Human protein tyrosine phosphatase inhibitors and methods of using said inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R denotes a substituted or unsubstituted thiazolyl group of formula or ; R4 and R5, each independently, are selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl; iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteratoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; or R4 and R5 can be taken together to form a saturated or unsaturated ring, having 5-7 atoms; said substitutes are independently selected from one or more groups, selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R6 denotes a group selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteroatoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R1 is selected from i) hydrogen; ii) C1-C6 linear or C3-C6 branched alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted benzyl; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R2 is selected from i) C1-C6 linear or C3-C6 branched alkyl or ii) C1-C6 linear or C3-C6 branched alkoxy; R3 denotes hydrogen or C1-C4 linear or C3-C6 branched alkyl.

EFFECT: compounds of formula (I) are effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

20 cl, 10 tbl, 8 ex

 

The technical field

The present invention relates to compounds useful as inhibitors of protein person tyrosinosis beta (NRTR-β), thereby regulating angiogenesis. In addition, the present invention relates to compositions containing these inhibitors patientinitiated beta man (NRTR-β), and to methods for regulating angiogenesis.

Prior art

Angiogenesis, the sprouting (sprouting) of new blood vessels from pre-existing vasculature, plays a crucial 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 mediated communication between endothelial cells, which build up the blood vessels and their surrounding environment. In the early stages of angiogenesis tissue or tumor cells produce and secrete Pro-angiogenic growth factors in response to external stimuli, such as hypoxia. These factors diffuse in the surrounding endothelial cells and stimulate the receptors, which leads to the production and secretion of proteases that destroy surrounding xtracellular matrix. Activated endothelial cells begin to migrate and proliferate into the surrounding tissue towards the source of these growth factors (Bussolino, F., TrendsBiochem. Sci., 22, 251-256, (1997)). Then the endothelial cells cease proliferation and differentialmode in the tubular structure, which represents the first stage in the formation of a stable Mature blood vessels. Subsequently perinatally cells, such as pericyte and smooth muscle cells, proceed in the newly formed vessel to participate in the next stage of the maturation vessel.

Angiogenesis is regulated by the natural balance of Pro - and antiangiogenic factors. Endothelial growth factor vessels, fibroblast growth factor and angiopoietin represent a small number of the many potential Pro-angiogenic growth factors. These ligands bind to their respective receptor-tyrosine kinases on the surface of endothelial cells and transmit signals that stimulate the migration and proliferation of cells. Despite the fact that many regulatory factors have been identified, the molecular mechanisms of this process still remain completely unclear.

There are many pathological conditions, driven by persistent unregulated or wrongly (wrongly) regulated angiogenesis. Under such pathological conditions unregulated or inappropriately regulated angiogenesis can cause a specific disease or exacerbate an existing pathological condition. For example, clicks the use of new vessels (the formation of vascular pannus) in ocular tissues is the most common cause of blindness and underlies the pathology of approximately 20 eye diseases. When some previously diagnosed conditions, such as arthritis, the newly formed capillary blood vessels invade the joint and destroy cartilage. In diabetes, new capillaries formed in the retina, hit the vitreous body of the eye, causing bleeding and blindness. As the growth and metastasis of solid tumors are angiogenesis-dependent processes (Folkman et al., "Tumor Angiogenesis," Chapter 10, 206-32, in The Molecular Basis of Cancer, Mendelsohn et al., eds., W.B.Saunders, (1995)). It has been shown that tumors that grow more than 2 mm in diameter, must obtain their own blood supply and ensure that it inducyruya the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they ensure the delivery of nutrients and growth factors required for tumor growth, but are also a means of penetration into the bloodstream of tumor cells and metastasis to distant sites such as liver, lung or bone (Weidner, New Eng. J. Med., 324, 1, 1-8 (1991)). When used as medicines for animals with tumors, 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 decreasing and stopping tumor growth on the after end of treatment (O'reilly et al., Cell, 88, 277-85 (1997)). In addition, delivery of angiogenesis inhibitors in some tumors can potenzirovti their response to other treatment methods (Teischer et al., Int. J. Cancer, 57, 920-25 (1994)).

Although many pathological conditions stimulated by persistent unregulated or inappropriately regulated angiogenesis, some pathological conditions can be treated by increased angiogenesis. Growth and regeneration (healing) fabrics are biological events, where cell proliferation and angiogenesis. Thus, an important aspect of wound healing is revascularization of damaged tissue through angiogenesis.

Chronic, nezazhivayuschie wounds are a major cause of the increasing duration of the disease in the older population. This is particularly true in the case of bedridden or suffering from diabetes patients who develop severe non-healing skin ulcers. In many of these cases, the slow healing is the result of inadequate blood supply or as a result of continuous pressure or blockade of the vessel. Insufficient capillary blood flow due to atherosclerosis of small arteries or venous stasis contributes to adverse outcome of healing of damaged tissue. Such fabrics are often infected with microorganisms that proliferate neko is controlled manner from the side of the innate immune systems protect the body, moreover, the systems require well vascularizing fabric for the effective elimination of pathogens. The result is that most of the medical (therapeutic) effects focuses on restoring blood flow to ischemic tissues, thereby allowing nutrients and immunological factors to reach the wound.

Atherosclerotic disease of large blood vessels can cause tissue ischemia, which can be improved by modulating the growth of blood vessels in diseased tissue. For example, atherosclerotic disease of the coronary arteries can cause angina and myocardial infarction, which can be prevented if we could raise the blood flow by stimulating the growth of collateral arteries. Similarly, atherosclerotic disease of large arteries that supply the legs, can cause ischemia in skeletal muscle, which limits mobility and in some cases necessitates the amputation, which can also be prevented by improving blood flow using angiogenic therapy.

Other diseases such as diabetes and hypertension, are characterized by a reduction 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 pitate is lnyh substances. The reduction in the number and density of blood vessels contributes to adverse complications of hypertension and diabetes, including intermittent claudication, ischemic ulcers, progressive option hypertension and renal failure. These common disorders, and many other less frequent ailments, such as Buerger's disease, can be improved by increasing the number and increase the density of small blood vessels, using angiogenic therapy.

It has been suggested that one way of regulating angiogenesis is the treatment of patients with inhibitor protein of human tyrosinosis beta (NRTR-β) (Kruegar et al., EMBO J., 9, (1990)), and therefore there is a need to meet the needs of the compounds according to this invention.

A brief statement of the substance of the invention

The compounds of this invention represent a new class of compounds that can regulate angiogenesis in humans.

In addition, the present invention relates to pharmaceutical compounds and their pharmaceutically acceptable salts and/or pharmaceutical compositions based on them, containing

a) an effective amount of one or more compounds according to this invention; and

b) a filler ...

In addition, the present invention relates to methods of regulating Angie is ESA and thereby the development of a method of treatment of diseases, under the influence of angiogenesis, and these methods include introduction to the human an effective amount of the compounds according to this invention.

These and other objectives, features and advantages of the present invention become apparent to experts in this field from a consideration of the following detailed description and the accompanying claims. All percentages, ratios, and proportions are mass, unless otherwise noted. All temperatures are expressed in degrees Celsius (°C)unless noted. All cited documents, to the relevant extent, included in the present description by reference; the citation of any document should not be interpreted as recognition that it constitutes prior art against the present invention.

Detailed description of the invention

In this description and the attached below the claims refer to a number of terms, which, as will be defined below, have the following meanings:

The term "pharmaceutically acceptable" refers to a substance which is neither biologically nor otherwise undesirable, i.e. the substance can enter the individual along with the relevant active connection without showing clinically unacceptable biological effects or interacting otricatelniy effects with any of the other components of the pharmaceutical composition, in which it is contained.

In the description of the invention and below in the claims the word "contain" and other forms of words, such as "contains" and "contain"means, but is not limited to, the inclusion of, for example, other additives, components, integers or steps.

"Optional" or "optionally" means later described event or circumstance may occur or may not occur, and that the description includes some examples of when an event or circumstance occurs and some examples of when it occurs.

In the present description, the ranges can be expressed as from "about" one particular value and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximate representations by using the preceding words "about," it should be borne in mind that the particular value forms another aspect. In addition, it should be borne in mind that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also clear that there is a range of values disclosed in the description, and that each value is disclosed, in addition to its specific values, as that is new, also in the "about" of this specific value. For example, if you specify a value of "10"is specified and "about 10". It is also understood that when a value is specified, then unfold and "less than or equal to this value, greater than or equal to the value,and possible ranges between values, it is obvious that the experts in this field. For example, if you specify a value of "10", then open up and "less than or equal to 10", and "more than or equal to 10". In addition, mean that the application data are presented in several different formats and that these data represent endpoints and starting points and ranges for any combination of these basic points. For example, if you specify the particular base point "10" and a specific base point "15", we mean that the assumed open and values more than, more than or equal to, less than, less than, or equal to, and equal to 10 and 15, as well as the values between 10 and 15. It is also clear that each unit between two specific units is also disclosed. For example, if you specify 10 and 15, respectively, disclosed and 11, 12, 13 and 14.

The term "organic group" description refers to groups or parts 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 substitute groups (substituents), mentioned in about the Isani somewhere in another place, represent an organic group. For effective functioning in the context of their presence in the compounds and/or salts, disclosed in the description, the organic groups should have variable ranges of limited size and/or molecular weight, in order to provide the necessary binding with enzymes target, the desired solubility and the required characteristics of bioabsorable. For example, the organic group may contain, for example, 1-26 carbon atoms of 1-18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1-4 carbon atoms. Organic groups often contain hydrogen associated with at least several carbon atoms of organic groups, and can optionally contain common heteroatoms found in 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 contains no inorganic atoms, is a 5,6,7,8-tetrahydro-2-nattily radical. In some embodiments, the organic radical can contain 1-10 inorganic heteroatoms, to the same connected or located therein, including Halogens, oxygen, sulfur, nitrogen, phosphorus, etc. are Examples of organic radicals include, but are not limited to, alkyl, substituted al the ilen, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxy, carbalkoxy, alkylcarboxylic, replaced alkylcarboxylic, dialkylacrylamide, replaced dialkylacrylamide, alkylsulfonyl, alkylsulfanyl, thioalkyl, thiogalactoside, alkoxy, substituted alkoxy, halogenoalkane, halogenoalkane, aryl, substituted aryl, heteroaryl, geterotsiklicheskikh or substituted heterocyclic radicals, and these terms are defined here in a different location. Several non-limiting examples of organic radicals which contain heteroatoms include alkoxyalkyl, cryptomaterial, acetoxyacetyl, dimethylaminoethyl 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), cyclopentyl (C5), cyclohexyl (C6), and the like; whereas non-limiting examples of the linear, branched or cyclic alkyl include hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), 1-chlorine is ethyl (C 2), 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 of alkenyl include ethynyl (C2), 3-propenyl (C3), 1-propanyl (2-methylethenyl) (C3), Isopropenyl (2 methylated-2-yl) (3), butene-4-yl (C4), and the like; substituted linear or branched alkenyl, non-limiting examples of which include 2-chloranil (2-vinyl chloride) (2), 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 include ethinyl (C2), prop-2-inyl (also propargyl) (C3), propyne-1-yl (C2) and 2-metrex-4-in-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-in-2-yl (C8), 5-hydroxy-5-amilhat-3-inyl (C6and so on

Used in the description of the term substituted and unsubstituted "alkoxy" refers to a group having the General formula OR100where R100represents alkyl, alkylamino or alkylamino group as defined above such as methoxy, methoxymethyl, m is taximeter.

Used in the description of the term substituted and unsubstituted "halogenated" denotes an alkyl group having a hydrogen atom, substituted by one or more halogen atoms, for example trifluoromethyl, 1,2-dichloroethyl and 3,3,3-cryptochromes.

The term "aryl"used in the description refers to a cyclic organic group containing at least one benzene ring having a conjugated and aromatic six-membered ring, non-limiting examples of aryl include phenyl (C6), naphtalen-1-yl (C10), naphtalen-2-yl (C10). Aryl cyclic structure may have one or more hydrogen atoms replaced with another organic or inorganic radical. Non-limiting examples of substituted aryl cyclic structures 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" denotes an organic group containing five - or six-membered conjugated and aromatic ring in which at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur. Heteroaryl cyclic structure may be a single ring, such as ring containing 5 or 6 atoms in which at least one ring atom is a heteroatom, not limited by nitrogen, oxygen or sulfur, for example, such as a pyridine ring, furan ring or tournovo ring. In addition, heteroaryl" may also represent a condensed polycyclic and heteroaromatic structure in which at least one of the cycles is an aromatic cycle and at least one atom of the aromatic cycle is a heteroatom including nitrogen, oxygen, or sulfur.

The following is a non-limiting examples of heteroaryl cyclic structures according to this invention:

;;;and.

The term "heterocycle" means a cyclic system containing 3 to 10 atoms, where at least one of the atoms of the cyclic system is a heteroatom, not limited by nitrogen, oxygen or sulfur. The cyclic system may be monocyclic structures, condensed cyclic structures or bicyclic structures. Non-limiting examples of heterotic the practical structures include:

;and.

All of the above heteroaryl or heterocyclic structures may be optionally substituted by one or more substituents hydrogen, as described later.

Throughout the description of the present invention, the terms with the writing "thiophene-2-yl and thiophene-3-yl", used to describe heteroaryl groups having the formulas:

;;

while the title of the compounds according to this invention the chemical nomenclature for these parts are usually represented as "thiophene-2-yl and thiophene-3-yl respectively. The specialist should be borne in mind that the terms "thiophene-2-yl and thiophene-3-yl" in the present description is used in the description of the specified cyclic systems as groups or parts, which are compounds according to this invention.

The term "substituted" used in the description of the invention. The term "substituted" is defined as "a hydrocarbon radical, regardless of whether he or acyclic, cyclic, which has one or more hydrogen atoms substituted by a Deputy or more substituents defined below." Group, with the substitution of hydrogen atoms, the ability to replace one hydrogen atom, two hydrogen atoms or three and the Ohm hydrogen hydrocarbon part at the same time. In addition, these substituents may substitute two hydrogen atoms on two adjacent carbon with the formation of a specified substituent, a new part or group. For example, the substituted group, which requires the substitution of one hydrogen atom, include halogen, hydroxyl, etc. Substitution of two hydrogen atoms include carbonyl, oximino etc. Substitution of two hydrogen atoms from adjacent carbon atoms includes epoxy, etc. Replacement of three hydrogen atoms include cyano and the like, the Term "substituted" used in this description to show that the hydrocarbon portion of, inter alia, aromatic ring, the alkyl chain may have one or more hydrogen atoms replaced by a substituent. If the part is described as "substituted", then any number of hydrogen atoms may be substituted. For example, 4-hydroxyphenyl represents a substituted aromatic carbocyclic ring, (N,N-dimethyl-5-amino)octanol represents a substituted C8alkyl group, 3-guanidinopropionic represents a substituted C3alkyl group, and 2-carboxyphenyl represents a substituted heteroaryl group.

The following is a non-limiting examples of groups that can replace hydrogen atoms of the hydrocarbon group or the other:

i)1-C12linear, branched or CEC is practical alkyl, 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) (3), 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 With6or10aryl; for example, phenyl, naphthyl (also referred to naphtalen-1-yl (C10or naphtalen-2-yl (C10));

iii) substituted or unsubstituted With1-C9heterocyclic structure; described in the present description;

iv) substituted or unsubstituted With1-C9heteroaryl cyclic structure; described below;

v) -(CR13aR13b)zOR12; for example, -OH, -CH2HE, -och3, -CH2Och3, -Och2CH3, -CH2Och2CH3, -Och2CH2CH3and CH2Och2CH2CH3;

vi) -(CR13aR13b)zC(O)R12; for example, the PINES3, -CH2PINES3, -Och2CH3, -CH2PINES2CH3-The PINES2CH2CH3and-the N 2PINES2CH2CH3;

vii) -(CR13aR13b)zC(O)OR12; for example, -CO2CH3, -CH2CO2CH3, -CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3and-CH2CO2CH2CH2CH3;

viii) -(CR13aR13b)zC(O)N(R12)2; for example, -CONH2, -CH2CONH2, -CONHCH3, -CH2CONHCH3, -CON(CH3)2and-CH2CON(CH3)2;

ix) -(CR13aR13b)2N(R12)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) -(CR13aR13b)zCN;

xii) -(CR13aR13b)zNO2;

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

xiv) -(CR13aR13b)zSR12; -SH, -CH2SH, -SCH3, -CH2SCH3, -SC6H5and-CH2SC6H5;

xv) -(CR13aR13b)2SO2R12; -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5and-CH2SO2C6H5; and

xiii) -(CR13aR1b )zSO3R12; for example, -SO3H, -CH2SO3H, -SO3CH3, -CH2SO3CH3, -SO3C6H5and-CH2SO3C6H5;

where each R12represents independently hydrogen, substituted or unsubstituted With1-C4linear, branched or cyclic alkyl, phenyl, benzyl; or two radicals R12can be taken together to form a ring containing 3-7 atoms; R13aand R13bare each independently hydrogen or C1-C4linear or branched alkyl; the index p is from 0 to 4.

For the present invention, the terms "compound," "analog" and "composition" means other disclosed in the description of chemical compounds, including all enantiomeric forms, diastereomeric forms, salts and the like, and the terms "compound," "analog" and "composition (mechanical mixture of ingredients)" are used interchangeably throughout this description.

The present invention is directed to solving several unmet medical needs, including, inter alia:

1) Development of compositions useful as inhibitors of protein person tyrosinosis beta (NRTR-β); and thanks to this development of the method of regulating angiogenesis in case of violation, illness, disease or condition, in the cat the rum angiogenesis promoted;

2) Develop compositions useful as inhibitors of protein person tyrosinosis beta (NRTR-β); and thanks to this development of the method of regulating angiogenesis in case of violation, illness, disease or condition, and

3) Develop compositions useful as inhibitors of protein person tyrosinosis beta (NRTR-β); and thanks to this development of the method of regulating angiogenesis in case of violation, illness, disease or condition in which angiogenesis is understated.

These and other unmet medical needs are being addressed through the development of inhibitors of the protein human tyrosinosis beta (NRTR-β) according to this invention are able to regulate angiogenesis, and this serve as a tool for development on the basis of the method of treatment of elevated or reduced angiogenesis in humans or treatment of diseases which are caused by insufficient regulation of the protein human tyrosinosis beta (NRTR-β).

Proposed in the description of the compounds include all pharmaceutically acceptable salt forms, such as salts of basic groups, inter alia, amines, and salts of acid groups, inter alia, sulfamic and carboxylic acids. The following is a non-limiting examples of anions that can form salts with basic groups: chloride, bromide, iodide, is Ulfat, the bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, etc. the following is a non-limiting examples of cations that can form a salt of the acid group include sodium, lithium, potassium, calcium, magnesium, bismuth, etc.

The compounds of this invention have the formula (I):

where the carbon atom having the amino group has the stereochemistry of (S)as specified in the formula.

R represents a substituted or unsubstituted thiazolino group having the formula

or

R4, R5and R6represent substituents, which may be independently selected from a range of inorganic (hydrogen, hydroxyl, amino, halogen or the like) or organic substituting groups (substituents)such as alkali, cycloalkyl, heterocycles, heteroaryl and the like, and these substituents may optionally contain from 1 to 12 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms.

One example of compounds of formula (I), the radicals R are related to thiazolyl-2-ilen group having the formula

where R4and R5each independently selected from

i) hydrogen;

ii) samewe the aqueous or unsubstituted C 1-C6linear, branched or cyclic alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted heteroaryl; or

R4and R5can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.

