P38 kinase-inhibiting agents

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

 

The technical FIELD

The invention relates to heterobicyclic compounds that inhibit the action of p38 mitogen-activated protein kinase, protein kinase mammals, which is involved in cell proliferation, response of cells to stimuli and cell necrosis. In particular, the present invention relates to heterobicyclic compounds that are selective and effective inhibitors of p38 mitogen-activated protein kinase. The present invention also relates to pharmaceutical compositions containing data heterobicyclic compounds that inhibit p38 mitogen-activated the protein kinase.

The LEVEL of TECHNOLOGY

Mitogen-activated protein (MAP) kinase is a family of Proline-directed serine/treoninove kinases that are activated by dual phosphorylation and, in turn, phosphorylate their substrates, or on-site threonine-Proline or site serine-Proline.

MAP kinases are activated in response to a variety of signals, including stress caused by malnutrition, and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. p38 subgroup of MAP kinases (p38, also known as CSBP and RK) is a family of MAP kinases different isoforms that are responsible for the phosphorylation of a large set substrate is, including transcription factors (e.g., ATF2, CHOP and MEF2C), other kinases (e.g., MAPKAP-2 and MAPKAP-3), oncosuppressor (e.g., p53), and regulators of translation (for example, 3EBP, PRAK).

It is established that a large number of chronic and acute diseases associated with impaired inflammatory response. In this reaction involved a large number of cytokines, including IL-I, IL-6, IL-8 and TNF. Clarified that the expression, secretion and activation of these cytokines in the regulation of inflammation depends, at least in part, from activation of p38. This kinase is activated by dual phosphorylation after stimulation physiochemical stress, treatment with LPS or proinflammatory cytokines, such as IL-I and TNF.

TNF and interleukins, such as IL-I and IL-8, affect a large number of cells and tissues and are important inflammatory mediators large number of illnesses and diseases. TNF-α is a cytokine produced mainly activated monocytes and macrophages. Excessive or unregulated TNF synthesis involved in mediating a number of diseases. Recent studies have found that TNF plays a causal role in the pathogenesis of rheumatoid arthritis. Additional studies show that inhibition of TNF widely used for the treatment of inflammation, inflammatory bowel disease, mn is the divine sclerosis and asthma. TNF is also associated with viral infections, such as HIV, influenza virus and herpes virus, including herpes simplex virus type 1 (HSV-I), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr, human herpes virus-6 (HHV-6), human herpes virus-7 (HHV-7), human herpes virus-8 (HHV-8), pseudobalistes and intrachain, among others. IL-8 is a proinflammatory cytokine secreted by mononuclear cells, fibroblasts, endothelial cells and keratinocytes and is associated with pathological conditions, including inflammation.

IL-1 is synthesized by activated monocytes and macrophages and is involved in inflammatory response. IL-I is involved in many pathophysiological reactions, including rheumatoid arthritis, fever, and decreased bone resorption.

TNF, IL-I and IL-8 affect a large number of cells and tissues and are important mediators of inflammation a large number of diseases and conditions. Inhibition of these cytokines by inhibition of p38 kinase is useful for monitoring, mitigating and alleviating many of these diseases.

In the last few years it has been shown that p38 includes a group MAP I kinases, designated p38δ, p38γ, p38β, p38α. Jiang, Y. et al. (A Biol Chem I (1996) 271: 17920-17926) report classification p38β as protein, consisting of 372 s is nakilat, closely related p38-α. When comparing the activity of p38α activity p38β, the authors argue that while both of them are activated by proinflammatory cytokines and stress under the influence of the environment, p38β mainly activated MAP kinase-kinase 6 (MKK6) and preferentially activates the transcription factor 2, thereby indicating that these forms can be associated with different mechanisms of action. Kumar, S. et al. (Biochem Biophys Res Comm (1997) 235:533-538), and Stein, B. et al. (JBiol Chem (1997) 272: 19509-19517) reported second p38β isoforms--p38β2, containing 364 amino acids with 73% identity p38α. All of these messages prove that p38β is activated by proinflammatory cytokines and stress under the influence of the environment, although the latter reported p38β the isoform - p38β2, apparently, is predominantly expressed in the Central nervous system, heart and skeletal muscle, compared to the more widespread expression in tissues of p38α. In addition, it was observed that activated transcription factor-2 (ATF-2) is a better substrate for p38β2 than for p38α, thereby indicating that these forms can be associated with different mechanisms of action. Physiological role p38β1 was questioned in the last two messages, because it could not be detected in human tissue and it did not show noticeable kinase activity with substrates of p38α.

About about the narushenie p38γ reported Li, Z. et al. (Biochem Biophys Res Comm (1996)228:334-340), and p38δ reported Wang, X. et al. (JBiol Chem (1997) 272:23668-23674) and Kumar, S. et al. (Biochem Biophys Res Comm (1997) 235:533-538). The data suggest that these two p38 isoforms (γ and δ) are a unique subset of the MAPK family, based on their pattern of distribution in the tissues, the application of the substrate, the response to direct and indirect incentives and sensitivity to kinase inhibitors. About the different results regarding the different responses to drugs aimed at p38 family, as between p38α and assumed p38β1 or p38β2, or both, according to Jiang, Kumar and Stein, quoted above, as well as Eyers, P. A. et al. (Chem and Biol (1995)5:321-328). In an additional article, Wang, Y. et al. (JBiol Chem (1998)273:2161-2168) assumes the importance of these different effects. As noted by Wang et al., a number of incentives, such as myocardial infarction, hypertension, valvular heart diseases, viral myocarditis and dilated cardiomyopathy, lead to increased load on the heart and increased mechanical stress on cardiomyocytes.

It is reported that they lead to adaptive hypertrophic response which, if not controlled, is undoubtedly negative consequences. Wang et al. cite previous studies that showed that heart from ischemia-reperfusion damage, p38 MAPK activity increase due to hypertrophy what she and programmed cell death. Wang et al. indicate in the article that the activation of p38β activity results in hypertrophy, whereas activation of p38α activity leads to apoptosis of myocytes.

Thus, selective inhibition of p38α activity compared with p38β activity will be useful for the treatment of conditions associated with heart failure. State data I include congestive heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease, conditions associated with cardio-pulmonary bypass, aorta-coronary bypass grafts, and vascular grafts. Further, since the α-isoform is toxic in other types of muscle cells, α-selective inhibitors will be useful for conditions associated with cachexia attributed to TNF, or other conditions such as cancer, infection or autoimmune disease.

PCT application WO 98/06715, WO 98/07425, WO 98/28292 and WO 96/40143 describe the effect of inhibitors of p38 kinase in various diseases. As mentioned in these applications, inhibitors of p38 kinase are suitable for treatment of diseases associated with chronic inflammation. In these applications are rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic is OK gram-negative sepsis, toxic shock syndrome, asthma, syndrome of respiratory disorders in adults, stroke, reperfusion injury, damage to the Central nervous system, such as neuronal damage and ischemia, psoriasis, restenosis, cerebral malaria I, chronic pulmonary inflammatory disease, silicosis, excrescence of the soft tissues of the lung, diseases associated with bone resorption, such as osteoporosis, graft versus host, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), and fever.

The essence of the present invention

Compounds described by the chemical formula (A), or their pharmaceutically acceptable salts:

are inhibitors of p38 and are suitable for the treatment of inflammation, such as asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondilitis, osteoarthritis, gouty arthritis and other arthritic diseases; inflamed vessels, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; fever, pain, and other diseases associated with inflammation.

DETAILED DESCRIPTION of the PRESENT INVENTION

In one embodiment, the present invention relates to p38 and liberalsim compounds of chemical formula (A):

or their pharmaceutically acceptable salts, where:

L is chosen from the group consisting of:

(a) -C(O)-,

(b) -CH(OH)-,

(c) -CH(NR3R4)-,

(d) -C(=NOR3)-,

(e) -CH2and

(f) -S(O)n-where n is 0, 1 or 2;

Ar1represents optionally mono-, di - or tizamidine phenyl or heteroaromatic ring with 6 atoms, where the heteroaromatic ring may contain 1, 2 or 3 heteroatoms selected from N, S and O, where the substituents independently selected from the group consisting of:

(a) halogen,

(b)- (C1-4of alkyl,

(c) -O-C1-4of alkyl,

(d) -CF3,

(e) -NH2,

(f) -NH-CH3,

(g) -CN,

(h) -C(O)NH2and

(J) -S(O)n-CH3;

Ar2represents an optionally substituted thiadiazole or oxadiazole ring where the Deputy is a phenyl or 5 - or 6-membered monocyclic heteroaromatic or heterocyclic ring, or a bicyclic heteroaromatic or heterocyclic ring with 9 or 10 atoms, and mentioned heteroaromatic or heterocyclic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl, heteroaromatic or heterocyclic ring is optionally mono - or disubstituted by substituents, n is dependent selected from the group consisting of:

(a) halogen,

(b)- (C1-6the alkyl, optionally substituted by 1 to 4 fluorine atoms,

(s) -O-C1-6of alkyl,

(d) -CF3,

(e) -NH2and

(f) -NH2-CH3,

(g) -NH2-CH2CF3,

(h) -C(O)-morpholinyl,

(i) -C(O)-NR1R2,

(j) -C(O)OH,

(k) -CN,

(1) oxo, and

(m) C3-6cycloalkyl;

R1, R2, R3and R4independently selected from the group consisting of

(a) hydrogen, and

(b) C1-4of alkyl,

R1and R2or R3and R4can be connected, forming a 5 - or 6-membered saturated ring, and the said ring optionally contains a heteroatom selected from S, N and O.

In this embodiment, there is a group, where

L is chosen from the group consisting of:

(a) -C(O)- and

(b) -CH2-.

In this group there is a subgroup, where

L represents-C(O)-.

In this embodiment, there is a group, where

Ar1represents optionally mono-, di - or tizamidine phenyl or heteroaromatic ring with 6 atoms, where the heteroaromatic ring may contain 1, 2 or 3 heteroatoms selected from N, S and O, where the substituents independently selected from the group consisting of:

(a) halogen,

(b)- (C1-4the alkyl and

(c) -O-C1-4the alkyl.

