New substituted 8-heteroarylxantines and based pharmaceutical composition

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

 

The scope of the invention

The present invention relates to compounds and pharmaceutical compositions that are selective antagonists of receptors And2Badenosine (Ar). These compounds and compositions are useful as pharmaceutical agents.

Background of invention

Alkylcatechols (compound A) weak nonselective

antagonist of adenosine (see Linden, J., et al., Cardiovascular Biology of Purines, eds. G.Burnstock, et al., 1998, p.1-20) in therapeutic relationship is useful for the treatment of asthma. However, its use is associated with unpleasant side effects such as insomnia and diuresis. In recent years, the use of theophylline as bronchodilating agents to relieve or alleviate symptoms of asthma, was superseded by drugs of other classes, i.e. selective β2-adrenergic agonists, corticosteroids, and recently, leukotriene antagonists. These compounds also have limitations, therefore, still be desirable to develop theophylline-like drugs with reduced side effects.

It is recognized that theophylline and its closely related analogue of caffeine block endogenous adenosine acting as a local modulator of adenosine receptors in the brain and other organs in those who piticescu useful doses. Adenosine activates four subtypes of G protein-recombinant adenosine receptors (Ar), And1/A2A/A2B/A3. Enprofylline (compound) is another example of xanthine

reported that it blocks And2Badenosine receptors and is used to treat asthma. However, this connection is only weakly blocks And1And2Aand a3adenosine receptors. LaNoue et al it has been shown (U.S. patent 6060481)that are selective antagonists of the adenosine A2Bare useful to improve patients insulin sensitivity.

It was reported that therapeutic concentrations of theophylline and enprofylline block And2Breceptors of the man, and said that antagonists selective for this subtype may have potential application as anti-asthmatic agents (see Feoktistov, I., et al., Pharmacol. Rev. 1997, 49, 381-402; and Robeva, A.S., et al., Drug Dev. Res. 1996, 39, 243-252). It was reported that enprofylline has a value of Ki7 microns, and in some respects is selective in binding And2BAr man. (See Robeva, A.S., et al., Drug Dev. Res. 1996, 39, 243-252, and Linden, J., et al., Mol. Pharmacol. 1999, 56, 705-713). And2BAr is expressed in some cells of the mammary gland, such as the cell line BR of mastocytoma dog, which, apparently, are responsible for triggering acute m is stabilizing the solution of CA 2+and degranulation. (See Auchampach, J.A., et al., Mol. Pharmacol. 1997, 52, 846-860 and Forsyth, P., et al., Inflamm. Res. 1999, 48, 301-307). And2BAr also trigger the mobilization of CA2+and participate in slow IL8 release from HMC-1 cells human mammary gland. Other functions associated with a2BAR represents the control of cell growth and gene expresii (Cm. Neary, J., et al., Trends Neuroisci. 1996, 19, 13-18) endothelium-dependent vasodilatation (see Martin, P.L., et al., J. Pharmacol. Exp. Ther. 1993, 265, 248-253) and fluid secretion from the epithelium in the intestine (Cm. Strohmeier, G.R., et al., J. Biol. Chem. 1995, 270, 2387-2394). It was reported that adenosine, acting through And2BAr, stimulates chloride permeability in cells expressing a control transfer fibrosis of the gallbladder (See. Clancy, J.P., et al., Am. J. Physiol. 1999, 276, S-C369.)

Recently Linden and others (U.S. patent 6545002) described a new group of compounds and pharmaceutical compositions that are selective antagonists And2Badenosine receptors (Ar).

Although the fragments are selective in relation to the subtype of adenosine receptors available for a1And2Aand a3Ar, for a2Breceptor is known to only a small number of selective antagonists and is not aware of any non-selective agonists. Therefore, there is still a need for compounds which are selective antagonists And2Bthe receptor.

Brief the Scripture inventions

The present invention provides compounds that act as antagonists of receptors And2Badenosine. Accordingly, the present invention provides compounds of formula I:

where:

R represents hydrogen, (C1-C5)alkyl, halogen(C1-C8)alkyl, (C3-C5)alkenyl or (C3-C5)quinil;

R1and R2are independently hydrogen, (C1-C8)alkyl, (C3-With8)alkenyl, (C3-C8)quinil, (C1-C8)alkoxy, (C3-C8)cycloalkyl,

(C3-C8)cycloalkyl(C1-C8)alkyl, (C4-C10)heterocycle,

(C4-C10)heterocycle(C1-C8)alkyl, (C6-C10)aryl,

(C6-C10)aryl(C1-C8)alkyl, (C5-C10)heteroaryl or

(C5-C10)heteroaryl(C1-C8)alkyl-;

X represents a 5-10 membered heteroaryl ring having one nitrogen atom and optionally interrupted by 1, 2 or 3 naproxenum oxy (-O-), thio (-S-), sulfanilimide (-SO-), sulfanilimide (-S(O)2-) or amine-N(R9)- groups;

Z is-OR3, -SR3, halogen, -S(O)m-NR4R5, -NR4R5or (C4-C10)heterocycle, where the heterocycle optionally Samedan, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C1-C8)alkyl, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

each Z1is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, -OR6, -SR6, halogen,

R6About(C1-C8)alkyl, R7R8N(C1-C8)alkyl, halogen(C1-C8)alkyl,

-NR7R8, R7R8N(C1-C8)alkyl, -C(O)R6, -COOR6and-C(O)NR7R8;

R3is (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)quinil,

(C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl, (C5-C10)heteroaryl,

(C5-C10)heteroaryl(C1-C8)alkyl-, -C(O)R6or-C(O)NR7R8;

R4and R5are independently hydrogen, (C1-C8)alkyl,

(C3-C8)alkenyl, (C3-C8)quinil, (C1-C8)alkoxy, (C3-C8)cycloalkyl,

(C3-C8)cycloalkyl(C1-C8)alkyl, (C -C18)politically,

(C6-C18)politically(C1-C8)alkyl, (C3-C10)heterocycle,

(C3-C10)heterocycle(C1-C8)alkyl-, -NR7R8, (C6-C10)aryl,

(C6-C10)aryl(C1-C8)alkyl, (C5-C10)heteroaryl,

(C5-C10)heteroaryl(C1-C8)alkyl-, -(C2-C4-Y)q-(CH2)2-4-X1-C(O)R6,

-CO2R6-C(O)NR7R8or-S(O)2-NR7R8; or R4and R5together with the atoms to which they are attached, form a saturated or partially unsaturated, mono-, bicyclic - or aromatic ring having 3, 4, 5, 6, 7, or 8 ring atoms and optionally containing 1, 2, 3 or 4 heteroatoms selected from naproxeno oxy (-O-), thio (-S-), sulfinil (-SO-), sulfonyl (-S(O)2-and amine-N(R9- in the ring, where the ring is optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

X1is-OR6-C(O)R6, -CO2R or-NR7R8; and Y is oxy (-O-), thio (-S-), sulfinil (-SO-), sulfonyl (-S(O)2-and amine-N(R9)-;

where alkyl, Alchemilla, cycloalkyl, Alchemilla, aryl, heterocyclic or heteroaryl groups of R1, R2, R3, R4and R5groups optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

where R6represents hydrogen, (C1-C8)alkyl, RaAbout(C1-C8)alkyl,

RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, (C3-C10)heterocycle,

(C3-C10)heterocycle(C1-C8)alkyl, (C6-C10)aryl,

(C6-C10)aryl(C1-C8)alkyl, (C4-C10)heteroaryl,

(C4-C10)heteroaryl(C1-C8)alkyl-; where the heterocycle, heteroaryl or aryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C 8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

where R7, R8and R9are independently hydrogen, (C1-C8)alkyl, RaAbout(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, (C3-C10)heterocycle, (C6-C10)aryl, (C6-With10)aryl(C1-C8)alkyl, (C4-C10)heteroaryl, -COORa, -C(O)Raor C(O)NRbRc; where the heterocycle, heteroaryl or aryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc; or R7and R8together with the atoms to which they are attached, form a saturated or partially unsaturated, mono-, bicyclic - or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally containing 1, 2, 3 or 4 heteroatoms selected from naproxeno oxy (-O-), thio (-S-), sulfinil (-SO-), sulfonyl is (-S(O) 2-) or amine-N(R9- in the ring;

Randrepresents hydrogen or (C1-C6)alkyl; Rband Rwitheach independently represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C1-C6)alkylthio, (C6-C10)aryl, (C6-With10)aryl(C1-C6)alkyl-, heteroaryl or heteroaryl(C1-C6)alkyl-; or Rband Rwithtogether with the nitrogen to which they are attached, form pyrrolidine, piperidine, piperazinilnom, aspenlea, diazepinone, morpholinyl or thiomorpholine ring;

where n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; m is 1 or 2; and q is 1, 2, 3 or 4; or their pharmaceutically acceptable salts.

The invention also provides pharmaceutically acceptable salts of the compounds of formula (I). The invention is also a pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable diluent or carrier.

In addition, the invention provides a therapeutic method for the prevention or treatment of pathological conditions or symptoms in a mammal, such as man, in which one or more symptoms of a pathology involved activity, i.e. the activity, adenosine A2Breceptor is, and desirable antagonism (i.e. blocking) activity to ease these symptoms. Such diseases or conditions include, but are not limited to, asthma, allergies, allergic diseases (e.g. allergic rhinitis and sinusitis), autoimmune diseases (e.g. lupus), diarrhoeal diseases, insulin resistance, diabetes, prevent the degranulation of the cells of the breast associated with ischemic/reperfusion injury, heart attack, inhibition of angiogenesis in neoplastic tissues and inhibition of angiogenesis in diabetic retinopathy or hyperbaric induced oxygen retinopathy. The invention also provides a method of treating asthma, diarrhoeal diseases, resistance to insulin, diabetes, inhibition of angiogenesis in neoplastic tissues, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric induced oxygen retinopathy in a mammal (e.g. human), comprising the administration to a mammal in need of such treatment, an effective amount of at least one compound of formula I or its pharmaceutically acceptable salt(s).

The invention provides a compound of formula I for use in medical therapy, preferably for use in the treatment of diseases of Il the state, associated with destructive activation or activity And2Breceptor, including asthma, diarrhoeal diseases, insulin resistance, diabetes, ischemic/reperfusion injury, inhibition of angiogenesis in neoplastic tissues and inhibition of angiogenesis in diabetic retinopathy or hyperbaric induced oxygen retinopathy.

The invention also provides the use of compounds of formula I for the production of medicaments for the treatment of pathological conditions or symptoms in mammals, such as people that are associated with destructive activation or activity And2Breceptor, comprising the above disorders or diseases.

The invention also provides a process comprising contacting the compounds of formula I, optionally with a radioactive isotope (radionuclide), such as, for example, tritium, radioactive iodine (for example,125I for analyses linking or123I for spectral imaging) and the like, with the target areas or sites And2Badenosine receptor comprising said receptors, in vitro or in vivo, to connect with these receptors. Cell membranes, including sites And2Badenosine receptor, can be used to measure the selectivity of the subjects connect the deposits for subtypes of adenosine receptor, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions, associated with mediating And2B- receptor by contacting these agents with specified radio and receptors, and measuring the degree of displacement of radioligand and/or binding agent.

Detailed description of the invention

Applicants have discovered that compounds of the invention having formula I, can be useful for treating diseases or conditions associated with destructive activation or activity And2Bthe receptor.

Unless otherwise stated, the following definitions are used: halogen represents fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, alkenyl, quinil, etc. denote both straight and branched groups; and a reference to an individual radical such as “propyl”includes only radical with a straight chain, and the isomer branched chain, such as “isopropyl”, specifically refers to the radical branched chain. When the alkyl is partially unsaturated, alkyl chain may include one or more (e.g. 1, 2, 3, or 4) double or triple bonds in the chain.

“Aryl” means a phenyl radical or an ortho-condensed bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.

“Aralkyl or(C6-C10)aryl(C1-C8)alkyl-” refers to the GRU is PE formula aryl(C 1-C8)alkyl-, where the aryl and (C1-C8)alkyl are as defined above values.

“Heterocycle” includes a cyclic radical, attached or linked via a ring nitrogen atom or carbon monocyclic, condensed bicyclic or connected through the bridge bicyclic, saturated or unsaturated ring system containing 5-10 ring atoms and preferably from 5-6 ring atoms consisting of carbon and one, two, three or four heteroatoms, each selected from the group consisting of naproxene oxy (-O-), thio (-S-), sulfanilyl (-SO-), sulfanilic (-S(O)2-), amine-N(R9)- or-N=groups, where R9has the above specified values, and optionally containing 1-3 double bonds (e.g.,- CH=CH - or-CH=N-). The heterocycle includes, for example, tetrahydrofuryl, dihydrofuran, tetrahydroimidazo, asangroni, pyrrolidyl, piperidyl, piperidyl, morpholinyl, azepine, 1,3-diazepine, 1,3-benzodiazepine, 1,4-diazepine, 1,4-benzodiazepines, 1,5-diazepines, 1,5-benzodiazepine and the like.

“Heteroaryl” encompasses a radical attached via a ring atom of a monocyclic aromatic ring containing 5-10 ring atoms and preferably from 5-6 ring atoms consisting of carbon and one, two, three or four heteroatom is, each of which is selected from the group consisting of naproxene oxy (-O-), thio (-S-), sulfanilyl (-SO-), sulfanilic (-S(O)2-) or amine (-N(R9)-) groups, where R9has the above specified values. Preferred heteroaryl groups include imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridinyl, pyrimidinyl, indolyl, ethanolic, chinosol and the like.

As is clear to any average person skilled in the art, imidazole ring compounds of the present invention can exist in tautomeric forms or in the form of tautomers, and thus, they are also included in the scope of the invention. Tautomeric isomers are represented by structures (Ia) and (Ib):

When the name or the link on one connection (I), for example, for the purposes of the present invention should be understood that also mean tautomers (Ia) and (Ib). Similarly, when referring to compound (Ia) for the purposes of the present invention should be understood that also mean tautomers (I) and (Ib). The same is true for references to tautomer (Ib).

“Optional” or “optionally” means that the described subsequently, event, condition or state is optional, and that the description includes instances when the event is e or condition occurs and the cases when this does not happen. For example, “optionally substituted” means that the named Deputy may be present, but not necessarily present, and the description includes situations where the named Deputy enabled, and situations, when called by the Deputy is not enabled.

The terms “includes”, “example”, “such as” and the like are used to illustrate and not limit the present invention.

The uncertainty of the singular noun at his first mention of “means " at least one” or “one or more”when used in this specification, including the claims, unless specifically stated otherwise.

Specialists in this field will be obvious that the compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof of the compounds of the invention, which possess the useful properties described herein, and in this field it is well known how to obtain optically active forms (for example, splitting of racemic forms by using the method is in recrystallization, by synthesis from optically active starting substances, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine, for example, antitumor activity, herbicide activity or other therapeutic activity using the standard tests described herein, or using other similar tests which are well known in this field.

Specific and preferred values listed below for radicals, substituents, and ranges, are only illustrative; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

Specifically, (C1-C8)alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 3-pentyl, n-hexyl, n-heptyl, n-octyl or branched (C3-C8)alkyl, (C2-C8)alkenyl can be vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl or branched (C3-C8)alkenyl; and (C3-C8)alkenyl can be 2-propenyl (allyl), 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 1-GE is senile, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 2-octenyl, 3-octenyl, 4-octenyl or branched (C3-C8)alkenyl; and (C2-C8)quinil can be ethinyl, 1-PROPYNYL, 2-PROPYNYL (propargyl), 1-butinyl, 2-butinyl, 3-butinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl or branched (C3-C8)quinil; and (C3-C8)quinil can be 2-PROPYNYL (propargyl), 2-butinyl, 3-butinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl or branched (C3-C8)quinil; and (C1-With8)alkoxy can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, 3 pentox, n-hexyloxy, n-heptyloxy, n-octylamine or branched (C3-C8)alkoxy; halogen(C1-C8)alkyl may be iodomethyl, methyl bromide, chloromethyl, vermeil, trifluoromethyl, 2-chloroethyl, 2-bromacil, 2-foretel, 3-forproper, 2,2,2-triptorelin, pentafluoroethyl or branched halogen(C3-C8)alkyl, (C3-C8)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; and (C3-C8)cycloalkyl(C1-the 8)alkyl - may be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylmethyl, 2-cyclopentylmethyl or 2-cyclohexylethyl; and (C6-C10)aryl can be phenyl, indenyl or naphthyl; the heterocycle may be tetrahydrofuryl, dihydrofuran, tetrahydroimidazo, asangroni, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, azepine, 1,3-diazepine, 1,3-benzodiazepine, 1,4-diazepine, 1,4-benzodiazepines, 1,5-diazepines or 1.5-benzodiazepine.

Arylalkyl can be phenylethyl, benzyl, 2-phenylpropyl, 3-phenylpropyl, 2-navimeter or 3-naphthylmethyl; and heteroaryl can be imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, pyrimidinyl, indolyl, ethanolic, chinolin or oxide.

(C1-C8)Alkyl groups can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl; alkenylamine groups are ethynyl, propenyl, butenyl, pentenyl and hexenyl.

Specific cycloalkenyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Specific cycloalkylcarbonyl groups are cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylmethyl and 2-cyclohexylethyl.

Specific arylimine are phenyl, indenyl or naphthyl.

Specific arylalkyl groups are benzyl and 2-phenylethyl.

Specific halogenoalkane groups are bromacil, chloroethyl, foradil, trifluoromethyl, 2,2,2-triptorelin or 3-forproper.

A specific value for R is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl or halogen(C1-C4)alkyl.

Another specific value for R is hydrogen, methyl, ethyl, -CH2-CH2-Cl, -CH2-CH2-Br, or-CH2-CH2-CH2-F.

Another specific value for R is hydrogen.

A specific value for R1is hydrogen, (C1-C4)alkyl, (C3-C4)alkenyl, (C3-C4)quinil, phenyl or phenyl(C1-C4)alkyl.

Another specific value for R1is (C3-C6)cycloalkyl and (C3-C6)cycloalkyl(C1-C4)alkyl-.

