Human protein tyrosine phosphatase inhibitors and application method thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where R is a group selected from: i) hydrogen; ii) phenyl and iii) thiophenyl; Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl group, R1 is selected from: i) hydrogen; ii) straight C1-C6alkyl; iii) C6 or C10 aryl; iv) C(O)OR5; and v) 2-methylthiazol-4-yl; R5 denotes a straight or branched C1-C6alkyl; and index x equals 0 or 1. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent having human protein tyrosine phosphatase beta (HPTP-β) inhibiting action and use in treatment.

EFFECT: compounds can be used as human protein tyrosine phosphatase beta inhibitors.

11 cl, 1 dwg, 1 tbl, 1 ex

 

The present invention relates to compounds useful as inhibitors of protein-tyrosine phosphatase beta man (HPTP-β), thus regulating angiogenesis. The present invention additionally relates to compositions containing one or more inhibitors of protein-tyrosine phosphatase beta man (HPTP-β), and how the regulation of angiogenesis.

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, plays a critical role in a wide range of physiological and pathological processes (Nguyen L.L. et al., Int. Rev. Cytol., 204, 1-48, (2001)). Angiogenesis is a complex process that is mediated by the interaction between the endothelial cells that line the blood vessels and their surroundings. In the early stages of angiogenesis tissue or tumor cells produce and secrete Pro-angiogenic growth factors in response to stimuli from the environment, such as hypoxia. These factors diffused into neighboring endothelial cells and stimulate the receptors that lead to the production and secretion of proteases, which break down the surrounding extracellular matrix. Activated endothelial cells begin to migrate and proliferate into the surrounding tissue to the source of these growth factors (Bussolino F., Trends Biochem. Sci., 22, 251-256, (1997)). Then the endothelial cells cease to proliferate which differentiate into tubular structures, which represent the first stage in the formation of stable, Mature blood vessels. After that perinatally cells, such as pericyte and smooth muscle cells, included in the newly formed vessel at a later stage in the maturing of the vessel.

Angiogenesis regulates the natural balance of Pro - and antiangiogenic factors. Vascular endothelial growth factor, a growth factor, fibroblast and angiopoietin are a few of the many potential Pro-angiogenic growth factors. These ligands are associated with their corresponding receptor tyrosine kinases in endothelial cell surface and convert the signals that support the migration and proliferation of cells. Taking into account that the identified numerous regulatory factors, the molecular mechanisms of this process are still not fully clear.

There are many painful conditions, managed permanent unregulated or improperly regulated angiogenesis. In such painful conditions unregulated or improperly regulated angiogenesis can cause a specific disease, or enhance an existing pathological condition. For example, the formation of new eye blood vessels is understood as the most common cause of blindness and underlies the pathology of approximately 2 diseases of the eye. Under certain pre-existing conditions, such as arthritis, newly formed capillary blood vessels invade the joint and destroy cartilage. In diabetes, new capillaries are formed in the retina invade the vitreous body, causing bleeding and blindness. As the growth and metastasis of solid tumors depend on angiogenesis (Folkman et al., "Tumor Angiogenesis," Chapter 10, 206-32, in The Molecular Basis of Cancer, Mendelsohn et al., eds., W.B. Saunders, (1995)). It is shown that tumors that grow to more than 2 mm in diameter, must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. After these new blood vessels are embedded in the tumor, they supply nutrients and growth factors that are essential for tumor growth, as well as a means for tumor cells were enrolled in the circulation and metastasized to distant sites such as liver, lung or bone (Weidner, New Eng. J. Med., 324, 1,1-8 (1991)). When used as a drug in cancer animal natural inhibitors of angiogenesis can prevent the growth of small tumors (O'reilly et al., Cell, 79, 315-28 (1994)). In some protocols, the use of such inhibitors leads to regression of the tumor and the transition of tumors in a latent state even after cessation of treatment (O'reilly et al., Cell, 8, 277-85 (1997)). In addition, delivery of angiogenesis inhibitors in certain tumors can strengthen their response to other therapeutic regimes (Teischer et al., Int. J. Cancer, 57, 920-25 (1994)).

Although many painful conditions due to constant unregulated or improperly regulated angiogenesis, some state of the disease can be treated by increasing angiogenesis. Growth and repair of tissue are biological events that occur in cell proliferation and angiogenesis. Thus, an important aspect of wound healing is revascularization of damaged tissue due to angiogenesis.

Chronic, non-healing wounds are a major cause long-term complications in the elderly. This is especially true for bedridden or diabetic patients who have developed severe, non-healing skin ulcers. In many of these cases, delayed healing is the result of impaired blood supply or the result of continuous pressure or clogged blood vessels. Insufficient capillary circulation due to atherosclerosis of small arteries or venous stagnation contributes to the violation repair damaged tissue. Such fabrics are often infected by microorganisms that proliferate without obstacles withfrom innate protective systems of the body, require well-vascularized tissue to effectively eliminate pathogenic organisms. As a result, most therapeutic interventions focused on restoring blood flow to ischemic tissues, thus providing access of nutrients and immune factors to the wound.

Atherosclerotic lesions in large vessels can cause tissue ischemia, the process which could be improved by modulating the growth of blood vessels to the injured tissue. For example, atherosclerotic lesions in the coronary arteries can cause angina and myocardial infarction, which could be prevented if we could restore blood flow by stimulating the growth of lateral arteries. Similarly, atherosclerotic lesions in large arteries, which supply blood to the legs, can cause ischemia in skeletal muscle, which limits mobility and, in some cases, leads to the necessity of amputation, which can also be prevented by improving blood flow using angiogenic therapy.

Other diseases such as diabetes and hypertension, are characterized by a decrease in the number and density of small blood vessels such as arterioles and capillaries. These small blood vessels are important for the delivery of oxygen and p the test substances. Reducing the number and density of blood vessels contributes to the adverse effects of hypertension and diabetes, including claudication, ischemic ulcers, malignant hypertension, and renal failure. The course of such common disorders and many other less common diseases such as Buerger's disease, can be improved by increasing the number and density of small blood vessels using angiogenic therapy.

It was suggested that one remedy for the regulation of angiogenesis is the treatment of patients inhibitor of protein-tyrosine phosphatase beta man (HPTP-β) (Kruegar et al., EMBO J., 9, (1990)) and, therefore, to meet this demand were the compounds obtained in accordance with the present invention.

Compounds of the present invention represent a new class of compounds capable of regulating angiogenesis in humans.

The present invention additionally relates to pharmaceutical compounds and their pharmaceutically acceptable salts and/or their pharmaceutical compositions, containing

a) an effective amount of one or more compounds of the present invention; and

b) excipient.

The present invention also relates to a method of regulating angiogenesis and, thus, provide treatment, to which the s affects angiogenesis, these methods include the introduction to the human an effective amount of the compounds of the present invention.

These and other objectives, features and advantages will become apparent to experts in this field after reading the following detailed description and appended claims. All percentages, ratios, and proportions in the present description are given by weight, unless otherwise indicated. All temperatures are given in degrees Celsius (°C)unless otherwise stated. All cited in this description and the documents incorporated into this description by reference; references to any document should not be construed as an admission that it is prior art with respect to the present invention.