In this group there is a subgroup, where

Ar1is own the th optionally mono-, di - or tizamidine phenyl or pyridyl, where the substituents independently selected from the group consisting of

(a) fluorine,

(b) chlorine and

(C) -CH3.

In this subgroup have a class where

Ar1represents optionally mono-, di - or tizamidine phenyl, where the substituents independently selected from the group consisting of

(a) fluorine,

(b) chlorine and

(C) -CH3.

In this embodiment, there is a group, where

Ar2represents an optionally substituted thiadiazolyl.

In this group there is a subgroup where the Deputy is a phenyl or 5 - or 6-membered monocyclic heteroaromatic or heterocyclic ring or bicyclic heteroaromatic or heterocyclic ring with 9 or 10 atoms, and mentioned heteroaromatic or heterocyclic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl, heteroaromatic or heterocyclic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:

(a) halogen,

(b)- (C1-6the alkyl, optionally substituted CF3,

(c) -O-C1-4of alkyl,

(d) -CF3and

(e) C3-6cycloalkyl.

In this subgroup have a class where the Deputy is a phenyl or 5 - yl is 6-membered monocyclic heteroaromatic or heterocyclic ring, mentioned heteroaromatic or heterocyclic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl, heteroaromatic or heterocyclic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:

(a) halogen,

(b)- (C1-6the alkyl, optionally substituted CF3,

(c) -O-C1-4of alkyl,

(d) -CF3and

(e) C3-6cycloalkyl.

In this embodiment, there is a group, where

R1, R2, R3and R4independently selected from the group consisting of

(a) hydrogen, and

(b) bromide.

In this embodiment, there is a group of the formula I

or its pharmaceutically acceptable salt, where

L represents-C(O)-;

Ar1represents optionally mono-, di - or tizamidine phenyl, where the substituents independently selected from the group consisting of:

(a) F,

(b) Cl,

(c) -C1-4the alkyl and

(d) -O-C1-4of alkyl;

Ar2is optionally substituted by thiadiazolyl, and Deputy represents phenyl or 5 - or 6-membered monocyclic heteroaromatic or heterocyclic ring, and mentioned heteroaromatic or heterocyclic ring contains 1, 2 or 3 heteroatom is, selected from the group consisting of S, O and N, where mentioned phenyl, heteroaromatic or heterocyclic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:

(a) halogen,

(b)- (C1-4of alkyl,

(c) -O-C1-4of alkyl,

(d) -CF3,

(e) C3-6cycloalkyl.

In this group there is a subgroup of the formula II

or its pharmaceutically acceptable salt, where

Ar2is optionally substituted by thiadiazolyl where the Deputy is a phenyl or -5 or 6-membered monocyclic heteroaromatic or heterocyclic ring, and mentioned heteroaromatic or heterocyclic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl, heteroaromatic or heterocyclic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:

(a) halogen,

(b)- (C2-6of alkyl,

(c) -O-C1-4the alkyl and

(d) -CF3.

As discussed above, p38 subgroup of MAP kinase is a family of MAP kinases different isoforms (including p38δ, p38γ, p38β, p38α), which are responsible for the phosphorylation of a large set later in the chain substrates. Data which show that two p38 isoforms (γ and δ) represent a unique subset of the MAPK family, based on their pattern of distribution in the tissues, the application of the substrate, the response to direct and indirect incentives and sensitivity to kinase inhibitors. About the different results regarding the different responses to drugs aimed at p38 family, as between p38α and or suspected p38β1, or p38β2, or both, according to Jiang, Kumar and Stein, quoted above, as well as Eyers, P. A. et al. (Chem and Biol (1995)5:321-328). In an additional article, Wang, Y. et al. (J Biol Chem (1998)273:2161-2168) assumes the importance of these different effects of selective inhibition of p38-α. Traditional inhibitors of p38-α inhibit phosphorylation of the next in the chain of substrates, including, but not limited to, MK2, MK3, ATF2, Mnk2a, MSK1, TAB1, CREB and HSP27. Based on these data, p38-α inhibitors, which mainly inhibit phosphorylation of a subset of data in subsequent circuit substrates must have a high therapeutic index in comparison with traditional p38 inhibitors.

Accordingly, in one aspect, the present invention relates to compounds of the formula I, which are selectively and preferentially inhibit p38-α compared with p38β, and/or p38δ, and/or p38γ. This aspect relates to compounds of the formula I, which preferably inhibit p38-α compared the structure with p38β, and/or p38δ, and/or p38γ, as measured byin vitrokinase analysis.

In still another aspect, the present invention relates to compounds of the formula I, which are effective inhibitors of p38-α and selectively and preferentially inhibit the phosphorylation of one or more of MK2, MK3, ATF2, Mnk2a, MSK1 and TAB1, compared to the remaining or other subsequent circuit substrates. For example, in one aspect, the present invention relates to compounds of the formula I, which are selectively and preferentially inhibit phosphorylation of MK2 and MK3 compared with MSK1, ATF2 or peptide substrate. This aspect includes compounds of formula 1, which are effective inhibitors of p38-α and selectively and preferably inhibit phosphorylation of MK2 compared to the peptide substrate, as measured byin vitrokinase analysis.

The term "acetal" refers to a functional group or a molecule containing a CH group associated with two-OR groups. Thus, cyclic acetal" refers to a cyclic or ring structure containing acatalog group.

The term "alkyl" refers to a carbon chain that contains no double or triple links and which can be linear, branched or combination thereof. Thus, C1-C6alkyl determine to refer to the group as containing 1, 2, 3, 4, 5 �if 6 carbon atoms in such arrangement, which is a linear, branched or combination thereof. Examples of alkyl groups include methyl, ethyl, propyl,n-propyl, isopropyl, butyl,Deut- andtert-butyl, pentyl, hexyl, heptyl and the like. The term "C0-C4alkyl" includes alkali containing 4, 3, 2, 1, or does not contain carbon atoms. Alkyl not containing carbon atoms, is a Deputy, which is a hydrogen atom when a represents an alkyl end group. Alkyl not containing carbon atoms, a represents a direct bond, when the alkyl is a bridge group. The term "alkene" refers to linear or branched structures and combinations thereof, with the specified number of carbon atoms containing at least one double bond in the carbon-carbon, where the hydrogen can be replaced by the additional double bond carbon-carbon. C2-C6alkene, for example, include ethylene, propylene, 1-mutilation, butylene and the like.

The term "quinil" denotes a linear or branched structures and combinations thereof, with the specified number of carbon atoms containing at least one triple bond of carbon-carbon. Thus, C2-C6quinil determine to refer to groups containing 2, 3, 4, 5 or 6 volumes of carbon linear or branched structure, so that C2 -C6quinil more specifically includes 2-hexenal and 2-pentenyl.

The term "alkoxy", as used in the present invention, separately or in combination, include an alkyl group that is connected with the connecting oxygen atom. The term "alkoxy" also includes alkylamine group, where the term "alkyl" defined above, and "ether" denotes two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, isopropoxy,n-butoxy,Deut-butoxy,tert-butoxy, methoxymethyl (also called "dimethyl ether") and methoxyethane (also called "utilmately ether").

The term "amine", unless specifically indicated otherwise, includes primary, secondary and tertiary amines.

It is implied that the term "aryl", unless otherwise specified, refers to any stable monocyclic or condensed bicyclic carbon ring that contains up to 7 members in each ring, where at least one ring is aromatic. Examples of data aryl elements include phenyl, naphthyl and tolyl.

The term "aryloxy", unless otherwise specified, includes a large number of ring systems, and systems with a single ring, such as, for example, phenyl or naphthyl, United through the linking oxygen atom with the place is prisoedinenia.

The term "cycloalkyl" means carbocycle, not containing heteroatoms, and includes mono-, bi - or tricyclic saturated carbocycle, as well as the condensed ring system. Data condensed ring system may contain one ring that is a partially or fully unsaturated, such as a benzene ring to form a condensed ring systems, such as carbocyclic condensed with a benzene ring. Cycloalkyl includes data condensed ring system as Spiro-condensed ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantanol, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like. Similarly, "cycloalkenyl" means carbocycle, not containing heteroatoms and containing at least one double C-C bond, and include mono-, bi - and tri-cyclic, partially saturated carbocycle and cycloalkene condensed with a benzene ring. Examples cycloalkenyl include cyclohexenyl, indanyl and the like.

The term "cycloalkane", unless otherwise specified, includes cycloalkyl group connected with the connecting atom of oxygen.

The term "hetero", unless otherwise specified, includes one or more O, S, or N atoms, for Example, heteroseksualci and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of these atoms. Heteroatom substituted ring carbon atoms.

Examples of heterocyclization include azetidine, pyrrolidine, piperidinyl, piperazinil, morpholinyl, tetrahydrofuranyl, imidazolyl, cyclic acetals, cyclic ketals, pyrrolidin-2-it, piperidine-2-he and thiomorpholine. As used in the present invention, heteroseksualci" includes the bridge heterocicluri containing two or more geterotsiklicheskikh groups, connected via adjacent or non-adjacent atoms.

It is implied that the term "heteroaryl", as used in the present invention, except where specified, refers to a stable 5 - to 7-membered monocyclic or stable 9 - to 10-membered condensed bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and where the heteroatoms nitrogen and sulfur you do not necessarily oxidize and the nitrogen heteroatom can optionally be quaternaire, and containing ubuu bicyclic group, in which any of the above defined heterocyclic rings condensed with the benzene ring. The heterocyclic ring can join at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of data heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazin, thiophene, oxazole, thiazole, triazole, thiadiazole, oxadiazole, pyrrole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole and 1,2,4-triazole.

Additional examples of heteroaryl include chinoline, pyrimidinyl, ethenolysis, pyridazinyl, honokalani, furyl, benzofuran, dibenzofuran, thienyl, benzothiazyl, indolyl, indazoles, isoxazolyl, isothiazolin, imidazolyl, benzimidazolyl, thiadiazolyl, tetrazolyl.

The term "heteroaromatic", unless otherwise specified, refers to a heteroaryl group attached through a connecting atom of oxygen to the place of connection.