One example of compounds of formula (I) includes the radical R of formula

where R5represents hydrogen and R4represents a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), n-pentile (C5), 1-methylbutyl (C5), 2-methylbutyl (C5), 3-methylbutyl (C5), cyclopropyl (C5), n-hexyl (C6), 4-methylpentyl (C6) and cyclohexyl (C6).

Another example compounds of formula (I), the radicals R include groups, where R4represents a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4); and R5represents a group selected from methyl (C1) or ethyl (C2). Non-limiting examples of this aspect of R include 4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazole-2-yl, 4-methyl-5-triazol-2-yl and 4,5-dietitians-2-yl.

Additional example compounds of formula (I), the radicals R include groups, where R5represents hydrogen and R4represents a substituted alkyl group, the substituents selected from the

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

ii) -N(R11)2and

iii) -OR11;

where each R11represents independently hydrogen or C1-C4linear or branched alkyl.

Non-limiting examples of groups that may represent a Deputy of hydrogen radicals R include-CH2F, -CHF2, -CF3, -CH2CF3, -CH2CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2and-CH2NH (CH2CH3).

Other non-limiting examples of groups that contain radicals R include 2,2-divorcecare, 2-methoxycyclohexyl and 4-chlorcycloguanil.

The following additional example compounds of formula (I), the radicals R include groups, where R5represents hydrogen and R4represents phenyl or substituted phenyl, where non-limiting examples of radicals R4include phenyl, 3,4-dimetilfenil, 4-tert-butylphenyl, 4-cyclopropylmethyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(dift is methoxy)phenyl, 4-(triptoreline)phenyl, 3-chlorophenyl, 4-chlorophenyl and 3,4-dichlorophenyl, which when included in the definition of R, we give the following R groups: 4-phenylthiazol-2-yl, 3,4-dimethylphenylsilanol-2-yl, 4-tert-butylphenylmethyl-2-yl, 4-cyclopropylethanol-2-yl, 4-diethylaminophenyl-2-yl, 4-(trifluoromethyl)phenylthiazol-2-yl, 4-methoxyphenylazo-2-yl, 4-(deformedarse)phenylthiazol-2-yl, 4-(triptoreline)phenylthiazol-2-yl, 3-chlorophenyl, 4-chlorophenylthio-2-yl and 3,4-dichloroisothiazole-2-yl.

The following additional example compounds of formula (I) includes the radicals R, where R4selected from hydrogen, methyl, ethyl, n-propyl and isopropyl, and R5represents phenyl or substituted phenyl. A non-limiting example of the radical R according to the fifth aspect of the first category radicals R include 4-methyl-5-phenylthiazol-2-yl and 4-ethyl-5-phenylthiazol-2-yl.

Another additional example compounds of formula (I) includes the radicals R, where R5represents hydrogen and R4represents a substituted or unsubstituted heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazole-4-yl, [1,2,3]triazole-5-yl, [1,2,4]triazole-4-yl, [1,2,4]triazole-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazole-3-yl, [1,2,4]thiadiazole-5-yl, and [1,3,4]thiadiazole-2-yl.

Additional non-limiting example of compounds of formula (I) includes the radicals R, where R4represents a substituted or unsubstituted thiophene-2-yl, for example thiophene-2-yl, 5-chlorothiophene-2-yl and 5-methylthiophene-2-yl.

The following additional example compounds of formula (I) includes the radicals R, where R4represents a substituted or unsubstituted thiophene-3-yl, for example thiophene-3-yl, 5-chlorothiophene-3-yl and 5-methylthiophene-3-yl.

Another example compounds of formula (I) includes the radicals R, where R4and R5taken together form a saturated or unsaturated ring having from 5 to 7 atoms. Non-limiting examples of the sixth aspect of the first category groups R include 5,6-dihydro-4H-cyclopent[d]thiazol-2-yl and 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl.

Additional examples of compounds of formula (I) include the radicals R, which are thiazole-4-ilen group having the formula

where R6represents a group selected from the

i) hydrogen;

ii) substituted or unsubstituted C1-C6linear, branched or cyclic alkyl;

iii) substituted or not ameenah phenyl cyclic structures, having from 5 to 10 atoms in a cyclic structure; or

iv) substituted or unsubstituted heteroaryl cyclic structures having 5 to 10 atoms in the structure.

Example compounds of the formula (I) includes the radicals R, where R6represents hydrogen.

Additional example compounds of formula (I) includes the radicals R, where R6represents a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4). Non-limiting examples of this aspect of R include 2-methylthiazole-4-yl, 2-utiltity-4-yl, 2-(n-propyl)thiazol-4-yl and 2-(isopropyl)thiazol-4-yl.

The following additional example compounds of formula (I) includes the radicals R, where R6represents a substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were and 4-methoxyphenyl.

Another additional example compounds of formula (I) includes the radicals R, where R6represents a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-is inititiate-5-yl, 4-utiltity-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3-methyl-1,2,4-oxadiazol-5-yl.

Additional example compounds of formula (I) includes the radicals R, where R6represents a group having the formula

where R7represents a C1-C4substituted or unsubstituted alkyl and substituted or unsubstituted phenyl, non-limiting examples of R6include 4-chlorobenzenesulfonamide and tert-butylsulfonyl.

Additional example compounds of formula (I) includes the radicals R, where R6represents a group selected from substituted or unsubstituted of pyridinyl, pyrazinyl and pyrimidinyl, non-limiting examples of which include pyrazin-2-yl and 2-methyl)pyridine-5-yl.

The radicals R1

One example of the radical R1includes the compounds where R1represents hydrogen. Compounds according to this invention, where R1corresponds to hydrogen, have the formula

and so Saedinenie this category do not contain the second chiral center.

Another example compounds of formula (I) includes the radicals R1having a second chiral center, and such compounds are, for example, have the formula

or

(S),(S)-Diastereoisomer S), (R)-Diastereoisomer and the decree is absolute stereochemistry. Disclosed compounds can be a separate diastereomers or mixtures thereof, and such compounds can be obtained by any of the following ways:

i) a mixture of (S),(S)- and (S),(R)-diastereomers and be used as a mixture for the regulation of angiogenesis;

ii) a mixture of (S),(S)- and (S),(R)-diastereomers, which then later separated into individual diastereomers before you can use the latter for the regulation of angiogenesis; or

iii) get them directly in the form of individual (S),(S)- or (S), (R)-diastereoisomer, and this method of obtaining described below.

One example of compounds according to formula (I) includes the radicals R1that represent benzyl, non-limiting examples of such compounds include 4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}phenylsulfinyl acid, 4-{(S)-2-(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide-2-(2-phenylthiazol-4-yl)}phenylsulfinyl acid, 4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylsulfinyl acid and 4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(2-utiltity-4-yl)ethyl}phenylsulfinyl acid, and other compounds described below.

Another example of compounds according to formula (I) includes the radicals R1that represent substituted benzyl, neogenic the living examples of which include 4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanamide]-2-(4-utiltity-2-yl)ethyl}phenylsulfinyl acid; 4-{(S)-2-(S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanamide-2-(2-phenylthiazol-4-yl)}phenylsulfinyl acid and 4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-(4-were)propanamide]ethyl}phenylsulfinyl acid.

Additional example compounds according to formula (I) includes the radicals R1that represent phenyl, non-limiting examples of such compounds include 4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-2-fenretinide]-2-(4-utiltity-2-yl)ethyl}phenylsulfinyl acid, 4-{(S)-2-(S)-2-(tert-butoxycarbonylamino)-2-fenretinide-2-(2-phenylthiazol-4-yl)}phenylsulfinyl acid and 4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-2-fenretinide]ethyl}phenylsulfinyl acid.

The following additional example compounds according to formula (I) includes the radicals R1that represent1-C4linear or branched alkyl, non-limiting examples of such compounds include 4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanoate]ethyl}phenylsulfinyl acid, 4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-4-methylpentylamino]-2-(4-utiltity-2-yl)ethyl}phenylsulfinyl acid and 4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentylamino]ethyl}phenylsulfinyl acid, and other compounds described below.

R2is a group, selected from the

i) C1-C6linear or branched alkyl or

ii) C1-C6linear or branched alkoxy.

One example of R2includes C1-C6linear or branched alkoxygroup having the formula

-OR8

where R8is a group of C1-C6linear or branched alkyl selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), n-pentile (C5or n-hexyl (C6).

Another example of compounds according to formula (i) includes the radicals R2that represents a C1-C6linear or branched alkyl selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), n-pentile (C5or n-hexyl (C6).

R3represents hydrogen or C1-C4linear or branched alkyl.

One example of R3includes the compounds where R3represents hydrogen.

Another example of R3includes the compounds where R3represents methyl.

For example, R3includes the compounds where R3in the bran of ethyl (C 2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4).

The compounds of formula (I) can be classified by several categories for strictly non-limiting purposes of the description of alternatives synthetic strategies to obtain subgenera of compounds within the scope of formula (I)that in the linear form in the present description is not illustrated. This mental systematization into categories does not imply anything regarding the increase or decrease of biological activity in respect of any of the compounds or compositions described in the present description.

The first aspect of category I of the present invention relates to compounds having the formula

where R represents a substituted or an unsubstituted thiazole-2-ilen group and non-limiting examples of R and R1and, in addition, the stereochemistry at R1presented in table 1.

Table I
No.RR1
1the thiazole-2-yl(S)-benzyl
24-methylthiazole-2-yl(S)-benzyl
34-utiltity-2-yl(S)-benzyl
44-propertiesa-2-yl(S)-benzyl
54-isopropylthiazole-2-yl(S)-benzyl
64-cyclopropylmethyl-2-yl(S)-benzyl
74-butylthiazole-2-yl(S)-benzyl
84-tert-butylthiazole-2-yl(S)-benzyl
94-cyclohexylthio-2-yl(S)-benzyl
104-(2,2,2-triptorelin)thiazol-2-yl(S)-benzyl
114-(3,3,3-cryptochromes)thiazol-2-yl(S)-benzyl
12 4-(2,2-diversicolor)thiazol-2-yl(S)-benzyl
134-(methoxymethyl)thiazol-2-yl(S)-benzyl
144-(ethyl ether carboxylic acid)thiazol-2-yl(S)-benzyl
154,5-dimethylthiazol-2-yl(S)-benzyl
164-methyl-5-utiltity-2-yl(S)-benzyl
174-phenylthiazol-2-yl(S)-benzyl
184-(4-chlorophenyl)thiazol-2-yl(S)-benzyl
194-(3,4-dimetilfenil)thiazol-2-yl(S)-benzyl
204-methyl-5-phenylthiazol-2-yl(S)-benzyl
214-(thiophene-2-yl)thiazol-2-yl(S)-benzyl
224-(thiophene-3-yl)thiazol-2-yl(S)-benzyl
234-(5-chlorothiophene-2-yl)thiazol-2-yl(S)-benzyl
245,6-dihydro-4H-cyclopent[d]thiazol-2-yl(S)-benzyl
254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl(S)-benzyl

Compounds covered by the first aspect of Category I of the present invention, can be obtained by the method in General is presented in scheme I and described in example 1, below.

Scheme I

Reagents and conditions: (a) (i) (isobutyl)OCOCl, NMM, DMF; 0°C, 2 0 minutes

(ii) NH3; 0°C for 30 minutes

Reagents and conditions: (b) the reagent Lawesson, THF, room temperature, 3 hours

Reagents and conditions: (C) CH3CN; boiling under reflux, 3 hours

Reagents and conditions: (d) Boc-Phe, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours

Reagents and conditions: (e) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; the room is temperature, 2 hours

Example 1

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid (5)

Obtain tert-butyl ester [1-(S)-carbarnoyl-2-(4-nitrophenyl)stellabagirova acid (1): To a solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid, cooled to 0°C and N-methylmorpholine (1.1 ml, 9,65 mmol) in DMF (10 ml), cooled to 0°C. is added dropwise isobutylparaben (1.25 ml, 9,65 mmol). The mixture is stirred at 0°C for 20 minutes, after that time the reaction mixture miss NH3(g) for 30 minutes at 0°C. the Reaction mixture was concentrated and the residue is dissolved in EtOAc, washed sequentially with 5% citric acid, water, 5% NaHCO3, water and saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuo, obtaining a residue, which is triturated in a mixture of EtOAc/petroleum ether to obtain 2.2 g (74%) of the desired product as a white solid.

Obtain tert-butyl ester [2-(4-nitrophenyl)-1-(S)-thiocarbamoylation]carbamino acid (2): To a solution of tert-butyl methyl ether [1-(S)-carbarnoyl-2-(4-nitrophenyl)ethylcarbamate acid, 1, (0.400 g, 1,29 mmol) in THF (10 ml) is added a reagent Lawesson (0,262 g of 0.65 mmol). The reaction mixture is stirred for 3 hours and concentrated to a residue, which was purified on silica gel, the floor is th 0,350 g (83%) of the desired product.

1H NMR (300 MHz, CDCl3) δ 8,29 (s, 1H), 8,10 (d, J=8,4 Hz, 2H), 8,01 (s, 1H), 7,42 (d, J=8,4 Hz, 2H), 5,70 (d, J=7.2 Hz, 1H), around 4.85 (d, J=7.2 Hz, 1H), 3,11-3,30 (m, 1H), 1,21 (s, N).

Obtaining 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine (3): a Mixture of tert-butyl methyl ether [2-(4-nitrophenyl)-1-(S)-thiocarbamoylation]carbamino acid, 2, (0,245 g, 0,753 mmol), 1-bromo-2-butanone (0.125 g, 0,828 mmol) in CH3CN (5 ml) is refluxed for 3 hours. The reaction mixture is cooled to room temperature and the solution was added diethyl ether and the precipitate, which formed, isolated by filtration. The solid is dried in vacuum, obtaining 0,242 g (yield 90%) of the desired product. ESI+MS (Mass spectrometry with electrospray ionization) 278 (M+1).

Obtain tert-butyl ester {1-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylcarbamate]-2-phenylethyl}carbamino acid (4): To a solution of the hydrobromide 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine, 3, (0,393 g, 1.1 mmol), (S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid (0,220 g, 0,828 mmol) and 1-hydroxybenzotriazole (HOBt) (to 0.127 g, 0,828 mmol) in DMF (10 ml) at 0°C, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (strength of 0.159 g, 0,828 mmol), and then Diisopropylamine (0,204 g, was 1.58 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature over night. The reaction mixture was diluted with water and extracted with EtOAc. Obyedinenie the Yu organic phase is washed with 1N aqueous HCl, 5% aqueous NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,345 g of the desired product which is used without further purification. LC/MS ESI+ (a Combination of liquid chromatography and mass spectrometry with electrospray ionization) 525 (M+1).

Getting 4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid (5): tert-butyl ether ({1-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylcarbamate]-2-phenylethyl}carbamino acid, 4, (0,345 g) dissolved in Meon (4 ml). A catalytic amount of Pd/C (10% wt./wt.) added and the mixture is stirred in hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,314 g). The reaction mixture was stirred at room temperature for 5 minutes, then add 7% solution of NH4OH (50 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,222 g of the desired product in the form of ammonium salts.

1N (CD3OD): δ 7,50-6,72 (m, 10H), 5,44-5,42 (d, 1H, J=6.0 Hz), 4,34 (s, 1H), 3,34-and 2.79 (m, 4H), 2,83 was 2.76 (q, 2H, J=7,2 Hz), 1,40 (s, N), is 1.31 (t, 3H, J=7.5 Hz).

The final compounds according to this invention can be also edeleny in the form of the free acid. A non-limiting example of the methodology of this selection is described below in example 4.

The following is a non-limiting examples of compounds covered by the first aspect of category I of the present invention.

4-{(S)-2-[(R)-2-(tert-butoxycarbonyl)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid:1N (CD3OD): δ 7,22-7,02 (m, 10H), of 5.39 (s, 1H), 4,34 (s, 1H), 3,24 of 2.68 (m, 6N), to 1.37 (s, N), of 1.30 (t, 3H, J=7.5 Hz).

tert-Butyl ether ({1-[1-(4-utiltity-2-yl)-(S)-2-(4-sulfonylarenes)ethylcarbamate]-(S)-2-phenylethyl}methylcarbamate acid:1H NMR (300 MHz, Meon-d4) δ at 8.36 (d, J=8,1 Hz, 1H),? 7.04 baby mortality-7,22 (m, N), the 5.45 (s, 1H), 3,01-3,26 (m, 2H), 2,60-is 2.88 (m, 4H), of 2.33 (s, 3H), of 1.30 (s, N).

Tert-Butyl ether ({1-[1-(4-phenylthiazol-2-yl)-(S)-2-(4-sulfonylarenes)ethylcarbamate]-(S)-2-phenylethyl}methylcarbamate acid:1H NMR (300 MHz, Meon-d4) δ to 8.20 (d, J=8,1 Hz, 1H), of 7.96-to 7.99 (m, 2H), of 7.48-7,52 (m, 3H), 7,00-of 7.23 (m, 7H), 6.89 in (s, 1H), 5,28 (kV, J=7.5 Hz, 1H), 4,33 (t, J=6,6 Hz, 1H), 3,09-3,26 (m, 2H), 3,34 (DD, J=13.2 and an 8.4 Hz, 1H), 2,82 (DD, J=13,2 and 8.4 Hz, 1H), 1,38 (s, N).

The second aspect of category I of the present invention relates to compounds having the formula

where R represents a substituted or an unsubstituted thiazole-4-ilen group and non-limiting examples of R and R1and, the AOC is e, the stereochemistry at R1described in table II.

Table II
No.RR1
26the thiazol-4-yl(S)-benzyl
272-methylthiazole-4-yl(S)-benzyl
282-utiltity-4-yl(S)-benzyl
292-propertiesa-4-yl(S)-benzyl
302-isopropylthiazole-4-yl(S)-benzyl
312-cyclopropylethanol-4-yl(S)-benzyl
322-butylthiazole-4-yl(S)-benzyl
332-tert-butylthiazole-4-yl(S)-benzyl
342-cyclohexylthio-4-yl(S)-benzyl
35 2-(2,2,2-triptorelin)thiazol-4-yl(S)-benzyl
362-(3,3,3-cryptochromes)thiazol-4-yl(S)-benzyl
372-(2,2-diversicolor)thiazol-4-yl(S)-benzyl
382-phenylthiazol-4-yl(S)-benzyl
392-(4-chlorophenyl)thiazol-4-yl(S)-benzyl
402-(3,4-dimetilfenil)thiazol-4-yl(S)-benzyl
412-(thiophene-2-yl)thiazol-4-yl(S)-benzyl
422-(thiophene-3-yl)thiazol-4-yl(S)-benzyl
432-(3-chlorothiophene-2-yl)thiophene-4-yl(S)-benzyl
442-(3-methylthiophene-2-yl)thiazol-4-yl(S)-benzyl
452-(2-methylthiazole-4-yl)thiazol-4-yl(S)-benzyl
462-(furan-2-yl)thiazol-4-yl(S)-benzyl
472-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl
482-[(2-methyl)pyridine-5-yl]thiazol-4-yl(S)-benzyl
492-(4-chlorobenzenesulfonyl)thiazol-4-yl(S)-benzyl
502-(tert-butylsulfonyl)thiazol-4-yl(S)-benzyl

Compounds covered by the second aspect of category I of the present invention, can be obtained by the method in General is presented in scheme II and described in the following example 2.

Scheme II

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

(ii) CH2N2; room temperature for 3 hours.