In this description and in the claims below are several terms that must be defined with the following values.

By "pharmaceutically acceptable" refers to the material that is not biologically or otherwise undesirable, i.e. the material can be introduced together with a suitable active compound without causing clinically unacceptable biological effects and does not interact adversely with any of the other components of the pharmaceutical composition in which it is contained.

Throughout the description and fo is the mule of the invention, the word "contain" and other forms of the word, such as "contains" and "contain"means inclusion, but without limitation, and does not mean that they exclude, for example, other additives, components, integers or steps.

As used in the description and appended claims, the singular number include objects accessed, plural, unless the context explicitly prescribes otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions.

"Optional" or "optionally" means that the described event or circumstance may occur or not to occur, and that the description includes instances when the event or circumstance occurs and instances where it does not occur.

Ranges can be expressed in the present description as from "about" one particular value and/or to "about" another particular value. When expressed this range, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by means of the antecedent "about", it should be understood that the particular value forms another aspect. It should be further understood that the endpoints of each of the ranges are significant both in relation to the other horse is Noah point, and independently of the other endpoint. You should also understand that there are many values disclosed in the present description, and that each is also disclosed in the present description as "approximately" this particular value, in addition to the direct value. For example, if disclosed a value of "10", also revealed "about 10". You should also understand that when disclosed value, then also disclosed values less than or equal the given value "greater than or equal to the given value, and possible ranges between the values, respectively, it will be clear to the person skilled in the art. For example, if disclosed a value of "10", it also revealed a value less than or equal to 10", and "greater than or equal to 10". Also it should be understood that wherever in this description of the data is presented in several different formats, and that these data represent the final and initial points and ranges for any combination of data points. For example, if disclosed specific data point "10" and a specific data point "15", it should be understood that the values are large, greater than or equal to less than less than or equal to and equal to 10 and 15 is considered open, and values between 10 and 15. Also it should be understood that also disclosed each group between two specific groups. For example, if 10 and 15 are disclosed, 11,12, 13 and 14 are also disclosed.

The term "organic group"as described in the present description, means a group or compounds that contain one or more carbon atoms, and which form part of one of the compounds or their pharmaceutically acceptable salts. For example, many of the groups of the substituents described elsewhere in the present description, are organic groups. For effective functioning in the context of their presence in the compounds and/or salts, disclosed in the present description, the organic groups must often have variable ranges of limited size and/or molecular weight to provide the required characteristics of binding to target enzymes, solubility, bioabsorable. For example, the organic group may have a 1-26 carbon atoms of 1-18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1-4 carbon atoms. In the organic groups of the hydrogen associated with at least some of the carbon atoms of organic groups, and they may optionally contain conventional heteroatoms, which can be found in the substituted organic compounds, such as oxygen, nitrogen, sulfur and the like, or inorganic atoms such as halogen, phosphorus, etc. One example of an organic radical which does not contain inorganic atoms, is 5,6,7,8-tetrahydro-2-nattily for the al. In some embodiments, the implementation of the organic radical can contain 1-10 inorganic heteroatoms associated with it or in it, including Halogens, oxygen, sulfur, nitrogen, phosphorus, etc. are Examples of organic radicals include, without limitation, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxy, carbalkoxy, alkylcarboxylic, replaced alkylcarboxylic, dialkylacrylamide, replaced dialkylacrylamide, alkylsulfonyl, alkylsulfanyl, thioalkyl, tyokalupalkin, alkoxy, substituted alkoxy, halogenated, halogenoalkane, aryl, substituted aryl, heteroaryl, heterocyclic or substituted heterocyclic radical, where these terms are defined in the present description in another place. Several non-limiting examples of organic radicals which contain heteroatoms, include alkoxy radicals, triptoreline radicals, acetoxy radicals, dimethylamino radicals, etc.

Substituted and unsubstituted linear, branched or cyclic alkyl groups include the following non-limiting examples: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), cyclobutyl (C4), cyclo is until (C 5), cyclohexyl (C6and so on; whereas substituted linear, branched or cyclic alkyl, non-limiting examples of which include hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-dottorati (C2), 2,2,2-triptorelin (C3), 3-carboxypropyl (C3), 2,3-dihydroxycinnamate (C4and so on

Substituted and unsubstituted linear, branched or cyclic alkenyl include ethynyl (C2), 3-propenyl (C3), 1-propanyl (2-methylethenyl) (C3), isopropanol (2-mutilated-2-yl) (C3), butene-4-yl (C4and the like; substituted linear or branched alkenyl, non-limiting examples of which include 2-chloranil (2-vinyl chloride) (C2), 4-hydroxybutane-1-yl (C4), 7-hydroxy-7-Metalock-4-EN-2-yl (C9), 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C9and so on

Substituted and unsubstituted linear or branched quinil includes ethinyl (C2), prop-2-inyl (also propargyl) (C3), propyne-1-yl (C3) and 2-metrex-4-yl-1-yl (C7); substituted linear or branched quinil, non-limiting examples of which include 5-hydroxy-5-metrex-3-inyl (C7), 6-hydroxy-6-methylhept-3-yl-2-yl (C8), 5-hydroxy-5-amilhat-3-inyl (C9and so on

Zam is on and unsubstituted "alkoxy" used in the present description means a group having a General formula OR100where R100represents alkyl, alkylamino or alkylamino group, as defined in the present description above, for example, methoxy, methoxymethyl, ethoxymethyl.

Substituted and unsubstituted "halogenated" used in the present description means an alkyl group in which the hydrogen atom is substituted by one or more halogen atoms, e.g. trifluoromethyl, 1,2-dichloroethyl and 3,3,3-cryptochromes.

The term "aryl" used in the present description means a cyclic organic group containing at least one benzene ring containing conjugated and aromatic six-membered ring, non-limiting examples of which include phenyl (C6), naphtalen-1-yl (C10), naphtalen-2-yl (C10). In the aryl rings one or more hydrogen atoms can be replaced by other organic or inorganic radical. Non-limiting examples of substituted aryl rings include 4-forfinal (C6), 2-hydroxyphenyl (C6), 3-were (C6), 2-amino-4-forfinal (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8-hydroxynaphthalene-2-yl (C10), 4,5-dimethoxyaniline-1-yl (C10) and 6-cyanonaphthalene-1-yl (C10).

The term "heteroaryl the" means an organic group, containing five - or six-membered conjugated and aromatic ring, where at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur. Heteroaryl ring may contain a single ring, for example, a ring containing 5 or 6 atoms, where at least one atom of the ring is a heteroatom that is not limited by nitrogen, oxygen or sulfur, such as pyridine ring, furan ring or tournovo ring. "Heteroaryl" can also be a condensed multicyclonic and heteroaromatic ring system in which at least one of the rings is an aromatic ring, and at least one atom of the aromatic ring is a heteroatom including nitrogen, oxygen, or sulfur.