Examples heteroaryl(C1-6)alkyl include, for example, furylmethyl, purolater, thienylmethyl, titilate, parasailer, oxazolidinyl, oxazolyl, isoxazolyl, triazolylmethyl, triazolylmethyl, imidazolidinyl, imidazolylalkyl, benzimidazolinyl, oxadiazolyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, triazolylmethyl, triazolylmethyl, tetrazolyl, tet is azolylmethyl, pyridinylmethyl, pyridinylmethyl, pyridinylmethyl, pyrimidinyl, personality, hyalinella, izohinolinove and chynoxalinilmethylen.

Unless otherwise indicated, the term "carbarnoyl" is used to include-NHC(O)OC1-C4the alkyl and-OC(O)NHC1-C4the alkyl.

The term "halogen" includes fluorine atom, chlorine, bromine and iodine.

The term "ketal" refers to a functional group or a molecule containing carbon, coupled with the two-OR groups. Thus, the "cyclic ketal" means a cyclic or ring structure containing catalog group.

It is implied that the term "optionally substituted" includes both substituted and unsubstituted. Thus, for example, optionally substituted aryl can be panafcortelone or phenyl ring. Then, the substitution can be carried out by any of the groups. For example, substituted aryl(C1-6)alkyl includes substitution in the aryl group, and substitution in the alkyl group.

The term "oxide" heteroaryl group used in the standard well-known chemical sense, and it includes, for example, N-oxides of the nitrogen heteroatoms.

Compounds described in this invention contain one or more double bonds and thus can lead to CIS/TRANS isomers, as well as other conformational isomers. Now is sabreena includes all data of the possible isomers, as well as any mixture of these isomers.

If not specifically mentioned or not shown by the symbol of the relationship (dotted or double-dotted line), the point of joining this group will be at the extreme right of the specified group. That is, for example, fenilalanina group connected with the main structure via an alkyl, and phenyl is a Deputy in the alkyl.

Compounds of the present invention are suitable in various pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salt" refers to those salt forms, which are known to chemists working in the pharmaceutical field, i.e., the salt forms, which are virtually non-toxic and which have the desired pharmacokinetic properties, pleasant taste, absorption, distribution, metabolism or excretion. Other factors, more useful in nature, which are also important when choosing is the cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and fluidity of the resulting bulk drug. The pharmaceutical compositions can be conveniently obtained from the active ingredient in combination with pharmaceutically acceptable carriers.

Compounds described in this invention can contain one or is more asymmetric centers and may thus, to give the diastereomers and optical isomers. The present invention includes all of the data possible diastereomers as well as their racemic mixtures, their almost pure separated enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts. Formula I above is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of the formula I and their pharmaceutically acceptable salts. Then, a mixture of stereoisomers, as well as selected specific stereoisomers are also included. In the process of the synthetic methods used to produce these compounds, or in the application of methods racemization or epimerization, known to experts in the art, the products of these methods can be a mixture of stereoisomers.

The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently obtained from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper (+1 and +2), iron (+3), iron (+2),lithium, magnesium, manganese (+2 and +3), potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, and cyclic amines and substituted amines, such as natural and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which it is possible to obtain salts include ion exchange resins, such as arginine, betainovuyu, caffeine, kalinovye, N,N'-dibenzylethylenediamine, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylendiamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, his-tag, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, pieperazinove, piperidine, polianinova resins, procaine, purines, theobromine, trailmen, trimethylamine, Tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its corresponding salt can be conveniently obtained from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. These acids include, for example, acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamine is a new, Hydrobromic, chloroethanol, isatnbul, lactic, maleic, xiantao, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid and the like. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or the Quaternary ammonium salts related compounds formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include salts derived from inorganic acids, such as chloromethane, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, axentra, tartaric, citric, ascorbic, Panova, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova acid and the like.

Pharmaceutical is acceptable salts of the present invention can be obtained conventional chemical methods. Typically, the salts obtained by reaction of the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or combination of solvents.

Compounds of the present invention may contain asymmetric centers and can be in the form of the racemates, racemic mixtures and as individual diastereomers. All of these isomers, including optical isomers are included in the present invention.

The present invention described in the present description, also includes a pharmaceutical composition which comprises the compound described by formula (I)or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier.

The present invention described in the present description, also includes a pharmaceutical composition which comprises the compound described by formula (I)or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention contain the compound represented by formula I or its pharmaceutically acceptable salt as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or auxiliary ve is esta. These additional therapeutic ingredients include, for example, (i) antagonists of leukotriene receptors, (ii) inhibitors of leukotriene biosynthesis, iii) corticosteroids, iv) antagonists H1 receptor, v) agonists beta 2 adrenergic receptors, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drug ("NSAID") and (ix) M2/M3 antagonists.

The present invention described in the present description includes a method of treating arthritis which comprises the administration to the patient, which is a mammal in need of this treatment, the compounds described by formula (I)or its pharmaceutically acceptable salt, in an amount that is effective for the treatment of arthritis. The present invention described in the present description includes a method of treating arthritis which comprises the administration to the patient, which is a mammal in need of this treatment, the compounds described by formula (I)or its pharmaceutically acceptable salt, in an amount that is effective for the treatment of arthritis. The present invention includes methods of treating arthritis introduction to the patient, which is a mammal in need of this treatment, the compounds described by formula (I)or its pharmaceutically acceptable salt, in combination or simultaneously injected with COX-2 inhibitor.

On toadie the invention, described in the present invention also includes a method of treating diseases mediated by cytokines in a mammal, comprising administration to the patient, which is a mammal in need of this treatment, the number of compounds described by formula (I)or its pharmaceutically acceptable salt, in an amount that is effective for the treatment of the mentioned diseases, mediated by the cytokine.

Especially interesting is a method of treating inflammation in a patient, which is a mammal in need of this treatment, which comprises introducing said patient an anti-inflammatory effective amount of a compound described by formula (I)or its pharmaceutically acceptable salt.

Another way, which is of particular interest is a method of treating diseases mediated by cytokines, as described in the present invention, where the disease is a osteoporosis.

Another way, which is of particular interest is a method of treating diseases mediated by cytokines, as described in the present invention, where the disease is postupalsky bone resorption.

Another way, which is of particular interest is a method of treating diseases mediated by cytokine is, as described in the present invention, where the disease is a Crohn's disease.

The present invention also relates to a method of treating arthritis in need of this treatment of a mammal, which comprises introducing said mammal a certain amount of the compounds of formula I which is effective for the treatment of arthritis. This method involves the treatment of rheumatism and osteoarthritis.

When administered to a patient for treatment of arthritis, the dose administered may vary depending on the type of arthritis, age and General condition of the patient, specific input connections, availability or toxicity or adverse effects that occur with the drug and other factors. A typical example of the range of suitable dose range is from about 0.01 mg/kg to about 100 mg/kg, However, enter the dose remains at the discretion of the physician.

The present invention also relates to a method for inhibiting the action of p38 in need of it mammal, which comprises introducing said mammal an effective amount of a compound described by formula (I)or its pharmaceutically acceptable salt, for inhibiting the actions mentioned p38, to normal levels, or in some cases to near-normal levels, so in order to improve pre order to prevent or to treat a painful condition.

The compounds of formula I can be used in prophylactic or therapeutic treatment of painful conditions in a mammal, which is exacerbated or caused by excessive or unregulated cytokine cytokines, specifically IL-I, IL-6, IL-8 or TNF.

Since the compounds of formula I inhibit cytokines, such as IL-I, IL-6, IL-8 and TNF, p38 inhibition, the compounds are suitable for treating diseases in which the role played by the presence and activity of cytokines, such as pain, rheumatoid arthritis, rheumatoid spondaic, osteoarthritis, gouty arthritis and other arthritic diseases.

Compounds described by formula I, or their pharmaceutically acceptable salts are also useful to treat other painful conditions mediated by excessive or unregulated TNF synthesis or activity. These diseases include, but are not limited to, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, syndrome of respiratory disorders in adults, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, diseases associated with bone resorption, such as osteoporosis, reperfusion injury, graft vs. host rejection of the allograft, Liora the ku, myalgia due to infection, cachexia secondary to infection or malignant tumors, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS-associated complex), keloid formation, scar tissue, Crohn's disease, ulcerative colitis, fever, AIDS and other viral infections, such as cytomegalovirus (CMV), influenza virus and the family of herpes viruses, including herpes zoster or simply I and II.

Compounds described by formula (I)or their pharmaceutically acceptable salts are also useful for topical use to treat inflammation, such as the treatment of rheumatoid arthritis, rheumatoid spondilitis, osteoarthritis, gouty arthritis and other arthritic diseases; inflammation of the joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; fever, pain and other diseases associated with inflammation.

Compounds described by formula (I)or their pharmaceutically acceptable salts are also suitable for the treatment of diseases such as chronic obstructive pulmonary disease and diseases characterized by excessive IL-8 activity. Data painful conditions include psoriasis, inflammatory disease kiseon the ka, asthma, cardiac or renal reperfusion injury, syndrome of respiratory disorders in adults, thrombosis and glomerulonephritis.

Thus, the present invention includes a method of treating psoriasis, inflammatory bowel disease, asthma, cardiac or renal reperfusion injury, syndrome of respiratory disorders in adults, thrombosis and glomerulonephritis in a mammal in need of this treatment, which includes the introduction of said mammal of a compound described by formula (I)or its pharmaceutically acceptable salt, in an amount that is effective for the treatment of the aforementioned diseases or conditions.

Compounds described by formula (I)or their pharmaceutically acceptable salts are also suitable for the treatment of Alzheimer's disease. Thus, the present invention includes a method of treatment of Alzheimer's disease in a mammal in need of this treatment, which includes the introduction of said mammal the compounds of formula (I) or its pharmaceutically acceptable salt in an amount effective to treat the aforementioned diseases or conditions.

When administered to a patient for treatment of the disease, which plays the role of the cytokine or cytokines, the dose administered may vary depending on the type of disease, age and in common with the situation of the patient, specific input connections, availability or toxicity or adverse effects that occur with the drug and other factors. A typical example of a suitable dose range is the range from about 0.01 mg/kg to about 100 mg/kg, However, the input dose is usually left to the discretion of the physician.