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

Reagents and conditions: (C) (i) thiobenzamide, CH3CN; boiling under reflux, 2 hours

(ii) Boc-Phe, HOBt, DIPEA, DMF; room temperature, 18 hours

Reagents and conditions: (d) (i) H2:Pd/C, MeOH; (i) SO 3-pyridine, NH4OH; room temperature, 12 hours

Example 2

4-{(S}-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamide-2-(2-phenylthiazol-4-yl)}fenilalanina acid (9)

Obtain tert-butyl ether (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid (6): To a cooled to 0°C solution of 2-(S)-tert-butoxycarbonylamino-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), and then isobutylparaben (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, then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed successively with water and saturated salt solution, dried (Na2SO4), filtered and concentrated. The residue is purified on silica gel (hexane/EtOAc 2:1)to give 1.1 g (yield 82%) of the desired product as a slightly yellow 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), 1,41 (s, N).

Obtain (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutyl-2-ylcarbamate (7): To a solution of tert-butyl methyl ether (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid, 6, (0, 350 g, 1.04 mmol) in THF (5 ml), cooled to 0°C., added dropwise 48% aqueous HBr (of 0.14 ml, 1.25 mmol). The resulting mixture was stirred at 0°C for 1.5 hours, then the reaction mixture was 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 (Na2SO4), filtered and concentrated, obtaining 0.400 g of product, which is used in the next stage without additional 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=63 Hz, 1H), Android 4.04 (s, 2H), 1,42 (s, N).

Obtain tert-butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethylamino-1-oxo-3-phenylpropane-2-ylcarbamate (8): a Mixture of thiobenzamide (0,117 g, 0.85 mmol) and (S)-tert-butyl-4-bromo-1-(4-nitrophenyl)-3-oxobutyl-2-ylcarbamate, 7, (0,300 g, 0.77 mmol) in CH3CN (4 ml) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and add diethyl ether, precipitating the intermediate product, 2-(nitrophenyl)-(S)-1-(4-phenylthiazol-2-yl)ethylamine, which is marked by filtration in the form of hydrobromide salt. Hydrobromide salt is dissolved in DMF (3 ml) along with diisopropylethylamine (0,42 ml, 2,31 mmol), 1-hydroxybenzotriazole (amount of 0.118 g, 0,7 9 mmol) and (S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid (0,212 g, 0.80 mmol). The mixture plumage is eshivot at 0°C for 30 minutes, then at room temperature over night. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with 1N. aqueous HCl, 5% aqueous NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,395 g (yield 90%) of the desired product which is used without further purification. LC/MS ESI+573 (M+1).

Getting 4-{(S}-2-(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide-2-(2-phenylthiazol-4-yl)}phenylalaninol acid (9): tert-butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethylamino-1-oxo-3-phenylpropane-2-ylcarbamate, 8, (0,360 g) dissolved in Meon (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 12 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,296 g). The reaction mixture was stirred at room temperature for 5 minutes, then add 7% solution of NH4OH (10 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,050 g of the desired product in the form of ammonium salts.

1H NMR (300 MHz, MeOH-d4) δ to 8.20 (d, J=8,1 Hz, 1H), of 7.96-to 7.99 (m, 2H), of 7.48-7,52 (m, 3H), 7, 00-7,23 (m, 7H), 6.89 in (s, 1H), 5,28 (kV, J=7.5 Hz, 1H), 4,33 (t, J=6,6 Hz, 1 is), 3,09-3,26 (m, 2H), 3,34 (DD, J=13.2 and an 8.4 Hz, 1H), 2,82 (DD, J=13.2 and an 8.4 Hz, 1H), 1,38 (s, N).

The first aspect of category II of the present invention relates to compounds having the formula

where R represents a substituted or an unsubstituted thiazole-2-ilen group and non-limiting examples of R and R1and, in addition, the stereochemistry at R1in table III.

Table III
No.RR1
51the thiazole-2-yl(S)-benzyl
524-methylthiazole-2-yl(S)-benzyl
534-utiltity-2-yl(S)-benzyl
544-propertiesa-2-yl(S)-benzyl
554-isopropylthiazole-2-yl(S)-benzyl
564-cyclopropylmethyl-2-yl(S)-benzyl
574-Buti is a thiazol-2-yl (S)-benzyl
584-tert-butylthiazole-2-yl(S)-benzyl
594-cyclohexylthio-2-yl(S)-benzyl
604-(2,2,2-triptorelin)thiazol-2-yl(S)-benzyl
614-(3,3,3-cryptochromes)thiazol-2-yl(S)-benzyl
624-(2,2-diversicolor)thiazol-2-yl(S)-benzyl
634-(methoxymethyl)thiazol-2-yl(S)-benzyl
644-(ethyl ether carboxylic acid)thiazol-2-yl(S)-benzyl
654,5-dimethylthiazol-2-yl(S)-benzyl
664-methyl-5-utiltity-2-yl(S)-benzyl
674-phenylthiazol-2-yl(S)-benzyl
68 4-(4-chlorophenyl)thiazol-2-yl(S)-benzyl
694-(3,4-dimetilfenil)thiazol-2-yl(S)-benzyl
704-methyl-5-phenylthiazol-2-yl(S)-benzyl
714-(thiophene-2-yl)thiazol-2-yl(S)-benzyl
724-(thiophene-3-yl)thiazol-2-yl(S)-benzyl
734-(5-chlorothiophene-2-yl)thiazol-2-yl(S)-benzyl
745,6-dihydro-4H-cyclopent[d]thiazol-2-yl(S)-benzyl
754,5,6,7-tetrahydrobenzo[d]thiazol-2-yl(S)-benzyl

Compounds covered by the first aspect of category II of the present invention, can be obtained by the method in General is presented in scheme III and described in example 3, below.

Scheme III

Reagents and conditions: (a) (i) 4M HCl, dioxane, room temperature, 1 h;

(ii) methylchloroform, pyridine, CHCl3, 0°C to room temperature the tours, 48 hours

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; room temperature, 4 hours

Example 3

4-{(S)-2-(4-Utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid (11)

Obtain methyl(S)-1-[(S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamino]-1-oxo-3-phenylpropane-2-ylcarbamate (10): tert-butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethylamino-1-oxo-3-phenylpropane-2-ylcarbamate, 8, (0,460 mg, 0,881 mmol) is dissolved in a 4M solution of hydrochloride in 1,4-dioxane (4 ml). The reaction mixture was stirred 1 hour and the solvent is removed under reduced pressure. The crude amine was dissolved in CHCl3(8 ml) and added dropwise pyridine (1 ml). The temperature of the mixture is cooled to 0°C and added dropwise to methylchloroform (0.083 g, 0,881 mmol). The reaction mixture provides the opportunity to warm to room temperature and stirred for 2 days. Water is added, the solution stirred for 15 minutes and then extracted several times CHCl3. The combined organic layers are washed with 1N. HCl, 5% NaHCO3and saturated salt solution, dried over Na2SO4and filtered. The solvent is removed in vacuum, obtaining 0,297 g of the desired product.

Getting 4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}of Peninsula inovas acid (11): Methyl-(S)-1-[(S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamino]-1-oxo-3-phenylpropane-2-ylcarbamate, 10, (0,297 g) dissolved in Meon (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 4 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,196 g). The reaction mixture was stirred at room temperature for 5 minutes, then add 7% solution of NH4OH (25 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed-phase silica gel, receiving 0.172 g of the desired product in the form of ammonium salts.

1N (CD3OD): δ 7,26-to 7.00 (m, 10H), of 5.39 (t, 1H, J=5.7 Hz), to 4.38 (t, 1H, J=5.7 Hz), 3,62 (s, 3H), 3,34 is 2.75 (m, 6N), of 1.30 (t, 3H, J=7.5 Hz).

The following is a non-limiting examples of the first aspect of category II of the present invention.

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-thiazol-2-yl)ethyl}fenilalanina acid:1N (CD3OD): δ 7,78 to 7.75 (m, 1H), 7,51-7,47 (m, 1H), 7,30-7,02 (m, N), 5,49-5,43 (m, 1H), 4,39 (t, 1H, J=8.1 Hz), of 3.56 (s, 3H), 3,51-a 2.71 (m, 4H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4-methylthiazole-2-yl)ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ charged 8.52-8,49 (m, 1H), 7,20-6, 99 (m, 10H), lower than the 5.37 (users, 1H), 4,36 (users, 1H), 3,62-of 3.48 (m, 3H), 3,32-up 3.22 (m, 1H), 3,1-a 3.01 (m, 2H), 2,80-of 2.72 (m, 1H), 2,42 (s, 3H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4-propertiesa-2-yl)ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,51-8,49 (m, 1H), 7,22-6,99 (m, 10H), of 5.39 (t, J=6.0 Hz, 1H), to 4.38 (DD, J=14,4, 9.0 Hz, 1H), 3,62 (s, 2H), 3,59-of 3.48 (m, 1H), 3.27 to (DD, J=13,5, 6.3 Hz, 1H), 3,12-to 3.02 (m, 2H), 2,81-a 2.71 (m, 3H), 1,81-1,68 (m, 2H), 0,985 (t, J=7.5 Hz, 3H).

.

4-{(S)-2-(4-tert-Butylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7.23 percent-7,19 (m, 5H), 7,10-6,98 (m, 5H), 5,42 is 5.38 (m, 1H), 4,37 (DD, J=8,4, a 5.4 Hz, 1H), 3,61 (s, 2H), 3,48 (users, 1H), 3,32-of 3.25 (m, 1H), 3,13-of 3.07 (m, 2H), 2,77 (DD, J=13,5, and 9.3 Hz, 1H), 1,36 (s, N).

.

4-{(S)-2-(4-Cyclopropylmethyl-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H (CD3OD): δ 7,13-6,91 (m, 10H), for 6.81 (s, 1H), 5,23 (t, 1H, J=7.8 Hz), 4,24 (t, 1H, J=8,4 Hz), 3,50 (s, 3H), 3,12-of 2.66 (m, 4H), of 1.94 (t, 1H, J=5,1 Hz), 0,84-to 0.73 (m, 4H).

.

4-{(S)-2-(4-Cyclohexylthio-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,21-6,97 (m, 10H), the 5.45 is 5.25 (m, 1H), 5,42 and 5.36 (m, 1H), 5,10-5,02 (m, 1H), 4,03 is 4.35 (m, 1H), 3,63 (s, 2H), 3,60-to 3.49 (m, 1H), 3,12-of 3.06 (m, 1H), 2,95 (DD, J=14,1, 9.9 Hz, 1H), 2,82-of 2.72 (m, 2H), 2,07-1,77 (m, 3H), 1.56 to to 1.31 (m, 10H).

.

4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(m is oxycarbonyl)-3-phenylpropanamide]ethyl}fenilalanina acid: 1H NMR (300 MHz, CD3OD): δ to 8.45 (d, J=7.8 Hz, 1H), 7,22-7,03 (m, N), 5,28 (t, J=7.2 Hz, 1H), 4,36 (t, J=7.8 Hz, 1H), 3,62 (s, 2H), 3,52-of 3.46 (m, 1H), up 3.22 (DD, J=14,1, 6.3 Hz, 1H), 3,07-to 2.99 (m, 2H), 2,77 (DD, J=13,5, and 8.4 Hz, 1H), 2,32 (s, 3H), of 2.30 (s, 3H).

.

4-{(S)-2-(4-Ethyl-5-methylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ to 8.45 (d, J=8,1 Hz, 1H), was 7.36-7,00 (m, N), 5,31 (users, 1H), 4,37 (users, 1H), 3,62-of 3.46 (m, 3H), 3,28-of 2.64 (m, 6N), was 2.34 (d, J=5.4 Hz, 3H), 1,37 is 1.20 (m, 3H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(2,2,2-triptorelin)thiazol-2-yl]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,40 (d, J=11,1 Hz, 1H), 7,30-to 7.15 (m, 5H), 7,12-7,00 (m, 5H), 5,41 (DD, J=8,4, 5,1 Hz, 1H), 4,42 is 4.36 (m, 1H), of 3.77-to 3.52 (m, 5H), 3.33 and is 3.23 (m, 1H), 3,15-to 3.02 (m, 2H), 2,97-only 2.91 (m, 1H), 2,82-2,70 (m, 1H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide)-2-[4-(3,3,3-cryptochromes)thiazol-2-yl]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7.23 percent-7,03 (m, 10H), 5,46-of 5.34 (m, 1H), 4,54-of 4.44 (m, 1H), 3,63 (s, 2H), 3,62-to 3.35 (m, 1H), 3,34-3,24 (m, 1H), 3,17-to 2.99 (m, 4H), 2, 82-2,74 (m, 1H), 2,69-of 2.56 (m, 2H).

.

4-{(S)-2-[4-(2,2-Diversicolor)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,28-7, 00 (m, 10H), 5,42 lower than the 5.37 (m, 1H), to 4.41-to 4.38 (m, 1H), 3,60 (s, 2H), 3,61-to 3.52 (m, 1H), 3,35-3,23 (who, 1H), 3.04 from-2.91 in (m, 2H), 2,78-2, 68 (m, 1H), 1,99-1,90 (m, 2H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(methoxymethyl)thiazol-2-yl]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,55 (d, J=6,6 Hz, 1H), 7,31 (s, 1H), 7,21-7,05 (m, N), 5,41 (users, 1H), 4.53-in (s, 2H), 4,37 (users, 1H), 3,62 (s, 2H), 3,59-3, 46 (m, 1H), 3,41 (s, 3H), 3,28-up 3.22 (m, 1H), 3,13-3,00 (m, 3H), 2,80-2,72 (m, 1H).

.

4-{(S)-2-(4-(Etoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ of 8.25 (s, 1H), 7,20-7,07 (m, 10H), of 5.40 (DD, J=7.5 Hz, 1H), 4,45 is 4.36 (m, 3H), 3,63 (s, 2H), 3,60-3,51 (m, 1H), 3,34-of 3.27 (m, 1H), 3,17-3,00 (m, 2H), and 2.79 (DD, J=13,5, and 8.4 Hz, 1H), 1,42 (t, J=7.5 Hz, 3H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(5-phenylthiazol-2-yl)ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,63 (d, J=8,1 Hz, 1H), of 7.96 (s, 1H), to 7.59 (d, J=7.8 Hz, 2H), 7,47 and 7.36 (m, 3H), 7,19-7,10 (m, 10H), 5,42-of 5.40 (m, 1H), to 4.41 (t, J=7,2, 1H), 3,65-to 3.50 (m, 3H), 3,16-2,77 (m, 4H).

.

4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,50-7,38 (m, 4H), 7,21-7,11 (m, 10H), 5,45 to 5.35 (m, 1H), 5,42-4,37 (m, 1H), 3,63-to 3.50 (m, 3H), 3,34-3,29 (m, 3H), 3,15-3,03 (m, 2H), 2,84-to 2.74 (m, 3H), 1,31-to 1.21 (m, 3H).

.

4-{(S)-2-[4-(3,4-Dimetilfenil)thiazol-2-yl]-2-[(S)-2-(meth is ccarbonate)-3-phenylpropanamide]ethyl}fenilalanina acid: 1H NMR (300 MHz, CD3OD): δ at 8.60 (d, J=8,1 Hz, 1H), 7,73 (s, 1H), 7,65 (d, J=8,1 Hz, 1H), EUR 7.57 (s, 1H), 7,21-7,11 (m, 10H), vs. 5.47 (d, J=7.2 Hz, 1H), of 4.44-to 4.38 (m, 1H), 3,63 (s, 2H), 3,62-3,51 (m, 1H), 3,40-of 3.32 (m, 1H), 3,20-3, 05 (m, 2H), 2,84-2,77 (m, 1H), 2,35 (s, 3H), 2,32 (s, 3H).

.

4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,65 (d, J=8,4 Hz, 1H), 7.95 is-to $ 7.91 (m, 2H), of 7.70 (s, 1H), 7,46-7,41 (m, 2H), 7,19-7,10 (m, N), 5,50-of 5.45 (m, 1H), to 4.41 (t, J=6, 6 Hz, 1H), 3,63 (s, 2H), 3,62-3,51 (m, 1H), 3,41-to 3.33 (m, 1H), 3,20-totaling 3.04 (m, 2H), 2,81 (DD, J=13,8, 9.0 Hz, 1H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4-phenylthiazol-2-yl)ethyl}fenilalanina acid:1N (CD3OD): δ 7,94-a 7.92 (d, 2H, J=7,3 Hz), the 7.65 (s, 1H), 7,45-7,31 (m, 3H), 7,22-7,10 (m, N), 5,46 (t, 1H, J=6,8 Hz), 4,39 (m, 1H), 3,62 (s, 3H), 3,36-and 2.79 (m, 6N).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(thiophene-2-yl)thiazol-2-yl]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,63 (d, J=8,1 Hz, 1H), 7,52-7,51 (m, 2H), 7,39 (DD, J=5,1, 1.2 Hz, 1H), 7,20-was 7.08 (m, 10H), 5,50-of 5.40 (m, 1H), 4,39 (t, J=8,1 Hz, 1H), 3,63 (s, 2H), 3,50 (users, 1H), 3,39-of 3.32 (m, 1H), 3,18 totaling 3.04 (m, 2H), 2,80 (DD, J=13,5, and 8.7 Hz, 1H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(thiophene-3-yl)thiazol-2-yl]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ at 8.60 (d, J=7.8 Hz, 1H), 7,83 (d, J=1.5 G is, 1H), 7,56-7,46 (m, 3H), 7,14 (d, J=25,2 Hz, 10H), 5,46-5,43 (m, 1H), 4,40-to 4.38 (m, 1H), 3,62 (s, 3H), 3,55 is-3.45 (m, 1H), 3,19 totaling 3.04 (m, 4H), 2,84 is 2.75 (m, 1H).

.

4-{(S)-2-(4-Utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropionamide]ethyl}fenilalanina acid:1H NMR (300 MHz, Meon-d4) δ 8,45-8,56 (m, 1H), 7,01-7,25 (m, N), 7,03 (s, 1H), 5.40 to-5,50 (m, 1H), 3,48-the 3.65 (m, 3H), 3,36 (DD, J=14,4 and 6.0 Hz, 1H), 3,23 (DD, J=14,4 and 6.0 Hz, 1H), 2.95 and-3,10 (m, 1H), 2,75-of 2.86 (m, 3H), 2.57 m-of 2.64 (m, 3H), of 1.30 (t, J=7.5 Hz, 3H).

.

4-{(S)-2-(5,6-Dihydro-4H-cyclopent[d]thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,46 (users, 1H), 7,16-7,05 (m, N), 5,31 (users, 1H), 4,35 (users, 1H), 3,61 (s, 2H), 3,52-of 3.43 (m, 1H), 3,28-3,18 (m, 1H), 3,10-2,98 (m, 2H), 2,92-to 2.74 (m, 4H), 2,58 is 2.44 (m, 2H).

.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,21-was 7.08 (m, N), the 5.45 is 5.25 (m, 1H), 4,45-4,30 (m, 1H), 3,63 (s, 2H), 3,64-to 3.34 (m, 1H), 3.33 and-3,20 (m, 1H), 3,09-to 3.02 (m, 2H), 2,75 (users, 5H), 1,90 (users, 4H).

.

4-{(S)-2-[4-(5-Chlorothiophene-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,63 (d, J=8.7 Hz, 1H), 7,55 (s, 1H), 7,39-7,31 (m, 1H), 7.23 percent-7,10 (m, N), 7,00-6,97 (m, 1H), 5,43-of 5.40 (m, 1H), 5,39 (t, J=14,7 Hz, 1H), 3,63 (s, 2H), 3,60-3,51 (who, 1H), 3,34-of 3.27 (m, 1H), 3,17-3,03 (m, 2H), 2,80 (DD, J=14,1, and 8.4 Hz, 1H).

An additional iteration of the first aspect of category II relates to the compounds where R2contains-och2CH3(ethoxy); the following is a non-limiting example of such a connection.