Another specific value for R1is cyclopropyl or cyclopropylmethyl.

Another specific value for R1is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl.

Another specific value for R1is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl or (methoxyphenyl)ethyl.

<> Another specific value for R1is ethyl, n-propyl or allyl.

A specific value for R2is hydrogen, (C1-C4)alkyl, (C3-C4)alkenyl, (C3-C4)quinil, phenyl or phenyl(C1-C4)alkyl.

Another specific value for R2is (C3-C6)cycloalkyl and (C3-C6)cycloalkyl(C1-C4)alkyl-.

Another specific value for R2is cyclopropyl or cyclopropylmethyl.

Another specific value for R2is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl.

Another specific value for R2is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl or (methoxyphenyl)ethyl.

Another specific value for R2is ethyl, n-propyl or allyl.

A specific value for X is imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridinyl, pyrimidinyl, indolyl, ethanolic or chenail, each of which is optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)the Rila, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc.

Another specific value for X is 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, each optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc.

A specific value for X(Z1)nZ is a group having the formula

Another specific value for X(Z1)nZ is a group having the formula

Another specific value for X(Z1)nZ is a group having the formula

Another specific value for X(Z1)nZ is a group having the formula

A specific value for Z is-OH, -O(C1-C4)alkyl, -O(C6-C10)aryl, -O(C6-C10)aryl(C1-C4)alkyl, -NR4R5, F, Cl, Br or I.

Another specific value for Z is-NR4R5.

Another specific value for Z is

A specific value for R4is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl-,

(C3-C6)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl-,

(C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, -S(O)2-NH2,

-C(O)R6, -CO2R6or-C(O)NR6R7.

Another specific value for R4is hydrogen,

(C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)cycloalkyl,

(C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl,

-(CH2-CH2-Oh)q(CH2-CH2)-ORa, -(CH2-With the 2-Oh)q(CH2-CH2)-COORa,

-(CH2-CH2-Oh)q(CH2-CH2)-NRaRb, -NR7R8-C(O)R6, -CO2R6or

-C(O)NR7R8.

Another specific value for R4is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diatexites, methylbenzyl, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7.

Another specific value for R4is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C(O)R6, -CO2R6or-C(O)other7.

A specific value for R5is hydrogen, (C1-C6)alkyl,

(C3-C6)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl-,

(C3-C6)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl-,

(C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, -S(O)2NH2,

-C(O)R6, -CO2R6or-C(O)NR6R7.

Another specific value for R5is hydrogen,

(C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)t is cloaker,

(C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl,

-(CH2-CH2-Oh)q(CH2-CH2)-ORa, -(CH2-CH2-Oh)q(CH2-CH2)-COORa,

-(CH2-CH2-Oh)q(CH2-CH2)-NRaRb, -NR7R8-C(O)R6, -CO2R6or

-C(O)NR7R8.

Another specific value for R5is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diatexites, methylbenzyl, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7.

Another specific value for R5is methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C(O)R6, -CO2R6or-C(O)other7.

A specific value for R4and R5taken together with the nitrogen atom to which they are attached, is pyrrolidine, piperidine, piperazinilnom, aspenlea, diazepinone, morpholinyl or thiomorpholine ring, each optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1 -C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc.

A specific value for R6is (C1-C6)alkyl,

(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C4)alkyl-,

(C3-C6)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl-,

(C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, each optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc.

A specific value for R6is (C6-C10)aryl, (C5-C6)heteroaryl, each optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, halogen(C1-C8)alkyl, -COORaand-C(O)NRbRc.

A specific value for R6is pyridyl, optionally substituted by F, Cl, Br, I, CF3 , cyano, nitro, -COORaor-CONHRand.

Another specific value for a compound is the compound where R is hydrogen, methyl or ethyl; R1and R2represent independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl; X is 3-pyridyl substituted in the 6 position Deputy Z, where Z represents a C4-C10)heterocycle, or-NR4R5; R4represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, and R5represents-C(O)R6where R6is heteroaryl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, halogen(C1-C8)alkyl, -C(O)Ra, -COORaand-C(O)NRbRcand where Ra, Rband Rcare independently hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl.

Compounds of the invention can have the formula:

Aspects of the invention:

the present invention provides a compound of formula I:

in which:

R represents hydrogen, (C1-the 5)alkyl, halogen(C1-C8)alkyl, (C3-C5)alkenyl or (C3-C5)quinil;

R1and R2are independently hydrogen, (C1-C8)alkyl,

(C3-C8)alkenyl, (C3-C8)quinil, (C1-C8)alkoxy, (C3-C8)cycloalkyl,

(C3-C8)cycloalkyl(C1-C8)alkyl, (C4-C10)heterocycle,

(C4-C10)heterocycle(C1-C8)alkyl, (C6-C10)aryl,

(C6-C10)aryl(C1-C8)alkyl, (C5-C10)heteroaryl or

(C5-C10)heteroaryl(C1-C8)alkyl-;

X represents a 5-10 membered heteroaryl ring having one nitrogen atom and optionally interrupted by 1, 2 or 3 naproxenum oxy (-O-), thio (-S-), sulfanilimide (-SO-), sulfanilimide (-S(O)2-) or amine-N(R9)- groups;

Z is-OR3, -SR3, halogen, -S(O)m-NR4R5, -NR4R5or (C4-C10)heterocycle, where the heterocycle optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen,

cyano, nitro, -ORa, -SRa, (C1-C8)alkyl, (C6-C10)aryl,

-O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl,

halog is n(C 1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

each Z1is independently (C1-C8)alkyl,

(C2-C8)alkenyl, (C2-C8)quinil, -OR6, -SR6, halogen,

R6About(C1-C8)alkyl, R7R8N(C1-C8)alkyl, halogen(C1-C8)alkyl, -NR7R8,

R7R8N(C1-C8)alkyl, -C(O)R6, -COOR6and-C(O)NR7R8;

R3is (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)quinil, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -C(O)R6or-C(O)NR7R8;

R4and R5are independently hydrogen, (C1-C8)alkyl,

(C3-C8)alkenyl, (C3-C8)quinil, (C1-C8)alkoxy, (C3-C8)cycloalkyl,

(C3-C8)cycloalkyl(C1-C8)alkyl, (C6-C18)politically,

(C6-C18)politically(C1-C8)alkyl, (C3-C10)heterocycle,

(C3-C10)heterocycle(C1-C8)alkyl-, -NR7R8, (C6-C10)aryl,

(C6-C10)aryl(C1 -C8)alkyl, (C5-C10)heteroaryl,

(C5-C10)heteroaryl(C1-C8)alkyl-, -(C2-C4-Y)q-(CH2)2-4-X1-C(O)R6,

-CO2R6-C(O)NR7R8or-S(O)2-NR7R8; or R4and R5together with the atoms to which they are attached, form a saturated or partially unsaturated, mono-, bicyclic - or aromatic ring having 3, 4, 5, 6, 7, or 8 ring atoms and optionally containing 1, 2, 3 or 4 heteroatoms selected from naproxeno oxy (-O-), thio (-S-), sulfinil (-SO-), sulfonyl (-S(O)2-and amine-N(R9- in the ring, where the ring is optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

X1is-OR6-C(O)R6, -CO2R6or-NR7R8; and Y is oxy (-O-), thio (-S-), sulfinil (-SO-), sulfonyl (-S(O)2-and amine-N(R9)-;

where alkyl, Alchemilla, cycloalkyl, Alchemilla, aryl, heterocyclic or heteroaryl groups of R1, R2, R3, Rsup> 4and R5groups optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

where R6represents hydrogen, (C1-C8)alkyl, RaAbout(C1-C8)alkyl,

RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, (C3-C10)heterocycle,

(C3-C10)heterocycle(C1-C8)alkyl-,

(C6-C10)aryl,(C6-C10)aryl(C1-C8)alkyl, (C4-C10)heteroaryl,

(C4-C10)heteroaryl(C1-C8)alkyl-; where the heterocycle, heteroaryl or

aryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc;

where R7, R8and R9are independently hydrogen, (C1-C8)alkyl, Ra(The 1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, (C3-C10)heterocycle, (C6-C10)aryl, (C6-With10)aryl(C1-C8)alkyl, (C4-C10)heteroaryl, -COORa, -C(O)Raor C(O)NRbRc; where the heterocycle, heteroaryl or aryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc; or R7and R8together with the atoms to which they are attached, form a saturated or partially unsaturated, mono-, bicyclic - or aromatic ring having 3, 4, 5, 6, 7, or 8 ring atoms, the ring optionally has from 4 to eight ring atoms and optionally contains 1, 2, 3 or 4 heteroatoms selected from naproxeno oxy (-O-), thio (-S-), sulfinil (-SO-), sulfonyl (-S(O)2-) or amine-N(Rb- in the ring;

Randrepresents hydrogen or (C1-C6)alkyl; Rband Rwitheach independently represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C1 -C6)alkylthio, (C6-C10)aryl, (C6-With10)aryl(C1-C6)alkyl-, heteroaryl or heteroaryl(C1-C6)alkyl-; or Rband Rwithtogether with the nitrogen to which they are attached, form pyrrolidine, piperidine, piperazinilnom, aspenlea, diazepinone, morpholinyl or thiomorpholine ring; and

where n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; m is 1 or 2; and q is 1, 2, 3 or 4; or its pharmaceutically acceptable salt.

According to one aspect of the invention R is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl or halogen(C1-C4)alkyl. According to another aspect, R is hydrogen, methyl, ethyl, -CH2-CH2-Cl, -CH2-CH2-Br, or-CH2-CH2-CH2-F. In one embodiment, R is hydrogen.

According to one aspect of the invention provides the above compound, where R1represents hydrogen, (C1-C4)alkyl, (C3-C4)alkenyl, (C3-C4)quinil, phenyl or phenyl(C1-C4)alkyl. According to another aspect of R1is (C3-C6)cycloalkyl and (C3-C6)cycloalkyl(C1-C4)alkyl-. In one embodiment, R1is cyclopropyl or cyclopropylmethyl. In another embodiment, R1predstavljaet hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl, benzyl or (methoxyphenyl)ethyl. In another embodiment, R1represents ethyl, n-propyl or allyl.

According to one aspect of the invention provides the above compound, where R2represents hydrogen, (C1-C4)alkyl, (C3-C4)alkenyl, (C3-C4)quinil, phenyl, phenyl(C1-C4)alkyl or (methoxyphenyl)ethyl. In one embodiment, R2is (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-. In another embodiment, R2is cyclopropyl or cyclopropylmethyl. In another embodiment, R2represents hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl. In another embodiment, R2represents ethyl, n-propyl or allyl.

According to one aspect of the invention provides the above compound, where Z represents-OH, -O(C1-C4)alkyl, -O(C6-C10)aryl, -O(C6-C10)aryl(C1-C4)alkyl, -NR4R5, F, Cl, Br or I.

According to another aspect of the invention provides the above compound, where R4represents hydrogen,

(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6 1-C4)alkyl-,

(C3-C6)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl-,

(C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, -S(O)2-NH2,

-C(O)R6, -CO2R6or-C(O)NR6R7. In one embodiment, R4represents hydrogen, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl, -(CH2-CH2-Oh)q(CH2-CH2)-ORa, -(CH2-CH2-Oh)q(CH2-CH2)-COORa, -(CH2-CH2-Oh)q(CH2-CH2)-NRaRb, -NR7R8-C(O)R6, -CO2R6or-C(O)NR7R8. In another embodiment, R4represents hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diatexites, methylbenzyl, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7. In another embodiment, R4represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C(O)R6, -CO2R6or-C(O)other7.

According to another aspect and the gaining is provided above the connection, where R5represents hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C4)alkyl, (C3-C6)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl, (C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, -S(O)2NH2-C(O)R6, -CO2R6or-C(O)NR6R7. In one embodiment, R5represents hydrogen, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl, -(CH2-CH2-Oh)q(CH2-CH2)-ORa, -(CH2-CH2-Oh)q(CH2-CH2)-COORa, -(CH2-CH2-Oh)q(CH2-CH2)-NRaRb, -NR7R8-C(O)R6, -CO2R6or-C(O)NR7R8. In another embodiment, R5represents hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diatexites, methylbenzyl, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7. In another embodiment, R5represents methyl, ethyl, Cyclops is sawdust, cyclopropylmethyl, -C(O)R6, -CO2R6or-C(O)other7.

According to one aspect of the invention provides the above compound, where R4and R5taken together with the nitrogen atom to which they are attached, represent pyrrolidino, piperidine, piperazinilnom, aspenlea, diazepinone, morpholinyl or thiomorpholine ring, each optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc.

According to another aspect of the invention provides the above compound, where R6is (C1-C6)alkyl,

(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C4)alkyl-,

(C3-C6)heterocycle, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl-,

(C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, each optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc. In one embodiment, R6is (C6-C10)aryl, (C5-C6)heteroaryl, each optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, halogen(C1-C8)alkyl, -COORaand-C(O)NRbRc. In another embodiment, R6represents pyridyl, optionally substituted by F, Cl, Br, I, CF3, cyano, nitro, -COORaor CONHRand.

Another specific value for a compound is the compound where R is hydrogen, methyl or ethyl; R1and R2represent independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or n-butyl; X is 3-pyridyl substituted in the 6 position Deputy Z, where Z represents a C4-C10)heterocycle, or-NR4R5; R4represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, and R5represents-C(O)R6where R6is heteroaryl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, halogen(C1 8)alkyl, -C(O)Ra, -COORaand-C(O)NRbRcand where Ra, Rband Rcare independently hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl.

According to another aspect of the invention provides the above compound, where R is hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl or halogen(C1-C4)alkyl; R1and R2are independently hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl, phenyl, phenethyl or benzyl. In one embodiment, R is hydrogen, methyl, ethyl, -CH2-CH2-Cl, -CH2-CH2-Br, or-CH2-CH2-CH2-F; and R1and R2are independently hydrogen, methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or (methoxyphenyl)ethyl.

According to one aspect of the invention provides the above compound, where X is imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, thiadiazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridinyl, pyrimidinyl, indolyl, ethanolic or chenail, each optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, cyano, nitro, (C1-C8)alkyl, -ORa, -SRa, (the 6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc. In one variation of the above, X is 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, each optionally substituted by 1, 2 or 3 substituents, independently selected from the group consisting of halogen, cyano, nitro, (C1-C8)alkyl, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc. According to another variant, X(Z1)nZ has the formula:

According to another variant, X(Z1)nZ has the formula

According to one aspect of the invention provides the above compound, where Z represents-OH, -O(C1-C4)alkyl, -OC(O)NR7R8, (C1-C4)alkyl, -NR4R5, F, Cl, Br or I, in which R4and R5are independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocycle, (C6-C10)aryl, (C -C12)aralkyl, (C5-C6)heteroaryl or (C5-C6)heteroaryl(C1-C4)alkyl-, -S(O)2-NH2-C(O)R6, -CO2R6or-C(O)NR6R7. In one embodiment, Z is-NR4R5.

According to one aspect of the invention provides the above compound, where R4and R5together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, piperazinilnom, aspenlea, diazepinone, morpholinyl or thiomorpholine ring, where the ring is optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc. In one variation of the above, R4and R5are independently hydrogen, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl, -(CH2-CH2-Oh)q(CH2-CH2)-ORa, -(CH2-CH2-Oh)q(CH2-CH2)-COORa, -(CH2-CH2-O) q(CH2-CH2)-NRaRb, -NR7R8-C(O)R6, -CO2R6or-C(O)NR7R8. According to another variant of R4and R5are independently hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diatexites, methylbenzyl, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7. According to another variant of R6represents methyl, methoxy or pyridyl, and R7represents phenyl, forfinal or methoxyphenyl.

According to one aspect of the invention provides the above compound, where R is hydrogen, methyl or ethyl; R1and R2represent independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl; and Z represents a (C4-C10)heterocycle, where the heterocycle optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, cyano, nitro, -ORa, -SRa, (C6-C10)aryl, -O(C6-C10)aryl, hydroxy(C1-C8)alkyl, RbRcN(C1-C8)alkyl, halogen(C1-C8)alkyl, -NRbRc, -C(O)Ra, -COORaand-C(O)NRbRc.

According to one aspect of izopet the deposits is provided above the connection, where Z is selected from the group consisting of:

In one variation of the above, -X(Z1)nZ is selected from the group consisting of:

In another embodiment, R1and R2represent n-propyl; R is hydrogen and n is zero.