Below are non-limiting examples of heteroaryl rings of the present invention:

and

The term "heterocyclic" means a ring system containing from 3 to 10 atoms in which at least one of the ring atoms is a heteroatom that is not limited by nitrogen, oxygen or sulfur. Rings can be a single ring, condensed ring or bicyclic ring. Non-limiting examples of heterocyclic to the LEC include:

and

All of the above heteroaryl or heterocyclic ring may be optionally substituted by one or more substituents hydrogen, as described in the present description below.

Everywhere in the description of the present invention, the terms containing "spelling thiophene-2-yl and thiophene-3-yl", used to describe heteroaryl groups having the formulas:

then, as in the title of the compounds of the present invention, the chemical nomenclature for these groups is often written as "thiophene-2-yl and thiophene-3-yl, respectively. In the present description, the terms "thiophene-2-yl and thiophene-3-yl" is used in the description of such rings as fragments or groups that are exclusively compounds of the present invention, to ensure unambiguous interpretation of the specialist in this area, which ring is referred to in the present description.

Below are non-limiting examples of groups which can substitute for hydrogen atoms:

i) linear, branched or cyclic C1-C12alkyl, alkenyl and quinil; for example, methyl (C1), ethyl (C2), ethynyl (C2), ethinyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), 3-propenyl (C3), 1-propanyl (2-mutilate the l) (C 3), isopropanol (2-mutilated-2-yl) (C3), prop-2-inyl (also propargyl) (C3), propyne-1-yl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), cyclobutyl (C4), butene-4-yl (C4), cyclopentyl (C5), cyclohexyl (C6);

ii) substituted or unsubstituted C6or C10aryl; for example, phenyl, naphthyl (also referred to in the present description naphtalen-1-yl (C10or naphtalen-2-yl (C10));

iii) substituted or unsubstituted C1-C9heterocyclic rings; as described in the present description below;

iv) substituted or unsubstituted C1-C9heteroaryl rings; as described in the present description below;

v) -(CR12aR12b)zOR11; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3and-CH2OCH2CH2CH3;

vi) -(CR12aR12b)zC(O)R11; for example, -COCH3, -CH2COCH3, -OCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3and-CH2COCH2CH2CH3;

vii) -(CR12aR12b)zC(O)OR11; for example, -CO2CH3, -CH2CO2CH3, CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH 3and CH2CO2CH2CH2CH3;

viii) -(CR12aR12b)zC(O)N(R11)2; for example, -CONH2, -CH2CONH2, CONHCH3, -CH2CONHCH3, -CON(CH3)2and-CH2CON(CH3)2;

ix) -(CR12aR12b)zN(R11)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3);

x) halogen; -F, -Cl, -Br and-I;

xi) -(CR12aR12b)zCN;

xii) -(CR12aR12b)zNO2;

xiii) -CHjXk; where X is a halogen, j is equal to from 0 to 2, j+k=3; for example, -CH2F, -CHF2, -CF3, -CCl3or-CBr3;

xiv) -(CR12aR12b)zSR11; -SH, -CH2SH, -SCH3, -CH2SCH3, -SC6H5and CH2SC6H5;

xv) -(CR12aR12b)zSO2R11; -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, SO2C6H5and-CH2SO2C6H5; and

xiii) -(CR12aR12b)zSO3R11; for example, -SO3H, -CH2SO3H, -SO3CH3CH2SO3CH3, -SO3C6H5and-CH2SO3C6H5;

where each R13independently represents waters of the genus, substituted or unsubstituted linear, branched or cyclic C1-C4alkyl, phenyl, benzyl; or two groups R13together may form a ring containing 3-7 atoms; R14aand R14beach independently represents hydrogen or linear or branched C1-C4alkyl; the index z is from 0 to 4.

For the purposes of the present invention, the terms "connection", "analog" and "composition of matter" are suitable to indicate phenylalaninol acids described in the present description, including all enantiomeric forms, diastereoisomers forms, salts and the like, and the terms "connection", "analog" and "composition of matter" are used interchangeably everywhere in the present description.

In the present invention is considered major unmet medical need, among other things; by providing compositions effective inhibitors of protein-tyrosine phosphatase beta man (HPTP-β); and thus, it provides a means for regulating angiogenesis and restructuring blood vessels disorders in which impaired angiogenesis or in which the blood flow in the tissues is insufficient, or in which increased blood flow would be preferred.

This and other unmet medical needs addressed by inhibitors of protein-tyrosine phosphatase beta man (HPTP-β) this is the total of the invention, are able to regulate angiogenesis and restructuring of the blood vessels and, thus, serve as a means for the treatment of diseases caused by insufficient regulation of protein-tyrosine phosphatase beta man (HPTP-β).

Compounds disclosed in the present description, include all pharmaceutically acceptable forms of salts, for example salts as major groups, among others, amines, and salts of acid groups, among other things, sulfamic acids and carboxylic acids. The following are non-limiting examples of anions that can form salts with basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, etc. the following are non-limiting examples of cations that can form a salt of the acid group include sodium, lithium, potassium, calcium, magnesium, bismuth, etc.

Group R

R represents a group chosen from:

i) hydrogen;

ii) substituted or unsubstituted phenyl and

iii) substituted or unsubstituted heteroaryl ring.

One example R refers to compounds where R represents hydrogen, these compounds have the General formula:

where Z is additionally defined in the present description n the same.

Another example of compounds of formula I includes compounds where R is a phenyl or substituted phenyl, and these compounds have the General formula:

where R10represents one or more optional substituents of hydrogen.

The following are non-limiting examples of groups R10that can substitute for hydrogen atoms on the phenyl group:

i) linear, branched or cyclic C1-C12alkyl, alkenyl and quinil; for example, methyl (C1), ethyl (C2), ethynyl (C2), ethinyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), 3-propenyl (C3), 1-propanyl (2-methylethenyl) (C3), isopropanol (2-mutilated-2-yl) (C3), prop-2-inyl (also propargyl) (C3), propyne-1-yl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), cyclobutyl (C4), butene-4-yl (C4), cyclopentyl (C5), cyclohexyl (C6);

ii) substituted or unsubstituted C6or C10aryl; for example, phenyl, naphthyl (also referred to in the present description naphtalen-1-yl (C10or naphtalen-2-yl (C10));

iii) substituted or unsubstituted C1-C9heterocyclic rings; as described in the present description below;

iv) substituted or unsubstituted C1-C 9heteroaryl rings; as described in the present description below;

v) -(CR12aR12b)zOR11; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3and-CH2OCH2CH2CH3;

vi) -(CR12aR12b)zC(O)R11; for example, -COCH3, -CH2COCH3, -OCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3and-CH2COCH2CH2CH3;

vii) -(CR12aR12b)zC(O)OR11; for example, -CO2CH3, -CH2CO2CH3, CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3and-CH2CO2CH2CH2CH3;

viii) -(CR12aR12b)zC(O)N(R11)2; for example, -CONH2, -CH2CONH2, CONHCH3, -CH2CONHCH3, -CON(CH3)2and-CH2CON(CH3)2;

ix) -(CR12aR12b)zN(R11)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3);

x) halogen; -F, -Cl, -Br and-I;

xi) -(CR12aR12b)zCN;

xii) -(CR12aR12b)zNO2;

xiii) -CHjXk; where X represents halog is h, j is equal to from 0 to 2, j+k=3; for example, -CH2F, -CHF2, -CF3, -CCl3or-CBr3;

xiv) -(CR12aR12b)zSR11; -SH, -CH2SH, -SCH3, -CH2SCH3, -SC6H5and CH2SC6H5;

xv) -(CR12aR12b)zSO2R11; -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, SO2C6H5and-CH2SO2C6H5; and

xiii) -(CR12aR12b)zSO3R11; for example, -SO3H, -CH2SO3H, -SO3CH3CH2SO3CH3, -SO3C6H5and-CH2SO3C6H5;

where each R13independently represents hydrogen, substituted or unsubstituted linear, branched or cyclic C1-C4alkyl, phenyl, benzyl; or two groups R13together may form a ring containing 3-7 atoms; R14aand R14beach independently represents hydrogen or linear or branched C1-C4alkyl; the index p is from 0 to 4.