.

4-{(S)-2-[(S)-2-(Ethoxycarbonyl)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid:1N (CD3OD): δ 7,22-7, 00 (m, 10H), of 5.39 (t, 1H, J=6.0 Hz), 4,37 (t, 1H, J=6,1 Hz), 4,08-of 4.00 (q, 2H, J=7,1 Hz), 3.25 to to 2.74 (m, 6N), of 1.30 (t, 3H, J=7.5 Hz), of 1.20 (t, 3H, J=6.9 Hz).

The second aspect of category II of the present invention relates to compounds having the formula

where R represents a substituted or an unsubstituted thiazole-4-ilen group and non-limiting examples of R and R1and, in addition, the stereochemistry at R1presented in table IV.

Table IV
No.RR1
76the thiazol-4-yl(S)-benzyl
772-methylthiazole-4-yl(S)-benzyl
782-this is a thiazol-4-yl (S)-benzyl
792-propertiesa-4-yl(S)-benzyl
802-isopropylthiazole-4-yl(S)-benzyl
812-cyclopropylethanol-4-yl(S)-benzyl
822-butylthiazole-4-yl(S)-benzyl
832-tert-butylthiazole-4-yl(S)-benzyl
842-cyclohexylthio-4-yl(S)-benzyl
852-(2,2,2-triptorelin)thiazol-4-yl(S)-benzyl
862-(3,3,3-cryptochromes)thiazol-4-yl(S)-benzyl
872-(2,2-diversicolor)thiazol-4-yl(S)-benzyl
882-phenylthiazol-4-yl(S)-benzyl
892-(4-chlorophenyl)thiazol-4-yl (S)-benzyl
902-(3,4-dimetilfenil)thiazol-4-yl(S)-benzyl
912-(thiophene-2-yl)thiazol-4-yl(S)-benzyl
922-(thiophene-3-yl)thiazol-4-yl(S)-benzyl
932-(3-chlorothiophene-2-yl)thiazol-4-yl(S)-benzyl
942-(3-methylthiophene-2-yl)thiazol-4-yl(S)-benzyl
952-(2-methylthiazole-4-yl)thiazol-4-yl(S)-benzyl
962-(furan-2-yl)thiazol-4-yl(S)-benzyl
972-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl
982-[(2-methyl)pyridine-5-yl]thiazol-4-yl(S)-benzyl
992-(4-chlorobenzenesulfonyl)thiazol-4-yl(S)-benzyl
1002-(tert-is ethylsulfonyl)thiazol-4-yl (S)-benzyl

Compounds covered by the second aspect of category II of the present invention, can be obtained by the method in General is presented in scheme IV and described in the following example 4.

Scheme IV

Reagents and conditions: (a)(i) proportioned, CH3CN; boiling under reflux, 2 hours

(ii) Boc-Phe, HOBt, DIPEA, DMF; room temperature, 18 hours

Y

Reagents and conditions: (b) (i) H2:Pd/C, Meon; (ii) SO3-pyridine, NH4OH; room temperature, 18 hours

Example 4

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(2-utiltity-4-yl)ethyl}fenilalanina acid (13)

Obtain methyl (S)-1-[(S)-1-(2-utiltity-4-yl)-2-(4-nitrophenyl)ethyl]amino-1-oxo-3-phenylpropane-2-ylcarbamate (12): a Mixture of proportioned (69 mg, 0.78 mmol) and (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutyl-2-ylcarbamate 7, (0,300 g, 0.77 mmol) in CH3CN (4 ml) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and add diethyl ether, precipitating the intermediate 2-(nitrophenyl)-(S)-1-(4-utiltity-2-yl)ethylamine, which is marked by filtration in the form of hydrobromide salt. Hydrobromide salt is dissolved in DMF (8 ml) together with diisopropylethylamine (0,38 ml, 2,13 mmol), 1-hydroxybenzotriazole (107 mg, 0,71 IMO is s) and (S)-(2-methoxycarbonylamino)-3-phenylpropionic acid (175 mg, 0.78 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature over night. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with 1N. aqueous HCl, 5% aqueous NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,300 g (yield 81%) of the desired product which is used without further purification. LC/MS ESI+MS 483 (M+1).

Obtaining ammonium salt of 4-((S)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamide)-2-(2-utiltity-4-yl)ethyl)phenylalaninol acid (13): tert-Butyl (S)-l-(S)-2-(4-nitrophenyl)-1-(2-utiltity-4-yl)ethylamino-1-oxo-3-phenylpropane-2-ylcarbamate, 12, (0,300 g) dissolved in the Meon (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (223 mg, of 1.40 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add 7% solution of NH4OH (12 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 25 mg of the desired product in the form of ammonium salts.

1H NMR (300 MHz, MeOH-d4) δ 7,14-7,24 m, 6N), 6,97-7,0 (m, 4H), 6,62 (s, 1H), 5,10-and 5.30 (m, 1H), 4,36 (t, J=7.2 Hz, 1H), 3,63 (s, 3H), 3,14 (DD, J=13.5 and 6.3 Hz, 1H), 2,93-of 3.07 (m, 5H), of 2.81 (DD, J=13.5 and 6.3 HZ, 1H), 1,39 (t, J=7.8 Hz, 3H).

In another iteration of the method of the present invention, the connection 13, as well as other analogues, which are included in the present invention may be provided in the form of the free acid by modifying the method described below.

Reagents and conditions: (a) H2:Pd/C, Meon; room temperature, 40 p.m.

Reagents and conditions: (b) SO3-pyridine, CH3CN; heat 45 minutes

Example 4A

4-((S)-2-((S)-2-(Methoxycarbonylamino)-3-phenylpropanamide)-2-(2-utiltity-4-yl)ethyl)fenilalanina acid [form of the free acid] (13)

Obtaining methyl ester {1-[2-(S)-(4-(S)-AMINOPHENYL)-1-(2-utiltity-4-yl)ethylcarbamate]-2-phenylethyl}carbamino acid (12A): the Vessel of the apparatus for hydrogenation Parra download tert-butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2-utiltity-4-yl)ethylamino-1-oxo-3-phenylpropane-2-ylcarbamate, 12, (18,05 g, or 37.4 mmol, 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 Meon (270 ml, 15 ml/g)to give a suspension. The vessel is equipped with equipment necessary for Parr apparatus for hydrogenation. The vessel is subjected to a degassing operation by repeated filling of N2(3×20 psi) and later in the coumarouna to an inert state, followed by a similar operation using H2(3×40 psi). Vessel fill N2and the vessel shaken under a pressure of H240 lb/in2for ~40 hours the vacuum Vessel and to create an inert atmosphere by blowing N2(5×20 psi). The sample was filtered and analyzed by HPLC to monitor the completeness of the transformation. The suspension is filtered through a layer of cellite, removing the catalyst and homogeneous yellow filtrate is concentrated by rotary evaporation, getting 16,06 g (yield 95%) of the desired product as a yellowish brown solid which is used without further purification.

Getting 4-((S)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamide)-2-(2-utiltity-4-yl)ethyl)phenylalaninol acid (13): 100 ml RBF load methyl ester, {1-[2-(S)-(4-(S)-AMINOPHENYL)-1-(2-utiltity-4-yl)ethylcarbamate]-2-phenylethyl}carbamino acid, 12A, (10,36 g is 22.9 mmol, 1.0 EQ.), obtained at the stage described above. Add acetonitrile (50 ml, 5 ml/g) and the yellow suspension is stirred at room temperature. The second 3-necked 500-ml RBF download SO3·PIR (5,13 g is 32.2 mmol, 1.4 EQ.) and acetonitrile (50 ml, 5 ml/g) and the white suspension stirred at room temperature. Both the suspension is gently heated until then, while the reaction solution containing methyl ester {1-[2-(S)-(4-(S)-aminophen is)-1-(2-utiltity-4-yl)ethylcarbamate]-2-phenylethyl}carbamino acid, will not be red-orange in color (usually for this example, about 44°C). This substrate-containing solution was poured in one portion into a stirred suspension of SO3·the feast at 35°C. the Obtained opaque mixture (39°C) vigorously stirred, allowing them to cool to room temperature. After stirring for 45 min the reaction, as determined by HPLC, is completed. Orange suspension type H2O (200 ml, 20 ml/g)to give a yellow-orange homogeneous solution having a pH of approximately 2.4. Concentrated H3PO4add slowly for 12 minutes, lowering the pH to approximately 1.4. During this setting the pH of the formed no white residue and the solution was stirred at room temperature for 1 hour. The suspension is filtered and the filter residue is washed with the filtrate. The filter residue is dried in air to filter through the night, getting 10,89 g (yield 89%) of the desired product as a yellowish brown solid.

The following is an additional non-limiting examples of the second aspect of category II of the present invention.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(2-methylthiazole-4-yl)ethyl}fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ of 8.15 (d, J=8.4 and the C, 1H), 7,16-7,25 (m, 5H), 6,97-7,10 (m, 4H), of 6.61 (s, 1H), 5,00-5,24 (m, 1H), 4,36 (t, J=7.2 Hz, 1H), to 3.64 (s, 2H), 3,11-3,19 (s, 1H), 2,92 totaling 3.04 (s, 2H), 2,81 (DD, J=13.5 and 8.1 Hz, 1H), 2,75 (s, 3H).

4-{(S)-2-(2-Utiltity-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ 7,16-7,29 (m, 5H), 7,02 for 7.12 (m, 4H), 6,83 (s, 1H), 5,10 to 5.35 (m, 1H), 3,52-to 3.67 (m, 3H), 3,18-of 3.25 (m, 2H), 3,05 (kV, J=7.5 Hz, 2H), 2,82-2,95 (m, 2H), 2,65 (s, 3H), of 1.39 (t, J=7.5 Hz, 3H).

4-{(S)-2-(2-Isopropylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1H NMR (CD3OD) δ is 8.16 (d, 1H, J=8.1 Hz), 7,22-7,13 (m, 3H), 7,07 (d, 1H, J=8,4 Hz), of 6.96 (d, 1H, J=8.1 Hz), 6,62 (s, 1H), 5,19 (t, 1H, J=7,2 Hz), 4,36 (t, 1H, J=7.8 Hz), 3,63 (s, 3H), is 3.08 (1H, BUT avj, J=3,6, 14,5 Hz), 2,99 (1H, from avj, J=7,2, to 13.8 Hz), 2,85-2,78 (m, 1H), 1,41 (d, 6N, J=6,9 Hz).

4-{(S)-2-(2-Cyclopropylmethyl-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1N (CD3OD): δ 7,15-7,02 (m, 5H), of 6.96-6,93 (d, 2H, J=8,4 Hz), 6,86-6,83 (d, 2H, J=8,3 Hz), to 6.39 (s, 1H), free 5.01 (t, 1H, J=5.0 Hz), 4,22 (t, 1H, J=7.4 Hz), 3,51 (s, 3H), 2,98-2,69 (m, 2H), 2,22-of 2.21 (m, 1H), 1.06 a-1,02 (m, 2H), 0,92-0,88 (m, 2H).

4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1N (CD3OD): δ of 7.96-to 7.93 (d, 2H, J=8.6 Hz), 7,83-7,80 (d, 2H, J=8.6 Hz), 7,44-7,34 (m, 5H), 7,29-,27 (d, 2H, J=8,4 Hz), 7,14-7,11 (d, 2H, J=8,4 Hz), 6,97 (s, 1H), 5,31 (t, 1H, J=6,8 Hz), 5,22-of 5.15 (m, 2H), 4,55 (t, 1H, J=7,3 Hz), of 3.84 (s, 3H), 3,20-2,96 (m, 4H).

4-{(S)-2-[2-(tert-Butylsulfonyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1N (CD3OD): δ 7,40-7,30 (m, 5H), 7,21-7,10 (m, 4H), 7,02 (s, 1H), lower than the 5.37 (t, 1H, J=6.9 Hz), 5,01-to 4.98 (m, 2H), 4,51 (t, 1H, J=7,1 Hz), of 3.77 (s, 3H), 3,34-only 2.91 (m, 4H), 1,58 (s, N).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamide]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid:1H NMR (300 MHz, DMSO-d6) δ of 7.96-to 7.99 (m, 2H), 7,51-7,56 (m, 3H), 7,13-7,38 (m, 6N), 6,92-to 6.95 (m, 4H), 5,11-5,16 (m, 1H), 4,32 is 4.35 (m, 1H), 3,51 (s, 3H), 3,39 is 3.40 (m, 2H), 3,09-3,19 (m, 1H), 2,92-to 3.02 (m, 2H), 2,75 (DD, J=10.5 Hz and 9.9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid:1N (CD3OD): δ to 7.61-7,56 (m, 2H), 7,25-7,01 (m, 10H), 6.75 in (s, 1H), 5,24-to 5.21 (q, 1H, J=7,2 Hz), to 4.38 (t, 1H, J=7,2 Hz), 3,60 (s, 3H), 3,23-3,14 (m, 1H), is 3.08 3.00 for (m, 2H), 2,87 is 2.80 (m, 1H).

4-{(S)-2-[2-(3-Chlorothiophene-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1N (CD3OD): δ 7,78-7,76 (d, 1H, J=5.4 Hz), of 7.36-7,14 (m, 10H), 7,03 (s, 1H), 5,39 (t, 1H, J=6.9 Hz), of 4.54 (t, 1H, J=7,3 Hz), 3,80 (s, 3H), 3,39 are 2.98 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-FeNi is propanamide]-2-[2-(3-methylthiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid: 1N (CD3OD): δ 7,38 (d, 1H, J=5,1 Hz), 7,15-6,93 (m, 10H), was 6.73 (s, 1H), 5,17 (t, 1H, J=6.9 Hz), or 4.31 (t, 1H, J=7,3 Hz), 3,57 (s, 3H), 3,18-3,11 (m, 1H), 3,02-to 2.94 (m, 2H), 2,80-by 2.73 (m, 1H), 2,46 (s, 3H).

4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid:1N (CD3OD): δ 7,54-7,46 (m, 1H), 7,02-6,79 (m, 10H), 6,55-6,51 (m, 1H), 6,44-6,41 (m, 1H), 5,02-5,00 (kV, 1H, J=6.4 Hz), 4,16-to 4.14 (q, 1H, J=7,1 Hz), 3.43 points (s, 3H), 2,96-of 2.58 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(2-methylthiazole-4-yl)thiazol-4-yl]ethyl}fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ of 8.27 (d, J=5.4 Hz, 1H), of 7.97 (s, 1H), 6,99-7,21 (m, 8H), 5,18-and 5.30 (m, 1H), 4,30-4,39 (m, 1H), to 3.64 (s, 3H), 3,20 (DD, J=14.1 and 6.6 Hz, 1H), 2,98-is 3.08 (m, 2H), 2,84 (DD, J=14.1 and 6.6 Hz, 1H), 2,78 (s, 3H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(2-pyrazin-2-yl)thiazol-4-yl}fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ 9,34 (s, 1H), 8,65 (s, 2H), 8.34 per (d, J=8,1 Hz, 1H), 7,00-5,16 (m, N), and 5.30 (q, J=7.2 Hz, 1H), to 4.41 (t, J=7.2 Hz, 1H), the 3.65 (s, 3H), 3,23 (DD, J=13.8 and 6.9 Hz, 1H), 2,98-3,13 (m, 2H), 2,85 (DD, J=13.8 and 6,9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}fenilalanina acid:1N (CD3OD): δ of 8.90 (s, 1H), 8,19-8,13 (m, 1H), 7,39 and 7.36 (d, 1H, J=8,2 Hz), 7,07-to 6.88 (m, N), 6,79 (s, 1H), 5,17 (t, 1H, J=7,0 Hz), the 4.29 (t, 1H, J=7.4 Hz), of 3.54 (s, 3H) 3,10-by 2.73 (m, 4H), of 2.53 (s, 3H).

Category III of the present invention relates to compounds having the formula

where R represents a substituted or an unsubstituted thiazole-2-ilen group and non-limiting examples of R and R1and, in addition, the stereochemistry at R1presented in table V.

Table V
No.RR1
101the thiazole-2-yl(S)-benzyl
1024-methylthiazole-2-yl(S)-benzyl
1034-utiltity-2-yl(S)-benzyl
1044-propertiesa-2-yl(S)-benzyl
1054-isopropylthiazole-2-yl(S)-benzyl
1064-cyclopropylmethyl-2-yl(S)-benzyl
1074-butylthiazole-2-yl(S)-benzyl
1084-tert-butylthiazole-2-yl(S)-benzyl
1094-cyclohexylthio-2-yl(S)-benzyl
1104-(2,2,2-triptorelin)thiazol-2-yl(S)-benzyl
1114-(3,3,3-cryptochromes)thiazol-2-yl(S)-benzyl
1124-(2,2-diversicolor)thiazol-2-yl(S)-benzyl
1134-(methoxymethyl)thiazol-2-yl(S)-benzyl
1144-(ethyl ether carboxylic acid)thiazol-2-yl(S)-benzyl
1154,5-dimethylthiazol-2-yl(S)-benzyl
1164-methyl-5-utiltity-2-yl(S)-benzyl
1174-phenylthiazol-2-yl(S)-benzyl
1184-(4-chlorophenyl)thiazol-2-yl(S)-b is nil
1194-(3,4-dimetilfenil)thiazol-2-yl(S)-benzyl
1204-methyl-5-phenylthiazol-2-yl(S)-benzyl
1214-(thiophene-2-yl)thiazol-2-yl(S)-benzyl
1224-(thiophene-3-yl)thiazol-2-yl(S)-benzyl
1234-(5-chlorothiophene-2-yl)thiazol-2-yl(S)-benzyl
1245,6-dihydro-4H-cyclopent[d]thiazol-2-yl(S)-benzyl
1254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl(S)-benzyl

Compounds covered by the category IV of the present invention, can be obtained by the method in General is presented in scheme VI and described in example 6, below.

Scheme V

Reagents and conditions: (a) Ac-Phe, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours

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

Example 5

4-[(S)-2-((S)-2-Acetamido-3-fenil is openmode)-2-(4-utiltity-2-yl)ethyl]fenilalanina acid (15)

Obtain (S)-2-acetamido-1H-[(S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-3-phenylpropanamide (14): To a solution of the hydrobromide 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine, 3, (0,343 g, 0,957 mmol), N-acetyl-L-phenylalanine (0,218 g), 1-hydroxybenzotriazole (HOBt) (0,161 g), diisopropylethylamine (0.26 g) in DMF (10 ml) at 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0,201 g). The mixture is stirred at 0°C for 30 minutes, then at room temperature over night. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with 1N. aqueous HCl, 5% aqueous NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,313 g (yield 70%) of the desired product which is used without further purification. LC/MS ESI+ 467 (M+1).

Getting 4-((S)-2-((S)-2-acetamido-3-phenylpropanamide)-2-(4-utiltity-2-yl)ethyl)phenylalaninol acid (15): (S)-2-acetamido-N-[(S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-3-phenylpropanamide, 14, (0,313 g) dissolved in Meon (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,320 g). The reaction mixture was premesis the Ute at room temperature for 5 minutes, then add 7% solution of NH4OH (30 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,215 g of the desired product in the form of ammonium salts.

1N (CD3OD): δ 7.23 percent-6,98 (m, 10H), lower than the 5.37 (t, 1H), with 4.64 (t, 1H, J=6.3 Hz), 3,26-to 2.74 (m, 6N), at 1.91 (s, 3H), of 1.29 (t, 3H, J=7.5 Hz).

The following is an additional non-limiting examples of compounds covered by the category III of the present invention.