Methods of treatment can be controlled delivery of the compounds of formula I parenterally. The term "parenteral"as used in the present invention include intravenous, intramuscular or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. The present invention can also be accomplished by delivery of the compounds of formula I, subcutaneously, intranasally, vnutriuretrale, transdermal or vnutrivaginalno.

The compounds of formula I can also enter by inhalation. Under "inhalation" refers to intranasal and oral inhalation administration. Suitable dosage forms for this introduction, such as aerosol formulations or dosing inhaler, can be obtained by using common methods.

The present invention also relates to pharmaceutical compositions containing a compound of formula I and a pharmaceutically acceptable carrier. The compounds of formula I can also be included in the pharmacist is ical composition in combination with a second therapeutically active compound.

Applied pharmaceutical carrier may be, for example, solid, liquid or gaseous. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Examples of gaseous carriers include carbon dioxide and nitrogen. Similarly, the carrier or diluent may contain a substance that slows the release, well known in the art, such as glycerol monostearate or distearate glycerol alone or with a wax.

You can use a large set of pharmaceutical dosage forms. When used in solid dosage forms for oral administration, the preparation may be in the form of tablets, hard gelatin capsules, tablets or lozenges. The amount of solid carrier will vary widely but will usually be in the range of from about 0.025 mg to about 1, optionally in a liquid dosage form for oral administration, the drug is usually a syrup, emulsion, soft gelatin capsule, suspension or solution. When you want to apply parenteral dosage form, the drug can be the solid or liquid form and can be formulated for administration directly or it can be suitable for dissolution.

Also includes dosage forms for local use. Examples of dosage forms for local use are solid, liquid and semi-solid forms. Solid forms may include powders, lotions and the like. Liquid include solutions, suspensions and emulsions. Semi-include creams, ointments, gels and the like.

The amount used of the compounds of formula I will normally be, of course, vary depending on the selected connection, the nature and severity of the disease, and it may change at the discretion of the physician. The typical dose for topical use the compounds of formula I is from about 0.01 mg to about 2.0 g, administered from one to four or, preferably, from one to two times a day.

The active ingredient may comprise, for topical administration, from about 0,001% to about 10% V/C.

Drops according to the present invention may contain sterile or non-sterile aqueous or oily solutions or suspensions, and may be obtained by dissolving the active ingredient in a suitable aqueous solution, optionally containing a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally contain a surface-active agent. Then, the resulting solution can be filtered by filtration, transferred to approach the total capacity, which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for 30 minutes. Alternatively, the solution can be sterilized by filtration and transferred into the container under sterile conditions. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops, are nitrate or acetate of finalstate (0,002%), benzalkonium chloride (0.01 per cent) and chlorhexidine acetate (0.01 per cent). Suitable solvents to obtain an oil solution include glycerol, diluted alcohol, and propylene glycol.

Lotions according to the present invention include lotions, suitable for application on the skin or eyes. Lotion for the eyes may contain a sterile aqueous solution, optionally containing a bactericidal agent, and can be obtained by methods similar to the methods of production drops. Lotions or liniments for application to the skin may also contain an agent for accelerating the drying and cooling of the skin, such as alcohol or acetone, and/or moisturizing agent such as glycerin or oil, such as castor oil or peanut oil.

Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They can be obtained by mixing the active ingredient in finely divided or powdered form, alone or in solution or su is pensii in aqueous or non-aqueous liquid, with oily or amelanistic basis. The base may contain hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; gum Arabic; an oil of natural origin such as almond, corn, peanut, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or microheli. The composition can contain any suitable surface active agent such as anionic, cationic or non-ionic surfactant, such as esters sorbitan or polyoxyethylene derivatives. You can also include suspendresume agents such as natural gums, cellulose derivatives or inorganic substances such as silicon dioxide, and other ingredients such as lanolin.

With regard to compositions for inhalation, the number one introduction is usually smaller than the number of oral composition such as a tablet or capsule. For example, the daily dose of active compound, administered through composition for inhalation may be in the range from 0,010 mg to 10 mg, in particular from 0,010 mg to 2.5 mg, you Can apply day in a single dose or multiple doses for inhalation, but a single dose for inhalation is before occhialini.

With regard to the introduction of inhalation, salts of compounds of formula I of this invention are conveniently delivered in the form of an aerosol suitable for delivery of drugs to the lungs. Data aerosol dosage forms include, but are not limited to, sprayable solutions or suspensions, dosing or powder inhalers inhalers. For spraying the active ingredient (ingredients) is usually formulated in water and injected jet or electronic device capable of generating a suspension of fine aerosol. In the dosing inhaler (MDI) is used propellants, such as hydrofluorocarbons for dissolution or suspension of the active ingredient in the container under pressure, able to generate dispersed aerosol. As for powder inhalers, salts of compounds of the formula I is used alone or with auxiliary substances, in combination with a device for delivery that can deliver the active substance in the lung.

In one embodiment, the drug is adapted for use with dosing inhaler under pressure, which releases a metered dose of the medicinal product each time it is pressed. Composition for pMDI may be in the form of solutions or suspensions in a halogenated hydrocarbon propellant. The type of propellant, which note is in both pMDI, replaced by hydrofluroalkane (HFA), also known as hydrofluorocarbons (HFC), since renounced the use of chlorofluorocarbons (also known as freons or CFCs). In particular, 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227) is used in several currently marketed in the market of pharmaceutical products for inhalation. The composition may contain other pharmaceutically acceptable excipients for inhalation use, such as ethanol, oleic acid, polyvinylpyrrolidone and the like.

MDI under pressure usually contain two components. Firstly, there is a capacitive component, in which particles of a medicinal product is stored under pressure in the form of a suspension or solution. Secondly, there is a component, which is the holder used to hold and actuate the capacity. Typically, the container will contain a large number of doses of the composition, although it is also possible capacity with a single dose. Capacitive component usually contains the exhaust valve, from which you can release the contents of the vessel. Aerosol drug release from pMDI force on capacitive component in order to push it into the component, which is the holder, through which the exhaust valve opens, and this causes pumping of the drug particles environments is tion of the exhaust valve via the component, which is the holder, and the release of the outlet of the holder. After release from the container, the particles of the medicinal product sprayed, forming the aerosol. It is assumed that the patient has a flow of aerosol medications in relation to his or her face so that the particles medicines fall into the respiratory flow of the patient and delivered to the lungs. Usually, pMDI use propellants to create pressure on the contents of the tank and for the movement of the particles of the medicinal product from the outlet component, which is the holder. In pMDI, the composition provides in the form of a liquid or suspension, and he is in the tank along with the propellant. The propellant can take many forms. For example, the propellant may contain little gas or liquefied gas.

In another embodiment, the drug tailored for use with a powder inhaler. Composition for inhalation suitable for use in DPI, usually contains particles of the active ingredient particles pharmaceutically acceptable carrier. The particle size of the active substance can vary from about 0.1 microns to about 10 microns; however, for effective delivery to the distal lung, at least 95 percent of the particles of the active agent have a size of 5 μm or less. It is jdy active component may be present in a concentration of from 0.01 to 99%. However, typically, each of the active agents is present in a concentration of about 0.05-50%, more typically about 0.2-20% of the total weight of the composition.

As noted above, in addition to the active ingredients of the powder for inhalation preferably contains a pharmaceutically acceptable carrier, which may consist of a pharmacologically inert substance or combination of substances that are acceptable for inhalation. Preferably, the particles of the medium consisted of one or more crystalline sugars; the particles of the medium may consist of one or more sugar alcohols or polyols. Preferably, the carrier particles were particles of dextrose or lactose, especially lactose. In embodiments implementing the present invention, in which use conventional powder inhalers, such as Rotohaler, Diskhaler and Turbohaler, the particle size of the carrier may range from about 10 microns to about 1000 microns. In some of these embodiments, the particle size of the carrier may be in the range from about 20 microns to about 120 microns. In some other embodiments, the implementation of size at least 90% by weight of the carrier particles is less than 1000 microns and preferably lies in the range from 60 μm to 1000 is iron. The relatively large size of the particles of the medium gives good flow characteristics and Hobbies. If available, the number of particles of the medium will usually be up to 95%, for example up to 90%, preferably up to 80% and preferably up to 50% by weight relative to the total weight of the powder. The amount of any fine material of the filler, if present, may be up to 50% and preferably up to 30%, especially up to 20% by weight relative to the total weight of the powder.

The present invention in one embodiment provides a composition for use in powder inhaler, which contains montelukast acid and the compound of formula I and lactose for inhalation as a carrier, where the composition is adapted for the simultaneous, sequential or separate introduction of active agents. The weight ratio of lactose to montelukast acid is from about 1:1 to about 30:1 and the compound X is from about 20:1 to about 30:1. In one example, the weight ratio of lactose to montelukast acid is from about 2:1 to about 25:1 and the compound of formula I is from about 20:1 to about 25:1.

The present invention in one embodiment provides what song to use in a powder inhaler, which contains montelukast acid and corticosteroid inhalation and lactose for inhalation as a carrier, where the composition is adapted for the simultaneous, sequential or separate introduction of active agents. In these compositions the weight ratio of lactose to montelukast acid typically ranges from about 1:1 to about 30:1. In one arrangement, where the corticosteroid inhalation is a mometasone furoate, the weight ratio of lactose to the mometasone furoate is from about 130:1 to about 4:1, and in one embodiment, the ratio ranges from approximately 124:1 to about 60:1. In compositions where the corticosteroid inhalation is ciclesonide, the weight ratio of lactose to ciclesonide is from about 350:1 to about 100:1.

The powder may also contain finely divided particles of the filler, which can represent, for example, a substance such as one of the substances mentioned above as suitable for use as carrier substances, especially crystalline sugar such as dextrose or lactose. Finely ground substance of the filler can represent the same or different from the particles of the carrier substance, in the presence of both. The particle size Mellis elchinova substances filler will typically not exceed 30 μm, and preferably not to exceed 20 μm. In some circumstances, for example when the particles of the carrier and/or any finely ground substance of the filler itself can cause a sensation in the oropharyngeal region, the particles of the carrier and/or finely ground filler substances can form the indicator substance. For example, the particles of the carrier and/or any finely divided filler in the form of particles may contain mannitol.