Another example of compounds of formula I includes compounds where R represents a substituted or unsubstituted heteroaryl ring. For the purposes of the present invention the following non-limiting examples of heteroaryl rings, suitable as group R of the compounds of this is part II of the invention: 1,2,3,4-tetrazolyl; [1,2,3]triazolyl; imidazolyl; pyrrolyl; oxazolyl; isoxazolyl; [1,2,4]oxadiazolyl; [1,3,4]oxadiazolyl; furanyl; thiophenyl; isothiazole; thiazolyl; [1,2,4]thiadiazolyl and [1,3,4]thiadiazolyl.

Heteroaryl groups which contain a group R may be substituted by one or more groups selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropane, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropane, fluorine, chlorine, formatie, diformate and trifloromethyl.

Example compounds of formula I includes compounds where the group R include groups having the formula:

Another example of compounds of formula I includes compounds where the group R include groups having the formula:

Additional example compounds of formula I includes compounds where the group R include groups having the formula:

Z represents a substituted or unsubstituted [1,3,4]thiadiazole-2-ilen group having the formula:

and R1is a surrogate group which may be independently selected from a wide variety of inorganic (hydrogen, hydroxyl, amino, halogen is whether the like) or organic substituting groups, such as alkali, cycloalkyl, heterocycles, heteroaryl, etc. in which such replacement optional group can have from 1 to 12 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to six carbon atoms. In many aspects of the invention R1chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic C1-C6of alkyl;

iii) substituted or unsubstituted C6or C10aryl;

iv), OR4;

v) -C(O)OR5;

vi-COR6and

vii) -NR7C(O)OR8;

R4represents hydrogen or substituted or unsubstituted linear, branched or cyclic C1-C6alkyl; R5represents a linear or branched C1-C6alkyl or benzyl; R6represents a linear, branched or cyclic C1-C6alkyl or phenyl; R7represents hydrogen or methyl; R8represents a linear or branched C1-C6alkyl or benzyl.

One example of compounds of the formula (I), includes a group of R1that represents hydrogen, thus providing compounds having the General formula:

where R is defined in the present description above.

Another example compounds of formula (I) includes the soedineniya, where R1substituted or unsubstituted linear, branched or cyclic C1-C6the alkyl, non-limiting examples of which include groups of R1selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and cyclopropylmethyl.

Additional example compounds of formula I includes compounds where R represents a substituted or unsubstituted C6or C10aryl group include phenyl, naphtalen-1-yl and naphtalen-2-yl. Non-limiting examples of this aspect include phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-were, 3-were, 4-were 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-AMINOPHENYL, 2-(N-methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-AMINOPHENYL, 3-(N-methylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4-AMINOPHENYL, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, 4-(N,N-diethylamino)phenyl, naphtalen-1-yl and naphtalen-2-yl.

One additional example compounds of formula I includes compounds where R1has the formula-NR7C(O)OR8; R7represents the t of a hydrogen, and R8selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3and cyclopropyl (C3).

Group Z of the present invention may further comprise a linking group L, which, when present, serves to bind [1,3,4]thiadiazole-2-strong group from the group R1. When the index x is equal to 0, the linking group is absent. When the index x is equal to 1, the linking group is present.

L represents a linking group having the formula:

-[C(R9aR9b)]y-;

where R9aand R9beach independently represents hydrogen, linear or branched C1-C6alkyl or phenyl, and the index y is from 1 to 4.

One example of groups L include group, where R9aand R9b,each represents hydrogen, and the index y is equal to 1, such groups have the formula:

-CH2-,

also referred to in the present description methylene linking groups.

Another example of group L includes groups, where all groups of R9aand R9brepresent hydrogen, and the index y is equal to 2, this group has the formula:

-CH2CH2-,

and also referred to in the present description the ethylene linking group.

Described in the present description above, the compounds of the present izobreteny shall include all forms of pharmaceutically acceptable salts. The compound having the formula:

may form a salt, for example, salt of sulfonic acid:

and

Compounds can also exist in zwitterionic form, for example:

or

in the form of salts of strong acids, for example:

Analogues (compounds) of the present invention is divided into several categories in order to help the developer formulation in the application of rational synthetic strategy to obtain analogues, which are not illustrated explicitly in the present description. The categorization does not imply a higher or lower efficiency for any of the compositions of the substances described in the present description.

Compounds of the present invention can be obtained by applying the methodology described in the present description below for stages (a)-(f), or by modifications which are known to experts in this field, and which can be achieved without the need for undue experimentation.

Stage (a)

Pr=protective group

Stage (b)

Stage (c)

Stage (d)

Stage (e)

Stage (f)

In scheme I in the present description the following is a technique to obtain analogues of the present invention, described in detail in example 1.

Scheme I

Reagents and conditions: (a) (i) (isobutyl)OCOCl, Et3N, THF; 0°C, 20 minutes

(ii) CH2N2; from 0°C to room temperature for 3 hours.

Reagents and conditions: (b) 48% HBr, THF; 0°C, 1.5 hours.

Reagents and conditions; (c) CH3CN; boiling under reflux for 2 hours.

Reagents and conditions: (d) thiophosgene, CaCO3, CCl4H2O; room temperature, 18 hours.

Reagents and conditions: (e) (i) CH3C(O)NHNH2, EtOH; boiling under reflux for 2 hours. (ii) POCl3, room temperature 18 hours; 50°C for 2 hours.

Reagents and conditions: (f) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 1

(S)-4-(2-(5-methyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina acid (6)

Obtain tert-butyl ester [3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid (1):

To a 0°C solution of 2-(S)-tert-butoxycarbonylamino is about-3-(4-nitrophenyl)propionic acid (1.20 g, 4.0 mmol) in THF (20 ml) was added drop wise addition of triethylamine (and 0.61 ml, 4.4 mmol) followed by the addition of isobutylphthalate (or 0.57 ml, 4.4 mmol). The reaction mixture was stirred at 0°C for 20 minutes and filtered. The filtrate is treated with ethereal solution diazomethane (~16 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue is dissolved in EtOAc and washed successively with water and saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (hexane/EtOAc 2:1), to obtain 1.1 g (82% yield) of the desired product as a yellowish solid.