4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamide)-2-(4-tert-butylthiazole-2-yl)ethyl]fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,22-7,17 (m, 5H), 7,06 (DD, J=14,1, and 8.4 Hz, 4H), 6,97 (d, J=0.9 Hz, 1H), 5,39 (DD, J=8,4, 6.0 Hz, 1H)and 4.65 (t, J=7.2 Hz, 1H), 3.33 and-3,26 (m, 1H), 3,13-3,00 (m, 3H), 2,80 (DD, J=13,5, and 8.7 Hz, 1H), 1.91 a (, 3H), of 1.36 (s, N).

4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamide)-2-[4-(thiophene-3-yl)thiazol-2-yl]ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 8,58 (d, J=8,1 Hz, 1H), 7,83-of 7.82 (m, 1H), EUR 7.57-7,46 (m, 3H), 7,28-6,93 (m, 11N), 5,54-5,43 (m, 1H), 4,69-4,55 (m, 2H), 3,41-to 3.33 (m, 1H), 3,14-of 3.06 (3H), 2,86-and 2.79 (m, 1H), 1.93 and (s, 3H).

The first aspect of category IV of the present invention relates to compounds having the formula

where R represents a substituted or unsubstituted thiophene-2-yl group and non-limiting examples of R and R1and, in addition, the stereochemistry at R1not only the us in table VI.

147
Table VI
No.RR1
126the thiazole-2-ylhydrogen
1274-methylthiazole-2-ylhydrogen
1284-utiltity-2-ylhydrogen
1294-propertiesa-2-ylhydrogen
1304-isopropylthiazole-2-ylhydrogen
1314-cyclopropylethanolhydrogen
1324-butylthiazole-2-ylhydrogen
1334-tert-butylthiazole-2-ylhydrogen
1344-cyclohexylthio-2-ylhydrogen
1354,5-dimethylthiazol-2-yl1364-methyl-5-utiltity-2-ylhydrogen
1374-phenylthiazol-2-ylhydrogen
138the thiazole-2-yl(S)-isopropyl
1394-methylthiazole-2-yl(S)-isopropyl
1404-utiltity-2-yl(S)-isopropyl
1414-propertiesa-2-yl(S)-isopropyl
1424-isopropylthiazole-2-yl(S)-isopropyl
1434-cyclopropylmethyl-2-yl(S)-isopropyl
1444-butylthiazole-2-yl(S)-isopropyl
1454-tert-butylthiazole-2-yl(S)-isopropyl
1464-cyclohexylthio-2-yl(S)-isopropyl
4,5-dimethylthiazol-2-yl(S)-isopropyl
1484-methyl-5-utiltity-2-yl(S)-isopropyl
1494-phenylthiazol-2-yl(S)-isopropyl
1504-(thiophene-2-yl)thiazol-2-yl(S)-isopropyl

Compounds covered by the category III of the present invention, can be obtained by the method in General is presented in scheme V and described in the following example 5.

Scheme VI

Reagents and conditions: (a) Boc-Val; EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH, room temperature, 2 hours

Example 6

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanoate]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid (17)

Obtain tert-butyl ester {1-[1-(utiltity-2-yl)-2-(4-nitrophenyl)ethylcarbamate]-2-methylpropyl}carbamino acid (16): To a solution of the hydrobromide 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine, 3, (0,200 g, 0,558. mmol), (S)-(2-tert-butoxycarbonylamino)-3-methylmalonic acid (of 0.133 g) and 1-hydroxybenzotriazol the La (HOBt) (0, 094 g) in DMF (5 ml) at 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (amount of 0.118 g), and then Diisopropylamine (0,151 g). The mixture is stirred at 0°C for 30 minutes, then at room temperature over night. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with 1N. aqueous HCl, 5% aqueous NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,219 g (yield 82%) of the desired product which is used without further purification. LC/MS ESI+ 477(M+1).

Getting 4-{(S)-2-[(S}-2-(tert-butoxycarbonylamino)-3-methylbutanoate]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid (17): tert-butyl ether {{1-[1-(utiltity-2-yl)-2-(4-nitrophenyl)ethylcarbamate]-2-methylpropyl}carbamino acid, 16, (0,219 g) dissolved in Meon (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (5 ml) and treated SO3-pyridine (0,146 g). The reaction mixture was stirred at room temperature for 5 minutes, then add 7% solution of NH4OH (30 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed phase, in which the learn 0,148 g of the desired product in the form of ammonium salts.

1H (CD3OD): δ was 7.08 (s, 4H), 7,02 (s, 1H), 5,43 (s, 1H), 3,85 (s, 1H), 3,28-2,77 (m, 4H), of 1.94 (s, 1H), 1,46 (s, N), of 1.29 (s, 3H, J=7,3 Hz), or 0.83 (s, 6N).

The following is an additional non-limiting examples of the first aspect of category IV of the present invention.

(S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid:1N (CD3OD): δ 7,09-6,91 (m, 5H), and 5.30 (t, 1H, J=8,4 Hz), 3,60-of 2.64 (m, 6N), of 1.34 (s, N), of 1.16 (t, 3H, J=7.5 Hz).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentylamino]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid:1H NMR (CD3OD) δ 7,19-7,00 (m, 4H), 5,50-of 5.40 (m, 1H), 4,13-4,06 (m, 1H), 3,32 (1H, BUT avj, J=7,5,18 Hz), 3,12 (1H, from avj, J=8,1, to 13.8 Hz), and 2.79 (q, 2H, J=7,8, of 14.7 Hz), 1.70 to 1.55V (m, 1H), 1,46 (s, N), of 1.33 (t, 3H, J=2.7 Hz), 0,92 (kV, 6N, J=6, and 10.8 Hz).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentan-amido]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid:1H NMR (CD3OD) δ of 8.06 (d, 1H, J=8,4 Hz), to 7.61-7,58 (m, 1H), EUR 7.57 (s, 1H), 7,15 (t, 1H, J=0.6 Hz), 7,09-6,98 (m, 6N), and 5.30-5,20 (m, 1H), 4,10-4,00 (m, 1H), 3,19-3,13 (m, 2H), 1,63-of 1.55 (m, 2H), 1,48-of 1.33 (m, 10H), 0,95-0, 89 (m, 6N).

The following is a non-limiting examples of the second aspect of category IV of the present invention.

(S)-4-{2-(4-utiltity-2-yl)-2-[2-(methoxycarbonylamino)-acetone is up]ethyl}-fenilalanina acid: 1H NMR (CD3OD) δ 7,12-7,07 (m, 4H), 7,03 (s, 1H), 5,42 (t, 1H, J=5.7 Hz), 3,83-3,68 (q, 2H, J=11,4 Hz), 3,68 (s, 3H), 3,34 totaling 3.04 (m, 2H), 2,83 was 2.76 (q, 2H, J=7.8 Hz), is 1.31 (t, 3H, J=7.5 Hz).

4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanoate]ethyl}fenilalanina acid:1H NMR (CD3OD) δ 8,56 (d, 1H, J=7.8 Hz), to 7.09 (s, 4H), 7,03 (s, 1H), 5,26-5,20 (m, 1H), 3,90 (d, 1H, J=7.8 Hz), 3,70 (s, 3H), 3,30 (1H, BUT AWH, hidden by solvent), is 3.08 (1H, from avj, J=9,9, 9 Hz), and 2.79 (q, 2H, J=11,1, 7,2 Hz), 2.05 is-of 1.97 (m, 1H), 1,31 (t, 3H, J=7.5 Hz), to 0.88 (s, 3H), of 0.85 (s, 3H), 0.79, which is to 0.75 (m, 1H).

4-{(S)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl)ethyl}fenilalanina acid:1H NMR (CD3OD) δ by 8.22 (d, 1H, J=9 Hz), a 7.62 EUR 7.57 (m, N), to 7.15 (t, 1H, J=0.6 Hz), 7,10-6,97 (m, 4H), and 5.30-5,20 (m, 1H), 4,16-4,11 (m, 1H), to 3.67 (s, 2H), UP 3.22 (1H, BUT avj, J=6,9, and 13.5 Hz), 3,11 (1H, from avj, J=7,8, or 13.6 Hz), 1,65 is 1.58 (m, 1H), 1,50-of 1.45 (m, 2H), 0,95-0,88 (m, 6N).

4-{(S)-2-(4-Utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentylamino]ethyl}fenilalanina acid:1H NMR (CD3OD) δ 7,12-7,03 (m, 5H), at 6.84 (d, 1H, J=8,4 Hz), of 5.40 (t, 1H, J=5.7 Hz), 4,16 (t, 1H, J=6.3 Hz), of 3.69 (s, 3H), 3,61-3,55 (m, 1H), 3,29-of 3.27 (m, 1H), 3,14-of 3.07 (m, 1H), 2,81 (q, 2H, J=3,9, 11.2 Hz), 1,66-1,59 (m, 1H), 1,48 was 1.43 (m, 2H), 1,31 (t, 3H, J=4.5 Hz), 0,96-of 0.90 (m, 6N).

4-((S)-2-(4-Utiltity-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)acetamido]-3-phenylpropanamide}ethyl)phenylsulfanyl the Wai acid: lH (CD3OD): δ 7,22-7,01 (m, N), 6,97 (s, 1H), lower than the 5.37-5,32 (m, 1H), with 4.64 (t, 1H, 3=1.1 Hz), 3,71-3,68 (m, 2H), to 3.64 (s, 3H), 3,28-3,26 (m, 1H), 3,03-2,96 (m, 2H), 2,83-of 2.72 (m, 3H), of 1.28 (t, 3H, J=7.5 Hz).

Category V of the present invention relates to non-limiting examples of the second aspect:

where R represents a substituted or unsubstituted thiophene-2-ilen, or thiophene-4-ilen group and non-limiting examples of R2below in table VII.

2-phenylthiazol-4-yl -Och3
Table VII
No.RR2
151the thiazole-2-yl-OC(CH3)3
1524-methylthiazole-2-yl-OC(CH3)3
1534-utiltity-2-yl-OC(CH3)3
1544-cyclopropylmethyl-2-yl-OC(CH3)3
1554-tert-butylthiazole-2-yl-OC(CH3)3
156 4-cyclohexylthio-2-yl-OC(CH3)3
1574-(2,2,2-triptorelin)thiazol-2-yl-OC(CH3)3
1584-(3,3,3-cryptochromes)thiazol-2-yl-OC(CH3)3
1594-(2,2-diversicolor)thiazol-2-yl-OC(CH3)3
1604,5-dimethylthiazol-2-yl-OC(CH3)3
1614-methyl-5-utiltity-2-yl-OC(CH3)3
1624-phenylthiazol-2-yl-OC(CH3)3
1634-(4-chlorophenyl)thiazol-2-yl-OC(CH3)3
1644-(3,4-dimetilfenil)thiazol-2-yl-OC(CH3)3
1654-methyl-5-phenylthiazol-2-yl-OC(CH3)3
166/td> 4-(thiophene-2-yl)thiazol-2-yl-OC(CH3)3
167the thiazol-4-yl-OC(CH3)3
1682-methylthiazole-4-yl-OC(CH3)3
1692-utiltity-4-yl-OC(CH3)3
1702-cyclopropylethanol-4-yl-OC(CH3)3
1712-tert-butylthiazole-4-yl-OC(CH3)3
1722-cyclohexylthio-4-yl-OC(CH3)3
1732-(2,2,2-triptorelin)thiazol-4-yl-OC(CH3)3
1742-(3,3,3-cryptochromes)thiazol-4-yl-OC(CH3)3
1752-(2,2-diversicolor)thiazol-4-yl-OC(CH3)3
178-OC(CH3)3
1792-(4-chlorophenyl)thiazol-4-yl-OC(CH3)3
1802-(3,4-dimetilfenil)thiazol-4-yl-OC(CH3)3
1822-(thiophene-2-yl)thiazol-4-yl-OC(CH3)3
183the thiazole-2-yl-Och3
1844-methylthiazole-2-yl-Och3
1854-utiltity-2-yl-Och3
1864-cyclopropylmethyl-2-yl-Och3
1874-tert-butylthiazole-2-yl-Och3
1884-cyclohexylthio-2-yl-OCH3
1894-(2,2,2-triptorelin)thiazol-2-yl-Och3
1904-(3,3,3-cryptochromes)thiazol-2-yl-Och3
1914-(2,2-diversicolor)thiazol-2-yl-Och3
1924,5-dimethylthiazol-2-yl-Och3
1934-methyl-5-utiltity-2-yl-Och3
1944-phenylthiazol-2-yl-Och3
1954-(4-chlorophenyl)thiazol-2-yl-Och3
1964-(3,4-dimetilfenil)thiazol-2-yl-Och3
1974-methyl-5-phenylthiazol-2-yl-Och3
1984-(thiophene-2-yl)thiazol-2-yl-Och3
199the thiazol-4-yl-Och3
2002-methylthiazole-4-yl-Och3
2012-utiltity-4-yl-Och3
2022-cyclopropylethanol-4-yl-Och3
2032-tert-butylthiazole-4-yl-Och3
2042-cyclohexylthio-4-yl-Och3
2052-(2,2,2-triptorelin)thiazol-4-yl-Och3
2062-(3,3,3-cryptochromes)thiazol-4-yl-Och3
2072-(2,2-diversicolor)thiazol-4-yl-Och3
2102-phenylthiazol-4-yl-Och3
2112-(4-chlorophenyl)thiazol-4-yl-Och3
2122-(3,4-dimetilfenil)thiazol-4-yl-Och3
2132-methyl-5-phenylthiazol-4-yl
2142-(thiophene-2-yl)thiazol-4-yl-Och3

215the thiazole-2-yl-CH3
2164-methylthiazole-2-yl-CH3
2174-utiltity-2-yl-CH3
2184-cyclopropylmethyl-2-yl-CH3
2194-tert-butylthiazole-2-yl-CH3
2204-cyclohexylthio-2-yl-CH3
2214-(2,2,2-triptorelin)thiazol-2-yl-CH3
2224-(3,3,3-cryptochromes)thiazol-2-yl-CH3
2234-(2,2-diversicolor)thiazol-2-yl-CH3
224 4,5-dimethylthiazol-2-yl-CH3
2254-methyl-5-utiltity-2-yl-CH3
2264-phenylthiazol-2-yl-CH3
2274-(4-chlorophenyl)thiazol-2-yl-CH3
2284-(3,4-dimetilfenil)thiazol-2-yl-CH3
2294-methyl-5-phenylthiazol-2-yl-CH3
2304-(thiophene-2-yl)thiazol-2-yl-CH3
231the thiazol-4-yl-CH3
2322-methylthiazole-4-yl-CH3
2332-utiltity-4-yl-CH3
2342-cyclopropylethanol-4-yl-CH3
2352-tert-Buti is a thiazol-4-yl -CH3
2362-cyclohexylthio-4-yl-CH3
2372-(2,2,2-triptorelin)thiazol-4-yl-CH3
2382-(3,3,3-cryptochromes)thiazol-4-yl-CH3
2392-(2,2-diversicolor)thiazol-4-yl-CH3
2422-phenylthiazol-4-yl-CH3
2432-(4-chlorophenyl)thiazol-4-yl-CH3
2442-(3,4-dimetilfenil)thiazol-4-yl-CH3
2452-methyl-5-phenylthiazol-4-yl-CH3
2462-(thiophene-2-yl)thiazol-4-yl-CH3

Compounds covered by the category V of the present invention, can be obtained by the method in General is presented in scheme VI and described in nigelle the ith example 7.

Scheme VI

Reagents and conditions: (a) (i) CH3CN; boiling under reflux, 1,5 hours

(ii) Boc2O, pyridine, CH2Cl2; room temperature, 2 hours

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; boiling under reflux

(ii) SO3-pyridine, NH4OH; room temperature, 12 hours

Example 7

tert-Butyl ether [1-(S)-(phenylthiazol-2-yl)-2-(4-sulfonylarenes)ethyl]carbamino acid (19)

Obtain tert-butyl ester [2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]carbamino acid (18): a Mixture of tert-butyl methyl ether 2-(4-nitrophenyl)-1-(S)-thiocarbamoylation]carbamino acid, 2, (0,343 g, 1.05 mmol), 2-bromoacetophenone (0,231 g, 1.15 mmol) in CH3CN (5 ml) is refluxed for 1.5 hours. The solvent is removed under reduced pressure and the residue again dissolved in CH2Cl2then add pyridine (of 0.24 ml, 3.0 mmol) and Boc2O (0,24 ml, 1.1 mmol). The reaction mixture is stirred for 2 hours and the solution was added diethyl ether, and the precipitate which is formed is removed by filtration. The organic layer is dried (Na2SO4), filtered and concentrated to a residue, which was purified on silica gel, receiving 0,176 g (39%) of the desired product ESI+ MS 426 (M+1).

Obtain tert-butyl ester [1-(S)-(phenylthiazol-2-yl)-2-(4-sulfo AMINOPHENYL)ethyl]carbamino acid (19): tert-butyl ether [2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]carbamino acid, 18, (0,176 g, 0.41 mmol) was dissolved in Meon (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 12 hours. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (of € 0.195 g of 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add 7% solution of NH4OH (10 ml). The mixture is then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,080 g of the desired product in the form of ammonium salts.

1H NMR (300 MHz, MeOH-d4) δ 7, 93 (d, J=6.0 Hz, 2H), 7,68 (s, 1H), 7,46-7,42 (m, 3H), 7,37-7,32 (m, 1H), 7,14-to 7.18 (m, 3H), 5,13-by 5.18 (m, 1H), 3,40 (DD, J=4,5 and 15.0 Hz, 1H), 3.04 from (DD, J=9.6 and 14.1 Hz, 1H), USD 1.43 (s, N).

The following is an additional non-limiting examples of category V of the present invention.

(S)-(4-(2-(4-Methylthiazole-2-yl)-2-evalidator)phenyl)-sulfamic acid:1N (CD3OD): δ 7,31 (s, 4H), 7,20 (s, 1H), 5,61-to 5.56 (m, 1H), 3, 57-3,22 (m, 2H), 2,62 (s, 3H), of 1.31 (s, 3H).

(S)-(4-(2-(4-Utiltity-2-yl)-2-evalidator)phenyl)-sulfamic acid:1H NMR (300 MHz, MeOH-d4) δ a 7.92 (d, J=8,1 Hz, 1H), 7,12-7,14 (m, 4H), 7,03 (s, 1H), 5,38-5,46 (m, 1H), 3,3-3,4 (m, 1H), is 3.08 (DD, J=10,2 and 13.8 Hz, 1H), and 2.79 (q, J=7.2 Hz, 2H), of 1.30 (t, J=2 Hz, 3H), 1,13 (s, N).

(S)-(4-(2-(4-(Hydroxymethyl)thiazol-2-yl)-2-evalidator)-phenyl)sulfamic acid:1H NMR (300 MHz, Meon-d4) δ a 7.92 (d, J=8,1 Hz, 1H), 7,24 (s, 1H), was 7.08 (d, J=8.7 Hz, 2H), 7,00 (d, J=8.7 Hz, 2H), from 5.29 lower than the 5.37 (m, 1H), 4,55 (s, 2H), 3,30 (DD, J=4.8 and 13.5 Hz, 1H), 2,99 (DD, J=10.5 and 13.5 Hz, 1H), 0,93 (s, N).

(S)-4-(2-(4-Phenylthiazol-2-yl)-2-evalidator)fenilalanina acid:1H NMR (300 MHz, Meon-d4) δ 7,94 shed 8.01 (m, 3H), of 7.70 (s, 1H), 7,42-7,47 (m, 2H), 7,32-7,47 (m, 1H), 7,13-7,20 (m, 3H), 5,48-of 5.55 (m, 1H), 3,50 (DD, J=5.1 and 14.1 Hz, 1H), 3,18 (DD, J=10.2 and 14.1 Hz, 1H), 1,67 (s, N).