The compositions described in this invention may also contain one or more additives in an amount of from about 0.1% to about 10% by weight, and preferably from about 0.15% to 5%, most preferred from about 0.5% to about 2%. Additives may include, for example, magnesium stearate, leucine, lecithin and sodium fumarate. When the additive is micronized leucine or lecithin, it is preferable to provide it in an amount of from about 0.1% to about 10% by weight, preferably from about 0.5% to about 5%, preferably about 2% micronized leucine. Preferably, at least 95% by weight of micronized leucine had a particle diameter less than 150 microns, preferably less than 100 microns, and most preferred less than 50 microns. Predpochtite is) to mass-median diameter of the micronized leucine was less than 10 microns.

When the supplementation of magnesium stearate or sodium fumarate, it is preferable to provide them in the amount of from about 0.05% to about 5%, preferably from about 0.15% to about 2%, most preferred from about 0.25 to about 0.5%.

When referring to the particle size of the powder clear that unless otherwise stated, the particle size is an average particle size. The particle size can be calculated by the method of laser diffraction. When the particles also contain indicator substance on the surface of the particles, it is preferable that the size of the coated particles was within the preferred ranges of dimensions are given for bare particles.

Pharmaceutical compositions in the form of a dry powder according to the present invention can be obtained using standard methods. Pharmaceutically active agents, the particles of the carrier and other excipients, if any, can be carefully mixed using any suitable apparatus for mixing, such as a drum mixer. The individual components of the composition can be mixed in any order. You may find that the premixing of specific components is preferred is sustained fashion in certain circumstances. Then, the powder mixture used for filling capsules, blisters, tanks or other facilities for storage for use in combination with a powder inhalers.

In powder inhaler dose, which will be entered, stored in the form of a dry powder, not under pressure, and, when clicking on the inhaler, the powder particles are inhaled by the patient. DPI can be a device with a single dose, in which the powder is contained in a separate capsule, the combined dose, which used a large number of capsules or blisters, and the device in a container in which the powder is measured at the time of dispensing from the container for storage. Powder inhalers may be a "passive" device, in which the breathing of the patient is used for the dispersion of the powder for delivery to the lungs, or "active" device, in which the dispersion of the powder used different mechanism from actuating through breathing. Examples of "passive" powder inhalation devices include Spinhaler, Handihaler, Rotahaler, Diskhaler, Diskus, Turbuhaler, Clickhaler, etc. Examples of active inhalers include Nektar Pulmonary Inhaler (Nektar Therapeutics), Vectura Limited's Aspirair™ device, Microdose DPI (MicroDose) and Oriel DPI (Oriel). However, it should be clear that the composition of the present invention can be entered either active or passive inhalation devices.

p> Tests

Expression and purification of protein

Mouse p38, containing a FLAG epitope tag, expressed in cells of Drosophila S2 under the transcriptional control induced by copper metallothionein promoter. The expression of recombinant p38 caused by the processing of transfected cells 1 mm CuSO4within 4 hours. To obtain active recombinant murine p38 processed CuSO4S2 cells were stimulated for 10 minutes to collect 400 mm NaCl, 2 mm Na3VO4and 100 µg/l okadigbo acid. Debris were washed in phosphate-saline buffer solution, 2 mm Na3VO4and literally in 20 mm Tris HCl, pH 7.5, 120 mm NaCl, 1% Triton X-100, 2 mm EDTA, 20 mm NaF, 4 mm Na3VO4, 2 mm Prefabloc SC (Boehringer Mannheim). Cell lysates were centrifuged for 10 minutes at 13,000×g, and recombinant activated murine p38 was purified immunoaffinity column chromatography from lysates using anti-FLAG M2 resin (Kodak), which was balanced with buffer for lysis. After downloading extract the resin was washed with 10 volumes of column buffer for lysis, 10 column volumes of buffer A (10 mm Tris HCl, pH 7.5, 500 mm NaCl, 20% glycerol) and 10 column volumes of buffer B (10 mm Tris HCl pH 7.5, 150 mm NaCl, 20% glycerol). The chimeric protein was suirable buffer B containing 100 μg/ml FLAG peptide (Kodak).

N-conceive 115 amino acids ATF-2 expressed in E. coli in the form of a chimeric protein with glutathione S-Tran is Ferati. The chimeric protein was purified using glutathiones according to standard methods (Pharmacia).

p38 kinase analysis

p38 kinase analysis was performed in a reaction volume of 100 μl in 96-well-plate at 30° for 45-1200 minutes under the following conditions: 25 mm Hepes, pH of 7.4, 10 mm MgCl2, 20 mm β-glycerophosphate, 2 mm DTT, 5 μm ATP, 10 MK CI [γ-33P]-ATP and ~2 μm GST-ATF2. Serial dilutions of compounds were added to each reaction, 2 μl of DMSO. 2 μl of DMSO was added to the last row of each tablet for the reaction as a control, containing no inhibitor, for each titration inhibitor. The reaction was stopped an equal volume of stop solution containing 100 mm EDTA and 15 mm sodium pyrophosphate. PVDF filter plates (MAIPNOB50, Millipore) was pre-wet with methanol and washed the stop solution. 50 ál aliquots from the same reaction mixture was applied on the filter under vacuum and the filter was washed twice with 75 mm phosphoric acid. Filter plate considered in the acquired scintillation counter (Top Count, Packard) and determined the inhibition percentage for each concentration of the compound.

Alternatively, p38 kinase assays were performed in a reaction volume of 70 ál in 384-well-plate at 30° for 45-1220 minutes under the following conditions: 50 mm Hepes, pH of 7.4, 10 mm MgCl21 mg/ml of FA-Free BSA, 1 mm DTT, 10 μm ATP, 10 μm p38 peptide [Caliper Life Sciences FL-peptide 8 (5-FAM-IPTSPITTTYFFFKKK-COOH)] and 5.7 nm p38-α (Millipore) or 14.3 nm inactivated MAPKAP kinase-2, 0.18 nm p38-α (Millipore) and 2 μm RSK peptide [Caliper Life Sciences FL-peptide 11 (5-FAM-KKLNRTLSVA-COOH)]. Serial dilutions of compounds were added to each reaction at 700 nl DMSO. 700 nl DMSO was added to control wells for the reaction as a control, containing no inhibitor, for each titration inhibitor. The reaction was stopped by adding 15 μl of 100 mm EDTA. The formation of the product was analyzed, using the Caliper LabChip 3000. The buffer for the separation contained 100 mm HEPES pH 7.5, of 0.015% Brij-35, A 2.5% Coating Reagent #3 (Caliper Life Sciences) and 10 mm EDTA. Calculations of the relationship of product to substrate was performed using the software HTS Well Analyzer provided by Caliper Life Sciences, and determined the inhibition percentage for each concentration of the compound.

Analysis of the release of TNF-α

Blood was obtained from healthy volunteers by venipuncture, using heparin sodium is an anticoagulant. Mononuclear cells of peripheral blood (PBMC) were isolated using the environment for fractionation of lymphocytes (ICN) according to the manufacturer's instructions. Selected PBMC were washed 3 times with HBSS and were diluted to a density of 2×106cells/ml in RPMI + 5% autologous human plasma. 50 μl of serial dilutions of inhibitor was added to the wells of 96-hole of a tablet for growing tissues, followed by addition of 100 μl of PBMC, and then 50 μl of RPMI complete medium containing 400 ng/ml LPS. Control link the cells without compounds but with LPS (control with maximum stimulation) and the hole without connection and without LPS (control background) included in each titration. The cells were kept for 16 hours in a humid chamber at 37°C, 5% CO2. Then the conditioned medium was collected and TNF-α concentration was determined quantitatively by immunoanalysis, using the reagents are commercially available (R&D, Inc).

Compounds of the present invention and, in particular, the examples showed efficacy (IC50) in the above analyses with the results of less than 10 μm. Preferred compounds had results less than 1 μm. Even more preferred compounds had results less than 0.1 μm. Even more preferred compounds had results in the analysis of less than 0.01 μm. This is followed by illustration of efficiency, demonstrated by concrete examples:

Abbreviations used in the present invention are as follows, unless otherwise specified:

These compounds can be obtained according to the General schemes shown below, and is the means, presented in the intermediate compounds, and examples. The following diagrams, examples, and intermediate connections are additionally describe, but not limit, the scope of the present invention. The substituents are the same as in the above formula, except where specified to the contrary, or otherwise clearly professionals.

The methods described in this invention to produce compounds can include one or more stages of manipulation of protective groups and purification such as recrystallization, distillation, column chromatography, flash chromatography, thin layer chromatography (TLC), the radial chromatography and chromatography high pressure (HPLC). The products can be characterized using various methods well known in the chemical engineering field, including proton and carbon-13 nuclear magnetic resonance (1H and13C NMR, IR and UV spectroscopy (IR and UV), x-ray crystallography, elemental analysis and HPLC and mass spectrometry (LC-MS). The methods of manipulation with protective groups, purification, structure determination and definition of variables are known to experts in the field of chemical synthesis.

It is clear that you can perform additional manipulation of functional groups present in the compounds described in the diagrams below, where appropriate, when ENEA standard methods of transformation of functional groups well-known experts in the art, to obtain the required compounds described in this invention.

Other variations or modifications which will be clear to experts in the art, is included in the scope and idea of the present invention. The present invention should not be limited, except as set forth in the claims.

These compounds can be obtained according to the General schemes provided below as well as to the methods described in the intermediate compounds, and examples. The following diagrams, examples, and intermediate connections are additionally describe, but not limit, the scope of the present invention. The substituents are the same as in the above formula, except where specified to the contrary or otherwise clearly professionals.

The methods described in this invention to produce compounds can include one or more stages with protective groups and purification such as recrystallization, distillation, column chromatography, flash chromatography, thin layer chromatography (TLC), the radial chromatography and chromatography high pressure (HPLC). The products can be characterized using various methods well known in the chemical engineering field, including proton and carbon-13 nuclear magnetic resonance (1H and13C NMR), IR - and UV-spectroscopy (IR and UV), x-ray crystallography, elemental analysis and HPLC and mass spectrometry (LC-MS). The methods of manipulation with protective groups, purification, structure determination and definition of variables are known to experts in the field of chemical synthesis.