According to one aspect of the invention provides the above compound, where X(Z1)nZ is selected from the group consisting of:

In one aspect of the invention provides a compound selected from the group consisting of:

(62) 1,3-diethyl-8-[6-[N-(2-parsingerror)methylamino]-3-pyridyl]xanthine;
(1)1,3-dipropyl-8-(6-chloro-3-pyridyl)xanthine;
(2)1-propyl-3-propargyl-8-(6-chloro-3-pyridyl)xanthine;
(3)1,3-dipropyl-8-(6-ethylamino-3-pyridyl)xanthine;
(4)1,3-dipropyl-8-(6-(2-hydroxyethyl)amino-3-pyridyl)xanthine;
(5)1,3-dipropyl-8-[6-(4-acetylpiperidine)-3-pyridyl]xanthine;
(6)1,3-dipropyl-8-[6-(benzylamino)-3-pyridyl]xanthine;
(7)1,3-dipropyl-8-[6-(1-piperidinyl)-3-pyridyl]xanthine;
(8)1,3-dipropyl-8-(6-pyrrolidinone-3-yl)xanthine;
(9)1,3-dipropyl-8-{6-[4-methyl(perhydro-1,4-diazepin-1-yl)]-3-pyridyl}xanthine;
(10)1,3-dipropyl-8-(6-methylamino-3-pyridyl)xanthine;
(11)1,3-dipropyl-8-[6-(4-methoxybenzylamine)-3-pyridyl]xanthine;
(12)1,3-dipropyl-8-[6-(3-methylpiperidino)-3-pyridyl]xanthine;
(13)1,3-dipropyl-8-[6-(2-hydroxypropyl)amino-3-pyridyl]xanthine;
(14)1,3-dipropyl-8-[6-(2,2-dimethoxymethyl)amino-3-pyridyl]xanthine;
(15)1,3-dipropyl-8-[6-(1-is hydroxy-2-propyl)amino-3-pyridyl]xanthine;
(16)1,3-dipropyl-8-(6-morpholino-3-pyridyl)xanthine;
(17)1,3-dipropyl-8-(6-dimethylamino-3-pyridyl)xanthine;
(18)1,3-dipropyl-8-[[6-(2-hydroxyethoxy)ethylamino]-3-pyridyl]xanthine;
(19)1,3-dipropyl-8-(6-piperazine derivatives-3-pyridyl)xanthine;
(20)1,3-dipropyl-8-[6-(2-hydroxy-2-phenylethyl)amino-3-pyridyl]xanthine;
(21)1,3-dipropyl-8-[6-(4-aminomethylbenzoic)-3-pyridyl]xanthine;
(22)1,3-dipropyl-8-(6-phenylamino-3-pyridyl)xanthine;
(23)1,3-dipropyl-8-(6-cyclopropylamino-3-pyridyl)xanthine;
(24)1,3-dipropyl-8-[6-(6-pyridylmethylamine)-3-pyridyl]xanthine;
(25)1,3-dipropyl-8-(6-(4-methylpiperazine)-3-pyridyl)xanthine;
(26)1,3-dipropyl-8-[6-(3-pyridylmethylamine)-3-pyridyl]xanthine;
(27)1,3-dipropyl-8-[-(2-methylbenzylamino)-3-pyridyl]xanthine;
(28)1,3-dipropyl-8-[6-[2-(3,4-acid), ethylamino]-3-pyridyl]xanthine;
(29)1,3-dipropyl-8-[6-[(N-propellerblades)methylamino]-3-pyridyl]xanthine;
(30)1,3-dipropyl-8-[6-(3-pentylamine)-3-pyridyl]xanthine;
(31)1,3-dipropyl-8-[6-(2,2-diphenylethylamine)-3-pyridyl]xanthine;
(32)1,3-dipropyl-8-[6-[2-(1-ethylpyridinium)]-3-pyridyl]xanthine;
(33)1,3-dipropyl-8-[6-(3-methoxybenzylamine)-3-pyridyl]xanthine;
(34)1,3-dipropyl-8-[6-[(N-phenylcarbamoyl)methylamino]-3-pyridyl]xanthine;
(35)1,3-dipropyl-8-[6-(furfurylamine)-3-pyridyl]xanthine;
(36)1,3-dipropyl-8-[6-[2-(4-methoxyphenyl)ethylamino]-3-pyridyl]xanthine;
(37)1,3-dipropyl-8-[6-(2-methoxybenzylamine)-3-pyridyl]xanthine;
(38)1,3-dipropyl-8-[6-(propylamino)-3-pyridyl]xanthine;
(39)1,3-dipropyl-8-[6-(cyclopentylamine)-3-pyridyl]xanthine;
(40)1,3-dipropyl-8-[6-(cyclohexylamino)-3-pyridyl]xanthine;
(41)1,3-dipropyl-7-ethyl-8-(6-chloro-3-pyridyl)xanthine;
(42)1,3-dipropyl-7-(3-forproper)-8-(6-chloro-3-pyridyl)xanthine;
(43)1,3-dipropyl-7-methyl-8-(6-chloro-3-pyridyl)xanthine;
(44)1,3-dipropyl-7-(2-bromacil)-8-(6-chloro-3-pyridyl)xanthine;
(45)1,3-dipropyl-8-[6-(2-thiophenemethylamine)-3-pyridyl]xanthine;
(46)1,3-dipropyl-8-[6-[N-(4-methoxyphenylacetyl)methylamino]-3-pyridyl]xanthine;
(47)1,3-dipropyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(48)1,3-dipropyl-8-[6-[N-(4-tortenelmebol)methylamino]-3-pyridyl]xanthine;
(49)1,3-dipropyl-8-[6-[N-isonicotinoyl]-3-pyridyl]xanthine;
(50)1,3-dipropyl the-8-[6-[N-methoxycarbonylmethylene]-3-pyridyl]xanthine;
(51)1,3-dipropyl-8-[6-[N-phenylcarbamoyl-N-(2-phenylcarbamoyloxy)amino]-3-pyridyl]xanthine;
(52)1,3-dipropyl-8-{6-[4-(N-phenylcarbamoyl)]piperazine derivatives-3-pyridyl}xanthine;
(53)1,3-dipropyl-8-{6-[4-(N-isonicotinoyl)]piperazine derivatives-3-pyridyl}xanthine;
(54)1-propyl-3-(4-methoxyphenyl)ethyl-8-(6-chloro-3-pyridyl)xanthine;
(55)1-propyl-3-(methoxyphenylacetyl)-8-(6-piperazine derivatives-3-pyridyl)xanthine;
(56)1,3-dipropyl-8-[6-(4-pyridylamino)-3-pyridyl]xanthine;
(57)1,3-dipropyl-8-{6-[4-(N-nicotinoyl)]piperazine derivatives-3-pyridyl}xanthine;
(58)1,3-dipropyl-8-[6-(hexahydro-1,4-diazepin-1-yl)-3-pyridyl]xanthine;
(59)1,3-diethyl-8-(6-chloro-3-pyridyl)xanthine;
(60)1,3-diethyl-8-(6-piperazine derivatives-3-pyridyl)xanthine;
(61)1,3-diethyl-8-[6-[(N-phenylcarbamoyl)methylamino]-3-pyridyl]xanthine;
1,3-diethyl-8-[6-[N-nicotinanilide]-3-pyridyl]xanthine;
(63)1,3-diethyl-8-(6-methylamino-3-pyridyl)xanthine;
(64)1,3-diethyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(65)1,3-diethyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(66)1,3-dicyclopropyl-8-(6-methylaminomethyl-3-yl)xanthine;
(67)1-propargyl-3-methyl-8-(6-methylamino-3-pyridyl)xanthine;
(68)8-[6-(2,5-diazabicyclo[2.2.2]Oct-2-yl)pyridine-3-yl]-1,3-dipropyl-3,7-dihydropyran-2,6-dione;
(69)1,3-dicyclopropyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(70)1,3-dicyclopropyl-8-[6-[N-nicotinanilide]-3-pyridyl]xanthine;
(71)1,3-diallyl-8-(6-methylamino-3-pyridyl)xanthine;
(72)1-cyclopropylmethyl-3-ethyl-8-(6-methylaminomethyl-3-yl)xanthine
(73) 1,3-diethyl-8-[6-(2-pyridylmethylamine)-3-pyridyl]xanthine;
(74)1,3-diethyl-8-[6-(3-pyridylmethylamine)-3-pyridyl]xanthine;
(75)1,3-diethyl-8-[6-(3-methoxybenzylamine)-3-pyridyl]xanthine;
(76)1,3-dipropyl-8-[6-[2-(3-pyridyl)ethylamino]-3-pyridyl]xanthine;
(77)1,3-diethyl-8-[6-[2-(3-pyridyl)ethylamino]-3-pyridyl]xanthine;
(78)1,3-dipropyl-8-[6-[2-(2-pyridyl)ethylamino]-3-pyridyl]xanthine;
(79)1,3-diethyl-8-[6-[2-(2-pyridyl)ethylamino]-3-pyridyl]xanthine;
(80)1,3-diethyl-8-(6-pyrrolidinone-3-yl)xanthine;
(81)1,3-diethyl-8-[6-[2-(1-pyrrolidinyl)ethylamino]-3-pyridyl]xanthine;
(82)1,3-dipropyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;
(83)1,3-dipropyl-8-(6-(2-acetylamino)amino-3-pyridyl)xanthine;
(84)1,3-diethyl-8-(6-bromo-3-pyridyl)xanthine;
(85)1,3-dipropyl-8-{6-[4-(2-pyridyl)piperazine derivatives]-3-pyridyl}xanthine;
(86)1,3-diethyl-8-{6-[4-(2-pyridyl)piperazine derivatives]-3-pyridyl}xanthine;
(87)1,3-diethyl-8-[6-(TRANS-2,5-dimethylpiperazine)-3-pyridyl]xanthine;
(88)1,3-dipropyl-8-{6-[4-(2-pyrimidinyl)piperazine derivatives]-3-pyridyl}xanthine;
(89)1,3-diethyl-8-{6-[4-(2-pyrimidinyl)piperazine derivatives]-3-pyridyl}xanthine;
(90)1,3-diethyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;
(91)1-propargyl-3-methyl-8-(6-bromo-3-pyridyl)xanthine;
(92)1,3-diethyl-8-[6-[N-nicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine;
(93)1-propargyl-3-methyl-8-(6-(2-methoxyethyl)-3-pyridyl)xanthine;
(94)1,3-diethyl-8-[6-[N-isonicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine;
(95)1-(5-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purine-8-yl)pyridine-2-yl)-1-(2-methoxyethyl)-3-(pyridin-4-yl)urea;
(96)1,3-dimethyl-8-(6-bromo-3-pyridyl)xanthine;
(97)1,3-dimethyl-8-(6-methylamino-3-pyridyl)xanthine;
(98)1,3-dimethyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(99)1,3-dipropyl-8-[6-[N-nicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine;
(100)1-propargyl-3-methyl-8-[6-[N-nicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine;
(101)1-propargyl-3-methyl-8-(6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(102)1,3-dipropyl-8-(2,6-dichloro-3-pyridyl)xanthine;
(103)1,3-dipropyl-8-(2,6-dimethylamino-3-pyridyl)xanthine;
(104)1,3-dipropyl-8-(2,6-di(2-methoxyethyl)-3-pyridyl)xanthine;
(105)1,3-dipropyl-8-[2,6-di[N-nicotinylcodeine]-3-pyridyl]xanthine;
(106)1,3-dipropyl-8-[2,6-di[N-nicotinoyl-N-methoxyethyl]-3-pyridyl]xanthine;
(107)
(108)1,3-diethyl-8-[6-[N-(isoxazol-5-carbonyl)methylamino]-3-pyridyl]xanthine;
(109)1,3-dipropyl-8-[6-[N-(2-parsingerror)methylamino]-3-pyridyl]xanthine;
(110)1,3-dipropyl-8-[6-[N-(isoxazol-5-carbonyl)methylamino]-3-pyridyl]xanthine;
(111)1,3-dipropyl-8-[6-[N-(5-methylisoxazol-3-yl-3-carbonyl)methylamino]-3-pyridyl]xanthine;
(112)1,3-dipropyl-8-[6-[N-(2-chloro-6-methoxypyridine-4-carbonyl), N-methylamino]-3-pyridyl]xanthine;
(113)1,3-dipropyl-8-[6-[N-(isonicotinoyl N-oxide) N-methylamino]-3-pyridyl]xanthine;
(114)1-propyl-3-(4-methoxyphenyl)ethyl-8-(6-methylamino-3-pyridyl)xanthine;
(115)1,3-diethyl-8-[6-[N-(isonicotinoyl N-oxide) N-methylamino]-3-pyridyl]xanthine;
(116)1,3-diallyl-8-(6-chloro-3-pyridyl)xanthine;
(117)1-propyl-3-(4-methoxyphenyl)ethyl-8-[6-(N-n is Latinoamericano)-3-pyridyl]xanthine;
(118)1-propyl-3-(4-methoxyphenyl)ethyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;
(119)1,3-diallyl-8-[6-(N-nicotinylcodeine)-3-pyridyl]xanthine;
(120)1,3-diallyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;
(121)1,3-dipropyl-8-[6-(N-[6-(trifluoromethyl)nicotinoyl]methylamino)-3-pyridyl]xanthine;
(122)1,3-diethyl-8-[6-(2-hydroxy-5-methyl)benzaldehyde]-3-pyridyl]xanthine;
(123)1-cyclopropyl-3-propyl-8-[6-(N-[6-trifluoromethyl)nicotinoyl]methylamino)-3-pyridyl]xanthine;
(124)1,3-diethyl-8-[6-(bromopyridin-3-carbaldehydes)-3-pyridyl]xanthine;
(125)1-cyclopropyl-3-ethyl-8-(6-methylamino-3-pyridyl)xanthine;
(126)1-cyclopropyl-3-propyl-8-(6-methylamino-3-pyridyl)xanthine;
(127)1-propyl-3-cyclopropyl-8-(6-methylamino-3-pyridyl)xanthine;
(128) 1-cyclopropyl-3-propyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;
(129)1-cyclopropyl-3-propyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
(130)1,3-diethyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;
(131)1,3-dipropyl-8-(2-chloro-6-methoxyethylamine)-4-pyridyl]xanthine;
(132)1,3-dipropyl-8-(2-chloro-6-methylamino)-4-pyridyl]xanthine;
(133)1,3-dipropyl-8-[2-[N-nicotinoyl-N-(2-methoxyethyl)amino]-6-chloro-4-pyridyl]xanthine;
(134)1,3-dipropyl-8-[2-[N-nicotinoyl-N-methylamino]-6-chloro-4-pyridyl]xanthine;
(135)1-cyclopropyl-3-propyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl]xanthine;
(136)1-ethyl-3-cyclopropyl-8-(6-methylamino-3-pyridyl)xanthine;
(137)1-ethyl-3-cyclopropyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;
(138)1,3-diethyl-8-[6-hydrazino-3-pyridyl]xanthine;
1,3-diethyl-8-[6-(cyclopropylamino)-3-pyridyl]xanthine;
(140)1,3-diethyl-8-[6-(cyclopropylamino)-3-pyridyl]xanthine;
(141)N'-[5-(1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)pyridine-2-yl]hydrazide;
(142)N-[5-(1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)pyridine-2-yl]-N'-(pyridine-3-carbonyl)hydrazide;
(143)1,3-diethyl-8-[6-(ethylamino)-3-pyridyl]xanthine;
(144)1,3-diethyl-8-[6-[N-nicotinereplacement]-3-pyridyl]xanthine and
(145)1-cyclopropylmethyl-3-ethyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl]xanthine;

or their pharmaceutically acceptable salts, optionally in the form of a single stereoisomer or mixture of stereoisomers.

In one aspect of the invention provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of the compounds described above; and (b) pharmaceutically acceptable excipient. In another aspect is provided a pharmaceutical composition comprising: (a) therapeutically effective amounts of the compounds above; and (b) pharmaceutically acceptable excipient.

In one aspect of the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, which involved the activity of adenosine A2Breceptors and desirable antagonism of their actions, including introduction to the mammal an effective amount of the compounds of the present invention. According to another aspect provides a method of treating asthma, allergies, allergic diseases or autoimmune diseases, comprising the administration to a mammal in need of such treatment, an effective amount of the compounds of the present invention.

According to another aspect provides a method of treating diarrhoeal diseases, resistance to insulin, diabetes, cancer, ischemic/reperfusion injury, diabetic retinopathy or retinopathy caused by hyperbaric oxygen, comprising the administration to a mammal in need of such treatment, an effective amount of the compounds of the present invention or its pharmaceutically acceptable salt. According to another aspect provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, which involved the activity of adenosine A2Bthe recipe is the moat desirable antagonism of their actions, includes introduction to the mammal an effective amount of the compounds of the present invention.

According to another aspect is a compound of the present invention for use in therapeutic medicine. According to another aspect provides the use of compounds of the invention for the production of pharmaceuticals useful in the treatment of diseases in mammals, such as man.

It is quite clear that any aspect or feature of the present invention is characterized by whether or not it is characterized as preferred, may be combined with any other aspect or characteristic of the invention, regardless of whether characterized by whether or not it is characterized as preferred. For example, aspect or characteristic described as preferred, for example, a particular R group or specific R1a group of specific compounds of formula I (for example, in which R1represents hydrogen, (C1-C5)alkyl, halogen(C1-C8)alkyl, (C3-C5)alkenyl or (C3-C5)quinil) can be combined with any other groups, such as R2, X, Z, Z1and other, forming a compound of the invention having a different combination of substituents, without deviating from the present invention.

Additional compounds useful for the implementation of the image is the shadow in practice are presented in the table below:

Table 1
Activity Aw antagonist
Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BK/b> i(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.
R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1 R2R-X(Z1)n-ZRat-A2BKi(nm)

Connection.R1R2R-X(Z1)n-ZRat-A2BKi(nm)
Note: +: Ki<10000 nm, ++: Ki<5000 nm, +++: Ki<500 nm, ++++: Ki<100 nm.

The synthesis of compounds of formula I

The compounds of formula IA can be obtained using the methods described in P.J. Scammells, et al., J. Med. Chem.37, 2704-2712 (1994). Diamino-1,3-disubstituted uracil acelerou 6-chloronicotinamide in pyridine at 5°C To produce compounds of the formula (5A). The resulting amide (5A) cyclist by boiling under reflux in aqueous sodium hydroxide solution to obtain compound IA. 6-Chloronicotinoyl obtained by boiling under reflux for 6-hydroxynicotinic acid thionyl is loride using DMF as catalyst, as shown in reaction scheme 1.

Compound IA can be alkilirovanii alkylbromides or iodide with obtaining compounds of formula IB. Compounds IA or IB is subjected to interaction with substituted amine in 150-160S in a tubular autoclave, obtaining the compounds of formula IC. The compounds of formula IC, where R4represents hydrogen, can be subjected to interaction with the isocyanate or acylchlorides, obtaining the compounds of formula I, where R4represents-C(O)other7(ID) or-C(O)R6(IE), respectively.

The scheme of reactions 1

Compounds of the invention where Z is-NR4R5and R4and R5together with the atoms to which they are attached, form a ring containing NH group, such as an IC or IA1, can be obtained by the interaction of the compounds with isocyanate or acylchlorides, obtaining compounds having the Formula IF and IG, as shown in scheme 2, below:

The scheme of reactions 2

Scheme 3 shows that compound IA may be subject to interaction with hydrazine or substituted hydrazine at 100-160°C., obtaining the compounds of formula IA2. The compounds of formula IA2, where R8represents hydrogen, may be subjected to interaction with acylchlorides, obtaining the compounds of formula IH and IJ. Compound IA can be subjected to interaction with keto is om or aldehyde, receiving the compound of formula IL.