4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-evalidator)fenilalanina acid:1N (CD3OD): δ of 7.96-to 7.93 (d, 1H, J=8.1 Hz), 7,69 (s, 1H), 7,51-7,49 (d, 2H, J=7.9 Hz), 7,33 (t, 1H, J=8.0 Hz), 7,14 (s, 4H), 6,92-of 6.90 (d, 1H, J=7.8 Hz), of 5.50 (t, 1H, J=5,1 Hz), a 3.87 (s, 3H), 3,50-3,13 (m, 2H), to 1.15 (s, N).

4-((S)-2-(4-(3-methoxyphenyl)thiazol-2-yl)-2-evalidator)fenilalanina acid:1N (CD3OD): δ 7,98 is 7.85 (m, 3H), 7,53 (s, 1H), 7,26 for 7.12 (m, 3H), 7.03 is-6,98 (m, 2H), 5,54-5,46 (m, 1H), 3,52-3,13 (m, 2H)and 1.15 (s, N).

4-((S)-2-(4-(2,4-Acid)thiazol-2-yl)-2-evalidator)fenilalanina acid:1N (CD3OD): δ 8,11-of 8.09 (d, 1H, J=7.8 Hz), of 7.96-to 7.93 (d, 1H, J=8,4 Hz), 7,74 (s, 1H), 7.18 in-7,16 (m, 4H), 6,67-only 6.64 (d, 2H, J=9.0 Hz), 5,55-vs. 5.47 (m, 1H), 3,95 (s, 3H), a 3.87 (s, 3H), 3,52-3,13 (m, 2H), 1,17 (s, N).

(S)-4-(2-(4-Sensitiza-2-yl)-2-evalidator)fenilalanina acid:1H NMR (CD3OD) δ a 7.85 (d, 1H, J=8,4 Hz), 7, 38-7,20 (m, 4H), 7,11-7,02 (m, 1H), 7,00 (s, 1H), 5,42 lower than the 5.37 (m, 1H), 4,13 (s, 2H), 3,13-is 3.08 (m, 2H), 1,13 (s, N).

(S)-4-(2-Pialligo-2-(4-(thiophene-2-ylmethyl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (CD3OD) δ 7,88-a 7.85 (d, 1H), 7,38-7,35 (m, 1H), 7,10-7,01 (m, 4H), 7,02 (s, 1H), the 5.45 is 5.38 (m, 1H), 4,13 (s, 2H), 3,13 was 3.05 (m, 2H), 1,13 (2, N).

(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-evalidator)fenilalanina acid:1H NMR (CD3OD) δ a 7.85 (d, 1H, J=8,4 Hz), 7,25-7,20 (m, 1H), 7,11-7,02 (m, 4H), 7,01 (s, 1H), 6.90 to-6,79 (m, 2H), the 5.45 to 5.40 (m, 1H), 4.09 to (s, 2H), 3,79 (s, 3H), 3,12-is 3.08 (m, 2H), 1,10 (s, N).

4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-evalidator)fenilalanina acid:1N (CD3OD): δ 7,53 (s, 1H), 7,45 (s, 1H), 7,42-7,40 (d, 1H, J=8,4 Hz), 7,19-to 7.15 (m, 4H), 6,91-to 6.88 (d, 2H, J=8,4 Hz), 5,51-5,46 (m, 1H), 4,30 (s, 4H), 3,51-of 3.12 (m, 2H), 1,16 (s, N).

(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-evalidator)fenilalanina acid:1H (CD3OD): δ 7,63-of 7.60 (d, 2H, J=7,1 Hz), 7,49-7,35 (m, 3H), 7,14 (s, 4H), 5,43 is 5.38 (m, 1H), 3,42-to 3.09 (m, 2H), 2.49 USD (s, 3H), 1.14 in (C, N).

(S)-4-(2-(4-(Biphenyl-4-yl)thiazol-2-yl)-2-evalidator)fenilalanina acid:1N (CD3OD): δ 8,04 shed 8.01 (m, 2H), 7,72-7,66 (m, 5H), of 7.48-7,35 (m, 3H), 7,15 (C, H), of 5.50 (t, 1H, J=5.0 Hz), 3,57 is 3.15 (d, 2H), 1,16 (s, N).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-methylthiazole-4-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, D2O) δ 6,99-7,002 (m, 4H), PC 6.82 (s, 1H), and 2.26 (DD, J=13.8 and 7.2 Hz, 1H), was 2.76 (DD, J=13.8 and 7.2 Hz, 1H), 2,48 (s, 3H), 1,17 (s, N).

(S)-(4-(2-((tert-Butoxycarbonyl)amino)-2-(4-propertiesa-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7.18 in-7,02 (m, 5H), 5,06-to 5.03 (m, 1H), 3,26 (DD, J=13,8, 4.8 Hz, 1H), 2,95 (DD, J=13,8, and 9.3 Hz, 1H), 2,74 (DD, J=15,0, 7.2 Hz, 2H), 1,81-1,71 (m, 2H), 1,40 (s, 7H), 1,33 (users, 2H), 0,988 (t, J=7, 5 Hz, 3H).

(S)-(4-(2-((tert-Butoxycarbonyl)amino)-2-(4-tert-butylthiazole-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ for 7.12 (s, 4H), 7,01 (s, 1H), 5,11-of 5.06 (m, 1H), 3,32-of 3.25 (m, 1H), 2,96 (m, 1H), 1,42 (s, 8H), to 1.38 (s, N), 1,32 (s, 1H).

(S)-(4-(2-((tert-Butoxycarbonyl)amino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ was 7.36 (s, 1H), 7,14-7,05 (m, 4H), of 5.06 (DD, J=9,0, 5,1 Hz, 1H), 4,55 (s, 2H), 3,42 (s, 3H), 3,31-3,24 (m, 1H), 2,97 (DD, J=13,8, 9.9 Hz, 1H), 1,47 to 1.31 (m, N).

(S)-(4-(2-((tert-Butoxycarbonyl)amino)-2-(4-(2-hydroxymethyl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, Meon-d4) δ 7,22-7,25 (m, 1H), 7,09-to 7.15 (m, 4H), 5,00-5,09 (m, 1H), 4,32 is 4.35 (m, 1H), a 3.87 (t, J=6, 6 Hz, 2H), 3,23-3,29 (m, 1H), 3,09-3,18 (m, 1H), 2,98 (t, J=6.6 Hz, 2H), 1,41 (s, N).

(S)-(4-(2-((tert-Butoxycarbonyl)amino)-2-(4-(2-ethoxy-2-oxoethyl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ 7.29 trend (s, 1H), 7,09-7,16 (m, 4H), 5,04-5,09 (m, 1H), 4,20 (kV, J=6,9 Hz, 2H), 3,84 (s, 2H), 3,30 (DD, J=4.8 and 14.1 Hz, 1H), 2,97 (DD, J=9.6 Hz and 13.8 Hz, 1H), 1,41 (s, N), of 1.29 (t, J=7.2 Hz, 3H).

(S)-(4-(2-((tert-Butoxycarbonyl)amino)-2-(4-(2-(2-methoxy-2-oxoethylidene)-2-oxoethyl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ 7,31 (s, 1H), 7,01-7,16 (m, 4H), 5,04-5,09 (m, 1H), 4,01 (s, 2H), of 3.78 (s, 2H), 3,74 (s, 3H), 3,29 (DD, J=5,1 and 13.8 Hz, 1H), 2,99 (DD, J=9,3 and 13.8 Hz, 1H), 1,41 (s, N).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-pivaloyloxy)-thiazol-4-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, D2O) δ to 6.95 (s, 4H), 6,63 (s, 1H), equal to 2.94 (DD, J=13.5 and 4.8 Hz, 1H), 2,75 (DD, J=13.5 and 4.8 Hz, 1H), 1,16 (s, N), 1,13 (s, N).

(S)-(4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,98 (s, 1H), 7.62mm (d, J=7.2 Hz, 2H), 7,46-7,35 (m, 4H), 7,14 (s, 4H), 5,09 (users, 1H), 3,07-to 2.99 (m, 2H), USD 1.43 (s, N).

4-((S)-(2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ of 8.28 (s, 1H), they were 8.22-8,19 (m, 1H), 7,89 (s, 1H), 7,65 (d, J=5,1 Hz, 2H), 7,45 (who, J=8,1 Hz, 1H), 7,15 (s, 4H), 5,17-5,14 (m, 1H), 3.43 points-of 3.32 (m, 1H), 3,05 (DD, J=14,1, 9.6 Hz, 1H), 1,42 (s, N).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-phenylthiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ 7,98 (s, 1H), 7,94 (d, J=7.2 Hz, 2H), 7,46-7,35 (m, 4H), 7,14 (s, 4H), 5,09 (users, 1H), 3,07-to 2.99 (m, 2H), USD 1.43 (s, N).

(S)-{4-[2,2-Dimethylpropanolamine)-2-(2-phenylthiazol-4-yl)ethyl]fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ 7,92-of 7.96 (m, 2H), 7,65 (d, J=8,4 Hz, 1H), 7,45-7,49 (m, 3H), 7,18 (s, 1H), 7,08-to 7.15 (m, 4H), 5,34-5,41 (m, 1H), 3,26 (DD, J=14.1 and 6.0 Hz, 1H), is 3.08 (DD, J=13.8 and 9.0 Hz, 1H), 1,47 (s, N).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-phenyl)-2-(4-phenylthiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, MeOH-d4) δ to 7.93 (d, J=6.0 Hz, 2H), 7,68 (s, 1H), 7,46-7,42 (m, 3H), 7,37-7,32 (m, 1H), 7,14-to 7.18 (m, 3H), 5,13-by 5.18 (m, 1H), 3,40 (DD, J=4,5 and 15.0 Hz, 1H), 3.04 from (DD, J=9.6 and 14.1 Hz, 1H), USD 1.43 (s, N).

Methyl ether (S,S)-2-(2-{2-[2-tert-butoxycarbonylamino-2-(4-sulfonylarenes)ethyl]thiazol-4-yl}acetylamino)-3-phenylpropionic acid:1H NMR (300 MHz, MeOH-d4) δ 6,85-6,94 (m, N), only 6.64 (s, 1H), a 4.83 (s, 1H), 4,54-4,58 (m, 1H), 3,49 (s, 3H), 3,39 (s, 2H), 2,80-of 2.97 (m, 1H), 2,64-2,78 (m, 1H), 1,12 (s, N).

Tert-Butyl ether (S)-[1-{1-oxo-4-[2-(1-phenyl-1H-tetrazol-5-sulfonyl)ethyl]-1H-1λ4-thiazol-2-yl}-2-(4-sulfamidate)ethyl]carbamino acid:1H NMR (300 MHz, Meon-d4) δ 7,22 to 7.75 (m, 2H), 7,627,69 (m, 2H), 7,55 (s, 1H), 7,10-7,20 (m, 5H), 5.25 in (m, 1H), 4,27 is 4.36 (m, 1H), 4,11-is 4.21 (m, 1H), 3.33 and-3,44 (m, 4H), 2,84-2,90 (m, 1H), 1,33 (s, N).

4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophene-3-yl)thiazol-2-yl)ethyl)fenilalanina acid:1H NMR (300 MHz, CD3OD): δ to 7.84 (DD, J=3,0, 1.5 Hz, 1H), EUR 7.57-of 7.55 (m, 2H), 7,47 (DD, J=4,8, 3.0 Hz, 1H), 7,15 (s, 4H), 5,15-5,10 (m, 1H), 3,39-to 3.34 (m, 1H), 3,01 (DD, J=14,1, 9.6 Hz, 1H), 1,42 (s, 8H), 1,32 (s, 1H).

(S)-4-(2-(Benzo[d]thiazol-2-ylamino)-2-(tert-butoxycarbonyl)ethyl)fenilalanina acid:1H NMR (CD3OD) δ 7,86-of 7.82 (m, 2H), 7,42 (t, 2H, J=7,1 Hz), 7,33 (t, 1H, J=8,2 Hz), 7,02 (s, 4H), 5,10-of 5.05 (m, 1H), 2,99-only 2.91 (m, 2H), 1,29 (s, N).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazole-4-yl)fenilalanina acid:1H NMR (300 MHz, D2O) δ 6,99-7,002 (m, 4H), PC 6.82 (s, 1H), and 2.26 (DD, J=13.8 and 7.2 Hz, 1H), was 2.76 (DD, J=13.8 and 7.2 Hz, 1H), 2,48 (s, 3H), 1,17 (s, N).

Regulation NRTR-β provides a method of modulating the activity of angiopoietin receptor-type tyrosine kinase Tie-2 and thereby mediates pathological conditions where angiogenesis mistakenly regulated by the human body. Compounds according to this invention serves as a means for regulation of angiogenesis. Essentially, the present invention is directed to several unmet medical needs, among which inter alia:

1) develop compositions that are effective as inhibitors of the protein human tyrosinosis beta (NRTR-β); and through this ensure development of a method of regulating angiogenesis in case of violation, in which angiogenesis is promoted;

2) develop compositions useful as inhibitors of protein person tyrosinosis beta (NRTR-β); and through this ensure development of a method of regulating angiogenesis in violation; and

3) develop compositions useful as inhibitors of protein person tyrosinosis beta (NRTR-β); and through this ensure development of a method of regulating angiogenesis in case of violation, in which angiogenesis is understated.

For the present invention, the term "regulate" is defined according to its generally accepted dictionary meanings. So, the meaning of the term "regulate" includes, but is not limited to, increase the level of regulation or lower the level of regulation, to fix, to bring order or uniformity, manage or direct a variety of ways. In one aspect, the antibody can be used in the method of treatment of disorders with increased angiogenesis" or "disorders with reduced angiogenesis. Used the term "violation with increased angiogenesis is a violation, which includes unwanted or increased angiogenesis in a biological manifestation of diseases, disorders and/or state; in the biological cascade leading to the violation; or as a symptom of disturbance. Similarly, "violation reduced angiogenesis is a violation, which includes unwanted or reduced angiogenesis in a biological manifestations. This "involvement" angiogenesis in violation with increased/decreased angiogenesis include, but are not limited to, the following:

1. Angiogenesis as a "cause" of a violation or biological manifestations, regardless of whether the level of angiogenesis higher or lower genetically, due to infection, autoimmunity, trauma, biomechanical reasons, lifestyle, or for some other reasons.

2. Angiogenesis as part of the observable symptoms of disease or disorders. Ie, the disease or disorder can be measured in terms of increase or decrease angiogenesis. From a clinical point of view, angiogenesis indicates the disease; however, angiogenesis is not necessarily a sign (token)" diseases or disorders.

3. Angiogenesis is part of the biochemical or cellular cascade that leads to the development of diseases or disorders. In this regard, regulation of angiogenesis may break (interrupt) cascade and can control the disease. Non-limiting examples of regulated angiogenesis disorders that can be treated according to this invention described in the present description below.

Ready-made medicine what forms

The present invention also relates to compositions or finished dosage forms that contain inhibitors of potassium channel Kvl.5 according to the present invention. In General, the compositions of this invention contain

a) an effective amount of one or more phenylalaninol acids and their salts according to this invention, which are effective as inhibitors of the protein human tyrosinosis beta (NRTR-β); and

b) one or more fillers.

For the present invention, the term "filler" and "carrier" are used interchangeably throughout the description of the present invention and these terms define here as "ingredients, which are used in the practice of creating a reliable and effective composition."

For the originator of this recipe it is obvious that the fillers are mainly used to ensure the delivery of safe, stable and functional pharmaceuticals, fulfilling a role not only part of the overall filler for delivery, but also the means to achieve effective absorption of the active ingredient in the recipient. The filler can act as a simple and direct inert filler, or used in the description of the filler may be part of a pH-stabilizing systems or coatings providing DOS is avko ingredients safely in the stomach. The originator of this recipe can also take advantage of the fact that the compounds according to this invention have an increased cellular activity, improved pharmacokinetic properties, and improved bioavailability when administered orally.

Non-limiting examples of compositions according to this invention include

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

b) one or more fillers.

Another variant according to the invention includes the following songs:

a) from about 0.01 mg to about 100 mg of one or more phenylalaninol acids according to this invention, and

b) one or more fillers.

Additional variant according to the present invention includes the following songs:

a) from about 0.1 mg to about 10 mg of one or more phenylalaninol acids according to this invention, and

b) one or more fillers.

Used in the description, the term "effective amount" means a quantity of one or more phenylalaninol acids, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result." The effective amount may vary according to factors known in the field, such as pathologizes the condition, age, sex and body weight of the human or animal to be treated. Although specific regimens medicines can be described in the description of the examples, the person skilled in the art it is obvious that for optimal therapeutic response regimen of the drug may change. Therefore, it is impossible to determine the exact "effective amount". For example, you can enter multiple small doses of medicines, repeated at intervals of time daily, or the dose may be proportionally reduced as shown acute need of therapeutic situation. In addition, the compositions of this invention can be entered as often as necessary to achieve a therapeutic amount.

Method of use

The present invention relates to a method of regulating angiogenesis in humans, comprising the administration to a human one or more of the inventive compounds.

One example of the proposed methods include a method of treating regulated by angiogenesis disorder of a subject, in which regulated angiogenesis violation constitutes a violation with increased angiogenesis, and that the breach is selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, Seth is Fox, pseudoxanthoma elastic, Paget's disease, occlusion of the venous vessels, occlusion of the artery, occlusion of the carotid artery, chronic uveitis/vitrite, mycobacteriosis, Lyme disease, systemic lupus erythematosus, juvenile retinopathy, disease ILSA, disease behceta, infections causing retinitis and chorioidea, presumed ocular histoplasmosis, a disease of the best, myopia, congenital holes in the optic nerve head, Stargardt disease; clinical syndrome that includes inflammation of the peripheral retina and ciliary circle, chronic retinal detachment, syndrome of increased viscosity, toxoplasmose, traumatic complications of laser treatment; diseases associated with redness; and proliferating vitreoretinopathy.

Another example of the proposed methods include a method of treating regulated by angiogenesis disorder of a subject, in which regulated angiogenesis violation constitutes a violation with increased angiogenesis, and that the breach is selected from inflammatory bowel disease such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, illness Rendu-Weber-Osler or hereditary hemorrhagic telangiectasia, solid tumors or tumors of blood and syndrome acquired immune de is icita.

An additional example of the proposed methods include a method of treating regulated by angiogenesis disorder of a subject, in which regulated angiogenesis violation constitutes a violation of reduced angiogenesis and selected from ischemia in skeletal muscle and infarction, stroke, coronary heart disease, peripheral vascular disease (arteries).

The following additional example of the proposed methods include a method of vascularization of ischemic tissue. Used in the description, the term "ischemic tissue" means tissue that is deprived of necessary and sufficient blood flow. Examples of ischemic tissue include, but are not limited to, a fabric, which has no necessary and sufficient blood supply, which is the result of myocardial infarction and cerebral, mesenteric ischemia or ischemia of the extremities or the result of occlusion of a vessel or stenosis. In one example, the interruption of the supply oxygenated blood may be caused by occlusion of the vessel. Occlusion of blood vessels can be caused by atherosclerosis, trauma, surgery, disease and/or other etiology. Within the methods of treatment according to this invention also includes the treatment of ischemic skeletal muscle and myocardium, stroke, ischemic heart disease, peripheral vascular disease (arteries).

