65, 92, 114, 130, 135 and 136, respectively.

On the shapes of the thick solid line denotes the group with medium thin dashed line denotes the group which was administered 0.1 mg/kg/day of each connection, and the thin solid line denotes the group which was administered 1.0 mg/kg/day of each connection.

*: P<0,05, **: P<0,01, ***: P<0,001 relative to the medium in the test of Wilcoxon.

The results indicate that each of the compounds of example 65, 92, 114, 130, 135 and 136 of the present invention results in increased survival of the femoral artery/vein of the lower limb and therefore is highly effective in improving the condition of critical ischemia of the extremities.

Test example 5: the Ability to improve cardiac function in models of myocardial infarction in rats

In accordance with the method of Masakatsu Vacano and others [Masakatsu Wakeno et al., Circulation 114: 1923-1932 (2006)], male rats Slc:SD 10 weeks of age were anestesiologi pentobarbital and opened in the thoracic region. Completely occludable anterior interventricular branch of the left coronary artery (LAD) to create a model of myocardial infarction. Lonaprisan group were subjected to only the operations on the thorax.

Used the test compound was connection Note the RA 65, which is administered orally once daily at a dose of 0.01 mg/kg 0.1 mg/kg or 1.0 mg/kg for 28 days starting from the date of creation of model of myocardial infarction (after removal of the anesthetic).

4 weeks after creation of myocardial infarction animals were anestesiologi pentobarbital and controlled their cardiac hemodynamics using an optical catheter. Then collected blood samples from the abdominal aorta, determined the size of pulmonary edema and measured the levels of MNP (BNP, brain natriuretic peptide) in plasma (RIA) after sampling of arterial blood.

The results are shown in Fig.7-10.

7, 8, 9 and 10 show the results in the case of LVEDP (LV EDV, end-diastolic pressure in the left ventricle), LVdP/dt max, light weight and MNP levels in plasma, respectively.

#: P<0,05, ##: P<0,01 between linearizovannykh and control by t-criterion of student.

*: P<0,05, **: P<0,01: relative to the control criterion Dannetta.

The compound of example 65 was restrained by reducing the maximum contraction of the left ventricle and diastolic velocity after myocardial infarction, increased end-diastolic pressure and increased pulmonary oedema, stagnation of blood in the lungs. The compound also inhibited the increase of MNP levels in plasma. These results demonstrate that the compound of Example 65 in the present the invention is highly effective in improving the state of reduction of cardiac function and heart failure associated with myocardial infarction.

Test example 6: the Ability to improve the function on the model induced microspheres (microemboli), in rats

In accordance with the method of Ichiro date [Ichiro Date et al., Journal of Neuroscience Research 78; 442-453 (2004)] have used male rats Crl:CD(SD) at the age of 8 weeks. Animals were subjected to anesthesia with halothane gas and did the middle section. The right carotid artery was separated and tied with a thread of common carotid artery and external carotid artery. The pterygopalatine artery was temporarily covered with aneurysm clips. The blood flow through the common carotid artery and external carotid artery was temporarily stopped and were injected with in the common carotid artery 0.1 ml of a suspension of microspheres consisting of microspheres, dispersed in 30% sucrose solution (1800 microspheres/0.1 ml). After injection of slurry injection from the injection needle was filled instantly seizing glue until the blood flow was stopped. Then the blood flow was restored and the operative wound was stitched. Observed neurological symptoms the next day after surgery. Animals were determined in each group of treatment randomly based on an assessment of neurological symptoms, the weight loss from the previous day and body mass on this day.

Used tested compounds were compounds of examples 65, 108, 130, 135 and 137, each of which was administered on the se 1.0 mg/kg The compound of example 65 was also administered at a dose of 0.1 mg/kg of Each compound was administered orally once daily for 10 days starting with the next transaction day. Coordinated motor function was evaluated by 5-fold on an accelerating rotating rod (4-40 rpm/5 min) 2 weeks after the operation.

As a standard option on 11-15 summarizes the total time 5 measurements on a rotating rod.

In particular, on 11-15 demonstrates the effect of various compounds 2 weeks after injection of microspheres (standard option test "spinning rod"). On the figures presents the results of tests of the rotating rod" 2 weeks after the events of ischemia, in which each compound was administered orally at 1.0 mg/kg once daily for 10 days (the compound of example 65 was administered at 0.1 mg/kg or 1.0 mg/kg). What is presented on the figures is the total time 5 measurements on a rotating rod as a standard option.

On 11, 12, 13, 14 and 15 shows the results for compounds of examples 65, 108, 130, 135 and 137, respectively.

***: p<0,0001, according to the method of multiple comparisons Dannetta relative to the media.

These results indicate that each connection examples 65, 108, 130, 135 and 137 of the present invention is highly effective in the improvement in ischemic heart attack the brain and its consequences.