The reaction scheme 3

In the present description uses the following abbreviations:

[125I]ABA[125I]N6-(4-aminobenzyl)adenosine
125I ABOPX125I-3-(4-amino-3-iodobenzyl)-8-oxyacetic-1-profilkanten
ARadenosine receptor or receptor adenosine
CGS 216802-[4-[(2-carboxyethyl)phenyl]ethylamino]-5N-N-ethylcarbamate
CPX8-cyclopentyl-1,3-DIPROPYLENE
DMEMmodified Dulbecco Wednesday needle
DMFN,N-dimethylformamide
DMSOthe sulfoxide
EDTAethylenediaminetetraacetate
HEK cellsthe kidney cells of a human embryo
Kiconstant Engibarov the Deposit balance
NECA5'-(N-ethylcarbazole)adenosine
R-PIAR-N6-phenylisopropylamines
TEAthe triethylamine
TCXthin-layer chromatography
ZM 2413854-(2-[7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazine-5-Illuminati]phenol

In cases where compounds are sufficiently basic or acidic to formation of stable non-toxic salts of acids or bases, it may be advantageous to introduce a connection in the form of salts. Examples of pharmaceutically acceptable salts are additive organic acid salts formed with acids, which give physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-Ketoglutarate, and α-glycerol. You can also get suitable inorganic salts, including cleaners containing hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standard techniques, well known in the art, for example, through reaction rises the primary connection, such as an amine with a suitable acid, producing a physiologically acceptable anion. Can be also obtained salts of carboxylic acids with alkali metals (e.g. sodium, potassium or lithium) and alkaline earth metals (e.g. calcium).

Specialists in this field will be obvious that the compounds of the invention having a chiral center may exist in and to stand out in optically active and racemic forms. Some compounds may exhibit polymorphism. It should be clear that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof of the compounds of the invention, which possess the useful properties described above, and in this area it is known how to obtain optically active forms (for example, splitting of racemic form using the methods of recrystallization, by synthesis from optically active starting compounds or by using chiral synthesis or by chromatographic separation using a chiral stationary phase). Common also to determine the activity of the antagonist And2Badenosine using the standard tests described herein, or by using similar test or tests, which are well known in this field.

The compounds of formula I which may be formed in the form of pharmaceutical compositions and administered to a mammalian host, such as the patient in the form of a wide variety of forms adapted to the chosen route of administration, i.e. oral or parenteral, intravenous, intramuscular, topical, inhalation or subcutaneous routes. Examples of pharmaceutical compositions are described in the publication “Remington: The Science and Practice of Pharmacy, A.Gennaro. ed., 20thedition, Lippncott, William & Wilkins, Philadelphia, PA.

Thus, these compounds may be introduced to the system by, for example, orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or assimilated edible carrier. They may be enclosed in hard or soft gelatin capsules, may be compressed into tablets, or may be entered directly in food intake with the diet of the patient. For oral therapeutic injection of the active compound may be combined with one or more excipients and used in the form of digestible tablets, buccal tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions or preparations should contain at least 0.1% of active compound. The percentage composition of the compositions and preparations may, of course, be varied and may conveniently be between about 2 and 60% by weight of a given unit dosage form. The number of active compounds the Oia in such therapeutically useful compositions is such that to ensure the effective dose.

Tablets, lozenges, pills, capsules and the like may also contain the following ingredients: a binder such as gum tragakant, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrity agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and can be added sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring or flavoring agent such as peppermint, oil of Grushenka or cherry flavoring. When the unit dosage form is a capsule, it may contain in addition to the substances of the above type, a liquid carrier, such as vegetable oil or polyethylene glycol. Various other substances may be present as coatings or to otherwise modify the physical solid form of a unit dose. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar or similar. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparaben as preservatives, a dye and flavoring such as cherry or Apelsin the second odorant. Of course, any material used in the preparation of any shape with a single dose should be pharmaceutically acceptable and sufficiently non-toxic in the quantities used. In addition to the above, the active compound can be used as drugs and devices slow-release.

The active compound may also be administered intravenously or intraperitoneally using infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally in a mixture with non-toxic surface-active substance. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin and their mixtures, and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the preparation of sterile injectable or infusium solutions or dispersions for immediate acceptance or administration, optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid and stable under conditions of manufacture and storage. Liquid is a carrier or diluent may be a solvent or liquid dispersion medium, including, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol and the like), vegetable oils, nontoxic glyceriae esters and their suitable mixtures. The proper fluidity can be maintained, for example, through the formation of liposomes, the maintenance of the required particle size in the case of dispersions or through the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases it is preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of injectable compositions can be achieved by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active ingredient in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by sterilization using filters. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred the ways of obtaining methods are vacuum drying and freeze-drying, which give a powder of the active ingredient plus any additional desired ingredient present in the previously known sterile filtered solutions.

For the local introduction of these compounds can be used in pure form, namely, when they are liquids. However, it is often desirable to apply them to the skin as compositions or ready-made forms of the drugs in combination with a dermatologically acceptable carrier, which may be solid or liquid.

Useful solid carriers include finely ground solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or a mixture of water-alcohol/glycol in which the present compounds can be dissolved or dispergirujutsja at effective levels, optionally with the aid of non-toxic surfactants. To optimize the properties for a given use of an adjuvant may be added, such as flavors and additional antimicrobial agents. The resulting liquid composition can be applied using absorbent pads, used to impregnate bandages and other dressings, or sprayed on the skin surface using a spray pump type or Aeros the selected nozzles or sprayers.

Liquid media can be used thickeners such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified cellulose or modified mineral materials, forming a distributed pastes, gels, ointments, Soaps and the like, for direct use to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. patent No. 4608392), Geria, (U.S. patent No. 4992478), Smith et al. (U.S. patent No. 4559157) and Wortzman (U.S. patent No. 4820508). Useful dosages of the compounds of formula I can be determined by comparing the in vitro activity and in vivo activity in animal models. Methods of extrapolation of effective dosages in mice and other animals to humans are known in this area, see U.S. patent No. 4938949.

Typically, the concentration of the compound(s) of formula I in a liquid composition, such as a lotion, is about 0.1-25 wt.%, preferably about 0.5-10 wt.%. Concentration in semi-solid or solid composition such as a gel or powder, is about 0.1-5 wt.%, preferably about 0.5-2.5 wt.%.

The number of connections, or an active salt or derivative required for use in treatment will vary not only according to otsypannoy specific salt, but also on the method of administration, the nature of the condition being treated, and on the dose and the condition of the patient, and ultimately at the discretion of the attending physician or Clinician.

Usually, however, a suitable dose is in the range of from about 1.0 to 100 mg/kg, preferably about 10 to about 75 mg/kg of body weight per day, more preferably from 5 to about 20 mg per kilogram of body weight of the recipient per day.

The connection may conveniently be in the form of dosage units; for example, tablets, drops, etc. containing 4-400 mg, preferably 10-200 mg, most preferably 20-100 mg of the active ingredient in the form of a unit dose.

Ideally the active ingredient should be introduced to achieve the peak plasma concentrations of the active compound of from about 0.02 to about 20 microns, preferably about 0.1-10 microns, most preferably about 0.5 to about 5 microns. These concentrations can be achieved, for example, by intravenous injection of 0.005-0.5% solution of the active ingredient, or be administered orally in the form of a bolus containing about 4-400 mg of the active ingredient.

Compounds of the invention can be administered via inhalation from an inhaler, insufflator, sprinklers or spray or using a sealed vial or other means of delivering an aerosol spray. Sealed, flako is s may include a suitable propellant, such as carbon dioxide or other suitable gas. In the case of a pressurized aerosol dosage unit may be determined by providing a valve, measuring metered quantity. Inhalers, insufflator, sprinklers fully described in the pharmaceutical reference literature, such as Remington's Pharmaceutical Sciences, Volumes 16 (1980) or 18 (1990) Mack Publishing Co.

The desired dose may conveniently be presented in the form of a single or a single dose or in separate doses, administered at appropriate intervals, for example, as two, three, four or more subds a day. Subdata itself can be further divided, for example, on a number of discrete injections with arbitrary intervals; such as multiple inhalations from insufflator or through the use of multiple drops in the eye.

All cited patents, patent applications, books or reference books and literature are included in this description by reference in its entirety. In the event of any irregularities dominated by the disclosure in the description of any definitions, data in it. The invention is described with reference to various specific and preferred embodiments and techniques. However, it should be understood that can be made in numerous variations and modifications without departing from the essence and scope of the invention.

From retina will now be illustrated using the following non-limiting examples.

EXAMPLES

Pharmacology

The ability of compounds of the invention act as antagonists And2Badenosine receptors may be determined using pharmacological models which are well known in this field, or using the testing procedures described below.

cDNA And2Breceptor of the rat was subcloned into the expression plasmid pDouble Trouble and techniques described Robeva, A. et al., inBiochem. Pharmacol.,51, 545-555 (1996). The amplified plasmid into competent JM109 cells and plasmid DNA purified using columns Wizard Megaprep (Promega Corporation, Madison, WI). And2Badenosine receptors were introduced into HEK-293 cells using lipofectin, as described by Felgner, P.L. et al.,Proc. Natl. Acad. Sci, USA,84, 7413-7417 (1987).

Cell culture

Transfetsirovannyh HEK cells were grown in 5% CO2/95% O2moist atmosphere at a temperature of 37aboutC. Colonies were selected in the growth of cells in 0.6 mg/ml G418. Transfetsirovannyh cells were kept in DMEM with the addition of a nutrient mixture of Hams F12 (1/1), 10% fetal calf serum, 2 mm glutamine, containing 50 IU/ml penicillin, 50 mg/ml streptomycin and 0.2 mg/ml geneticin (G418, Boehringer Mannheim). Cells were cultured in round cups with a diameter of 10 cm and subcultural before reaching the stage of confluence (approximately after 72 is Asa).

Research radioligand binding

And2Breceptors: Fused monolayers SOME AND2Bcells were washed in PBS followed by washing of the ice with buffer A (10 mm HEPES, 10 mm EDTA, pH 7.4) with protease inhibitors (10 μg/ml of benzamidine, 100 μm of phenylmethanesulfonyl and 2 µg/ml each of Aprotinin, pepstatin and leupeptin). Cells are homogenized in Polytron (Brinkmann) for 20 sec, centrifuged at 30,000×g and the precipitates were washed twice with buffer (10 mm HEPES, 1 mm EDTA, pH 7.4 with protease inhibitors). The final precipitates after centrifugation resuspendable in the buffer with the addition of 10% sucrose and frozen in aliquot at -80aboutC. For analyses linking, the membranes were thawed and diluted 5-10 fold NOT to a final protein concentration of approximately 1 mg/ml To determine the protein concentrations of the membrane and standards of bovine serum albumin was dissolved in 0.2% NaOH/0.01% of SDS and protein was determined using fluorescence fluorescamine. Stowell, C.P. et al.,Anal. Biochem.,85, 572-580 (1978).

Analysis of saturation binding for a2Badenosine receptor in rats was performed with [3H]ZM214,385 (17 CI/mmol, Tocris Cookson, Bristol UK)(Ji, X. et al.,Drug Design Discov.,16, 216-226 (1999)) or125I ABOPX (2200 CI/mmol). For cooking125I ABOPX, 10 ál of 1 mm AVOR in methanol/1M NaOH (20:1) was added to 50 μl of 100 mm phosphate buffer, the N 7.3. Added one or 2 MCI of Na125I followed 10 ál of 1 mg/ml chloramine-T in water. After incubation for 20 minutes at room temperature was added 50 μl of 10 mg/ml Na-metabisulfite in water for quenching the reaction. The reaction mixture was applied to a C18 HPLC column was suirable mixture of methanol and 5 mm phosphate, pH 6.0. After 5 min with 35% methanol concentration of methanol was increased to 100% for 15 minutes the Unreacted AVOR was elyuirovaniya in 11-12 minutes;125I ABOPX was elyuirovaniya through 18-19 min with access 50-6% compared to the original125I.

In the analysis of the binding ratio127I/125I ABOPX was 10-20/1. Experiments radioligand binding was repeated three times with 20-25 μg of membrane protein in a total volume of 0.1 ml NO buffer with the addition of 1 U/ml adenozindezaminazy and 5 mm MgCl2. The incubation time was 3 hours at 21aboutC. Nonspecific binding was measured in the presence of 10 μm NECA. Competition experiments were performed using a 0.6 nm125I ABOPX. Membranes were filtered in the filters Whatman GF/C using the collector cells Brandel (Gaithersburg, MD) and washed 3 times for 15-20 seconds of ice-cold buffer (10 mm Tris, 1 mm MgCl2, pH 7.4). Inmaxand KDvalues were calculated by non-linear interpolation by the method of least squares Marquardt for a single site-binding models. Marquardt, D.M.,J. Soc. Indst. Appl. Math.,11, 431-441 .21 (1963). The Ki values for the various compounds was calculated from the values of the IC50as described Linden, J.,J. Cycl. Res.,8, 163-172 (1982). Data from repeated experiments are given in the table as mean values ±SEM.

Other adenosine receptors: [3H]CPX. Bruns, R.F. et al.,Naunyn-Schmiedeberd''s Arch. Pharmacol.,335, 59-63 (1987).125I-ZM241385 and125I-AAD was used in the analysis of radioligand binding in relation to the membranes obtained from HEK-293 cells expressing recombinant rat And1And2Aand a3Ar, respectively. Binding of [3H]R-N6-phenylisopropylamine Schwabe, U. et al.,Naunyn-Schmiedeberd''s Arch. Pharmacol.,313, 179-187 (1980). ([3H]R-PIA, Amersham, Chicago, IL) with a1receptors of the membranes of the cerebral cortex of rats and [3H]CGS 21680. Jarvis, M.F. et al.,J. Pharmacol. Exp. Therap.,251, 888-893 (1989). (Dupont NEN, Boston, MA) with a2Areceptors of the membrane striatum of rats was performed as described. Adenosylmethionine (3 units/ml) was present during the preparation of the membranes of the brain, with prior incubation of 30 min at 30aboutTo and during incubation with the radio. All non-radioactive compounds were initially dissolved in DMSO and diluted with buffer to a final concentration at which the amount of DMSO did not exceed 2%. The incubation was ended by rapid filtration on a filter, the Ah Whatman GF/B collector cells Brandell (Brandell, Gathersburg, MD). Each tube was rinsed three times with 3 ml of buffer.

Used at least six different concentrations of the competitive substance in the range of 3 orders of magnitude, brought about for IC50each connection. The value of the IC50calculated using nonlinear regression, performed on the (Graph-Pad Prism, San Diego, CA), was turned into Ki values, as described. Linden, J.,J. Cycl. Nucl. Res.,8:163-172 (1982). Hill coefficients of the tested compounds was in the range of 0.8 to 1.1.

Functional analysis:

Cells SOME AND2Bone of the merging Kzt75 flask was rinsed free of CA2+and Mg2+buffered phosphate saline, Dulbecco (PBS) and then incubated in a free of CA2+and Mg2+HBSS with 0.05% trypsin and 0.53 mm EDTA as long as the cells are not separated. Cells were rinsed twice by centrifugation at 250×g in PBS and resuspendable in 10 ml HBSS, consisting of 137 mm NaCl, 5 mm KCl, 0.9 mm MgSO4, 1.4 mm CaCl2, 3 mm NaHCO3, 0.6 mm Na2HPO4, 0.4 mm KH3PO4, 5.6 mm glucose and 10 mm HEPES, pH 7.4 and CA2+-sensitive fluorescent dye indo-1-AM (5 μm) 37aboutC for 60 minutes. The cells were rinsed once and resuspendable in 25 ml of free dye in HBSS with the addition of 1 unit/ml adenozindezaminazy and kept at room temperature is round. Added antagonists adenosine receptor, prepared in the form OF 100 initial solutions in DMSO or diluent and cells transferred into the bath with the 37aboutWith in 2 minutes. Then cells (1 million in 2 ml) was transferred into a cuvette for mixing, sustained at 37aboutWith that in SLM Aminco 8000 an (SML instruments, Urbana, IL). Registered ratio of indo-1 fluorescence obtained at 400 and 485 nm (excitation, 332 nm) using a slit width of 4 nm. After 100 sec period equilibrium was added NECA.

The accumulation of cyclic AMR

Generating cyclic AMR was performed in DMEM/HEPES buffer (DMEM containing 50 mm HEPES, pH 7.4, 37aboutC). Each well with cells were washed twice in DMEM/HEPES buffer and then added 100 μl of solutions of adenozindezaminazy (final concentration of 10 IU/ml) and 100 μl of solutions of rolipram and cilostamide (final concentration of each 10 IU/ml) followed by addition of 50 μl of the test compounds (respective concentration) or buffer. After 15 minutes incubation at 37aboutWith ended with the removal of medium and addition of 200 μl of 0.1 m HCl. The acid extracts were stored at -20aboutWith up to analysis. Number of cyclic AMR was determined in accordance with the Protocol used by camp binding protein (PKA) [van der Wenden et al., 1995], with subsequent minor modifications. Buffer for analysis is osteal of 150 mm K 2HPO4/10 mm EDTA/0.2% BSA FV at pH 7.5. Samples (20 ml) were incubated for 90 minutes at 0aboutC. Incubate filtered through GF/C glass-fiber filters in the collection of cells Brandel M-24. Filters were additionally rinsed 4 times in 2 ml of 150 mm K2HPO4/10 mm EDTA (pH 7.5, 4aboutC). Filters with punched holes were counted in scintillation fluid Packard Emulsifier Safe after 2 hours of extraction.

Available test data on the affinity of the compounds of the invention are shown in table 1. The data for a2Brepresent the degree of substitution of specific [125I[ABOPX link in A2Bthe receptors in rats (rA2B), expressed in SOME 293 cells.