Another example of rscr the mentioned methods includes a method of recovery (healing) tissue. Used in the description, the term "tissue repair" means the stimulation of healing (recovery), regeneration, growth and/or tissues, including but not limited to, wound healing or tissue engineering. The person skilled in the art it is obvious that for tissue repair requires the formation of new blood vessels. In turn, the fabric can be damaged, including, but not limited to, personal injury or the presence of conditions including arthritis, osteoporosis and other disorders of the skeleton, and burns. The fabric can be damaged by injuries due to surgical intervention, exposure, education, lacerations, exposure to toxic chemicals, viral or bacterial infections or burns. Fabric, requiring such restoration, includes nezazhivayuschie wounds. Examples nezazhivayuschie RAS include nezazhivayuschie skin ulcers resulting from diabetic pathology; or fractures, which quickly are not consolidated.

The proposed compounds are also suitable for use for effects on tissue repair in the context of methods for controlled (controlled) tissue regeneration (GTR). Such methods currently used by specialists in this area to accelerate healing of wounds after invasive chirurgiche the fir operations.

Another further example of the disclosed methods includes a method of promoting repair of tissue, characterized by increased tissue growth during the process of tissue engineering. Used in the description, the term "tissue engineering" is defined as the development, design (design) and production of biological prostheses, in combination with the use of synthetic or natural materials to build or replace tissues or organs of the body. Thus, the present methods can be used for expansion and growth of human tissues outside of the organism, with subsequent implantation to repair or replace diseased tissues. For example, antibodies can be used to stimulate growth of the samples substitute full-thickness skin graft (transplant), which is used as a therapy in the treatment of burns.

Other examples of the disclosed methods relevant to tissue engineering include containing cells or cell-free devices that induce the regeneration of functional human tissues during implantation in a place that requires regeneration. As discussed in the present description, the biomaterial - guided tissue regeneration, can be used to stimulate the growth of bone tissue in, for example, periodontal disease. Thus,antibodies can be used to stimulate growth of the reconstructed tissues, collected in the spatial (volumetric) configurations at the site of a wound or other tissue, requiring such restoration.

Other examples of the disclosed methods relevant to tissue engineering, are that disclosed in the present description, the compounds may be included in external or internal devices containing human tissue intended to replace the functioning of the diseased internal tissues. This approach enables the selection of cells from the body, placing them in the structural matrix and the implantation of a new system inside the body or the use of the system outside the body. For example, antibodies can be included in a lined (saturated) by the cells of the vascular graft to stimulate growth of the cells contained in the graft. It seems that the methods according to this invention can be used to stimulate the recovery, regeneration and tissue engineering in such parts of the human body as cartilage and bone tissue of the Central nervous system, muscle, liver and cells of the islet of Langerhans (producing insulin).

The present invention also relates to the use of disclosed phenylalaninol acids to obtain drugs to stimulate growth samples substitute full-thickness skin graft (graft is (a).

The present invention also relates to the use of disclosed phenylalaninol acids according to this invention for obtaining a medicinal product for use, for effects on tissue repair in the context of methods for controlled tissue regeneration (GTR).

Disclosed compounds can be used to obtain one or more drugs, non-limiting examples of these medicines are

Medicines for the treatment of regulated angiogenesis disorder of a subject, in which regulated angiogenesis violation constitutes a violation with increased angiogenesis.

Medicines for the treatment of regulated angiogenesis disorder of a subject, in which regulated angiogenesis violation constitutes a violation with increased angiogenesis, selected from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, illness Rendu-Weber-Osler or hereditary hemorrhagic telangiectasia, solid tumors or tumors of the blood system and the acquired immune deficiency syndrome.

Medicines used for engineering tissues, thus inducing increased tissue growth.

Medicines for the treatment of an adjustable what johaneson disorder of a subject, this regulated angiogenesis violation constitutes a violation of reduced angiogenesis.

Methods

Screening tests using a model of angiogenesis in vitro and in vivo

Antibodies according to this invention can be skanirovaniya in the analysis of angiogenesis, which are known in this field. Such assays include in vitro, when measured surrogates growth of blood vessels in cultured cells or the formation of vascular structures from tissue explants and in vivo analyses, when measuring the growth of blood vessels directly or indirectly (Auerbach. R., et al. (2003). Clin Chem 49, 32-40, Vailhe. C., et al. (2001). Lab Invest 81, 439-452).

1. Model of angiogenesis in vitro

The in vitro model, which is suitable for use in the present invention, use of cultured endothelial cells or tissue explants and measure the effectiveness of the response of the "angiogenic cells or the formation of blood capillarity structures. Non-limiting examples of analysis of angiogenesis in vitro include, but are not limited to, migration and proliferation of endothelial cells, the formation of capillaries, sprouting endothelial cells, a sample of Explant, aortic rings and a sample of the aortic arc of chicken.

2. Model of angiogenesis in vivo

In vivo means or antibodies that are suitable for use in the present who eat the invention, injected locally or systemically in the presence or in the absence of growth factors (i.e. VEGF or angiopoietin 1) and measure the growth of new blood vessels by direct observation or by measuring surrogate marker, such as hemoglobin or fluorescent indicator. Non-limiting examples of assays of angiogenesis in vivo include, but are not limited to, analysis chorioallantoic membrane of a chicken, the analysis of angiogenesis in the cornea and analysis of Matrigel® plug (thrombus).

3. Methods for determining the vascularization of ischemic tissue

To determine whether the tissue is a risk to be affected by ischemia as a result of undesirable occlusion of the vessel, fit standard methods. For example, diseases of the myocardium, these methods include various imaging techniques (e.g., using a radioactive label, x-rays; MRI magnetic resonance imaging) and physiological tests. Therefore, the induction of angiogenesis as an effective way of preventing or reducing symptoms of ischemia in the tissues affected or a risk to be affected due to occlusion of the vessel, can be easily defined.

Specialist in the use of standard methods can measure the vascularization of tissue. Non-limiting examples of measurement of vascularization in a subject include SPECT(single photon emission computed tomography, The mect); PET (positron emission tomography, PET); MRI (magnetic resonance imaging, MRI); and their combination, by measuring blood flow in the tissue before and after treatment. Angiography can be used to estimate the (macroscopic) the presence of blood vessels in the tissue. Histological assessment can be used to quantify the presence of blood vessels at the level of small vessels. These and other methods are discussed in Simons, et al., "Clinical trials in coronary angiogenesis," Circulation, 102, 73-86 (2000).

In the following Table VIII provides non-limiting examples of inhibitors HPTPβ and RTRV and relevant activities of inhibiting β (IC50μm) and RTRW (IC50microns).

Table VIII
Connectionβ IC50mcmRTRV IC50mcm
A10,0001570,722
(S)-{4-[2-(4-utiltity-2-yl)-2-phenylacetylamino)ethyl]phenyl}sulfamic acid
A24-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid0,0047,12
A3tert-butyl ether ({1-[1-(5-utiltity-2-yl)-(S)-2-(4-sulfonylarenes)ethylcarbamate]-(S)-2-phenylethyl}methylcarbamate acid0,0317,05

A4tert-butyl ether ({1-[1-(5-phenylthiazol-2-yl)-(S)-2-(4-sulfonylarenes)ethylcarbamate]-(S)-2-phenylethyl}methylcarbamate acid<5×10-80,754
A54-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamide-2-(2-phenylthiazol-4-yl)}fenilalanina acid<5×10-80,905
A64-{(S)-2-(4-Utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid0,0001620,49

A74-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(thiazol-2-yl)ethyl}fenilalanina acid0,0061,02
A84-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4-methylthiazole-2-yl)ethyl}phenyl is altamirova acid 0,0010,48
A94-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4-propertiesa-2-yl)ethyl}fenilalanina acid0,00011,03

is 0.00020,708
A104-{(S)-2-(4-tert-Butylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-ethyl}fenilalanina acid
A114-{(S)-2-(4-Cyclopropylmethyl-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid0,000010,3
A124-{(S)-2-(4-Cyclohexylthio-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid<5×10-81,78

0,0010,31
A134-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-ethyl}fenilalanina acid
0,00011,12
A144-{(S)-2-(4-Ethyl-5-methylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino) -3-phenylpropanamide]ethyl}-fenilalanina acid
A154-{(is)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(2,2,2-triptorelin)thiazol-2-yl]ethyl}fenilalanina acid 0,00031,63

A164-{(S)-2-[(S}-2-(Methoxycarbonylamino)-3-phenylpropanamide)-2-[4-(3,3,3-cryptochromes)thiazol-2-yl]ethyl}fenilalanina acid0,000080,12
A174-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(methoxymethyl)thiazol-2-yl]ethyl}fenilalanina acid0,0010,64
A184-{(S)-2-(4-(Etoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acidis 0.00020,07

A190,00030,81
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(5-phenylthiazol-2-yl)ethyl}fenilalanina acid
A20<5×10-80,39
4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-ethyl}fenilalanina acid
<2×10-60,597
A214-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(4-phenylthiazol-2-yl)ethyl}fenilalanina acid

A224-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(thiophene-2-yl)thiazol-2-yl]ethyl}fenilalanina acid<5×10-80,99
A234-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(thiophene-3-yl)thiazol-2-yl]ethyl}fenilalanina acid0,000090,44
A244-{(S)-2-(5,6-Dihydro-4H-cyclopent[d]thiazol-2-yl)-2-[(S)-
2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid
0,0010,18

A254-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenyl what propanamide]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}fenilalanina acid 0,00040,089
A264-{(S)-2-[4-(5-Chlorothiophene-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}fenilalanina acid<5×10-80,37
A274-{(S)-2-[(S)-2-(Ethoxy-carbylamine)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid0,000140,68

A284-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(2-utiltity-4-yl)ethyl}fenilalanina acid0,00011,01
A294-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-(2-methylthiazole-4-yl)ethyl}fenilalanina acid0,0011,16
A304-{(S)-2-(2-Cyclopropylmethyl-4-yl)-2-[(S)-2-(methoxycarbonylamino) -3-phenylpropanamide]ethyl}fenilalanina acidis 0.00021,35

A314-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxycarbonylamino) -3-phenylpropanamide]-ethyl}fenilalanina acid0,000082,54
A32 4-{(S)-2-[2-(tert-Butylsulfonyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}-fenilalanina acid0,0021,21
A334-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamide]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid7×10-70,508

A344-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid5×10-80,604
A354-{(S)-2-[2-(3-Chlorothiophene-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylsulfanyl the Wai acid <5×10-80,95
A364-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(3-methylthiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid<5×10-81,09

0,00045
A374-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino) -3-phenylpropanamide]-ethyl}fenilalanina acid
A384-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(pyrazin-2-yl)thiazol-4-yl]ethyl}fenilalanina acid0,0030,295
A394-[(S)-2-((S)-2-Acetamido-3-phenylpropanamide)-2-(4-utiltity-2-yl)ethyl]fenilalanina acid0,0011,97

A404-[(S)-2-((S)-2-Acetamido-3-phenylpropanamide)-2-(4-tert-butylthiazole-2-yl)ethyl]fenilalanina acid0,00031,52
A414-{(S)-2-((S)-2-Acetamido-3-phenylpropanamide)-2-[4-(thiophene-3-yl)thiazol-2-yl]ethyl}fenilalanina acid0,000241,16
A4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl the Mino)-3-methylbutanoate]-2-(4-utiltity]-2-yl)ethyl}-fenilalanina acid 0,0061,06

A43(S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid0,02816,0
A44(S)-4-{2-(4-Utiltity-2-yl)-2-[2-(methoxycarbonylamino)-acetamido]ethyl}fenilalanina acid0,0205,26
A454-{(S)-2-(4-Utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanoate]ethyl}fenilalanina acid0,0031,03

A464-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentylamino]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid0,0010,48
A4-{(S)-2-(4-Utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentylamino]ethyl}fenilalanina acid0,00030,07
A48 motorway4-((S)-2-(4-Utiltity-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)-acetamido]-3-phenylpropanamide}ethyl)-fenilalanina acid0,00030,299

A4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-4-methylpentylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid<5×10-80,52
A50(S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-utiltity-2-yl)ethyl}-fenilalanina acid0,02816,0
A51 motorwaytert-Butyl ether [1-(S)-(phenylthiazol-2-yl)-2-(4-sulfonylarenes)ethyl]carbamino acid0,04933,02
A52(S)-4-(2-(4-Methylthiazole-2-yl)-2-evalidator)fenilalanina acid0,11250
A53(S)-4-(2-(4-Utiltity-2-yl)-2-evalidator)fenilalanina acid0,085142

A54(S)-4-{2-[4-(hydroxymethyl)thiazol-2-yl]-2-evalidator}fenilalanina acid0,26650
A55(S)-4-{[2-(4-Etoxycarbonyl)thiazol-2-yl]-2-evalidator}fenilalanina acid0,58444,9
A56(S)-4-(2-(4-Phenylthiazol-2-yl)-2-evalidator)fenilalanina to the slot 0,04282,3
A574-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-evalidator)fenilalanina acid0,11040,1

A58 motorway4-((S)-2-(4-(2,4-Acid)thiazol-2-yl)-2-evalidator) fenilalanina acid0,086to 43.1
A59(S)-4-(2-(4-Sensitiza-2-yl)-2-evalidator)fenilalanina acid0,11338,2
A60(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-evalidator)fenilalanina acid0,13250
A614-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxidul)thiazol-2-yl)-2-evalidator)fenilalanina acidwas 0.138to 38.3

A62(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-evalidator)fenilalanina acid0,098a 50.5
A63(S)-4-(2-(4-(Bifen-4-yl)thiazol-2-yl)-2-evalidator)fenilalanina acid0,38128,6
A(S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazole-4-yl)ethyl)fenilalanina acid0,03318,9
A65(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-propertiesa-2-yl)ethyl)fenilalanina acid0,0435,6

A66(S)-4-(2-(tert-Butoxycarbonylamino) -2-(4-tert-butylthiazole-2-yl)ethyl)fenilalanina acid0,02750
A67(S)-4-(2-(tert-Butoxycarbonylamino) -2-(4-(methoxymethyl)TIA the ol-2-yl)ethyl)fenilalanina acid 0,1827,6
A68(S)-4-(2-(tert-Butoxycarbonylamino) -2-(4-(hydroxymethyl)thiazol-2-yl)ethyl)fenilalanina acid0,64431,6

A(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)thiazol-2-yl)ethyl)fenilalanina acid0,16750
A70(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(2-(2-methoxy-2-oxoethylidene)-2-oxoethyl)thiazol-2-yl)ethyl)fenilalanina acid0,13250
A71(S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-Pavlogradugol-4-yl)ethyl)fenilalanina acid0,5559,12

A72(S)-4-(2-(tert-Butoxycarbonylamino) -2-(5-phenylthiazol-2-yl)ethyl)fenilalanina acid0,30811,4
A73 motorway4-((S)-2-(tert-Butoxycarbonylamino) -2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)fenilalanina acid0,25311,8
A744-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophene-3-yl)thiazol-2-yl)ethyl)fenilalanina acids is 0,04514,6

The model of the hind limb of rats used for evaluation of angiogenic characteristics of new inhibitors β. In particular, the denition is also increased if the blood flow in the collateral-dependent region of the limb after ischemia in the case when the animal is in a state provoked by physical exertion. Specific connection, subject to assessment in this example is (4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid.

Model for the development of collaterals on the hind limb of the rat

The selection of the animal

To achieve the ability to control the variables that affect the execution of running on the simulator, rats are introduced to the nature of the tests on the simulator ("treadmill") one week before surgery. It was in running rats on the simulator during intermittent races, the components of the daily 5 minutes, at speeds in the range of 20-25 m/s and an angle of elevation of 7°. Prior experience has shown that animals that are not performed properly running (on the simulator) during the trial period, were also bad and during the subsequent definitions bloodstream, possibly affecting the measurement of the collateral circulation. Based on this experience, the rat, the cat who are not performed correctly, this exercise during the evaluation period, in this study not included.

Surgical techniques

Conduct initial surgery to cause ischemia of the hind limbs and implanted osmotic pumps basically as described previously, with minor modifications. Briefly, adult rats-males line Sprague-Dawley (weight 340-390 g) is first placed in the chamber for induction of anaesthesia with a flow rate O21 l/min and content izoflurana (ISO) at 2.5 percent, the temperature of the body support using heating pads under the camera. After induction the animals move on surgical litter and continue anesthesia with anesthesia apparatus of the open type. Lamp for heating position above the rat and to control body temperature in the animal host rectal probe. Groin bilateral kopiruyut and spend processing-cleaning brush, alternating the Betadine and alcohol (3×), and served a rat sterile surgical towel. The left femoral artery naked by dissection of the skin and then the artery are ligated in two positions at a distance of 1 cm distal to the inguinal ligament and proximal femoral circumflex artery. The skin is sewn together, using either a sewing machine for skin tissue, or Vetbond. The same procedure is repeated on the right side. Animals in groups with continuous infusion had on the OS Alzet 2ML2 (already seasoned), inserted in SubQ space on their backs, which were delivered or 15 mg/kg/day or 5 mg/kg/day 4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid, or filler, depending on the processing teams. Animals in the group with the processing of VEGF were subjected to additional operations on placement osmotic pump (Alert™ model # 2004) on their neck. Prior to implantation of osmotic pumps filled with a solution of VEGF165 at the dose of 15 mg/kg/day and immersed overnight in a laboratory glasses with sterile saline solution in a water thermostat (37°C). Attach extra long RE catheters coated with PPG (polyethylene glycol Aldrich # 20-235-5), using sterile technique and in accordance with the manufacturer's instructions in the afternoon the period preceding the operation. For placement of the pump make the incision, exposing the right jugular vein, punch pass in SubQ on the right side of the neck to the back and the pump is placed in the resulting pocket SubQ. Vessel are ligated with 4-0 silk, with an incision in the vessel distal to the site and the catheter from the osmotic pump is passed in the direction of the flow (approximately 2 cm) and fix the second node. The skin is stitched in the same way as above.

The evaluation of blood flow

Placement of the catheter

Two weeks after surgery ligating a rat subjected to the second stroihidrotech operations consisting in placing resides catheters for measurement of the microspheres. Rats anaesthetize, as described above. Animal kopiruyut, dissect and at each point of entry (catheter) put the EMLA cream. First an incision in the longitudinal direction on the ventral base of the tail, using the blade 10. Wedge RE catheter is inserted approximately 3 cm ventral tail artery and fasten securely. Then the end of the catheter wrap around tail and punch pass in SubQ on the back, leaving between the bodies of the blades. After catheterization tail artery with an incision midline of the neck, exposing the left carotid artery for obtenerse catheterization. Klinoobraznyj PE 50 catheter was placed 3 cm in the carotid artery and the distal end are laid in SubQ, leaving between the bodies of the blades. Neck stitch or using a sewing machine for skin tissue, or Vetbond and put the EMLA cream. The output is sutured around the catheter purse string suture. The ends of the catheters close cauterization and rats provide the ability to recover from anesthesia for at least 4 hours.

Protocol testing on the simulator and measurement of microspheres

For measurements of blood flow in rats placed on a treadmill and catheters connected to the extension pipe system using incoming into each other connectors 22 size. D. the I selection of microspheres and measurement of blood pressure the tail artery catheter connected to a syringe (covered with twin or heparin), associated "T" Ed with suction pump and a pressure sensor. The carotid artery catheter is used for injection of microspheres. The rat started running with a speed of 20 m/min and at an angle of elevation of 7°. After 1 minute of Jogging include the pump with a feed rate of 0.5 ml/min, after ten minutes in the line of the carotid artery inject 0.5 ml (1×106spheres/ml) fluorescent microspheres with a further 0.5 ml of washing for 30 seconds. The pump has been adjusted to a stop for 90 seconds. Treadmill stop extending the system lines and replace line animal washed, and animals provide the opportunity to relax. The syringe and remove line from the pump and the reference blood sample is placed in a labeled tube for processing. Removed the syringe and extension system lines washed three times with 2% tween, loss (washing water) wash in a test tube with sample breakdown of the blood. A new syringe and a new line is placed on the pump and the procedure is repeated with the animal running at a faster speed (25 m/min), and inject microspheres of a different color. Upon completion of the second race the animal is subjected to euthanasia by 0.3 ml Buthaneasia.