It is clear that you can perform additional manipulation of functional groups present in the compounds described in the diagrams below, where appropriate, using standard methods of transformation of functional groups known to experts in the art, to obtain the required compounds described in this invention.

Other variations or modifications which will be clear to experts in the art, is included in the scope and idea of the present invention. The present invention should not be limited, except as set forth in the claims.

Compounds of the formulaIcan be obtained as described in scheme 1, 2 and 3. Suitable acid chloride acid1you can get way known to experts in the art from the corresponding acid or commercially available compounds. Connection2you can easily get from the connection1any of several known methods, such as acylation according to the Friedel-Crafts Pyrrhus is l-2-Kabanbai acid its ether derivatives. Connection3you can obtain the recovery of the ketone triethylsilane in TFA.

Connection6can be obtained from N-carbamoylation and appropriate carbohydrazide4(method A) or hydrazide N-carbamoylation and carboxylic acids5(method B), using the reagent for the formation of amide linkages, such as EEDQ. The process of joining6reagent Lawesson gives thiadiazoline connection7. Release carbamoyl group connection7network connection8. Alternatively, the connection8can be obtained as described in method C. Thus, the appropriately substituted carbohydrate4was etilirovany chloroacetylation, using a base such as sodium bicarbonate, to obtain compounds9. The process of joining9reagent Lawesson network connection10. The chlorine atom connection10replace the azide group, and the subsequent restoration of the azide group gives compound8.

Under standard conditions the reaction of a peptide condensing acid2or3and Amin8can be converted into a compound of formula I. the Standard reaction conditions, the peptide condensation denote the condensation of the carboxylic acid with an amine using a reagent that activates the acid, such as EDC, DCC or BOP, in a suitable solvent is, such as methylene chloride or DMF, in the presence of HOBt.

The intermediate connection 1

4-(2,4,6-triterpenoid)-1H-pyrrole-2-carboxylic acid

Stage A: 2,4,6-triterpenoid

For DCM, 200 ml of a solution of 2,4,6-triterpenoids acid (20 g, 0.11 mol) and DMF (0.5 ml, 6,46 mmol) was added dropwise oxalicacid (21,6 g to 0.17 mol). The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure, in order to get mentioned in the title compound in the form of the crude product (22 g).

Stage B: 4-(2,4,6-triterpenoid)-1H-pyrrole-2-carboxylic acid

To 120 ml of dichloromethane to a solution of 2,4,6-triterpenoid (4.3 g, of 0.022 mol) was added AlCl3(8.8 g, of 0.066 mol) in an atmosphere of N2at room temperature. After stirring for 15 minutes was added in small portions 1H-pyrrole-2-carboxylic acid (2.4 g, of 0.022 mol) over a 10 minute period.

Stirring was continued at room temperature for 1 hour, then the reaction mixture was treated by adding dropwise an ice water (20 ml) and 1N HCl to bring to pΗ 1. After stirring for an additional 30 minutes, the reaction mixture was extracted with AcOEt (3×30 ml). The combined organic layers were washed with brine, sushi is over anhydrous Na 2SO4was filtered and concentrated, in order to get mentioned in the title compound (5.8 g, 97% yield).1H-NMR (500 MHz, CDCl3): δ 12,48 (Shir.s, 1H), of 7.48 (s, 1H), 7,28-7,38 (m, 2H), 6,83 (s, 1H).

The following intermediate compounds were obtained following the method for intermediate 1, stage A and B, using the appropriately substituted carboxylic acid instead of 2,4,6-triterpenoids acid.

Intermediate compound 2: 4-(2,6-differentail)-1H-pyrrole-2-carboxylic acid

Intermediate compound 3: 4-(2,4-differentail)-1H-pyrrole-2-carboxylic acid

Intermediate compound 4

4-(2,6-debtor-4-methylbenzoyl)-1H-pyrrole-2-carboxylic acid

Stage A: 1,3-debtor-5-methylbenzo

A mixture of 1-(methyl bromide)-3.5-diferente (50 g, 0.24 mol), 10% Pd/C (3 g) and sodium acetate (140 g, 1.7 mol) in anhydrous ether (250 ml) was stirred in hydrogen atmosphere at atmospheric pressure for 24 hours. The mixture was filtered and the filtrate was dried over anhydrous Na2SO4was filtered and then used directly in the next stage.

1H-NMR (500 MHz, CDCl3): δ 6,56 (d, 2H, J=6.0 Hz), 6,47 (t, 1H, J=9.0 Hz), 2,22 (s, 3H).

Stage B: 2,6-debtor-4-methylbenzaldehyde

To a solution of 1,3-debtor-5-methylbenzene (10.2 g, 80 mmol) in anhydrous ether (8 ml) was added n-BuLi (2.5 M solution in hexane, 48 ml, 120 mmol) over 20 minutes and maintained the internal temperature in the region of -50°C. After stirring at this temperature for 1.5 hours was added DMF (14.6 g, 200 mmol) over 20 minutes. After stirring at the same temperature for an additional 1.5 hours, the reaction mixture was slowly poured into 1N aqueous sulfuric acid (300 ml) and was extracted with ether three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4was filtered and concentrated, in order to get mentioned in the title compound (11.2 g, 90%).

1H-NMR (500 MHz, CDCl3): δ of 10.25 (s, 1H), 6.75 in (d, 2H, J=9.9 Hz), 2,39 (s, 3H).

Stage C: 2,6-debtor-4-methylbenzoic acid

The silver oxide (43,8 g, 0,189 mol) was placed in a flask with water (200 ml) and sodium hydroxide (33,7 g, 0,842 mol). It was added in small portions 2,6-debtor-4-methylbenzaldehyde (29,23 g, 0,187 mol) over 30 minutes. After a vigorous exothermic reaction the color of the reaction mixture changed from black to grey. The resulting thick suspension was stirred for 1 hour and then filtered through a Buechner funnel. The filtrate was acidified to pH 2 with concentrated HCl, to obtain a suspension. The precipitate was collected by filtration with suction, dissolved in ether, dried over betwedn the m Na 2SO4, filtered and concentrated to obtain a white solid residue (17.0 g, 53%).

1H-NMR (500 MHz, d6-DMSO): δ 13,7 (Shir.s, 1H), 7,02 (d, 2H, J=9,3 Hz), 2,32 (s, 3H).

Stage D: 4-(2,6-debtor-4-methylbenzoyl)-1H-pyrrole-2-carboxylic acid

Stated in the title compound was obtained following the method for intermediate 1, stage A and B, using 2,6-debtor-4-methylbenzoic acid instead of 2,4,6-triterpenoids acid.

1H-NMR (500 MHz, d6-DMSO): δ 12,9 (Shir.s, 1H), and 12.6 (s, 1H), 7,46 (s, 1H), 7,05 (d, 2H, J=8,8 Hz), to 6.95 (s, 1H), 2,35 (s, 3H).

The intermediate compound 5

4-(2,4,6-triptorelin)-1H-pyrrole-2-carboxylic acid

Stage A: methyl 4-(2,4,6-triterpenoid)-1H-pyrrole-2-carboxylate

To dichlormethane 70 ml suspension of 4-(2,4,6-triterpenoid)-1H-pyrrole-2-carboxylic acid (intermediate compound 1) (3 g, and 11.2 mmol) was added a solution of diazomethane in diethyl ether while cooling in a water bath with ice. After stirring for 3 hours the reaction mixture was concentrated and was chromatographically on silica gel, elwira gradient mixture of solvent AcOEt and hexane, to get declared in the header connection (2,74 g).

1H-NMR (500 MHz, d6-DMSO): δ by 12.9 (s, 1H), 7,65 (s, 1H), 7,34 (t, 2H, J=9 Hz), was 7.08 (s, 1H), 3,79, 3H).

Stage B: methyl 4-(2,4,6-triptorelin)-1H-pyrrole-2-carboxylate

To 30 ml TFA solution of methyl 4-(2,4,6-triterpenoid)-1H-pyrrole-2-carboxylate in a sealed tube was added triethylsilane (2.55 g, 22 mmol). The resulting reaction mixture was heated in an oil bath at 70°C during the night. The reaction was concentrated and diluted with isopropylacetate and saturated aqueous sodium bicarbonate. The organic layer was separated. The aqueous layer was extracted with isopropylacetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and chromatographically on silica gel, elwira gradient mixture of solvent AcOEt and hexane, in order to get mentioned in the title compound (840 mg).

1H-NMR (500 MHz, d6-DMSO): δ 11,7 (s, 1H), 7,16 (t, 2H, J=9 Hz), 6,79 (s, 1H), of 6.52 (s, 1H), and 3.72 (s,2H), 3,70 (s, 3H).

Stage C: 4-(2,4,6-triptorelin)-1H-pyrrole-2-carboxylic acid

To a methanol (30 ml solution of methyl 4-(2,4,6-triptorelin)-1H-pyrrole-2-carboxylate (840 mg, 3.1 mmol) was added a 5N solution of sodium hydroxide (3.1 ml, 16 mmol) and the reaction mixture was stirred in an oil bath at 70°C during the night. After cooling to room temperature, pΗ reaction mixture was brought to 1.5, in order to obtain a gray suspension. Sediment own the rali by filtration with suction and dried in vacuum, in order to get mentioned in the title compound (796 mg).

1H-NMR (500 MHz, d6-DMSO): δ 12,2 (s, 1H), and 11.5 (s, 1H), 7,15 (t, 2H, J=8 Hz), 6.73 x (s, 1H), 6,47 (s, 1H), of 3.73 (s, 2H).

Example 1

N-[(5-methyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Stage A: tert-butyl[2-(2-acetylhydrazine)-2-oxoethyl]carbamate

In an atmosphere of N2to dichloromethane 10 ml of a solution of N-tert-butyloxycarbonyl (500 mg, 2,85 mmol) was added EEDQ (706 mg, 2,85 mmol). After stirring for 15 minutes, thereto was added acethydrazide (260 mg, 3,51 mmol) and stirring continued at room temperature overnight. The precipitate was collected by filtration with suction, in order to get mentioned in the title compound as a white solid friable residue (496 mg).