Synthesis and characterization

Proton nuclear magnetic resonance spectroscopy was performed on the spectrometer Varian 300 MHz spectrometer and spectra were taken in DMSO-d6or CDCl3. Unless otherwise stated, the chemical shifts were expressed as ppm in the weak field from tetramethylsilane or relative ppm from DMSO (2,5 ppm). Mass spectrometry with electrospray ionization (ESI) was performed using a mass spectrometer (ThermoFinnigan LCQ.

All derivatives of xanthine were homogeneous, as judged using TLC (silica gel 60 F254, 0.25 mm on an aluminum substrate, EM Science, Gibbstown, NJ) and HPLC (Shimadzu)using analytical column Varian C1 5 microns (4,6 nm×150 mm) in a linear gradient or isocratic solvent, with a volumetric flow of 1 ml/min is Used, the solvent system consisted of Meon (0,1% formic acid):N2On (0,1% formic acid). Peaks were detected by UV-absorbance at 232 nm and 254 nm. It was shown that the NMR and mass spectra consistent with the proposed structure.

Example 1. General methods

Getting 6-chloronicotinamide:

6-Hydroxynicotinic acid (1,444 g, 10.4 mmol) suspended in thionyl chloride (8 ml). Was added DMF (0,50 ml). The mixture was heated at the boil under reflux for 2 hours. After the reaction mixture was allowed to cool, the thionyl chloride was removed by a stream of nitrogen, the residue was dried in vacuum overnight and used directly in the next stage.

Obtaining 1,3-dipropyl-8-(6-chloro-3-pyridyl)xanthine (1):

6-Chloronicotinoyl obtained from 6-hydroxynicotinic acid (1.44 g, 10.4 mmol)in CH2Cl2(20 ml) was added dropwise to a solution of 5,6-diamino-1,3-dipropionate (1,81 g, 8 mmol) in dry pyridine (8.2 ml)maintained at 5aboutC. the Reaction mixture was heated to room temperature and was stirred for additional 3 hours. For damping the reaction was added water (50 ml). The solvent is evaporated, getting a dark colored oil. The oil was heated at the boil under reflux for 2 hours in the 2 norm. NaOH (20 ml). P is, after cooling the pH was carefully brought to 7 with concentrated HCl. The resulting solid was collected and washed with water (20 ml), ether (20 ml) and chloroform (20 ml), receiving not quite white solid (1.9 g). The product was used in the next stage without additional purification.

General methods of interaction 1,3-dipropyl-8-(6-chloro-3-pyridyl)xanthine (1) with substituted amines.

Compound 1 (40 mg, 0,115 mmol) and the appropriate substituted amine (0.5 ml or 0.5 g) was placed in a test tube under pressure. (If the boiling point of the amine was above 80aboutWith, as a solvent was added ethanol, 4 ml). The tube pressure was purged with argon, sealed and stirred the mixture at 160aboutC for 48-60 hours. After cooling, was added ether (10 ml). The obtained solid was collected and purified column chromatography on silica gel or preparative TLC (solvent: CH2Cl2:Meon=20:1 to 10:1 solvent: CH2Cl2:Meon:TEM=20:1:0.1 to 4:1:0,1).

General methods of preparing compounds of urea:

Aminosilane peregrinae connection (IC) (10 mg) suspended in dry THF (5 ml) in a test tube under pressure. Added isocyanate (0.25 ml). The mixture was stirred at 90aboutWith in 48 hours. After cooling, the solvent was evaporated. The residue was purified preparative TLC (CH2Cl2:Meon=11:1).

The General methodology of the amide compounds:

The amine is substituted peregrinae compound (15 mg) and the desired acid chloride of acid (4-6 equivalents) is suspended in dry DMF (2 ml). To the mixture was added pyridine (0.1-0.15 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed and the residue was purified column chromatography on silica gel or preparative TLC (CH2Cl2:Meon=11:1 or ethyl acetate:hexane:Meon=15:85:5).

Obtaining 1,3-diethyl-8-[6-hydrazino-3-pyridyl]xanthine (138):

Compound 1 (500 mg, 1.44 mmol) and hydrazine (4 ml) was placed in a test tube under pressure. Added ethanol (30 ml). The tube pressure was purged with argon, sealed and the mixture was stirred at 100-160aboutC for 10-16 hours. After cooling, the resulting solid substance was collected and washed with methanol and ether, receiving a connection 138 (40 mg). The product was used in the next stage without additional purification.

General methods of preparing compounds of formula IL:

Compound 138 (31.5 mg, 0.1 mmol) suspended in acetic acid (5 ml) in a test tube under pressure. Added the aldehyde or ketone (0.12 mmol). The tube pressure was purged with argon, sealed and the mixture was stirred at 160aboutC for 2-10 hours. After cooling, the resulting solid substance was collected and purified column chromatography on silica gel or preparative TLC (CH2Cl2: Meon=20:1 to 10:1)to give compound of formula IL.

Examples

Using the techniques described above, shall receive the following compounds of the invention.

Connection 1: 1,3-Dipropyl-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO, d6): δ 0,89 (m, 6H), to 1.59 (m, 2H), 1,73 (m, 2H), 3,88 (t, 2H, J=7.2 Hz), 4.00 points (t, 2H, J=7,2 Hz), to 7.68 (d, 1H, J=8,4 Hz)and 8.50 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), 9,07 (d, 1H, J=2.4 Hz).

MS: m/z 348 (M+H)+.

Connection 2: 1-Propyl-3-propargyl-8-(6-chloro-3-pyridyl)xanthine

MS: m/z 316 (M+H)+

Connection 3: 1,3-Dipropyl-8-(6-ethylamino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0,89 (m, 6H), 1.14 in (1,3H, J=7,2 Hz), and 1.56 (m, 2H), 1,72 (m, 2H), 3.33 and (m, 2H), 3,84 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), of 6.52 (d, 1H, J=8.7 Hz), to 7.09 (t, 1H), 8,00 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,72 (d, 1H, J=2.4 Hz).

MS: m/z 357 (M+H)+.

Connection 4: 1,3-Dipropyl-8-(6-(2-hydroxyethyl)amino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1.57 in (m, 2H), 1,71 (m, 2H), 3,36 (m, 2H), 3,53 (m, 2H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), to 4.73 (t, 1H, J=5.4 Hz), to 6.57 (d, 1H, J=8.7 Hz), 7,11 (t, 1H), to 7.99 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), to 8.70 (d, 1H, J=2.4 Hz).

MS: m/z 373 (M+H)+.

Connection 5: 1,3-Dipropyl-8-[6-(4-acetylpiperidine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0,84 (m, 6H), of 1.52 (m, 2H), by 1.68 (m, 2H), from 2.00 (s, 3H), 3,52 (m, 8H), 3,81 (t, 2H, J=7,2 Hz), of 3.96 (t, 2H, J=7,2 Hz), 6,92 (d, 1H, J=8.7 Hz), 8,14 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,79 (d, 1H, J=2.4 Hz).

MS: m/z 440 (M+H)+.

Connection 6: 1,3-Dipropyl-8-[6-(benzylamino)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.54 (m, 2H), 1,71 (m, 2H), 3,84 (t, 2H, J=7,2 Hz), 3,98 (who, 2H, J=7,2 Hz), of 4.54 (d, 2H, J=6.5 Hz), is 6.61 (d, 1H, J=8.7 Hz), 7,22 (m, 1H), 7,31 (m, 4H), 7,66 (t, 1H, J=6.0 Hz), 8,02 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,71 (d, 1H, J=2.4 Hz).

MS: m/z 419 (M+H)+.

Connection 7: 1,3-Dipropyl-8-[6-(1-piperidinyl)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.63 (m, 10H), 3,61 (t, 4H, J=5.7 Hz), 3,85 (t, 2H, J=7.2 Hz), 4.00 points (t, 2H, J=7,2 Hz), 6,91 (d, 1H, J=9.0 Hz), to 8.12 (DD, 1H, Ji=2.4 Hz, J2=9,0 Hz), 8,79 (d, 1H, J=2.4 Hz).

MS: m/z 397 (M+H)+.

Compound 8: 1,3-Dipropyl-8-(6-pyrrolidinone-3-yl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), of 1.55 (m, 2H), 1,73 (m, 2H), 1,95 (m, 4H), 3.43 points (m, 4H), 3,85 (t, 2H, J=7.5 Hz), 4.00 points (t, 2H, J=7.5 Hz), is 6.54 (d, 1H, J=9.0 Hz), to 8.12 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,79 (d, 1H, J=2.4 Hz).

MS: m/z 383 (M+H)+.

Connection 9: 1,3-Dipropyl-8-{6-[4-methyl(perhydro-1,4-diazepin-1-yl)]-3-pyridyl}xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (ush, 2H), 1,72 (m, 2H), of 1.88 (m, 2H), 2,47 (m, 5H), 2,60 (m, 2H), to 3.64 (t, 2H, J=6.0 Hz), of 3.77 (m, 2H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 6.73 x (d, 1H, J=9.0 Hz), to 8.12 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,78 (d, 1H, J=2.4 Hz).

MS: m/z 426 (M+2).

Connection 10: 1,3-Dipropyl-8-(6-methylamino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,8l(d, 3H, J=4.5 Hz), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), of 6.52 (d, 1H, J=8.7 Hz), 7,08 (kV, 1H, J=4.5 Hz), 8,01 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,73 (d, 1H, J=2.4 Hz).

MS: m/z 343 (M+H)+.

Connection 11: 1,3-Dipropyl-8-[6-(4-methoxybenzylamine)-3-pyridi is]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), to 1.59 (m, 2H), 1,71 (m, 2H), 3,71 (s, 3H), a 3.87 (t, 2H, J=7,2 Hz), 3,98 (t, 2H, J=7,2 Hz), of 4.45 (d, 2H, J=6.3 Hz), to 6.58 (d, 1H, J=9.0 Hz), 6.87 in (d, 2H, J=8.7 Hz), 7,25 (d, 2H, J=8,7 Hz), 7,60 (t, 1H), 8,01 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,71 (d, 1H, J=2.4 Hz).

MS: m/z 449 (M+H)+.

Connection 12: 1,3-Dipropyl-8-[6-(3-methylpiperidino)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 9H), 1.14 in (m, 1H), of 1.40 and 1.80 (m, 8H), to 2.55 (dt, 1H, J1=l Hz, J2=10.5 Hz), 2,86 (dt, 1H, J1=2.1 Hz, J2=10.5 Hz), 3,85 (t, 2H, J=7.5 Hz), 4.00 points (t, 2H, J=7.5 Hz), 4,30 (d, 2H, J=13.5 Hz), 6,92 (d, 1H, J=9.0 Hz), 8,10 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,79 (d, 1H, J=2.4 Hz).

MS: m/z 411 (M+H)+.

Connection 13: 1,3-Dipropyl-8-[6-(2-hydroxypropyl)amino-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), of 1.08 (d, 3H, J=6.0 Hz), and 1.56 (m, 2H), 1,72 (m, 2H), 3,26 (m, 2H), of 3.77 (m, 1H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), was 4.76 (d, 1H, J=4.5 Hz), 6,60 (d, 1H, J=9.0 Hz), 7,10 (t, 1H, J=6.0 Hz), to 7.99 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,69 (d, 1H, J=2.4 Hz).

MS: m/z 387 (M+H)+.

The connection 14: 1,3-Dipropyl-8-[6-(2,2-dimethoxymethyl)amino-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 3,29 (s, 6H), of 3.45 (t, 2H, J=5.7 Hz), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 4,49 (t, 1H, J=5.4 Hz), 6,62 (d, 1H, J=9.0 Hz), 7,19 (t, 1H, J=5,7 Hz), 8,00 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,71 (d, 1H, J=2.4 Hz).

MS: m/z 417 (M+H)+.

The connection 15: 1,3-Dipropyl-8-[6-(1-hydroxy-2-propyl)amino-3-pyridyl]xanthine

1H NMR (who MCO-d 6): δ 0.88 to (m, 6H), of 1.12 (d, 3H, J=6.6 Hz), and 1.56 (m, 2H), 1,74 (m, 2H), 3.27 to (m, 2H), 3.46 in (m, 1H), 3,85 (t, 2H, J=7,2 Hz), 3,98 (t, 2H, J=7,2 Hz), 4,74 (t, 1H, J=5.4 Hz), 6,56 (d, 1H, J=9.0 Hz), 6.90 to (d, 1H, J=7.5 Hz), 7,98 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,69 (d, 1H, J=2.4 Hz).

MS: m/z 387 (M+H)+.

The connection 16: 1,3-Dipropyl-8-(6-morpholino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), 1.57 in (m, 2H), 1,73 (m, 2H), 3,55 (m, 4H), of 3.69 (m, 4H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 6,94 (d, 1H, J=9.0 Hz), 8,17 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,83 (d, 1H, J=2.4 Hz).

MS: m/z 399 (M+H)+.

Connection 17: 1,3-Dipropyl-8-(6-dimethylamino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), of 1.55 (m, 2H), of 1.75 (m, 2H), to 3.09 (s, 6H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 6.73 x (d, 1H, J=9.0 Hz), 8,13 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,80 (d, 1H, J=2.4 Hz).

MS: m/z 357 (M+H)+.

The connection 18: 1,3-Dipropyl-8-[[6-(2-hydroxyethoxy)ethylamino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1.57 in (m, 2H), 1,72 (m, 2H), 3,49 (m, 8H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 4,59 (t, 1H, J=5.4 Hz), to 6.58 (d, 1H, J=9.0 Hz), to 7.15 (t, 1H), 8,00 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,71 (d, 1H, J=2.4 Hz), 13,42 (s, 1H).

MS: m/z 417 (M+H)+.

Connection 19: 1,3-Dipropyl-8-(6-piperazine derivatives-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,78 (m, 4H), 3,52 (m, 4H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), to 6.88 (d, 1H, J=9.0 Hz), 8,13 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,80 (d, 1H, J=2.4 Hz).

MS: m/z 398 (M+H)+.

Link is 20 : 1,3-Dipropyl-8-[6-(2-hydroxy-2-phenylethyl)amino-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 3,32 (m, 1H), 3,55 (m, 4H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), was 4.76 (m, 1H), of 5.55 (d, 1H, J=4.5 Hz), 6,63 (d, 1H, J=8.7 Hz), 7,20-7,40 (m, 6H), of 8.00 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,72 (d, 1H, J=2.4 Hz), 13,42 (s, 1H).

MS: m/z 449 (M+H)+.

Connection 21: 1,3-Dipropyl-8-[6-(4-aminomethylbenzoic)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0,86 (m, 6H), of 1.55 (m, 2H), 1,71 (m, 2H), and 3.72 (s, 2H), 3,84 (t, 2H, J=7,2 Hz), of 3.97 (t, 2H, J=7,2 Hz), 4,50 (d, 1H, J=6.0 Hz), to 6.57 (d, 1H, J=9.0 Hz), 7,27 (s, 4H), 7,54 (t, 1H, J=6.0 Hz), 8,00 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,68 (d, 1H, J=2.4 Hz).

MS: m/z 448 (M+H)+.

The connection 22: 1,3-Dipropyl-8-(6-phenylamino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), of 1.55 (m, 2H), 1,76 (m, 2H), 3,86 (t, 2H, J=7.5 Hz), to 4.01 (t, 2H, J=7.5 Hz), 6,93 (m, 2H), 7,29 (t, 2H, J=7.8 Hz), to 7.68 (d, 2H, J=7.8 Hz), 8,19 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,87 (d, 1H, J=2.4 Hz), to 9.45 (s, 1H).

MS: m/z 405 (M+H)+.

The connection 23: 1,3-Dipropyl-8-(6-cyclopropylamino-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ of 0.44 (m, 2H), 0,72 (m, 2H), 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,58 (m, 1H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), of 6.66 (d, 1H, J=9.0 Hz), was 7.36 (d, 1H, J=2.7 Hz), 8,10 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), a total of 8.74 (d, 1H, J=2.4 Hz).

MS: m/z 369 (M+H)+.

Connection 24: 1,3-Dipropyl-8-[6-(6-pyridylmethylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 3,84 (who, 2H, J=7,2 Hz), 3,98 (t, 2H, J=7,2 Hz), to 4.62 (d, 2H, J=6.0 Hz), to 6.67 (d, 1H, J=8.7 Hz), 7,25 (m, 2H), 7,73 (m, 2H), 8,04 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,51 (d, 1H, J=4,8 Hz), 8,69 (d, 1H, J=2.4 Hz).

MS: m/z 420 (M+H)+.

The connection 25: 1,3-Dipropyl-8-(6-(4-methylpiperazine)-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), of 2.21 (s, 3H), of 2.38 (t, 4H, J=4,8 Hz)and 3.59 (t, 4H, J=4,8 Hz), 3,85 (t, 2H, J=7.5 Hz), 4.00 points (t, 2H, J=7.5 Hz), 6,93 (d, 1H, J=9.0 Hz), 8,15 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,81 (d, 1H, J=2.4 Hz).

MS: m/z 412 (M+H)+.

The connection 26: 1,3-Dipropyl-8-[6-(3-pyridylmethylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,71 (m, 2H), 3,84 (t, 2H, J=7.5 Hz), 3,98 (t, 2H, J=7.5 Hz), 4,56 (d, 2H, J=5.7 Hz), 6,63 (d, 1H, J=8.7 Hz), 7,33 (DD, 1H, J1=4.5 Hz, J2=7,8 Hz), 7,71 (m, 2H), 8,04 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,43 (DD, 1H, J=1.8 Hz, J2=4.5 Hz), 8,55 (d, 1H, J=1.8 Hz), 8,71 (d, 1H, J=2.4 Hz).

MS: m/z 420 (M+H)+.

Connection 27: 1,3-Dipropyl-8-[6-(2-methylbenzylamino)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,31 (s, 3H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 4,50 (d, 2H, J=5.4 Hz), 6,62 (d, 1H, J=8.7 Hz), 7,10-7,25 (m, 4H) 7,51 (t, 1H, J=5.4 Hz), 8,01 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,72 (d, 1H, J=2.4 Hz).

MS: m/z 433 (M+H)+.