Collection and analysis of tissue

After euthanasia tissue extract, trim (put in order), weighed, recorded and placed into a labeled test tubes for processing. Samples are the following, both right-and left the party: Soleus, Plantaris, Gastroc, Red Quads and kidneys. Blood samples digested by 0.75 ml n. CON during the night. The tissue is digested by the 5 ml of 4n. CON during the night. Then the sample was filtered in vacuum, using an 8-micron polycarbonate filters, and filter paper are placed in a labeled test tube with 1 ml of 2-ethoxyethylacetate (EEA). After digestion over night samples are read using black polypropylene tablet fluorimetry configured to wavelengths 495-506 and 534-552. Exactly 270 ml samples will pipeinput in each well. Any additional demand for breeding noted in form for recording data of the animal, and with this in mind, breeding introduced the amendment in fluorescence raw data. The raw data is converted into the bloodstream, expressed in units of ml/min/100 g tissue, according to the equation ({(fluorescence tissue/mass tissue d)/(Fluorescence of the reference blood samples/sample Rate blood ml/min)}*100 g). Values of blood flow to the tissues of the left and right extremities average, obtaining a single value for each animal, because an even distribution between the kidneys.

In this study, the group with the processing of VEGF had expected a significant improvement in GPS blood flow compared with the control group, the treated filler. Based on geodinamica the fir data, in blood pressure-treated groups there is a just noticeable difference between any of the groups. These pressures, in fact, lower than in groups with the processing of VEGF and/or groups with the processing of filler, which indicates that the perfusion pressure in the GPS should also be quite low. This means that any changes that are measured in the bloodstream, are real, are not an artifact of the calculation. Blood flows as a result of continuous infusion in SubQ showed significant improvement in blood flow in the calf area than filler for two doses (5 mg/kg/day and 15 mg/kg/day) connections. The data also found that a lower dose (5 mg/kg/day) does not cause the maximum response of VEGF, suggesting that there is a dose dependency in the case of this connection.

The results of this experiment are summarized below.

Table IX
Blood pressure and heart rate
Continuous infusion in SubQ
VEGF 15 µg/kg/dayFillerLow 5 m is/kg/day High 15 mg/kg/dayANOVA p value
Blood pressure
To load146±2,5141±3,1132±3,9137±4,5Without specification of Wt (NS)
Load156±2,3151±4,6142±3,2144±4,6Without specifications Wt
After loading149±2,8148±5,3135±3,1133±3,7*<0,05
Heart rate
To load452±29,5463±18,1429+19,8 428±13,5Without specifications Wt
Load489±10,0577±15,2487+10,1456+13,0Without specifications Wt
After loading476±18,1468+15,9465+18,8462±14,8Without specifications Wt
N1081010
Data are expressed as mean ±CO(SE). ANOVA analysis using the test tuks; * significantly different from the filler,reliably excellent p<0,05 relative VEGF

Table X
Blood pressure and body weight
Continuous infusion in SubQ
VEGF 15 µg/kg/dayNab is lntel Low 5 mg/kg/dayHigh 15 mg/kg/dayANOVA p value
The bloodstream
During exercise
Calf
area (GPS)
76±1,1*53±1,469±2,0*75±1,7*<0,001
Kidney296±32,3248±24,9318±30,1319±37,9Without specifications
Weight
Initial body weight372±3,6369±2,7365±4,8364±4,8Final body weight421±5,5411±5,5413±5,6409±5,5Without specifications
N10898
data are expressed as mean ±CO(SE). ANOVA analysis using the test tuks; * significantly different from filler;reliably excellent p<0,05 relative VEGF

It should be borne in mind that the dimensions and the values specified here are not strictly limited to the quoted exact numerical values. Instead, unless otherwise noted, each such dimension is assumed to mean as recited value and a functionally equivalent range surrounding that quoted value. For example, the dimension indicated as "40 mm"is assumed to mean "about 40 mm"

All documents cited in the section 'Detailed description of the invention', to the relevant extent, included in the present description by reference; the citation of any document is not to be construed as an acknowledgment that he is a prior art in which the compared of the present invention. In the sense that any meaning or definition of a term in this document contradicts any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document will govern.

Although illustrated and described above specific embodiments of the invention, the experts in this field should be apparent, various modifications of the invention and make various other changes, not beyond being and scope of the invention. Therefore understood that this invention covers all such changes and modifications that are within the volume (protection) of the invention, formulated in the below claims.

1. The compound having the formula

where R represents a substituted or unsubstituted thiazolino group having the formula
or
R4and R5each independently selected from
i) hydrogen;
ii) substituted or unsubstituted C1-C6linear, With3-C6branched or3-C6cyclic alkyl;
iii) substituted or unsubstituted phenyl;
iv) substituted or unsubstituted heteroaryl containing 5 or 6 the volumes in the ring and 1 or 2 heteroatoms, where heteroatoms selected from nitrogen, oxygen, sulfur and combinations thereof; or
R4and R5can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
these substituents independently selected from one or more groups selected from C1-C6linear, With3-C6branched or3-C6cyclic alkyl, halogen, hydroxyl or cyano;
R6represents a group selected from
i) hydrogen;
ii) substituted or unsubstituted With1-C6linear, With3-C6branched or3-C6cyclic alkyl;
iii) substituted or unsubstituted phenyl or
iv) substituted or unsubstituted heteroaryl containing 5 or 6 atoms in the ring and 1 or 2 heteroatoms, where the heteroatoms selected from nitrogen, oxygen, sulfur and combinations of them;
moreover, these substituents independently selected from one or more groups selected from C1-C6linear, With3-C6branched or3-C6cyclic alkyl, halogen, hydroxyl or cyano;
R1selected from
i) hydrogen;
ii)1-C6linear or3-C6branched alkyl;
iii) substituted or unsubstituted phenyl or
iv) substituted or unsubstituted benzyl;
moreover, these substituents, the independent is IMO selected from one or more groups, selected from C1-C6linear, With3-C6branched or3-C6cyclic alkyl, halogen, hydroxyl or cyano;
R2selected from
i)1-C6linear or3-C6branched alkyl or
ii)1-C6linear or3-C6branched alkoxy;
R3represents hydrogen or C1-C4linear or3-C6branched alkyl.

2. The compound according to claim 1, where R has the formula

R5represents hydrogen and R4represents hydrogen, substituted or unsubstituted C1-C6linear, With3-C6branched or3-C6cyclic alkyl, or substituted or unsubstituted phenyl.

3. The compound according to claim 1, where R4selected from groups having the formula-CH2F, -CHF2, -CF3, -CH2CF3, -CH2CH2CF3, -CH2Cl, -CH2HE, -CH2CH2HE, 2,2-diverticulectomy, 4-chlorocyclohexane, phenyl, 3,4-dimetilfenil, 4-tert-butylphenyl, 4-cyclopropylethyl, 3-chlorphenyl, 4-chlorphenyl, 3,4-dichlorophenyl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, and thiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl.

4. The compound according to claim 1, where R6selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl, 2-ftoheia, 2-chlorphenyl, 2-methylphenyl, 3-ftoheia, 3-chlorphenyl, 3-methylphenyl, 4-ftoheia, 4-chlorphenyl, 4-methylphenyl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-silt, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl.

5. The compound according to claim 1, where R1represents hydrogen, isopropyl or benzyl.

6. The compound according to claim 1, where R3represents hydrogen or methyl.

7. The connection according to claim 6, where R3represents hydrogen.

8. The compound having the formula
i)
ii)
iii)
iv)
v)or
vi)
where R2selected from
i) C1-C6linear or3-C6branched alkyl or
ii) C1-C6linear or3-C6branched alkoxy;
R4and R5each independently selected from
ii) substituted or unsubstituted C1-C6linear, With3-C6branched or3-C6cyclic alkyl;
iii) substituted or unsubstituted phenyl;
iv) substituted or unsubstituted heteroaryl containing 5 or 6 atoms in the ring and 1 or 2 heteroatoms, where the heteroatoms selected from nitrogen, oxygen, sulfur and combinations thereof; or
R4and R5can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms;
these substituents independently selected from one or more groups selected from C1-C6linear, With3-C6branched or3-C6cyclic alkyl, halogen, hydroxyl or cyano; and
R6selected from
i) hydrogen;
ii) substituted or unsubstituted With1-C6linear, With3-C6branched or3-C6cyclic alkyl;
iii) substituted or unsubstituted phenyl and
iv) substituted or unsubstituted heteroaryl containing 5 or 6 atoms in the ring and 1 or 2 heteroatoms, where the heteroatoms selected from nitrogen, oxygen, sulfur and combinations of them;
these substituents independently selected from one or more groups selected from C1-C6linear, With3-C6branched or3-C6cyclic alkyl, halogen, hydroxyl and and cyano.

9. The compound according to claims 1-7, where the compounds are salts containing anions selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarata citrate, or a cation selected from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

10. The use of compounds according to claims 1 to 8 to obtain drugs for the treatment of diseases selected from diabetic retinopathy, macular degeneration, occlusion of the venous vessels, occlusion of the artery, occlusion of the carotid artery, chronic uveitis/vitrite, mycobacteriosis, chronic retinal detachment, syndrome of increased viscosity, toxoplasmosis, trauma and effects of laser treatment; diseases associated with redness; proliferating vitreoretinopathy, ischemia of skeletal muscles and myocardium, stroke, ischemic heart disease, peripheral vascular disease (arteries).

11. The use of compounds according to any one of claims 1 to 8 to obtain drugs for regulating angiogenesis, vascularization of ischemic tissue, stimulating the growth of samples substitute full-thickness skin graft (transplant) or stimulation of repair tissue in the context of the methods of managed rigenerazione (GTR).

12. The compound according to claims 1-8, suitable for treatment of a condition selected from diabetic retinopathy, macular degeneration, occlusion of the venous vessels, occlusion of the artery, occlusion of the carotid artery, chronic uveitis/vitrite, mycobacteriosis, chronic retinal detachment, syndrome of increased viscosity, toxoplasmosis, trauma complications of laser treatment; diseases associated with redness; and proliferating vitreoretinopathy, ischemia of skeletal muscles and myocardium, stroke, ischemic heart disease, peripheral vascular disease (arteries).

13. The compound according to claims 1-8, suitable for regulating angiogenesis, vascularization of ischemic tissue, stimulating the growth of samples substitute full-thickness skin graft (transplant), stimulation of repair tissue in the context of methods for controlled tissue regeneration (GTR).

14. A compound selected from
4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamide-2-(2-phenylthiazol-4-yl)}phenylalaninol acid;
4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}peninsul the amine acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(thiazol-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(4-methylthiazole-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(4-propertiesa-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-(4-tert-butylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(4-cyclopropylmethyl-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(4-cyclohexylthio-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(4,5-dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(4-ethyl-5-methylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(2,2,2-triptorelin)thiazol-2-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl, propanamide)-2-[4-(3,3,3-cryptochromes)thiazol-2-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[4-(2,2-diversicolor)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(labels shall imethyl)thiazol-2-yl]ethyl}phenylalaninol acid;
4-{(S)-2-(4-(etoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(5-phenylthiazol-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-(4-tert-butylthiazole-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(4-ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[4-(3,4-dimetilfenil)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[4-(4-chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(4-phenylthiazol-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(thiophene-2-yl)thiazol-2-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[4-(thiophene-3-yl)thiazol-2-yl]ethyl}phenylalaninol acid;
4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropionamide]ethyl phenylalaninol acid;
4-{(S)-2-(5,6-dihydro-4H-cyclopent[d]thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(45,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[4-(5-chlorothiophene-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(ethoxycarbonyl)-3-phenylpropanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(2-utiltity-4-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(2-methylthiazole-4-yl)ethyl}phenylalaninol acid;
4-{(S)-2-(2-utiltity-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(2-isopropylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-(2-cyclopropylmethyl-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-{2-[(4-chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[2-(tert-butylsulfonyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropionamide]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-fossabanda]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[2-(3-chlorothiophene-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl is amino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(3-methylthiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{[(S)-2-(2-(furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(2-methylthiazole-4-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-(2-pyrazin-2-yl)thiazol-4-yl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamide]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-[(S)-2-((S)-2-acetamido-3-phenylpropanamide)-2-(4-utiltity-2-yl)ethyl]phenylalaninol acid;
4-[(S)-2-((S)-2-acetamido-3-phenylpropanamide)-2-(4-tert-butylthiazole-2-yl)ethyl]phenylalaninol acid;
4-{(S)-2-((S)-2-acetamido-3-phenylpropanamide)-2-[4-(thiophene-3-yl)thiazol-2-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutanoate]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
(S)-4-{2-[2-(methoxycarbonylamino)ndimethylacetamide]-2-(4-thiophene-2-iltiazem-2-yl)ethyl}phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[2-(methoxycarbonylamino)-acetamido]ethyl}phenylalaninol acid;
4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanoate]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(tert-buto is starsonline)-4-methylpentylamino]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
4-{(S)-2-(4-utiltity-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentylamino]ethyl}phenylalaninol acid;
4-((S)-2-(4-utiltity-2-yl)-2-{(S)-2-[(3-methoxy-3-oxopropanoic)-3-phenylpropanamide]ethyl}phenyl)sulfamic acid;
4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-4-methylpentylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
tert-butyl ether [1-(S)-(phenylthiazol-2-yl)-2-(4-sulfonylarenes)ethyl]carbamino acid;
(S)-4-(2-(4-methylthiazole-2-yl)-2-evalidator)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-evalidator)phenylalaninol acid;
(S)-(4-(2-(4-(hydroxymethyl)thiazol-2-yl)-2-evalidator)phenyl)sulfamic acid;
(S)-4-(2-(4-phenylthiazol-2-yl)-2-evalidator
sulfamic acid;
4-((S)-2-(4-(3-methoxyphenyl)thiazol-2-yl)-2-evalidator)phenylalaninol acid;
4-((S)-2-(4-(2,4-acid)thiazol-2-yl)-2-evalidator)phenylalaninol acid;
(S)-(4-(2-(4-sensitiza-2-yl)-2-evalidator)phenyl)sulfamic acid;
(S)-(4-(2-pialligo-2-(4-(thiophene-2-ylmethyl)thiazol-2-yl)ethyl)phenyl)sulfamic acid;
(S)-(4-(2-(4-(3-methoxybenzyl)thiazol-2-yl)-2-evalidator)phenylalaninol acid;
4-((S)-2-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-ivalidator)phenylalaninol acid;
(S)-4-(2-(5-methyl-4-phenylthiazol-2-yl)-2-evalidator)phenylalaninol acid;
(S)-4-(2-(4-(4-biphenyl)thiazol-2-yl)-2-evalidator)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(2-methylthiazole-4-yl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(4-propertiesa-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(4-tert-butylthiazole-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(4-(methoxymethyl)-thiazol-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(4-(2-hydroxymethyl)thiazol-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-((tert-butoxycarbonyl)amino)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(2-(pivalate)thiazol-4-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(tert-butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)phenylalaninol acid;
4-((S)-2-(tert-butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)-phenyl)thiazol-2-yl)ethyl)phenylalaninol acid;
(S)-{4-[2,2-dimethylpropanolamine)-2-(2-phenylthiazol-4-yl)ethyl]phenylalaninol acid;
methyl ether (S,S)-2-(2-{2-[2-tert-butoxycarbonylamino-2-(4-sulfonylarenes)ethyl]thiazol-4-yl}acetylamino the-3-phenylpropionic acid;
4-((S)-2-(tert-butoxycarbonylamino)-2-(4-(thiophene-3-yl)thiazol-2-yl)ethyl)phenylalaninol acid; and
(S)-4-(2-(benzo[d]thiazol-2-ylamino)-2-(tert-butoxycarbonylamino)ethyl)phenylalaninol acid.

15. The connection 14, where the compounds are salts containing anions selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarata citrate, or a cation selected from ammonium, sodium, lithium, potassium, calcium, magnesium, and bismuth.

16. Application connection 14 to obtain drugs for the treatment of diseases selected from diabetic retinopathy, macular degeneration, occlusion of the venous vessels, occlusion of the artery, occlusion of the carotid artery, chronic uveitis/vitrite, mycobacteriosis, chronic retinal detachment, syndrome of increased viscosity, toxoplasmosis, trauma and effects of laser treatment; diseases associated with redness; proliferating vitreoretinopathy, ischemia of skeletal muscles and myocardium, stroke, ischemic heart disease, peripheral vascular disease (arteries).

17. Application connection 14 to obtain drugs for regulating angiogenesis, vascularization of ischemic tissue and, stimulate growth samples substitute full-thickness skin graft (transplant) or stimulation of repair tissue in the context of methods for controlled tissue regeneration (GTR).

18. The connection 14 is suitable for treatment of a condition selected from diabetic retinopathy, macular degeneration, occlusion of the venous vessels, occlusion of the artery, occlusion of the carotid artery, chronic uveitis/vitrite, mycobacteriosis, chronic retinal detachment, syndrome of increased viscosity, toxoplasmosis, trauma complications of laser treatment; diseases associated with redness; and proliferating vitreoretinopathy, ischemia of skeletal muscles and myocardium, stroke, ischemic heart disease, peripheral vascular disease (arteries).

19. The connection 14 is suitable for regulating angiogenesis, vascularization of ischemic tissue, stimulating the growth of samples substitute full-thickness skin graft (transplant), stimulation of repair tissue in the context of methods for controlled tissue regeneration (GTR).

20. The use of compounds according to any one of claims 1 to 8 to obtain a drug that inhibits protein human tyrosinosis beta (NRTR-β).



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present inventions refers to a new crystalline form of tetomilast hydrate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 20=10.6°, 12.9°, 21.1°, 22.3° and 25.0°, to a new crystalline form of anhydrous tetomilast type C of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=4.2°, 8.2°, 12.0°, 16.4°, 24.7° and 25.9°, to a new crystalline form of acetonitrile tetomilast solvate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=3.6°, 7.1°, 10.6°, 14.2° and 24.8°, to based pharmaceutical compositions and to methods for preparing.

EFFECT: new crystalline forms shows useful processing characteristics with relation to preparing pharmaceutical drugs of them.

13 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 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 , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 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: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products

The invention relates to the field exitlinks acids, in particular to the intermediate compounds - derivatives of 1-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(A) where R1-C1-C6-alkyl, and the method of obtaining derivatives complex alilovic esters of 4-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(I) where R1-C1-C6-alkyl, R2and R3may be the same or different and represent a hydrogen atom, chlorine or trifluoromethyl, which are inhibitors oldselected

FIELD: chemistry.

SUBSTANCE: invention relates to 5-member azacyclic compounds of formula

,

where X denotes S; Y denotes O; Q denotes O; R1 denotes methyl or, together with R2, forms a 6-member aliphatic ring, R2 denotes methyl or, together with R1, forms a 6-member aliphatic ring; R3 denotes hydrogen; R4 denotes benzyl; Z- is a pharmaceutically acceptable acid radical. The invention also relates to a pharmaceutical composition, use of formula (I) compounds, which are active in destruction of advanced glycosylation end products (AGE), to obtain a medicinal agent and a method producing formula (I) compounds.

EFFECT: obtaining compounds of formula (I) which are active in destruction of advanced glycosylation end products (AGE).

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

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