1H-NMR (CDCl3, 400 MHz): δ 8,84 (Shir.s, 1H), 8,27 (Shir.s, 1H), 5,22 (Shir.s, 1H), a 3.87 (d, 2H), 2,02 (s, 3H), of 1.41 (s, 9H).

Stage B: tert-butyl[(5-methyl-1,3,4-thiadiazole-2-yl)methyl]carbamate

To 37,5 ml THF solution of tert-butyl[2-(2-acetylhydrazine)-2-oxoethyl]carbamate (496 mg, of 2.15 mmol) was added to the reagent Lawesson (900 mg, of 2.23 mmol). The resulting reaction mixture is boiled under reflux for 3 hours. The reaction mixture was concentrated and was chromatographically on what silicagel, elwira gradient mixture of solvent AcOEt and dichloromethane, in order to get mentioned in the title compound as a white crystalline residue (391 mg).

1H-NMR (CDCl3, 500 MHz): δ 5,31 (Shir.s, 1H), 4,69 (d, 2H, J=6 Hz), 2,78 (s, 3H), 1,49 (s, 9H). LC/MS: m/z=230 (M+H), 252 (M+Na).

Stage C: the hydrochloride of 1-(5-methyl-1,3,4-thiadiazole-2-yl)methanamine

After cooling in a water bath with ice to 6 ml of a 4M solution of hydrogen chloride in 1,4-dioxane was added tert-butyl[(5-methyl-1,3,4-thiadiazole-2-yl)methyl]carbamate (391 mg, 1,71 mmol).

After stirring for 1 hour the reaction mixture was concentrated, in order to get mentioned in the title compound as a white solid residue (351 mg).

1H-NMR (d6-DMSO, 500 MHz): δ 8,88 (Shir.s, 2H), 4,49 (d, 2H, J=5.5 Hz), is 2.74 (s, 3H). LC/MS: m/z=130 (M+H).

Stage D: N-[(5-methyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

To 3 ml of DMF solution of 4-(2,4,6-triterpenoid)-1H-pyrrole-2-carboxylic acid (intermediate compound 1) (30 mg, 0.11 mmol), hydrate of 1-hydroxybenzotriazole (ΗOBT) (22 mg, 0.15 mmol) were added hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC hydrochloride) (28 mg, 0.15 mmol). The reaction mixture was stirred for 45 minutes before adding the hydrochloride of 1-(5-methyl-1,3,4-thiadiazole-2-yl)methanamine (19 mg, 0,17 mmol) and d is isopropylacrylamide (0.1 ml, 0.55 mmol). The reaction mixture was stirred at room temperature over night, concentrated and chromatographically on silica gel, elwira AcOEt, in order to get mentioned in the title compound 29 mg.

1H-NMR (d6-DMSO, 500 MHz): δ 12,6 (Shir.s, 1H), 9,24 (t, 1H, J=6 Hz), 7,52 (s, 1H), 7,25 (s, 1H), 4,74 (d, 2H, J=6 Hz), to 2.66 (s, 3H). LC/MS: m/z=381 (M+H), 403 (M+Na).

Example 2-20: mentioned in the title compound was obtained following the method described to obtain example 1 using the appropriately substituted carbohydrazide instead acethydrazide.

Example 2

N-[(5-butyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,59 (Shir.s, 1H), 9,25 (t, 1H, J=6 Hz), 7,51 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,25 (s, 1H), 4.75 in (d, 2H, J=6 Hz), 2,99 (t, 2H, J=7,6 Hz), 1,65 (p, 2H, J=7,6 Hz), 1,32 (Sextus, 2H, J=7,6 Hz)of 0.87 (t, 3H, J=7,6 Hz).

Example 3

N-[(5-isopropyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,6 (Shir.s, 1H), 9,25 (t, 1H, J=6 Hz), 7,51 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,25 (s, 1H), 4.75 in (d, 2H, J=6 Hz), at 3.35 (m, 1H, J=6.9 Hz), is 1.31 (d, 6H, J=6.9 Hz). LC/MS: m/z=409 (M+H).

Example 4

N-[(5-cyclopropyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,58 (Shir.s, 1H), 9,225 (t, 1H, J=6 is C), 7,51 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,24 (s, 1H), 4,71 (d, 2H, J=6 Hz), 2,46 (m, 1H), 1,16 (m, 2H), 0,955 (m, 2H). LC/MS: m/z=407 (M+H).

Example 5

N-[(5-tert-butyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,58 (Shir.s, 1H), 9,257 (t, 1H, J=6 Hz), 7,52 (s, 1H), 7,34 (t, 2H, J=8 Hz),of 7.25 (s, 1H), 4.75 in (d, 2H, J=6 Hz), of 1.37 (s, 9H). LC/MS: m/z=423 (M+H).

Example 6

N-[(5-cyclopentyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (CDCl3,500 MHz): δ 10,4 (Shir.s, 1H), 7,6 (Shir.s, lH), 7,46 (s, 1H), 7.23 percent (s, 1H), 6,78 (t, 2H, J=8 Hz), 5.0mm (d, 2H, J=6.2 Hz), 3,55 (p, 1H, J=7,8 Hz in), 2.25 (m, 2H), 1.7 to 1.9 (m, 6H). LC/MS: m/z=435 (M+H).

Example 7

N-[(5-phenyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,35 (t, 1H, J=6 Hz), of 7.96 (m, 2H), 7,54 (t, 2H, J=8 Hz), is 4.85 (d, 2H, J=6 Hz). LC/MS: m/z=443 (M+H).

Example 8

N-{[5-(4-forfinal)-1,3,4-thiadiazolyl-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,7 (s, 1H), 9,35 (t, 1H, J=6 Hz), 8,02 (m, 2H), 7,53 (s, 1H), 7,28 (s, 1H), 4,84 (d, 2H, J=6 Hz). LC/MS: m/z=461 (M+H).

Example 9

N-{[5-(3-forfinal)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H) 9,36 (t, 1H, J=6 Hz), 7,80 (d, 2H, J=7 Hz), a 7.6-7.5 (m, 2H), between 7.4 and 7.3 (m, 2H), 7,28 (s, 1H), a 4.86 (d, 2H, J=6 Hz). LC/MS: m/z=461 (M+H).

Example 10

N-{[5-(4-methoxyphenyl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), to 9.32 (t, 1H, J=6 Hz), 7,88 (d, 2H, J=7 Hz), was 7.36 (t, 2H, J=8 Hz), 7,28 (s, 1H), 7,07 (d, 2H, J=6 Hz), 4,82 (d, 2H, J=6 Hz), 3,82 (s, 3H). LC/MS: m/z=473 (M+H).

Example 11

N-{[5-(2,6-differenl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

LC/MS: m/z=479 (M+Η).

Example 12

N-[(5-pyridin-2-yl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), was 9.33 (t, 1H, J=6 Hz), 8,66 (d, 1H, J=5 Hz), 8,24 (d, 1H, J=8 Hz), 8,02 (t, 1H, J=6 Hz), 7,55 (m, 1H), 7,53 (s, 1H), was 7.36 (t, 2H, J=8 Hz), 7,28 (s, 1H), 4,85 (d, 2H, J=6 Hz). LC/MS: m/z=444 (M+H).

Example 13

N-[(5-pyridin-3-yl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,37 (t, 2H, J=6 Hz), 9,12 (d, 1H, J=2 Hz), 8,72 (m, 1H), 8.34 per (m, 1H), 7,55 (m, 1H), 7,53 (s, 1H), was 7.36 (t, 2H, J=8 Hz), 7,29 (1H), 4,87 (d, 2H, J=6 Hz). LC/MS: m/z=444 (M+H).

Example 14

N-{[5-(1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,6 (Shir.s, 1H), 12,0 (s,1H), 9,3 (t, 1H, J=6 Hz), 7,53 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,27 (s, 1H), 6,98 (m, 1H), of 6.71 (m, 1H), to 6.19 (m, 1H), and 4.8 (d, 2H, J=6 Hz). LC/MS: m/z=432 (M+H).

Example 15

N-{[5-(2-furyl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (CD3OD, 500 MHz): δ to 7.77 (d, 1H, J=1.4 Hz), and 7.5 (s, 1H), 7,24 (d, 1H, J=1.4 Hz), 7,22 (d, 1H, J=3,4 Hz)7,025 (t, 2H, J=8 Hz), of 6.68 (DD, 1H, J=1.4 Hz), to 4.92 (s, 2H), 4,59 (Shir.s, 1H). LC/MS:m/z=433 (M+H).

Example 16

N-{[5-(2-ethoxypyridine-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,29 (t, 2H, J=6 Hz), 8,63 (DD, 1H, J=2 Hz, 8 Hz), at 8.36 (DD, 1H, J=2 Hz, 5 Hz), 7,52 (d, 1H, J=2 Hz), 7,25 (m, 2H), 7,20 (s, 1H), 7,18 (m, 1H), a 4.86 (d, 2H, J=6 Hz), 4,51 (q, 2H, J=7 Hz), of 1.39 (t, 3H, J=7 Hz). LC/MS: m/=488 (M+H).

Example 17

N-{[5-(6-methoxypyridine-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,35 (t, 1H, J=6 Hz), 8,73 (d, 1H, J=2 Hz), of 8.25 (DD, 1H, J=2 Hz, 9 Hz), 7,53 (d, 1H, J=2 Hz), was 7.36 (d, 2H, J=8 Hz), 7,28 (s, 1H), 6,97 (d, 1H, 9 Hz), is 4.85 (d, 2H, J=6 Hz), to 3.92 (s, 3H). LC/MS: m/z=474 (M+H).

Example 18

N-{[5-(6-methoxypyridine-2-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,34 (t, 1H, J=6 Hz), to $ 7.91 (t, 1H, J=8 Hz), to 7.84 (d, 1H, J=7 Hz), 7,54 (s, 1H), was 7.36 (t, 2H, J=6 Hz), 7,28 (s, 1 is), of 7.00 (d, 1H, J=7 Hz), 4,84 (d, 2H, J=6 Hz), with 3.89 (s, 3H). LC/MS: m/z=474 (M+H).