The connection 28: 1,3-Dipropyl-8-[6-[2-(3,4-acid), ethylamino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,77 (t, 2H, J=7.5 Hz), 3,49 (m, 2H), 3,70 (s, 3H), of 3.73 (s, 3H), 3,85 (t, 2H, J=7.5 for the TS) to 3.99 (t, 2H, J=7.5 Hz), 6,55 (d, J=9.0 Hz), 6,74 (DD, 1H, J1=1,8 Hz; J2=8,4 Hz), 6,85 (m, 2H), 7,17 (t, 1H, J=5.4 Hz), 8,01 (DD, J1=2.4 Hz, J2=9,0 Hz), 8,73 (d, 1H, J=2.4 Hz).

MS: m/z 493 (M+H)+.

The connection 29: 1,3-Dipropyl-8-[6-[(N-propellerblades)methylamino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 9H), and 1.54 (m, 4H), 1,72 (m, 2H), 3,17 (m, 2H), 3,30 (d, 3H, J=5.4 Hz), 3,86 (t, 2H, J=7.5 Hz), to 4.01 (t, 2H, J=7.5 Hz), the 7.43 (d, 1H, J=9.0 Hz), 8,01 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,99 (d, 1H, J=2.4 Hz), 9,29 (t, 1H, 5,4 Hz).

MS: m/z 428 (M+H)+.

The connection 30: 1,3-Dipropyl-8-[6-(3-pentylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 12H), 1,37-of 1.65 (m, 6H), 1,72 (m, 2H), 3,84 (m, 3H), 3,98 (t, 2H, J=7,2 Hz), is 6.54 (d, 1H, J=8.7 Hz), 6.90 to (d, 1H, J=8,4 Hz), of 7.96 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,67 (d, 1H, J=2.4 Hz).

MS: m/z 399 (M+H)+.

The connection 31: 1,3-Dipropyl-8-[6-(2,2-diphenylethylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0,86 (m, 6H), and 1.54 (m, 2H), 1,72 (m, 2H), 3,82-4,00 (m, 6H), 4,36 (t, 1H, J=7.5 Hz), 6,53 (d, 1H, J=9.0 Hz), 7,15-7,34 (m, 11H), of 7.97 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), the rate of 8.75 (d, 1H, J=2.4 Hz).

MS: m/z 509 (M+H)+.

The connection 32: 1,3-Dipropyl-8-[6-[2-(1-ethylpyridinium)]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), was 1.04 (t, 2H, J=7,2 Hz), 1,50 is 1.86 (m, 8H), 2,12 (m, 1H, in), 2.25 (m, 1H), 2,58 (m, 1H), 2,86 (m, 1H), 3,09 (m, 2H), 3,51 (m, 1H), 3,84 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 6,60 (d, 1H, J=9.0 Hz), 6,98 (ush., 1H), to 7.99 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), to 8.70 (d, 1H, J=2.4 Hz).

MS: m/z 440 (MN) +.

The connection 33: 1,3-Dipropyl-8-[6-(3-methoxybenzylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.54 (m, 2H), 1,72 (m, 2H), 3,71 (s, 3H), 3,85 (t, 2H, J=7,8 Hz)to 3.99 (t, 2H, J=7.8 Hz), 4,51 (d, 2H, J=6.0 Hz), is 6.61 (d, 1H, J=9.0 Hz), 6,70-6,91 (m, 3H), 7,22 (t, 1H, J=7.5 Hz), to 7.64 (t, 1H, J=6.0 Hz), 8,02 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,71 (d, 1H, J=2.4 Hz).

MS: m/z 449 (M+H)+.

The connection 34: 1,3-Dipropyl-8-[6-[(N-phenylcarbamoyl)methylamino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ O,88 (m, 6H), 1.57 in (m, 2H), of 1.75 (m, 2H), 3,44 (s, 3H), 3,86 (t, 2H, J=7.5 Hz), was 4.02 (t, 2H, J=7.5 Hz),? 7.04 baby mortality (t, 1H, J=7,2 Hz), 7,32 (t, 2H, J=7.5 Hz), of 7.48 (d, 1H, J=9.0 Hz), 7,60 (m, 3H), of 8.47 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 9,12 (d, 1H, J=2.4 Hz).

MS: m/z 462 (M+H)+.

The connection 35: 1,3-Dipropyl-8-[6-(furfurylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1.57 in (m, 2H), 1,73 (m, 2H), a 3.87 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), to 4.52 (d, 2H, J=5.7 Hz), 6,27 (d, 1H, J=3.0 Hz), 6,38 (m, 1H), and 6.3 (d, 1H, J=9.0 Hz), 7,56 (m, 2H), 8,03 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,73 (d, 1H, J=2.4 Hz).

MS: m/z 409 (M+H)+.

The connection 36: 1,3-Dipropyl-8-[6-[2-(4-methoxyphenyl)ethylamino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,77 (t, 2H, J=7.5 Hz), 3,47 (kV 2H, t=7.5 Hz), 3,71 (s, 3H), 3,85 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 6,55 (d, J=9.0 Hz), 6,85 (d, 2H, J=8,4 Hz), 7,16 (d, 2H, J=8,4 Hz), 8,00 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,73 (d, 1H, J=2.4 Hz).

MS: m/z 463 (M+H)+.

The connection 37: 1,3-Dipropyl-8-[6-(2-methoxybenzo the laminitis)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0,86 (m, 6H), and 1.56 (m, 2H), 1,71 (m, 2H), 3,82 (s, 3H), a 3.87 (t, 2H, J=7,2 Hz), 3,98 (t, 2H, J=7,2 Hz), 4,48 (d, 2H, J=6.0 Hz), 6,62 (d, 1H, J=9.0 Hz), 6.87 in (t, 1H, J=7,2 Hz), 6,98 (d, 1H, J=7,5 Hz), 7,20 (m, 2H), 7,46 (t, 1H, J=6.0 Hz), 8 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), to 8.70 (d, 1H, J=2.4 Hz).

MS: m/z 449 (M+H)+.

Compound 38: 1,3-Dipropyl-8-[6-(propylamino)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 9H), of 1.53 (m, 4H), 1,72 (m, 2H), 3,24 (q, 2H, J=6.3 Hz), 3,85 (t, 2H, J=7.5 Hz), 3,98 (t, 2H, J=7.5 Hz), 6,53 (d, 1H, J=8.7 Hz), 7,13 (t, 1H, J=5.7 Hz), to 7.99 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), to 8.70 (d, 1H, J=2.4 Hz).

MS: m/z 371 (M+H)+.

Connection 39: 1,3-Dipropyl-8-[6-(cyclopentylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1,40 is 1.75 (m, 10H), 1,72 (m, 2H), 3,84 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 4,17 (m, 1H), of 6.52 (d, 1H, J=8.7 Hz), 7,10 (d, 1H, J=6.6 Hz), to 7.99 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), to 8.70 (d, 1H, J=2.4 Hz).

MS: m/z 397 (M+H)+.

The connection 40: 1,3-Dipropyl-8-[6-(cyclohexylamino)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1,13 is 1.91 (m, 14H), 1,72 (m, 2H), 3,76 (m, 1H), 3,84 (t, 2H, J=7.5 Hz), 3,98 (t, 2H, J=7.5 Hz), of 6.52 (d, 1H, J=9.0 Hz), 7,00 (d, 1H, J=7.8 Hz), of 7.97 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,69 (d, 1H, J=2.4 Hz).

MS: m/z 411 (M+H)+.

The connection 41: 1,3-Dipropyl-7-ethyl-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), of 1.33 (t, 3H, J=7.2 Hz), to 1.59 (m, 2H), 1,73 (m, 2H), a 3.87 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 7,74 (d, 1H, J=8,4 Hz), 8,19 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), 74 (d, 1H, J=2.4 Hz).

MS: m/z 376 (M+H)+.

The connection 42: 1,3-Dipropyl-7-(3-forproper)-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 2,09 (m, 1H), 2,18 (m, 1H), with 3.89 (t, 2H, J=7.5 Hz), 3,98 (t, 2H, J=7.5 Hz), the 4.29 (t, 1H, J=5.4 Hz), 4,43 (m, 3H), of 7.75 (DD, Jl=0.6 Hz, J2=8,4 Hz), 8,19 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), a total of 8.74 (DD, 1H, J1=0.6 Hz, J2=2,4 Hz).

MS: m/z 408 (M+H)+.

The connection 43: 1,3-Dipropyl-7-methyl-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 3,86 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), to 4.01 (s, 3H), 7,74 (d, 1H, J=8,4 Hz), compared to 8.26 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), 8,82 (d, 1H, J=2.4 Hz).

MS: m/z 362 (M+H)+.

The connection 44: 1,3-Dipropyl-7-(2-bromacil)-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), to 1.59 (m, 2H), 1,72 (m, 2H), 3,85 (m, 4H), to 3.99 (t, 2H, J=7.5 Hz), of 4.66 (t, 2H, J=6.0 Hz), 7,76 (d, 1H, J=8.1 Hz), 8,21 (DD, 1H, J1=2.7 Hz, J2=8.1 Hz), 8,76 (d, 1H, J=2.7 Hz).

MS: m/z 456 (M+H)+.

The connection 45: 1,3-Dipropyl-8-[6-(2-thiophenemethylamine)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,72 (m, 2H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 4,70 (d, 2H, J=6.0 Hz), 6,60 (d, 1H, J=8.7 Hz), 6,94-7,03 (m, 2H), 7,35 (DD, 1H, J1=l,5 Hz, J2=5,1 Hz), of 7.70 (t, 1H, J=6.0 Hz), of 8.04 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), the rate of 8.75 (d, 1H, J=2.4 Hz).

MS: m/z 425 (M+H)+.

The connection 46: 1,3-Dipropyl-8-[6-[N-(4-methoxyphenylacetyl)methylamino]-3-pyridyl]Xanthi is

1H NMR (DMSO-d6): δ 0,89 (m, 6H), and 1.56 (m, 2H), 1,73 (m, 2H), 3.43 points (s, 3H), of 3.73 (s, 3H), a 3.87 (t, 2H, J=7,2 Hz), was 4.02 (t, 2H, J=7.2 Hz), 6.89 in (DD, 2H, J=6.9 Hz), of 7.48 (m, 3H), of 8.47 (DD, 1H, J1=the 2.4 Hz, J2=9,0 Hz), 9,11 (d, 1H, J=2.4 Hz).

MS: m/z 492 (M+H)+.

Connection 47: 1,3-Dipropyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), 1.57 in (m, 2H), 1,73 (m, 2H), 3,49 (s, 3H), 3,86 (t, 2H, J=7,2 Hz), 3,99 (t, 2H, J=7,2 Hz), 7,35 (DD, 1H, J1=7.8 Hz, J2=7,8 Hz), 7,41 (d, 1H, J=8,4 Hz), 7,71 (dt, 1H, J1=1.5 Hz, J2=8,4 Hz), 8,32 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), 8,46 (d, 1H, J=2,1), 8,54 (DD, 1H, J1=2.1 Hz, J2=4,8 Hz), 8,98 (d, 1H, J=2.4 Hz).

MS: m/z 448 (M+H)+.

The connection 48: 1,3-Dipropyl-8-[6-[N-(4-tortenelmebol)methylamino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1.57 in (m, 2H), of 1.75 (m, 2H), 3,44 (s, 3H), 3,88 (t, 2H, J=7.5 Hz), a 4.03 (t, 2H, J=7.5 Hz), to 7.15 (t, 2H, J=8.7 Hz), 7,49 (d, 1H, J=9.0 Hz), a 7.62 (m, 2H), of 8.47 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 9,12 (d, 1H, J=2.4 Hz).

MS: m/z 480 (M+H)+.

The connection 49: 1,3-Dipropyl-8-[6-[N-isonicotinoyl]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1.57 in (m, 2H), of 1.75 (m,2H), 3,47 (s, 3H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 7,26 (d, 2H, J=5.4 Hz), 7,46 (d, 1H, J=8.7 Hz), a 8.34 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 8,54 (d, 2H, J=5.4 Hz), 8,96 (d, 1H, J=2.4 Hz).

MS: m/z 448 (M+H)+.

The connection 50: 1,3-Dipropyl-8-[6-[N-methoxycarbonylmethylene]-3-pyridyl]xanthine

MS: m/z 401 (M+H)+.

Obedinenie 51 : 1,3-Dipropyl-8-[6-[N-phenylcarbamoyl-N-(2-phenylcarbamoyloxy)amino]-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), 1.57 in (m,2H), of 1.75 (m, 2H), a 3.87 (t, 2H, J=7.5 Hz), a 4.03 (t, 2H, J=7.5 Hz), 4,34 (m, 4H), 6,92-EUR 7.57 (m, 11H), 8,44 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 9,12 (d, 1H, J=2.4 Hz), 9,58 (ush.), 1H).

MS: m/z 611 (M+H)+.

The connection 52: 1,3-Dipropyl-8-{6-[4-(N-phenylcarbamoyl)]piperazine derivatives-3-pyridyl}xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,73 (m, 2H), only 3.57 (m, 4H), to 3.67 (m, 4H), 3,86 (t, 2H, J=7,2 Hz), to 4.01 (t, 2H, J=7,2 Hz), 6,93 (t, 1H, J=7.8 Hz), of 6.99 (d, 1H, J=9.0 Hz), 7.23 percent (t, 2H, J=7.8 Hz), 7,46 (d, 2H, J=7.8 Hz), 8,19 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,61 (s, 1H), cent to 8.85 (d, 1H, J=2.4 Hz).

MS: m/z 517 (M+H)+.

The connection 53: 1,3-Dipropyl-8-{6-[4-(N-isonicotinoyl)]piperazine derivatives-3-pyridyl}xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,73 (m, 2H), 3,38 (m, 2H), to 3.64 (m, 2H, in), 3.75 (m, 4H), 3,86 (t, 2H, J=7.2 Hz), 4.00 points (t, 2H, J=7,2 Hz), of 6.96 (d, 1H, J=9.0 Hz), 7,44 (d, 2H, J=5,1 Hz), 8,19 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,69 (d, 2H, J=5,1 Hz), 8,84 (d, 1H, J=2.4 Hz).

MS: m/z 503 (M+H)+.

The connection 54: 1-propyl-3-(4-methoxyphenyl)ethyl-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 0,84 (t, 3H, J=7.2 Hz), 1,53 (m, 2H), with 2.93 (t, 2H, J=7,2 Hz) to 3.67 (s, 3H), 3,83 (t, 2H, J=7,2 Hz), 4,20 (t, 2H, J=7,2 Hz), for 6.81 (d, 2H, J=8.1 Hz), 7,12 (d, 2H, J=8.1 Hz), to 7.68 (d, 1H, J=8,4 Hz), 8,44 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), 8,98 (d, 1H, J=2.4 Hz).

MS: m/z 440 (MH-H)+.

The connection 55: 1-propyl-3-(methoxyphenylacetyl)-8-(6-piperazine derivatives-3-pyrid the l)xanthine

1H NMR (DMSO-d6): δ 0,84 (m, 3H), of 1.52 (m, 2H), 3,38 (m, 2H), 2,77 (m, 4H), to 2.94 (t, 2H, J=7.5 Hz), 3,51 (m, 4H), of 3.69 (s, 1H), 3,83 (t, 2H, J=7.5 Hz), 4,20 (t, 2H, J=7.5 Hz), 6,83 (d, 2H, J=8,4 Hz), 6.89 in (d, 1H, J=9,0 Hz), 7,14 (d, 2H, J=8,4 Hz)to 8.14 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,82 (d, 1H, J=2.4 Hz).

MS: m/z 490 (M+H)+.

The connection 56: 1,3-Dipropyl-8-[6-(4-pyridylamino)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,74 (m, 2H), a 3.87 (t, 2H, J=7.5 Hz), a 4.03 (t, 2H, J=7.5 Hz), 6.30-in (d, 2H, J=7.8 Hz), 7,94 (d, 1H, J=8.7 Hz), 8,53 (d, 1H, J=7.8 Hz), at 8.60 (DD, 1H, J1=2.4 Hz, J2=8,7 Hz), 9,17 (d, 1H, J=2.4 Hz).

MS: m/z 407 (M+2)+.

Connection 57: 1,3-Dipropyl-8-{6-[4-(N-nicotinoyl)]piperazine derivatives-3-pyridyl}xanthine

1H NMR (DMSO-d6): δ 0.88 to (m, 6H), and 1.56 (m, 2H), 1,74 (m, 2H), 3.46 in-a 3.83 (m, 8H), 3,88 (t, 2H, J=7.5 Hz), 4.00 points (t, 2H, J=7.5 Hz), of 6.96 (d, 1H, J=9.0 Hz), to 7.50 (DD, 1H, J1=7.8 Hz, J2=7,8 Hz), 7,89 (d, J=7.5 Hz), 8,19 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,66 (m, 2H), 8,84 (d, 1H, J=2.4 Hz).

MS: m/z 503 (M+H)+.

The connection 58: 1,3-Dipropyl-8-[6-(hexahydro-1,4-diazepin-1-yl)-3-pyridyl]xanthine

1H NMR (DMSO-d6): δ 0.87 (m, 6H), and 1.56 (m, 2H), 1,74 (m, 4H), to 2.66 (t, 2H, J=5.4 Hz), of 2.86 (t, 2H, J=5.4 Hz), 3,68 (m, 4H), 3,85 (t, 2H, J=7.5 Hz), 3,99 (t, 2H, J=7.5 Hz), 6,72 (d, 1H, J=9.0 Hz), 8,10 (DD, 1H, J1=2.4 Hz, J2=9,0 Hz), 8,77 (d, 1H, J=2.4 Hz).

MS: m/z 412 (M+H)+.

Connection 59: 1,3-Diethyl-8-(6-chloro-3-pyridyl)xanthine

1H NMR (DMSO-d6): δ 1.14 in (t, 3H, J=6.9 Hz), 1.26 in (t, 3H, J=6.9 Hz), of 3.94 (q, 2H, J=6.9 Hz), 4.09 to (q, 2H, J=6.9 Hz), and 7.6 (d, 1H, J=8,4 Hz), 8,46 (DD, 1H, J1=2.4 Hz, J2=8,4 Hz), 9,07 (d, 1H, J=2.4 Hz).