1H NMR (300 MHz, CDCl3) δ is 8.16 (d, J=8.7 Hz, 2H), 7,39 (d, J=8.7 Hz, 2H), 5,39 (s, 1H), 5,16 (d, J=6.3 Hz, 1H), 4,49 (s, 1H), 3,25 (DD, J=13.8 and 6.6 Hz, 1H), 3,06 (DD, J=13.5 and 6.9 Hz, 1H), of 1.41 (s, 9H).

Obtain tert-butyl ester [3-bromo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid (2):

To a 0°C solution of tert-butyl methyl ether [3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid 1 (0,350 g, 1.04 mmol) in THF (5 ml) is added dropwise 48% aqueous HBr solution (of 0.14 ml, 1.25 mmol). The reaction mixture was stirred at 0°C for 1.5 hours and quenched at 0°C with saturated Na2CO3. The mixture is extracted with EtOAc (3×25 ml) and the combined organic extracts washed with saturated salt solution, dried (Na 2SO4), filtered and concentrated in vacuo, obtaining 0.400 g of the desired product, which is used in the next stage without further purification.

1H NMR (300 MHz, CDCl3) δ to 8.20 (d, J=8,4 Hz, 2H), 7,39 (d, J=8,4 Hz, 2H), is 5.06 (d, J=7.8 Hz, 1H), 4,80 (kV, J=6.3 Hz, 1H), Android 4.04 (s, 2H), of 1.42 (s, 9H).

Getting hydrobromide salt (5)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine (3):

A mixture of tert-butyl methyl ether [3-bromo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid 2 (of 1.62 g of 4.17 mmol) and benzothioate (0,630 g, 4,59 mmol) in CH3CN (5 ml) is heated under reflux for 24 hours. The reaction mixture is cooled to room temperature, to the solution was added diethyl ether (50 ml) and the formed precipitate was separated by filtration. The solid is dried in vacuum, obtaining 1,059 g (63%) of the desired product. ESI+MS 326 (M+1).

Receive (5)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (4):

To a solution of hydrobromide salt (5)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine 3 (2,03 g, 5 mmol) and CaCO3(1 g, 10 mmol) in a mixture of CCl4/water (10:7.5 ml) add thiophosgene ones (0.46 ml, 6 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH2Cl2and water. The layers are separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with a saturated solution with the and, dried (Na2SO4) and concentrated in vacuo to a residue which is purified over silica (CH2Cl2), with 1,71 g (93%) of the desired product. ESI + MS 368 (M+1).

Obtain (S)-5-methyl-N-(2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl)-1,3,4-thiadiazole-2-amine (5):

A solution of (S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole 4 (332 mg, 0,876 mmol) and acetic hydrazide (65 mg, 0,876 mmol) in EtOH (5 ml) is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl3(3 ml) and the resulting solution was stirred at room temperature for 18 hours, then the solution is heated to 50°C for 2 hours. The solvent is removed in vacuum, the residue is dissolved in EtOAc (40 ml) and the resulting solution was treated with NaOH until the pH reaches about 8. The solution is extracted with EtOAc. The combined aqueous layers washed with EtOAc, the combined organic layers washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, obtaining 0,345 g (93%) of the desired product as a yellow solid.

1H NMR (CDC13) of 8.09 (d, J=8,4 Hz, 2H), to $ 7.91 (m, 2H), 7,46 (m, 4H), 7,44 (s, 1H), 5,23 (m, 1H)and 3.59 (m, 2H), 2.49 USD (s, 3H). ESI+ MS 424 (M+l).

Obtain (S)-4-(2-(5-methyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)phenylalaninol acid (6):

(5)-5-Methyl-N-(2-(4-nitrophen is)-1-(2-phenylthiazol-4-yl)ethyl)-1,3,4-thiadiazole-2-amine 5 (0,404 g, 0,954 mmol) dissolved in MeOH (5 ml). Add Pd/C (50 mg, 10% vol./about.) and stirred the mixture in an atmosphere of hydrogen until then, until the reaction is complete. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The raw product is dissolved in pyridine (4 ml) and treated SO3-pyridine (0,304 g, at 1.91 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then add the 7% solution of NH4OH (50 ml). The mixture is then concentrated and the resulting residue purified preparative HPLC with reversed phase, obtaining 0,052 g (11% yield) of the desired product in the form of ammonium salts.

1H (CD3OD): δ 8,00-of 7.97 (m, 2H), 7,51-7,47 (m, 3H), of 7.23 (s, 1H), 7,11? 7.04 baby mortality (q, 4H, J=9.0 Hz), 5,18 (t, 1H, J=7,2 Hz), 3,34-up 3.22 (m, 2H), 2,50 (s, 3H). ESI - MS 472 (M-l).

Below is a General method of selection the final connection in the form of free acid.

Restore arylnitrenes to highlight Amin:

In the vessel Parra for hydrogenation download nitrosoaniline [for example, the intermediate compound 5] (1.0 EQ) and Pd/C (10% Pd on C, 50% wet, Degussa type E101 NE/W, of 2.68 g, 15 wt.%) in the form of solids. Add MeOH (15 ml/g), with the suspension. The vessel is placed in the device Parra for hydrogenation. The vessel is subjected to processing filling/vacuum discharge with N2(3×20 lb./square inch) to obtain inert the atmosphere, followed the same procedure with H2(3×40 lb./square inch). The vessel is filled H2and the vessel shaken at 40 lb./square inch H2for ~40 hours. The vessel is empty and the atmosphere of the purge N2(5×20 lb./square inch). The aliquot was filtered and analyze WAHI to determine the complete transformation. The suspension is filtered through a layer of cellica to remove the catalyst and the homogeneous yellow filtrate concentrated on a rotary evaporator, to obtain the desired product which is used without further purification.

Free sulfamic acid:

100 ml RBF download free amine (1.0 EQ)obtained at the stage described in the present description above. Add acetonitrile (5 ml/g) and the yellow suspension, which usually varies from yellow to orange color, was stirred at room temperature. In the second 500 ml three-neck RBF download SO3Pyridin (1.4 EQ) and acetonitrile (5 ml/g) and the suspension is stirred at room temperature. Both the suspension is gently heated to until the reaction solution containing the amine, is not from orange to red-orange color (usually at about 40-45°C). The resulting solution containing the substrate, pour in one portion to mix the suspension SO3Pyridine at 35°C. the Obtained opaque mixture vigorously paramesh who live, at the same time allowing it to slowly cool to room temperature. After stirring for 45 minutes, or as soon as HPLC determines the completion of the reaction, the color of the suspension add water (20 ml/g), homogeneous solution having a pH of approximately 2.4. Slowly add concentrated H3PO4to lower pH to about 1.4. For setting the pH usually produces no white residue, and the solution was stirred at room temperature for an additional hour. The suspension is filtered and the filter cake washed with filtrate. The filter cake is dried in air overnight, to obtain the desired product in the form of the free acid.

Below are non-limiting examples of compounds of the present invention.