In accordance with article Kraft employees (Kraft et al., Eur. J. Neurosci. 2005 Jun; 21(11):3117-32), the experiment of test example 6, using microspheres to achieve cerebral infarction (ischemic stroke)caused by embolism, is a suitable model for microvascular abnormalities - sign of cognitive disorders. Thus, the results of test example 6 may indicate that the compounds of the present invention are effective in improving the symptoms in dementia.

Test example 7: the Ability to improve function in the model of lesion of the spinal cord (PSM, SCI) in rats

In accordance with the method Dasari [Venkata Ramesh Dasari et al., J Neurotrauma. 2007 Feb; 24 (2):391-410] used female rats Slc: SD 9 weeks of age. Animals were anestesiologi using pentobarbital and made an incision along the midline of the back. After exposing the spine when the section of the middle line of the back, removed the arc of the 9th thoracic spine using bone scissors, focusing on how not to damage the hard shell. The upper and lower bones were fixed in this position to place the exposed region of the spine directly under the device that shock (where applied shock load), and then it was applied a force of 200 kdyn. Controlled tonic stretching of the lower extremities when s is the reflection of the spinal cord.

Used the test compound was the compound of example 65, which was administered in the dose of 1 mg/kg, In particular, the compound was injected through the tail vein once a day for 10 days, starting 90 min after surgery. The motor function of the lower limbs was assessed in the scale BBB (Basso DM, Beattie MS, Bresnahan JC:J Neurotrauma, 1995; 12:1-21) once a week up to 5 weeks after surgery. The results are presented on Fig.

The results indicate that the compound of example 65 of the present invention is highly effective in improving the condition with lesions of the spinal cord.

Industrial applicability

Compounds of the present invention possess the ability to stimulate axonal growth, combined with the ability to stimulate angiogenesis and therefore are effective in reducing or treating lesions of the Central nervous system, such as head trauma and spinal injuries, ischemic stroke, ischemic heart diseases such as myocardial infarction and angina due to organic lesions, peripheral occlusive artery disease, such as critical limb ischemia, or consequences of these diseases or other diseases, against which the compounds of the present invention are effective. The present invention therefore has great medical the e value.

Brief description of drawings

Figure 1 is a chart showing the results for the compound of example 65 in test example 4.

Figure 2 is a chart showing the results for the compound of example 92 in test example 4.

Figure 3 is a chart showing the results for the compound of example 114 in test example 4.

Figure 4 is a chart showing the results for the compound of example 130 in test example 4.

Figure 5 is a chart showing the results for the compound of example 135 in test example 4.

6 is a chart showing the results for the compound of example 136 in test example 4.

Fig.7 is a diagram showing the results in the case of LVEDP in test example 5.

Fig is a chart showing the results in the case of LVdP/dt max in test example 5.

Fig.9 is a diagram showing the results of measuring the weight of the lungs in test example 5.

Figure 10 is a chart showing the results in the case of MNP levels in plasma in test example 5.

11 is a chart showing the results for the compound of example 65 in test example 6.

Fig is a chart showing the result of the ATA for connection of example 108 in test example 6.

Fig is a chart showing the results for the compound of example 130 in test example 6.

Fig is a chart showing the results for the compound of example 135 in test example 6.

Fig is a chart showing the results for the compound of example 137 in test example 6.

Fig is a diagram showing the results of test example 7.

1. The compound represented by the following formula (I-a)

where
R0is a group-NR3R4where R3and R4represent a hydrogen atom;
R1represents a methyl group;
R2represents a methyl group;
R5represents a hydrogen atom;
R6represents a hydrogen atom;
R7represents a methyl group;
E represents an oxygen atom;
represents a benzyl group, cyclohexylmethyl group, isobutylene group, cyclohexanecarbonyl, acetyl group, phenylsulfonyl group, tsiklogeksilnogo group, piperidine-1-carbonyl group, methylbenzyl group, phenyl group, tormentilla group, methoxybenzyl group or triptorelin group;
or its pharmaceutically pickup is acceptable salt.

2. The compound according to claim 1, selected from the group including:
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-benzylpiperidine-4-yl)-N-methylacetamide,
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-methylacetamide,
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-isobutylpyrazine-4-yl)-N-methylacetamide,
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(cyclohexanecarbonyl)piperidine-4-yl)-N-methylacetamide hydrochloride
N-(1-acetylpiperidine-4-yl)-2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methylacetamide hydrochloride
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(phenylsulfonyl)piperidine-4-yl)acetamide", she
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-cyclohexylpiperidine-4-yl)-N-methylacetamide,
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(piperidine-1-carbonyl)piperidine-4-yl)acetamide", she
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(2-methylbenzyl)piperidine-4-yl)acetamide", she
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-phenylpiperidine-4-yl)acetamide", she
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(4-terbisil)piperidine-4-yl)-N-methylacetamide,
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-(1-(3-methoxybenzyl)piperidine-4-yl)-N-methylacetamide hydrochloride, and
2-(5-amino-4,6-dimethylpyrimidin-2-yloxy)-N-methyl-N-(1-(3,4,5-triptorelin)piperidine-4-yl)ndimethylacetamide.