MS: m/z 320 (M+H)+,

The connection 60: 1,3-Diethyl-8-(6-piperazine derivatives-3-pyridyl)xanthine

MS: m/z 370 (M+H)+.

The connection 61: 1,3-Diethyl-8-[6-[(N-phenylcarbamoyl)methylamino]-3-pyridyl]xanthine

MS: m/z 434 (M+H)+.

The connection 62: 1,3-Diethyl-8-[6-[N-nicotinanilide]-3-pyridyl]xanthine

MS: m/z 434 (M+H)+.

Connection 63: 1,3-Diethyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 315 (M+H)+.

The connection 64: 1,3-Diethyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine

MS: m/z 420 (M+H)+.

The connection 65: 1,3-Diethyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine

MS: m/z 446 (M+H)+.

Compound 66: 1,3-Dicyclopropyl-8-(6-methylaminomethyl-3-yl)xanthine

MS: m/z 367 (M+H)+.

Connection 67: 1-Propargyl-3-methyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 311 (M+H)+.

The connection 68: 8-[6-(2,5-diazabicyclo[2.2.2]Oct-2-yl)pyridine-3-yl]-1,3-dipropyl-3,7-dihydropyran-2,6-dione

MS: m/z 410 (M+H)+.

Connection 69: 1,3-Dicyclopropyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine

MS: m/z 472 (M+H)+.

The connection 70: 1,3-Dicyclopropyl-8-[6-[N-nicotinanilide]-3-pyridyl]xanthine

MS: m/z 486 (M+H)+.

Connection 71: 1,3-Diallyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 339 (M+H)+.

The connection 72: 1-Cyclopropyl-3-ethyl-8-(6-methylaminomethyl-3-yl)xanthine

MS: m/z 342 (M+H)+.

Connection 73: 1,3-Diethyl-8-[6-(2-pyridylmethylamine)-3-pyridyl]xanthine

MS: m/z 392 (M+H)+.

The connection 74: 1,3-Diethyl-8-[6-(3-pyridylmethylamine)-3-pyridyl]xanthine

MS: m/z 392 (M+H)+.

Connection 75: 1,3-Diethyl-8-[6-(3-methoxybenzylamine)-3-pyridyl]xanthine

MS: m/z 421 (M+H)+.

The connection 76: 1,3-Dipropyl-8-[6-[2-(3-pyridyl)ethylamino]-3-pyridyl]xanthine

MS: m/z 434 (M+H)+.

Connection 77: 1,3-Diethyl-8-[6-[2-(3-pyridyl)ethylamino]-3-pyridyl]xanthine

MS: m/z 406 (M+H)+.

The connection 78: 1,3-Dipropyl-8-[6-[2-(2-pyridyl)ethylamino]-3-pyridyl]xanthine

MS: m/z 434 (M+H)+.

Connection 79: 1,3-Diethyl-8-[6-[2-(2-pyridyl)ethylamino]-3-pyridyl]xanthine

MS: m/z 406 (M+H)+.

The connection 80: 1,3-Diethyl-8-(6-pyrrolidinone-3-yl)xanthine

MS: m/z 355 (M+H)+.

Connection 81: 1,3-Diethyl-8-[6-[2-(1-pyrrolidinyl)ethylamino]-3-pyridyl]xanthine

MS: m/z 398 (M+H)+.

The connection 82: 1,3-Dipropyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine

MS: m/z 387 (M+H)+.

Connection 83: 1,3-Dipropyl-8-(6-(2-acetylamino)amino-3-pyridyl)xanthine

MS: m/z 414 (M+H)+.

The connection 84: 1,3-Diethyl-8-(6-bromo-3-pyridyl)xanthine

MS: m/z 364 (M+H)+.

Connection 85: 1,3-Dipropyl-8-{6-[4-(2-pyridi is)piperazine derivatives]-3-pyridyl}xanthine

MS: m/z 475 (M+H)+.

Connection 86: 1,3-Diethyl-8-{6-[4-(2-pyridyl)piperazine derivatives]-3-pyridyl}xanthine

MS: m/z 447 (M+H)+.

Connection 87: 1,3-Diethyl-8-[6-(TRANS-2,5-dimethylpiperazine)-3-pyridyl]xanthine

MS: m/z 398 (M+H)+.

The connection 88: 1,3-Dipropyl-8-{6-[4-(2-pyrimidinyl)piperazine derivatives]-3-pyridyl}xanthine

MS: m/z 476 (M+H)+.

Connection 89: 1,3-Diethyl-8-{6-[4-(2-pyrimidinyl)piperazine derivatives]-3-pyridyl}xanthine

MS: m/z 448 (M+H)+.

Connection 90: 1,3-Diethyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine

MS: m/z 359 (M+H)+.

Connection 91: 1-Propargyl-3-methyl-8-(6-bromo-3-pyridyl)xanthine

MS: m/z 360 (M+H)+.

The connection 92: 1,3-Diethyl-8-[6-[N-nicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine

MS: m/z 464 (M+H)+.

Connection 93: 1-Propargyl-3-methyl-8-(6-(2-methoxyethyl)-3-pyridyl)xanthine

MS: m/z 355 (M+H)+.

Connection 94: 1,3-Diethyl-8-[6-[N-isonicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine

MS: m/z 464 (M+H)+.

Connection 95: 1-(5-(1,3-Diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purine-8-yl)pyridine-2-yl)-1-(2-methoxyethyl)-3-(pyridin-4-yl)urea

MS: m/z 479 (M+H)+.

Connection 96: 1,3-Dimethyl-8-(6-bromo-3-pyridyl)xanthine

MS: m/z 460 (M+H)+.

Connection 97: 1,3-Dimethyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 287 (M+H)+.

Connection 98: 1,3-Dimethyl-8-[6-[N-nicotine is methylamino]-3-pyridyl]xanthine

MS: m/z 392 (M+H)+.

Connection 99: 1,3-Dipropyl-8-[6-[N-nicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine

MS: m/z 492 (M+H)+.

Connection 100: 1-Propargyl-3-methyl-8-[6-[N-nicotinoyl-N-(2-methoxyethyl)amino]-3-pyridyl]xanthine

MS: m/z 359 (M+H)+.

Connection 101: 1-Propargyl-3-methyl-8-(6-[N-nicotinylcodeine]-3-pyridyl]xanthine

MS: m/z 416 (M+H)+.

Connection 102: 1,3-Dipropyl-8-(2,6-dichloro-3-pyridyl)xanthine

MS: m/z 382 (M+H)+.

Connection 103: 1,3-Dipropyl-8-(2,6-dimethylamino-3-pyridyl)xanthine

MS: m/z 372 (M+H)+.

The connection 104: 1,3-Dipropyl-8-(2,6-di(2-methoxyethyl)-3-pyridyl)xanthine

MS: m/z 460 (M+H)+.

Connection 105: 1,3-Dipropyl-8-[2,6-di[N-nicotinylcodeine]-3-pyridyl]xanthine

MS: m/z 582 (M+H)+.

The connection 106: 1,3-Dipropyl-8-[2,6-di[N-nicotinoyl-N-methoxyethyl]-3-pyridyl]xanthine

MS: m/z 670 (M+H)+.

Connection 107: 1,3-Diethyl-8-[6-[N-(2-parsingerror)methylamino]-3-pyridyl]xanthine

MS: m/z 421 (M+H)+.

The connection 108: 1,3-Diethyl-8-[6-[N-(isoxazol-5-carbonyl)methylamino]-3-pyridyl]xanthine

MS: m/z 410 (M+H)+.

Connection 109: 1,3-Dipropyl-8-[6-[N-(2-parsingerror)methylamino]-3-pyridyl]xanthine

MS: m/z 449 (M+H)+.

The connection 110: 1,3-Dipropyl-8-[6-[N-(isoxazol-5-carbonyl)methylamino]-3-pyridyl]xanthine

MS: m/z 438 (M+H)+.

With the unity 111 : 1,3-Dipropyl-8-[6-[N-(5-methylisoxazol-3-yl-3-carbonyl)methylamino]-3-pyridyl]xanthine

MS: m/z 452 (M+H)+.

The connection 112: 1,3-Dipropyl-8-[6-[N-(2-chloro-6-methoxypyridine-4-carbonyl)-N-methylamino]-3-pyridyl]xanthine

MS: m/z 512 (M+H)+.

Connection 113: 1,3-Dipropyl-8-[6-[N-(isonicotinoyl N-oxide) N-methylamino]-3-pyridyl]xanthine

MS: m/z 464 (M+H)+.

The connection 114: 1-propyl-3-(4-methoxyphenyl)ethyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 435 (M+H)+.

Connection 115: 1,3-Diethyl-8-[6-[N-(isonicotinoyl N-oxide) N-methylamino]-3-pyridyl]xanthine

MS: m/z 436 (M+H)+.

The connection 116: 1,3-Diallyl-8-(6-chloro-3-pyridyl)xanthine

MS: m/z 344 (M+H)+.

Connection 117: 1-Propyl-3-(4-methoxyphenyl)ethyl-8-[6-(N-nicotinylcodeine)-3-pyridyl]xanthine

MS: m/z 540 (M+H)+.

The connection 118: 1-Propyl-3-(4-methoxyphenyl)ethyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine

MS: m/z 574 (M+H)+.

Connection 119: 1,3-Diallyl-8-[6-(N-nicotinylcodeine)-3-pyridyl]xanthine

MS: m/z 444 (M+H)+.

Connection 120: 1,3-Diallyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine

MS: m/z 478 (M+H)+.

Connection 121: 1,3-Dipropyl-8-[6-(N-[6-(trifluoromethyl)nicotinoyl]methylamino)-3-pyridyl]xanthine

MS: m/z 516 (M+H)+.

The connection 122: 1,3-Diethyl-8-[6-(2-hydroxy-5-methyl)benzaldehyde-3-pyridyl]xanthine

MS: m/z 434 (M+H)+.

Connection 123: 1-Cyclopropyl-3-propyl-8-[6-(N-[6-trifluoromethyl)nicotinoyl]methylamino)-3-pyridyl]xanthine

MS: m/z 446.

The connection 124: 1,3-Diethyl-8-[6-(bromopyridin-3-carbaldehydes)-3-pyridyl]xanthine

MS: m/z 483 (M+H)+.

Connection 125: 1-Cyclopropyl-3-ethyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 327 (M+H)+.

Connection 126: 1-Cyclopropyl-3-propyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 341 (M+H)+.

Connection 127: 1-Propyl-3-cyclopropyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 341 (M+H)+.

Connection 128: 1-Cyclopropyl-3-propyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine

MS: m/z 385 (M+H)+.

Connection 129: 1-Cyclopropyl-3-propyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine

MS: m/z 446 (M+H)+.

The connection 130: 1,3-Diethyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine

MS: m/z 454 (M+H)+.

Connection 131: 1,3-Dipropyl-8-(2-chloro-6-methoxyethylamine)-4-pyridyl]xanthine

MS: m/z 421 (M+H)+.

Connection 132: 1,3-Dipropyl-8-(2-chloro-6-methylamino)-4-pyridyl]xanthine

MS: m/z 377 (M+H)+.

Connection 133: 1,3-Dipropyl-8-[2-[N-nicotinoyl-N-(2-methoxyethyl)amino]-6-chloro-4-pyridyl]xanthine

MS: m/z 527 (M+H)+.

Connection 134: 1,3-Dipropyl-8-[2-[N-nicotinoyl-N-methylamino]-6-chloro-4-pyridyl]xanthine

MS: m/z 482 (M+H)+ .

Connection 135: 1-Cyclopropyl-3-propyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl]xanthine

MS: m/z 480 (M+H)+.

Connection 136: 1-Ethyl-3-cyclopropyl-8-(6-methylamino-3-pyridyl)xanthine

MS: m/z 327 (M+H)+.

Connection 137: 1-Ethyl-3-cyclopropyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine

MS: m/z 371 (M+H)+.

Connection 138: 1,3-Diethyl-8-[6-hydrazino-3-pyridyl]xanthine

MS: m/z 316 (M+H)+.

Connection 139: 1,3-Diethyl-8-[6-(cyclopropylamino)-3-pyridyl]xanthine

MS: m/z 341 (M+H)+.

The connection 140: 1,3-Diethyl-8-[6-(cyclopropylamino)-3-pyridyl]xanthine

MS: m/z 355 (M+H)+.

Connection 141: N'-[5-(1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)pyridine-2-yl]hydrazide

MS: m/z 421 (M+H)+.

Connection 142: N-[5-(1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)pyridine-2-yl]-N'-(pyridine-3-carbonyl)hydrazide

MS: m/z 526 (M+H)+.

Connection 143: 1,3-Diethyl-8-[6-(ethylamino)-3-pyridyl]xanthine

MS: m/z 329 (M+H)+.

Connection 144: 1,3-Diethyl-8-[6-[N-nicotinereplacement]-3-pyridyl]xanthine

MS: m/z 460 (M+H)+.

Connection 145: 1-Cyclopropylmethyl-3-ethyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl]xanthine

MS: m/z 480 (M+H)+.

1. The compound of formula I:

in which
R represents hydrogen, (C1-C5)al the sludge or halogen(C 1-C8)alkyl;
R1selected from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-;
R2selected from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)quinil, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl - or (C6-C10)aryl(C1-C8)alkyl-;
X represents 3-pyridyl substituted in the 6-th position Z;
Z represents a-NR4R5or (C4-C10)heterocycle, where the heterocycle optionally substituted by 1, 2, 3 or 4 substituents, independently selected from (C1-C8)alkyl;
each Z1represents independently halogen or-NR7R8;
R5selected from-C(O)R6, -CO2R6or-C(O)other7;
R4selected from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl, (C3-C10)heterocycle(C1-C8)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -(CH2)2-4Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6or-C(O)NR7R8;
or R4and R5together with ATO is AMI, to which they are attached, form a saturated mono - or bicyclic ring having 5, 6, 7, or 8 ring atoms and optionally containing 1 or 2 heteroatoms selected from naproxeno hydroxy
(-O-) and amine-N(R9- in the ring, where the ring is optionally substituted by 1, 2, 3 or 4 substituents, independently selected from-C(O)Raand-C(O)NRbRc;
X1represents-OR6; and Y is oxy (-O-);
where alkyl, Alchemilla, cycloalkyl, Alchemilla, aryl, heterocyclic or heteroaryl groups of R1, R2, R3, R4and R5groups optionally substituted by one or more substituents selected independently from (C1-C8)alkyl, -ORand, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl;
where R6is a (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl optionally substituted by 1, 2, 3 or 4 substituents, independently selected from halogen, -ORaand halogen(C1-C8)alkyl;
where R7, R8and R9are independently (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl optionally substituted by 1, 2, 3 or 4 substituents, n is dependent selected from halogen and-OR a;
Rarepresents hydrogen or (C1-C6)alkyl;
Rband Rceach independently represents hydrogen or (C6-C10)aryl; and
where n is 0, 1 or 2; and q is 1;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R represents hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or halogen(C1-C4)alkyl.

3. The compound according to claim 1, where R represents hydrogen, methyl, ethyl, -CH2-CH2-Cl, -CH2-CH2-Br, or-CH2-CH2-CH2-F.

4. The compound according to claim 1, where R represents hydrogen.

5. The compound according to claim 1, where R1is cyclopropyl or cyclopropylmethyl.

6. The compound according to claim 1, where R2is a (C1-C4)alkyl, (C3-C4)alkenyl,
(C3-C4)quinil, phenyl(C1-C4)alkyl or (methoxyphenyl)ethyl.

7. The compound according to claim 1, where R2is a (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-.

8. The compound according to claim 1, where R2is cyclopropyl or cyclopropylmethyl.

9. The compound according to claim 1, where R2represents methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, n-butyl, isobutyl, phenethyl or benzyl.

10. The compound according to claim 1, where R2represents the et is l, n-propyl or allyl.

11. The compound according to claim 1, where Z represents a-NR4R5.

12. The compound according to claim 1, where R4represents hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C4)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl, (C5-C6)heteroaryl, (C5-C6)heteroaryl(C1-C4)alkyl, -C(O)R6, -CO2R6or-C(O)NR7R8.

13. The compound according to claim 1, where R4represents hydrogen, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl, -(CH2-CH2-O)q(CH2-CH2)-ORa, -C(O)R6, -CO2R6or-C(O)NR7R8.

14. The compound according to claim 1, where R4represents hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diatexites, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7.

15. The compound according to claim 1, where R4represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, -C(O)R6, -CO2R6or-C(O)other7.

4and R5taken together with the nitrogen to which they are attached, represents pyrrolidine, piperidine, piperazinilnom, aspenlea, diazepinone or morpholinyl ring, each optionally substituted by 1, 2, 3 or 4 substituents, independently selected from-C(O)Raand-C(O)NRbRc.

17. The compound according to claim 1, where R6is a (C1-C6)alkyl or (C5-C6)heteroaryl, each optionally substituted by 1, 2 or 3 substituents, independently selected from the group consisting of halogen, -ORaand halogen(C1-C8)alkyl.

18. The compound according to claim 1, where R6is a (C5-C6)heteroaryl, which is optionally substituted by 1, 2 or 3 substituents, independently selected from halogen and halogen(C1-C8)alkyl.

19. The compound according to claim 1, where R6represents pyridyl, optionally substituted by F, Cl, Br, I or CF3.

20. The compound according to claim 1, where
R represents hydrogen, methyl or ethyl;
R1selected from cyclopropyl or cyclopropylmethyl;
R2selected from methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or n-butyl; and
X represents 3-pyridyl, substituted in position 6 by Deputy Z, where Z is a (C4-C10)heterocy the l or-NR 4R5where R4represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, and R5represents-C(O)R6where R6is heteroaryl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen and halogen(C1-C8)alkyl.

21. The compound according to claim 1, where R2selected from (C1-C4)alkyl, (C3-C4)alkenyl, (C3-C4)quinil or phenyl(C1-C4)alkyl.

22. The compound according to claim 1, where R represents hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or halogen(C1-C4)alkyl; and
R1selected from cyclopropyl and cyclopentenyl;
R2represents independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl, phenethyl or benzyl.