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina acid:

1H (CD3OD): δ 7,97-7,94 (m, 2H), 7,73-of 7.70 (m, 2H), 7,44-7,39 (m, 6H), 7,25 (s, 1H), 7,12 (s, 4H), from 5.29 (t, 1H, J=6.9 Hz), 3,35-3,26 (m, 2H).

4-((S)-2-(5-Propyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid:

1H (CD3OD): δ to 7.59-rate of 7.54 (m, 2H), 7,17-7,03 (m, 6H), 5,13 (t, 1H, J=7,2 Hz), 3,32-3,13 (m, 2H), of 2.81 (t, 2H, J=7.4 Hz), 1,76-to 1.63 (m, 6H, J=7,4 Hz)to 0.97 (t, 3H, J=7,3 Hz).

4-((S)-2-(5-Benzyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid:

1H (CD3OD): δ (m, 2H, 7,49 was 7.45 (m, 2H), 7,26-7,16 (m, 5H), 7,05-6,94 (m, 6H), 5,04 (t, 1H, J=7,1 Hz), 4,07 (s, 2H), 3,22 totaling 3.04 (m, 2H).

5-(3-Methoxybenzyl)-N-((S)-2-(4-nitrophenyl)-1-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)-1,3,4-thiadiazole-2-amine:

1H (CD3OD): δ 7.68 per-to 7.64 (m, 2H), 7,33 (t, 1H, J=8.6 Hz), 7.23 percent for 7.12 (m, 6H), 6,94-6,91 (m, 3H), 5,22 (t, 1H, J=7,1 Hz), 4,22 (s, 2H), 3,86 (s, 3H), 3,40-3,26 (m, 2H).

4-((S)-2-(5-(Naphthalene-1-ylmethyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid:

1H (CD3OD): δ 8,08-with 8.05 (m, 1H), 7,89-7,80 (m, 2H), 7,55-the 7.43 (m, 6H), 7,11-7,00 (m, 6H), to 5.08 (t, 1H, J=7,1 Hz), 4,63 (s, 2H), 3,26-is 3.08 (m, 2H).

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid:

1H (CD3OD): δ of 7.48-7,44 (m, 2H), 7.03 is-6,92 (m, 6H), 5,02 (t, 1H, J=7,2 Hz), 4,30 (s, 2H), 3,55 (s, 3H), 3,22-to 3.02 (m, 2H).

4-((5)-2-(5-((2-Methylthiazole-4-yl)metil)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid:

1H (CD3OD): δ 7,60-7,56 (m, 2H), 7,19 (s, 1H), 7,15 for 7.12 (m, 2H), to 7.09-7.03 is (q, 4H, J=8.7 Hz), 5,14 (t, 1H, J=7,2 Hz), 4,28 (s, 2H), 3.33 and-3,14 (m, 2H), to 2.67 (s, 3H).

Inhibition of HPTP-β provides a means for increasing the activity of endothelial receptor tyrosinekinase, including, but without limitation, angiopoietin receptor tyrosinekinase, Tie-2 and VEGF receptor tyrosinekinase, VEGFR2, and, thus, treatment of pathological States in which there is insufficient blood flow to the tissue. Compounds of the present invention are the means is to ensure the regulation of angiogenesis and other activities endothelial receptor tyrosinekinase. For this reason, among others, in the present invention is considered major unmet medical need.

Providing compositions effective inhibitors of protein-tyrosine phosphatase beta man (HPTP-β) and, thus, provide a means for the regulation of angiogenesis, correction of blood vessels and other activities endothelial receptor tyrosinekinase in disorders in which there is insufficient blood flow in the tissue or in which increased blood flow would be useful. It was shown that the effect of inhibitors of protein-tyrosine-phosphatase person affects several painful conditions or disorders of a man, with such disorders include, but are not limited to:

i) a disease of the peripheral arteries - I. Shiojima et al., Journal of Clinical Invest., 115, 3108-2118,(2005);

ii) coronary artery disease - A.J. Siddiqui et al., Biochem. Biophys. Res. Comm., 310, 1002-1009,(2003);

iii) myocardial infarction (acute coronary syndrome) - Takahashi K. et al., Molecular Therapy, 8, 584-592, (2003);

iv) stroke (cerebral vascular disease) - Stewart D. et al., Chest, 128, 633-642, (2005);

v) Heart failure - Thurston G., J. Anat., 200, 575-580, (2002);

vi) hypertension - Caravalho, R. S. et al., Bone, 34, 849-861, (2004);

vii) diabetic and ischemic neuropathy - Carano A.D. and E.H. Filvaroff, Drug Discovery Today, 8, 980-989, (2003);

viii) the healing of wounds and skin aging - Simons M., Circulation, 111,1556-1566 (2005);

xi) vascular FOTS the representation and atherosclerosis - Annex B.H. and M. Simons, Cardiovascular Research, 65, 649-655, (2005);

x) syndromes vascular leakage - Ardelt A.A. et al., Stroke, 36, 337-341 (2005); and

xi) the growth, maintenance and repair of the bone Cardiovascular Medicine, 12, 62-66, (2002).

Drugs

The present invention also relates to compositions or preparations that contain inhibitors HPTPβ of the present invention. In General, the compositions of the present invention contain:

a) an effective amount of one or more phenylalaninol acids and their salts of the present invention, are effective as inhibitors of protein-tyrosine phosphatase beta man (HPTP-β); and

b) one or more excipients.

For the purposes of the present invention, the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention, and these terms are defined in the present description, as the ingredients that are used in the practice of making safe and effective pharmaceutical compositions.

The developer compositing will be clear that the excipients used primarily to facilitate the supply of safe, sustainable and functional pharmaceutical products, contributing not only as part of the entire media delivery, but also as a means to achieve effective absorption of the active ingredient in the body of recipe the NTA. Excipient can perform simple and direct role inert filler, or excipient used in this sense may be part of the stabilization system pH or coating to ensure the safe delivery of the ingredients in the stomach. The developer composition may also take advantage of the fact that the compounds of the present invention have improved cell efficiency, pharmacokinetic properties, and improved bioavailability when administered orally.

Non-limiting examples of compositions of the present invention contain:

a) from about 0.001 mg to about 1000 mg of one or more phenylalaninol acids of the present invention; and

b) one or more excipients.

Another variant of implementation of the present invention relates to the following compositions containing:

a) from about 0.01 mg to about 100 mg of one or more phenylalaninol acids of the present invention; and

b) one or more excipients.

Additional option of implementing the present invention relates to the following compositions containing:

a) from about 0.1 mg to about 10 mg of one or more phenylalaninol acids of the present invention; and

b) one or more excipients.

Method of use

The present invention relates to a method of regulating angiogenesis in humans, comprising the administration to a human connection of the present invention, as described in the present description.

One variant of implementation of the methods of the present invention relates to a method of treating a disorder in an individual, which has a reserve of blood flow to danangoffice, and selected, but without limitation, coronary artery disease, peripheral vascular disease or cerebral vascular disease.