3. Pharmaceutical product that is capable of facilitating the ü axonal growth, combined with the ability to stimulate angiogenesis, containing the compound according to claim 1 or 2, or its pharmaceutically acceptable salt, as an active ingredient and a pharmaceutically acceptable carrier.

4. The method of treatment of lesions of the spinal cord, the Central nervous system as a result of head trauma, ischemic stroke, ischemic heart disease, peripheral occlusive artery disease, multi-infarct dementia, cerebrovascular dementia or senile dementia, comprising introducing a therapeutically effective amount of a compound according to claim 1 or 2, or its pharmaceutically acceptable salt to a patient in need.



 

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SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

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15 cl, 1 tbl, 213 ex

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16 cl, 24 ex, 1 tbl, 20 dwg

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10 cl, 1 tbl, 16 ex

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32 cl, 3 tbl, 118 ex

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5 cl, 1 ex, 2 tbl

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15 cl, 11 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of formula I or their pharmaceutically acceptable salts showing activity with respect to HIV reverse transcriptase, as well as to a based pharmaceutical composition (I). In formula I R1 means phenyl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, phenyl or heteroaryl optionally substituted by one-three substitutes independently specified in groups (a)-(r), R2 means -CN, -CH=CHCN or halogen; R3 means hydrogen, halogen, amino group, halogen(C1-C6)alkyl, -CN or methyl; R4 means hydrogen, Br or amino group; R5a and R5b independently mean hydrogen, C1-C6alkyl, C1-C6alkoxy group or halogen; R6a and R6b either independently mean hydrogen, or together mean ethylene; X means NH or O. The groups (a)-(r) are such as presented in the patent claim.

EFFECT: preparing pharmaceutically acceptable salts possessing activity with respect to HIV reverse transcriptase.

17 cl, 42 ex, 6 dwg, 5 tbl

FIELD: chemistry.

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

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

10 cl, 10 tbl, 178 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to crystalline forms A, B and F of racemic ilaprazole (2[[(4-methoxy-3-methyl-2-pyridinyl)-methyl]thionyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole). The invention also relates to a pharmaceutical composition based on crystalline ilaprazole and use of crystalline ilaprazole.

EFFECT: obtaining novel crystalline forms of ilaprazole which can be used to inhibit gastric acid secretion.

14 cl, 57 dwg, 39 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to new heterocyclic compounds of formula I wherein: n and m may have values 0, 1, 2 and 3; the sign (#) in what follows means the potential presence of a chiral centre; R represents optionally substituted C5-C10aryl or 5-6-member hetaryl containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur optionally condensed with a benzene ring with the substitutes specified in C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, NO2, CF3O, COOH, an unsubstituted amino group or mono-C1-6alkyl- or di(C1-6alkyl)substituted amino-group, C1-8alkylsulphanyl, C1-8alkoxycarbonyl; A1 and A2 independently represent optionally substituted 5-6 member saturated, or aromatic azaheterocycle containing 1 to 2 nitrogen atoms in the cycle and optionally condensed with the benzene ring; or to their pharmaceutically acceptable salts or alkyl esters in the form of isolated optical isomers, or their mixtures. Also, the invention refers to a pharmaceutical composition on the basis of the compound of formula I, to a drug on the basis of the compound of formula I, as well as to a method for preparing the compound of formula I.

EFFECT: there are prepared new non-peptide heterocyclic low-molecular peptidomimetics of a secretory amyloid peptide precursor sAAP showing an ability to have an effective effect on the processes of formation, storage and restoration of the memory lost in health and none.

10 cl, 4 dwg, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form of ilaprazole hydrate (2[[(4-methoxy-3-methyl-2-pyridinyl)-methyl]sulphinyl]-5-(1H-pyrrol-1-yl) 1H-benzimidazole). The invention also relates to a pharmaceutical composition for inhibiting gastric acid secretion, as well as a method of treating inflammatory gastrointestinal disorders.

EFFECT: novel crystalline form of ilaprazole hydrate is obtained.

7 cl, 21 dwg, 19 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) p equals 1 or 2; R1 is methyl, ethyl, propyl, isobutyl, 2-fluoroethyl or cyclobutyl; m equals 0; each R2 is absent; n equals 0; each R3 is absent; R4 is a hydrogen atom; R5 is a hydrogen atom; R6 is -C(O)O-R6a; R6a is a C1-C6alkyl group which can have 1-3 substitutes selected from a group of substitutes α, where the group of substitutes α is a group consisting of a halogen atom, a hydroxyl group, a C1-C6alkoxy group, a C3-C7cycloalkyl group, an amino group, a mono- or di(C1-C6alkyl)amino group, a phenyl group, and a furyl group; and R7 is a hydrogen atom.

EFFECT: compounds have the property of reducing the blood glucose level and can be used to treat and/or prevent type 1 sugar diabetes, type 2 sugar diabetes or diabetes-associated diseases caused by low glucose tolerance, as well as to prevent obesity caused by low glucose tolerance.

11 cl, 2 tbl, 119 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

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