23. The compound according to claim 1, where R represents hydrogen, methyl, ethyl, -CH2-CH2-Cl, -CH2-CH2-Br, or-CH2-CH2-CH2-F; and
R1selected from cyclopropyl and cyclopropylmethyl;
R2represents independently methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl or (methoxyphenyl)ethyl.

24. The compound according to claim 1, where Z represents a-NR4R5where R4selected from hydrogen, (C1-C6)alkyl, (C3 -C6)cycloalkyl, (C6-C10)aryl, (C7-C12)aralkyl, (C5-C6)heteroaryl, (C5-C6)heteroaryl(C1-C4)alkyl-, -C(O)R6, -CO2R6or-C(O)NR7R8.

25. The compound according to claim 1 where Z is-NR4R5.

26. The compound according to claim 1, where R4and R5together with the nitrogen to which they are attached, form pyrrolidine, piperidine, piperazinilnom, aspenlea, diazepinone or morpholinyl ring, where the ring is optionally substituted by 1, 2, 3 or 4 substituents, independently selected from-COORaand-C(O)NRbRc.

27. The compound according to claim 1, where R4selected from hydrogen, (C1-C4)alkyl, hydroxy(C2-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, (C7-C10)aralkyl, (C5-C6)heteroaryl, -(CH2-CH2-O)q(CH2-CH2)-ORa, -C(O)R6, -CO2R6or-C(O)NR7R8.

28. The compound according to claim 1, where R4selected from hydrogen, methyl, ethyl, propyl, penttila, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethane, aminomethylbenzoic, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, -C(O)R6, -CO2R6or-C(O)other7.

29. The compound according to claim 1, where R6the submitted is a methyl or pyridyl, and R7represents phenyl, forfinal or methoxyphenyl.

30. The compound according to claim 1, where
R represents hydrogen, methyl or ethyl;
R1selected from cyclopropyl or cyclopropylmethyl;
R2selected from methyl, ethyl, allyl, propargyl, isopropyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl and isobutyl; and
Z represents a (C4-C10)a heterocycle.

31. The compound according to claim 1 where Z is selected from the group consisting of

32. The compound according to claim 1, where X(Z1)nZ is selected from the group consisting of



33. The compound according to claim 1, where R2represents n-propyl; R is hydrogen and n is zero.

34. The compound according to claim 1, where X(Z1)nZ is selected from the group consisting of





35. The compound according to claim 1, which is:
1-cyclopropyl-3-propyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
or its pharmaceutically acceptable salt.

36. The compound according to claim 1, selected from the group consisting of:
1,3-dicyclopropyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
1,3-dicyclopropyl-8-[6-[N-nicotinanilide]-3-pyridyl]xanthine;
1-cyclopropyl-3-propyl-8-[6-[N-nicotinylcodeine]-3-pyridyl]xanthine;
1-cyclopropyl-3-propyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl]xanthine;
1-cyclopropyl-3-ethyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl]xanthine;
or their pharmaceutically acceptable salts.

37. Pharmaceutical composition having antagonist activity in a2Badenosine receptor containing:
(a) a therapeutically effective amount of a compound according to claim 1 and
(b) pharmaceutically acceptable excipient.

38. Pharmaceutical composition having antagonist activity in a2Badenosine receptor containing:
(a) a therapeutically effective amount of a compound according p and
(b) pharmaceutically acceptable excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers and new polymers based on such monomers, intended for use in making two-photon photochromic recording media for three dimensional optical memory and photoswitches of optical signals. Description is given of monomers

Q=; ; ;

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H and X=CH2, O, S, NAlk; Y=O, S, NAlk; n=0-6; Q=; ; ; ; ;

Alk=CH3-C10H21, methods of obtaining them, photochromic polymers based on them, method of obtaining photochromic monomers and their application. The proposed materials exhibit thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

EFFECT: obtaining materials with thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

15 cl, 46 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: chemistry.

SUBSTANCE: ergot alkaloid is extracted from ergot with high yield and purity level using method including extraction of Claviceps purpurea, i.e. ergot, mix of solvents toluene/ethanol that leads to production of primary extract. The primary extract can be additionally treated within two stages of liquid-liquid extraction to provide alkaloid purification that gives purified toluene extract. Toluene extract can be additionally partially softened by stream, and crystalline product is produced by toluene crystallisation or mixture of toluene and aliphatic hydrocarbon.

EFFECT: development of method of ergot extraction with high yield and purity level.

23 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds of formula I which can be used in photopolymer composition hardening with catalyst, possible during rays, and as photoinitiators for coating preparation. In formulas (I) and (II) $ , in which R1 denotes phenyl, naphthyl, phenanthryl, anthryl, pyrenil 5,6,7,8-tetrahydro-2-naphthyl,5,6,7,8-tetrahydro-1-naphthyl, thienyl, tiantrenyl, anthraquinonyl, xantenyl, thioxantyl, phenoxantyinyl, carbazol, phenantridinyl, akridinyl, fluorenyl or phenoxazinyl, besides radicals is unsubstituted or once or several times substituted by C1-C18alkyl, C2-C18alkenyl, C1-C18haloalkyl, NO2, NR10R11, CN, OR12, SR12, halogen atom or radical of formula II or radical R1 denotes radical of formula III . R2 and R3 independently denote a hydrogen atom; R10, R11 R12 independently denote a hydrogen atom or C1-C18alkyl; R4 and R6 form C2-C12alkylen bridge, which is not substituted or substituted by or several C1-C4alkyl radicals; R15 denotes H or radical of formula II.

EFFECT: production of the nitrogen bases that can be used as a photopolymer composition, hardening with catalyst, and as photoinitiator for coating.

11 cl, 4 tbl, 21 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for synthesis of compounds of the formula (I): wherein one of substitutes A or B means hydrogen atom (H) and another one means aryl substituted optionally with one or two R2, heteroaryl substituted optionally with one or two R2, and so on; R represents H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl or -CHR3-OCO-(C1-C6)-alkyl or salt; R2 represents hydrogen atom, optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, and so on; R3 represents hydrogen atom, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Method for synthesis of these compounds involves the following steps: (a) condensation of substituted aldehyde of the formula: (A'-CHO) (17) wherein A' represents A, such as given above when B represents hydrogen atom; or B, such as given above when A represents hydrogen with derivative of 6-bromopenem of the formula (16): wherein R represents p-nitrobenzyl in the presence of Lewis acid and a weak base at low temperature that results to formation of intermediate aldol product of the formula (18): ; (b) interaction of intermediate compound of the formula (18) with chloroanhydride or acid anhydride of the formula: (R8)Cl or (R8)2O or with tetrahalogen methane of the formula: C(X1)4 and triphenylphosphine wherein R8 represents alkyl-SO2, aryl-SO2, alkyl-CO or aryl-CO; X1 represents Br, J or Cl atoms to form intermediate compound of the formula (19): wherein R9 represents X1 or -OR8, and conversion of intermediate compound of the formula (19) to the end compound of the formula (I). Also, invention relates to 4-nitrobenzyl-(5R,6S)-6-bromopenem-3-carboxylate of the formula (16) and to a method for its synthesis. Method involves the following steps: (A) (i) interaction of 6-aminopenicillanic acid with hydrobromic acid in organic solvent and water to form 6-bromopenicillanic acid of the formula (21): and its conversion to p-nitrobenzyl-6-bromopenicillanate of the formula (22): wherein R represents p-nitrobenzyl by interaction with 4-nitrobenzyl bromide in the presence of a base in organic solvent; (B) oxidation of compound of the formula (22) to form p-nitrobenzyl-6-bromopenicillanate-1-oxide of the formula (23) given in the invention description; (C) boiling compound of the formula (23) with 2-mercaptobenzothiazole in aromatic solvent to form 4-nirobenzyl-(2R)-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-3-enoate of the formula (24) given in the invention description; (D) dissolving compound of the formula (24) in organic solvent and interaction with an organic tertiary base to form 4-nitrobenzyl-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (25) given in the invention description; (E) conversion of compound of the formula (25) to 4-nitrobenzyl-2-[(3S,4R)-3-bromo-4-formylthio-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (26) given in the invention description as result of interaction of with organic acid in aromatic organic medium in the presence of a mixture acetic anhydride/organic tertiary base and trialkyl- or triarylphosphine in the range of temperature from about -10°C to about -30°C, and (F) passing ozonized oxygen through solution of compound of the formula (26) in organic solvent for 3-4 h at temperature from -70°C to -90°C and the following the intramolecular cyclization reaction using a phosphite reagent. Invention provides the increased yield and economy method for synthesis of derivatives of 6-alkylidenepenem.

EFFECT: improved method of synthesis.

41 cl, 2 tbl, 42 ex

FIELD: organic chemistry, medicine, pharmacy, biochemistry.

SUBSTANCE: invention relates to a method for treatment of states caused by activity of p38 kinase. Method involves administration to a patient needed in this treatment of at least one compound of the formula (I): or its pharmaceutically acceptable salt or solvate wherein R3 means hydrogen atom, methyl, perfluoromethyl, methoxy-group, halogen atom, cyano-group or NH2-group; X is chosen from -O-, -OC(=O)-, -S-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2-, -NR10-, -NR10C(=O)-, -NR10C(=O)NR11-, -NR10CO2-, -NR10SO2-, -NR10SO2NR11-, -SO2NR10-, -C(=O)NR10, halogen atom, nitro- and cyano-group, or X is absent; Z is chosen from oxygen (O), sulfur (S), nitrogen (N) atoms, and -CR20 being wherein Z means -CR20 optionally substituted bicyclic aryl or heteroaryl with R4 or R5; R1 means hydrogen atom, -CH3, -OH, -OCH3, -SH, -SCH3, -OC()=O)R21, -S(=O)R22, -SO2NR23R25, -CO2R21, -C(=O)NR24R25, -NH2, -NR24R25, -NR21SO2NR24R25, -NR21SO2R22, -NR24C(=O)R25, -NR24CO2R25, -NR21C(=O)NR24R25, halogen atom, nitro- or cyano-group; R2 is chosen from the following group: (a) hydrogen atom under condition that R2 doesn't mean hydrogen atom if X means -S(=O)-, -SO2-, -NR10CO2- or -NR10SO2-; (b) alkyl, alkenyl and alkynyl comprising up to four R26 groups or pentafluoroalkyl as substitutes; (c) aryl and heteroaryl comprising up to three groups R27 as substitutes, and (d) heterocyclo-group or heteroalkyl optionally comprising keto-group (=O), up to three groups R27 as substitutes, and/or comprising carbon-carbon bridge comprising 3-4 carbon atoms, or (e) R2 is absent if X means halogen atom, nitro- or cyano-group; R4 means substituted aryl, aryl comprising NOSE-alkyl, substituted heteroaryl or optionally substituted bicyclic 7-11-membered saturated or unsaturated carbocyclic or heterocyclic fragment as a substitute, and R5 means hydrogen atom, alkyl or substituted alkyl with exception of cases when Z means O or S and then R5 is absent, or R4 and R5 in common with Z form optionally substituted bicyclic 7-11-membered aryl or heteroaryl; R6 means hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group, substituted heterocyclo-group, -NR7R8, -OR7 or halogen atom; R10 and R11 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo-group and substituted heterocyclo-group; R7, R8, R21, R24 and R25 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group and substituted heterocyclo-group; R20 means hydrogen, lower alkyl or substituted alkyl, or R20 can absent if carbon atom to which is bound and in common with R4 and R5 represents part of bicyclic aryl or heteroaryl; R22 means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group or substituted heterocyclo-group; R26 is chosen from the following group: halogen atom, trifluoromethyl, halogenalkoxy-group, keto (=O)-, nitro-, cyano-group, -SR28, -OR28, -NR28R29, -NR28SO2, -NR28SO2R29, -SO2R28, -SO2NR28R29, -CO2R28, -C(=O)R28, -C(=O)NR28R29, -OC(=O)R28, -C(=O)NR28R29, -NR28C(=O)R29, -NR28CO2R29,=N-OH, =N-O-alkyl; aryl optionally comprising as a substitute from one to three R27 groups; cycloalkyl optionally comprising a substituted keto-group (=O), from one to three R27 groups, or carbon-carbon-containing bridge comprising of 3-4 carbon atoms; and heterocyclo-group comprising optionally as a substitute keto-group (=O), from one to three R27 groups or comprising carbon-carbon bridge comprising 3-4 carbon atoms, and wherein each R28 and R29 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl and (C3-C7)-heterocycle, or they can form in common (C3-C7)-heterocycle; and each R28 and R29, in turn, can comprise optionally up to two substitutes representing alkyl, alkenyl groups, halogen atoms, halogenalkyl groups, halogenalkoxy-, cyano-, nitro-, amino-, hydroxy-, alkoxy-, alkylthio-groups, phenyl, benzyl, phenyloxy- and benzyloxy-groups; and R27 is chosen from the following group: alkyl, R32 and (C1-C4)-alkyl comprising as substitutes from one to three R32groups and wherein each R32 group is chosen independently from the following group: halogen atom, halogenalkyl, halogenalkoxy-, nitro-, cyano-groups, -SR30, -OR30, -NR30R31, -NR30SO2, -NR30SO2R31, -SO2R30, -SO2NR30R31, -CO2R30, -C(=O)R30, -C(=O)NR30R31, --OC(=O)R30, -OC(=O)NR30R31, -NR30C(=O)R31, -NR30CO2R31 and from 3-7-membered carbocyclic or heterocyclic ring comprising optionally as a substitute alkyl, halogen atom, hydroxy-, alkoxy-group, halogenalkyl, halogenalkoxy-, nitro-, amino- or cyano-group, and wherein each R30 and R31 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl, and heterocycle, or they in common can form (C3-C7)-heterocycle. Also, invention describes pyrrolotriazine compounds, a pharmaceutical composition based on thereof and a method for treatment of inflammatory diseases using above proposed compounds and pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 14 tbl, 152 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) , methods for their synthesis and their using for therapeutic treatment of the nervous system disorders associated with 5-HT-6 receptor. Invention provides synthesis of novel biologically active substances of the formula (I) and pharmaceutical compositions based on thereof used in treatment of the nervous system disorders and controlled by 5-HT-6 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 tbl, 82 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I) wherein radical values are given in the invention claim that are novel histamine receptors antagonist. Preferable compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo]2,1-b][3]benazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-α]benzimidazole-4(10H)-one or its salts, isomers and N-oxides. Proposed compounds are useful in prophylaxis and treatment of increased intracranial pressure and/or secondary ischemia caused by craniocerebral trauma.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

13 cl, 13 tbl, 5 dwg, 14 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new derivatives of hydrochloride 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine of general formula: where . Compounds under this invention display haemorheological activity surpassing that of common pentoxifylline compound. Compounds represent hydrochloride 1,3-dimethy-7-(2-hydroxy-3- piperidinopropyl-1)-8-phenylaminoxanthine or hydrochloride 1,3- dimethy-7-[2-hydroxy-3-(2- chlorophenoxy)-propyl-1]-8- piperazinoxanthine.

EFFECT: production of compounds displaying haemorheological activity.

4 cl, 2 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

The invention relates to new chemical substances suitable for use as medicaments, in particular to the xanthine derivative of General formula I

R3where R1and R2lower alkyl;

R3the rest of the group, including tetrahydrofurane, thiophene, dithiolane, dithienyl, furan, optionally substituted by a group: -CH2OH, CHO, COOH,

-CH=where Alk denotes alkyl with 1-4 carbon atoms,

-CH=CH-CO-NO,

-CONHN-CH< / BR>
-CH=C< / BR>
-CH=C< / BR>
-CONH-(CH2)2N(Alk)2where Alk has the specified value, tetrahydrofuran, optionally substituted lower alkyl or the group-CH2CH2-CO-NO, or furan or thiophene, substituted lower alkyl or nitro-group or the unsubstituted cycloalkyl with 6-8 carbon atoms, cycloalkane or ticlea, alseny of Gruppman2,N,NH-phenyl, whereby phenyl may be substituted,NOH, -OCONH-phenyl, and phenyl may be samisens-COOCH3, -CH2COOCH3, -CH2CH2NH2, -OC(C6H5)3, -OALK, where Alk has the specified value, ОСОR4where R4matter: the rest campanulas acid, lower alkyl, phenyl, substituted lower alkoxyl, phenyl, methoxymethyl, six-membered nitrogen-containing heterocycle; cyclohexane, substituted cyanomethylene or oxyalkyl1-C4or hydroxy-group, or cyclopentane, substituted lower alkyl or phenyl, which may have as a second Deputy in genialnom position relative to the first hydroxyl group or ketal formula

or R3residue selected from the group:

(CH2)1,2< / BR>
ororin VI

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compound of the formula (I): or (II): wherein R1 and R2 are chosen independently from hydrogen, optionally substituted alkyl or the group: -D-E wherein R represents a covalent bond or alkylene; E represents optionally substituted alkoxy-group, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl under condition that if D represents a covalent bond then E can't represents alkoxy-group; R3 represents hydrogen atom, optionally substituted alkyl or optionally substituted cycloalkyl; X represents optionally substituted arylene or heteroarylene; Y represents a covalent bond or alkylene wherein one carbon atom can be substituted optionally for -O-, -S- or -NH-, and optionally substituted hydroxy-, alkoxy-, optionally substituted amino-group or -COR wherein R represents hydroxy-, alkoxy- or amino-group under condition that if an optional substitute represents hydroxy- or amino-group then it can't be adjacent with a heteroatom; Z represents hydrogen atom, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl under condition that Z represents hydrogen atom only under condition that Y represents a covalent bond, and X represents optionally substituted 1,4-pyrazolene, and under condition that if X represents optionally substituted arylene then Z represents optionally substituted monocyclic heteroaryl. Also, invention describes a method for treatment of the morbid state by inhibition of adenosine receptors describes as A2B based on compounds of the formula (I) or the formula (II). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

32 cl, 35 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention proposes compound of the formula (1) in free form or as a salt wherein R1, R2, R3, R4 and R5 have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.

EFFECT: valuable biochemical properties of derivatives.

6 cl, 3 tbl, 87 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

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