The second variant implementation of the methods of the present invention relates to a method of vascularization of ischemic tissue. Used in this sense, "ischemic tissue" means tissue that lacks the required flow. Examples of ischemic tissue include, without limitation, the tissue that lacks the required blood supply resulting from myocardial infarction and brain mesenterina ischemia or ischemia of a limb, or as a result of occlusion or stenosis of blood vessels. In one example, the interruption of the supply of oxygenated blood may be caused by occlusion of the vessels. Such occlusion of blood vessels can occur as a result of arteriosclerosis, trauma, surgical procedures, disease and/or other etiology. Also in methods of treatment of the present invention included the treatment of ischemic skeletal muscle and myocardium, stroke, coronary artery disease, peripheral vascular disease, coronary artery disease.

The third variant of the implementation of the methods of the present invention relates to a method for recovery of the fabric. Used in this sense, "tissue repair" means the activation of reparation, the reg is erali, growth and/or maintenance of tissues, including, but not limited to, wound healing or tissue engineering. The person skilled in the art it is known that the formation of new blood vessels required for tissue repair. In turn, the fabric can be damaged, including, but without limitation, injuries or conditions including arthritis, osteoporosis and other disorders of the skeleton, and burns. Tissue may also be damaged as a result of injuries due to surgical procedures, radiation, rupture, toxic chemicals, viral or bacterial infections or burns. Tissue that needs repair, also includes non-healing wounds. Examples of non-healing wounds include non-healing ulcers of the skin resulting from diabetic pathology; or fissures that do not heal quickly.

Compounds of the present invention are also suitable for use in the implementation of the repair tissue in the context of procedures directed tissue regeneration (GTR). Such procedures currently used specialists in this area to accelerate healing of wounds after invasive surgical procedures.

The fourth variant of the implementation of the methods of the present invention relates to a method for maintaining repair tissue, characterized by increased tissue growth during tissue ingen the series. Used in this sense, "tissue engineering" is defined as the creation, design and manufacture of biological prosthetic devices in combination with synthetic or natural materials to complement or replacement of body tissues and organs. Thus, the present methods can be used to complement the design and growth of human tissues outside the body for subsequent implantation when repair or replacement of the affected tissues. For example, antibodies may be useful in maintaining the growth of skin grafts to replace, which is used as a therapy in the treatment of burns.

Additional variant of the implementation of tissue engineering methods of the present invention includes whether or not containing cells are devices that induce the regeneration of functional human tissues during implantation in the area requiring regeneration. As set forth in the present description, directed by biomaterial tissue regeneration can be used to support renewed growth in bone, for example, when periodontal disease. Thus, antibodies can be used to support the growth of the recovered tissue organized into a three-dimensional configuration in the wound or other tissue, which requires reparation.

Another extra is ariante implementation of tissue engineering methods of the present invention compounds described in the present description, may be contained in an external or internal devices containing human tissues, designed to replace the function of diseased internal tissues. This approach enables the selection of cells from the body, placing them in a structural matrix and implantation of a new system inside the body or the use of the system outside the body. For example, antibodies may be contained in lined cells of the vascular graft to support the growth of the cells contained in the graft. It is assumed that the methods in accordance with the invention can be used to Supplement the repair, regeneration and tissue engineering products such as cartilage cells and bone tissues of the Central nervous system, muscles, liver and islets (producing insulin) in the pancreas.

The present invention also relates to the use of phenylalaninol acids of the present invention in the manufacture of a medicinal product to support the growth of skin grafts to replace.

The present invention also relates to the use of phenylalaninol acids of the present invention in the manufacture of a medicinal product for use in the implementation of the repair tissue in the context of procedures directed tissue regeneration (GTR).

Compounds of the present invention can use the SQL in the production of one or more drugs, non-limiting examples of which include:

the compound for use in the manufacture of drugs useful for the purposes of tissue engineering, thus, acting on the reinforced tissue growth;

connection for use in the manufacture of a medicinal product for the treatment of ischemic disorders in the individual.

Methods

Tests for selection using in vitro and in vivo models of angiogenesis

Compounds of the present invention can be selected in the analysis of angiogenesis, which are known in this field. Such assays include in vitro assays, which measure the growth of substitutes blood vessels in cultured cells or the formation of vascular structures from tissue explants and in vivo assays that directly or indirectly measure the growth of blood vessels (Auerbach R., et al. (2003). Clin Chem 49, 32-40, Vailhe B., et al. (2001). Lab Invest 81, 439-452).

1. In vitro models of angiogenesis

In in vitro models, suitable for use in the present invention, use of cultured endothelial cells or tissue explants and measure the effect of the agents on the "angiogenic cell reaction or the formation of structures similar to blood capillaries. Non-limiting examples of in vitro assays of angiogenesis include, but are not limited to, migration and proliferation of endothelial cells, the formation of a capillary tube, the second tube, endothelial sprouting, analysis on the Explant rings of aorta and the aortic arch of a chicken.

2. In vivo models of angiogenesis

In vivo agents or antibodies suitable for use in the present invention, is administered locally or systemically in the presence or in the absence of growth factors (i.e. VEGF or angiopoietin 1) and the growth of new blood vessels is measured by direct observation or measurement of a surrogate marker, such as an indicator of hemoglobin or fluorescent indicator. Non-limiting examples of in vitro assays of angiogenesis include, but without limitation, the analysis on the chorioallantoic membrane of the chicken, the analysis of angiogenesis in the cornea and analysis on the tube of MATRIGELTM.

3. Methods of determining the vascularization of ischemic tissue

Available standard methods to determine if you suffer from tissue at risk of ischemic damage due to unwanted occlusion of vessels. For example, if the disease of the myocardium such techniques include a variety of visualization techniques (e.g., methods of radioactive indicator, x-ray and NMR) and physiological tests. In this regard, can easily be determined induction of angiogenesis, as an effective means of preventing or reducing ischemia in the tissues affected or at risk of destruction by occlusion of blood vessels.

Specialist in this field is the use of standard techniques can measure the vascularization of tissue. Non-limiting examples of measurement of vascularization in an individual include SPECT (single photon emission computed tomography); PET (positron emission tomography); MRI (magnetic resonance imaging) and their combination, by measuring blood flow to the tissue before and after treatment. Angiography can be used as a study macroscopic vascularization. Histological assessment can be used for quantification of vascularization in the low density of vessels. These and other techniques specified in Simons et al., "Clinical trials in coronary angiogenesis," Circulation, 102, 73-86 (2000).

The following non-limiting examples of activity HPTPβ (IC50μm) and PTP1B (IC50μm) are listed in the table below this description.

Table I
ConnectionHPTPβ IC50mcmPTP1B IC50mcm
(S)-4-(2-(5-methyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina acid0,0031,4
(S)-4-(2-(5-Phenyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina acid0,046 3,7
4-((S)-2-(5-Propyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acidis 0.00024,71
4-((S)-2-(5-Benzyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid0,00063,86
4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid0,0021,55
4-((S)-2-(5-((2-Methylthiazole-4-yl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid9x10-60,58

The dimensions and values disclosed in the present description, should not be construed as strictly limited to the exact aforementioned numerical designations. Instead, unless otherwise specified, it is assumed that each such measurement indicates how the above value and a functionally equivalent range on either side of this value. For example, it is assumed that the dimension disclosed as "40 mm" mean "about 40 mm".

All documents cited as references in the detail is the first description of the invention, how appropriate, incorporated into this description by reference; a reference to any document should not be construed as an admission that it is prior art with respect to the present invention. In the event that any meaning or definition of the term in this description conflicts with any meaning or definition of the same term in the incorporated by reference document, the meaning or definition assigned to that term in this document shall prevail.

Although illustrated and described specific embodiments of the present invention, for specialists in this area it is obvious that can be done in various other changes and modifications, without departing from the essence and scope of the invention. In this regard, it is assumed that the appended claims cover all such changes and modifications are included in the scope of this invention.

1. The compound having the formula:

where R represents a group chosen from:
i)hydrogen;
ii) phenyl and (iii) thiophenyl;
Z represents a substituted or unsubstituted [1,3,4]thiadiazole-2-ilen group having the formula:

R1chosen from:
i) hydrogen;
ii) linear C1-C6of alkyl;
iii)6 or10aryl;
iv) C(O)OR5;
v) 2-methylthiazole-4-yl;
R5represents a linear or branched C1-C6alkyl;
and the index x is equal to 0 or 1.

2. The compound according to claim 1, where R represents phenyl.

3. The compound according to claim 1, where R represents thiophene-2-yl or thiophene-3-yl.

4. The compound according to claim 1, where R1selected from methyl, ethyl, n-propyl and n-butyl.

5. The compound according to claim 1, where R1selected from phenyl or naphthalen-1-yl.

6. The compound according to claim 1, chosen from:
(S)-4-(2-(5-phenyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl) ethyl)phenylalaninol acid;
4-((S)-2-(5-propyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylalaninol acid;
4-((S)-2-(5-benzyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylalaninol acid;
4-((S)-2-(5-(naphthalen-1-ylmethyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylalaninol acid;
4-((S)-2-(5-((methoxycarbonyl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylalaninol acid and
4-((S)-2-(5-((2-methylthiazole-4-yl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylalaninol acid.

7. The compound according to any one of claims 1 to 6 for use as drugs having inhibitory activity against protein tyrosine phosphatase beta man (NRTR-β).

8. The compound according to any one of claims 1 to 6 for use for the treatment of a condition selected from the ischemic skeletal muscle and myocardium, stroke, peripheral vascular disease, ischemic heart disease.

9. The use of compounds according to any one of claims 1 to 6 to obtain drugs for the treatment of angiogenesis.

10. The use of compounds according to any one of claims 1 to 6 to obtain medicines for vascularization of ischemic tissue.

11. The use of compounds according to any one of claims 1 to 6 to obtain drugs to support the growth of skin grafts to replace.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compound has antibacterial activity and can be used as a medicinal agent. In formula ,

R1 is hydrogen, halogen, C1-4alkyl; R2 is selected from hydrogen, halogen, C1-4alkyl; R3 is selected from hydrogen, halogen, cyano, C1-4alkyl; W is -N(R6)-; X is a single bond; ring A is an unsaturated or partially saturated ring containing 5-6 atoms, one or two of which are independently selected from nitrogen and sulphur; or an unsaturated or partially saturated bicyclic ring containing 9-10 atoms, one, two or three of which are selected from nitrogen and sulphur; R4 and R5 are substitutes on a carbon atom and are independently selected from a halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, formyl, hydroxy iminomethyl, C1-4alkoxyminomethyl, C1-4alkyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkoxy)carbamoyl, N-(C1-4alkyl)-N-(C1-4alkoxy)carbamoyl, C1-4alkylS(O)a, where a equals 0-2, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, C1-4alkylsulphonylamino, (saturated or unsaturated carbocycle containing 3-7 atoms)-R10- or (saturated, partially saturated or unsaturated ring containing 5-6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R11-; where R4 and R5 can independently and optionally substituted at the carbon atom with one or more R12; R6 is hydrogen; n equals 1-4; where values of R4 can be identical or different; m equals 0-4; where values of R5 can be identical or different; R12 is selected from azido, halogen, cyano, hydroxy, amino, carboxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkylS(O)a, where a equals 0-2, (saturated or unsaturated cabocycle containing 3-7 atoms)-R14- or (saturated, partially saturated or unsaturated ring containing 5 or 6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R15-; where R12 can independently and optionally be substituted at the carbon atom with one or more R9; R10, R11, R14 and R15 are independently selected from a single bond, -C(O)-, -N(R19)C(O)- or -C(O)N(R20)-; where R19 and R20 are independently selected from hydrogen or C1-4alkyl; R16 is selected from halogen, cyano, hydroxy, carboxy, methyl and methoxy. The invention also relates to a pharmaceutical composition, having antibacterial activity, containing the disclosed compound as an active ingredient, use of the disclosed compound to prepare a medicinal agent and a method of producing the compound of formula (I).

EFFECT: high activity of the compounds.

22 cl, 52 tbl, 721 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a use of N-(2-thiazolyl)amide derivatives of formula

,

where R1 and R2 are independently selected from H, -NO2, halogen, C1-C6 alkyl with a straight chain, where at least one of R1 and R2 is different from H; m equals 0, 1, 2 or 3; X is selected from a group consisting of: indole of formula (A) bound in position 2, indole of formula (B) bound in position 3 and indazole of formula (C) bound in position 3:

, , ,

where R3 is selected from H and C1-C6 alkyl with a straight chain; R4, R5, R6 and R7 are independently selected from H and C1-C6 alkoxy group; R8 is selected from H and C1-C6 alkyl, or any of its pharmaceutically acceptable salts to obtain a medicinal agent for treating or preventing diseases or conditions mediated by GSK-3, especially neurodegenerative diseases such as Alzheimer's disease or insulin-independent sugar diabetes. The invention also relates to a compound of formula (I), a pharmaceutical composition based on said compound and synthesis method thereof.

EFFECT: high efficiency of using said derivatives.

30 cl, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula as well as separate enantiomers, diastereomers, racemic mixures and pharmaceutically acceptable salts thereof, having mitotic kinesin KSP inhibiting activity, as well as inhibitory action on tumour cells, use thereof in preparing a medicinal agent and a pharmaceutical composition based on said compounds. In said formula, R denotes Z-NR2R3, Z-OH, Ar1 and Ar2 independently denote a phenyl which, if needed, is substituted with one or more groups independently selected from: F, CI, Br, I, OH, Z denotes an alkylene having 1-6 carbon atoms which, if needed, is substituted with C1-6alkyl, and R1 assumes values given in the claim.

EFFECT: improved method.

16 cl, 3 dwg, 124 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns a EP2 agonist which exhibits the EP3 agonist action, and induce a neurotising and/or protective effect and thereby is effective as a therapeutic agent for a peripheral nerve disease, such as lower and upper motor neuron disorder, nerve root disease, plexopathy, brachial plexus compression syndrome, peripheral neuropathy, neurofibromatosis and nervomuscular conduction disease.

EFFECT: EP2 agonist which exhibits the EP3 agonist action; it is a safe and effective neurotisation and/or protection agent which has an insignificant impact on the cardiovascular system.

13 cl, 36 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

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