Example 19

N-{[5-(2-methoxypyridine-4-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,38 (t, 1H, J=6 Hz), 8,32 (t, 1H, J=6 Hz), 7,52 (m, 2H), was 7.36 (t, 2H, J=8 Hz), 7,32 (s, 1H), 7,29 (s, 1H), 4,87 (d, 2H, J=6 Hz), 3,90 (s, 3H). LC/MS: m/z=474 (M+H).

Example 20

N-{[5-(3-methyl-1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 13,1 (s, 1H), 12,6 (Shir.s, 1H), 9,3 (t, 1H, J=6 Hz), 7,53 (s, 1H), 7,33 (t, 2H, J=8 Hz), 7,27 (s, 1H), 6,59 (s, 1H), and 4.8 (d, 2H, J=6 Hz), 2,28 (s, 3H). LC/MS: m/z=447 (M+H).

Example 21

N-[(5-pyrazin-2-yl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Stage A: tert-butyl{2-oxo-2-[2-(pyrazin-2-RUPERTI)hydrazino]ethyl}carbamate

In an atmosphere of N2to dichloromethane 5 ml of the solution pyrazin-2-carboxylic acid (328 mg, of 2.64 mmol) was added EEDQ (653 mg, of 2.64 mmol). After stirring for 45 minutes, thereto was added N-(tert-butyloxycarbonyl)glycolytic (500 mg, of 2.64 mmol). Stirring was continued at room temperature overnight. The reaction mixture was concentrated and triturated from dichloromethane, to get declared in the header soy is inania (666 mg).

Stage B-D: Following the method described in example 1, stage B-D, has been declared in the header connection.

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,44 (s, 1H), 9,38 (t, 2H, J=6 Hz), 8,82 (s, 1H), 8,78 (s, 1H), 7,54 (s, 1H), was 7.36 (t, 2H, J=8 Hz), 7,28 (s, 1H), 4,88 (d, 2H, J=6 Hz). LC/MS: m/z =445 (M+H).

Declared in the header of the compounds in the examples 22-31 received, following the method described in example 21, using the appropriately substituted carboxylic acid.

Example 22

N-[(5-cyclobutyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,59 (s, 1H), 9,25 (t, 1H, J=6 Hz), 7,516 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,25 (s, 1H), 4.75 in (d, 2H, J=6 Hz), 3,93 (p, 1H, J=8.5 Hz), 2,4 (m, 2H), 2,234 (DD, 2H, J=9,2 Hz, J=2.4 Hz), 2,015 (Sextus, 1H, J=9 Hz), 1,89 (m, 1H). LC/MS: m/z=421 (M+H).

Example 23

N-{[5-(1-methylcyclopropyl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,57 (Shir.s, 1H), 9,24 (t, 1H, J=6 Hz), 7,51 (s, 1H), 7,34 (t, 2H, J=8 Hz), 7,24 (s, 1H), 4.72 in (d, 2H, J=6 Hz), for 1.49 (s, 3H)and 1.15 (m, 2H), 1.04 million (m, 2H). LC/MS: m/z=421 (M+H).

Example 24

N-[(5-sec-butyl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,59 (s, 1H), 9,26 (t, 1H, J=6 Hz), 7,52 (s, 1H), 7,35 (m, 2HJ=8 Hz), 7,26 (s, 1H), amounts to 4.76 (d, 2H, J=6 Hz), 3,195 (kW, 1H, J=6,9, 6,8 Hz)of 1.66 (m, 2H, J=7,4, 6 Hz), of 1.29 (d, 3H, J=6.9 Hz), 0,833 (t, 3H, J=7.4 Hz). LC/MS: m/z=423 (M+H).

Example 25

N-{[5-(3-isopropyl-1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 13,16 (s, 1H), was 12.61 (s, 1H), 9,29 (t, 1H, J=6 Hz), 7,52 (s, 1H), 7,34 (t, 2H, J=8 Hz), 7,26 (s, 1H), is 6.61 (s, 1H), and 4.8 (d, 2H, J=6 Hz), is 3.08 (Sept, 1H, J=6.9 Hz), 1,24 (d, 6H, J=6,9 Hz). LC/MS: m/z=475 (M+H).

Example 26

N-{[5-(3-isobutyl-1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9,29 (t, 1H, J=6 Hz), 7,52 (s, 1H), 7,34 (t, 2H, J=8 Hz), 7,26 (s, 1H), and 6.6 (s, 1H), and 4.8 (d, 2H, J=6 Hz), of 2.51 (d, 2H, J=7,1 Hz), at 1.91 (m, 1H, J=6,8 Hz, J=7,1 Hz), to 0.88 (d, 6H, J=6.8 Hz). LC/MS: m/z=489 (M+H).

Example 27

4-(2,4,6-triterpenoid)-N-({5-[3-(trifluoromethyl)-1H-pyrazole-5-yl]-1,3,4-thiadiazole-2-yl}methyl)-1H-pyrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ br12.62 (s, 1H), 9,39 (t, 1H, J=5,8), 7,54 (s, 1H), 7,47 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,285 (s, 1H), 4,87 (d, 2H, J=5.8 Hz). LC/MS: m/z=501 (M+H).

Example 28

N-{[5-(1H-indazol-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ br12.62 (s, 1H), 9,35 (t, 1H, J=6 Hz), 8,31 (d, 1H, J=8,3 Hz); 7,66 (d, 1H, J=8,3 Hz), 7,54 (s, 1H), 7,49 (t, 1H, J=7.4 Hz), 7,35 (m, 3H), 7,29 (s, 1H), 4,87 (d, 2H, J=6 Hz). LC/MS: m/z=483 (M+H).

Example 29

N-[(5-pyrazolo[1,5-a]pyrimidine-2-the l-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ br12.62 (s, 1H), 9,36 (t, 1H, J=6 Hz), 9,17 (d, 1H, J=7 Hz), 8,65 (d, 1H, J=4 Hz), 7,53 (s, 1H), 7,342 (t, 2H, J=8 Hz), 7,32 (s, 1H), 7,28 (s, 1H), 7,176 (DD, 1H, J=7 Hz, J=4 Hz), 4,88 (d, 2H, J=6 Hz). LC/MS: m/z=484 (M+H).

Example 30

N-{[5-(1,2,3-thiadiazole-4-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ br12.62 (s, 1H), to 9.93 (s, 1H), 9,4 (t, 1H, J=6 Hz), 7,53 (s, 1H), 7,34 (t, 2H, J=8 Hz), 7,27 (s, 1H), 4,89 (d, 2H, J=6 Hz). LC/MS: m/z=451 (M+H).

Example 31

N-{[5-(2,4,5,6-tetrahydrocyclopent[c]pyrazole-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,99 (Shir.s, 1H), br12.62 (s, 1H), 9,29 (t, 1H, J=6 Hz), 7,53 (s, 1H), 7,343 (t, 2H, J=8 Hz), 7,27 (s, 1H), and 4.8 (d, 2H, J=6 Hz), 2,73 (m, 4H), of 2.53 (m, 2H). LC/MS: m/z=473 (M+H).

Example 32

N-{[5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Stage A: N'-(2-chloroacetyl)-1H-pyrazole-5-carbohydrazide

To a suspension of 1H-pyrazole-5-carbohydrazide (102 mg, 0.81 mmol) in 7 ml of AcOEt was added 1.8 ml of 1M sodium bicarbonate solution and the original white suspension was stirred for several minutes, until it will become almost transparent two-phase solution. After cooling in a water bath with LDO which were added 0.7 ml of AcOEt solution chloroacetanilide (110 mg, 0.97 mmol). After stirring over night the reaction mixture was poured into a separating funnel. The organic layer was separated and the aqueous layer was extracted with AcOEt twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid residue (110 mg).

1H-NMR (d6-DMSO, 500 MHz): δ 13,4 (s, 1H), 10,2 (s, 1H), 10,1 (s, 1H), 7,86 (s, 1H), of 6.71 (s, 1H), 4,17 (s, 2H).

Stage B: 2-(chloromethyl)-5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole

N-(2-chloroacetyl)-1H-pyrazole-5-carbohydrazide (110 mg, 0.54 mmol) and reagent Lawesson (220 mg, 0.54 mmol) suspended in 5.5 ml TΗF and then boiled under reflux for 3 hours. The reaction mixture was concentrated and was chromatographically on silica gel, elwira gradient mixture of solvent AcOEt and hexane, in order to get mentioned in the title compound as a white solid residue (of 60.5 mg).

1H-NMR (d6-DMSO, 500 MHz): δ of 7.97 (s, 1H), 6,91 (s, 1H), 5,26 (s, 2H).

Stage C: 2-(azidomethyl)-5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole

To a 1 ml DMF solution of 2-(chloromethyl)-5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole (58 mg, 0.29 mmol) was added sodium azide (20 mg, 0.30 mmol). Stirring was continued for 3 hours. The reaction mixture was concentrated and diluted with AcOEt and water. The organic layer was separated. Water is Loy was extracted with AcOEt twice and the combined organic layers were dried over anhydrous sodium sulfate, was filtered and concentrated, in order to get mentioned in the title compound (60 mg).

1H-NMR (d6-DMSO, 500 MHz): δ 13,5 (s, 1H), of 7.97 (s, 1H), 6.90 to (s, 1H), 5,00 (s, 2H).

Stage D: 1-[5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methanamine

To 3 ml of a methanol solution of 2-(azidomethyl)-5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole (50 mg, 0.24 mmol) was added anhydrous tin chloride (II) (82 mg, 0.43 mmol) and the resulting yellow solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified HPLC (eluent acetonitrile-water-ammonium hydroxide), in order to get mentioned in the title compound (37 mg).

1H-NMR (d6-DMSO, 500 MHz): δ 13,4 (s, 1H), 7,92 (s, 1H), 6,84 (s, 1H), 4,12 (s, 2H).

Stage E: N-{[5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Following the method of example 1, step D, has been declared in the header connection.

1H-NMR (d6-DMSO, 500 MHz): δ 13,48 (s, 1H), 12,64 (s, 1H), 9,35 (t, 1H, J=5.7 Hz), to 7.93 (s, 1H), 7,53 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,28 (s, 1H), 6,86 (s, 1H), 4,81 (d, 2H, J=5.7 Hz). LC/MS: m/z=433 (M+H).

Declared in the header of the compounds in the examples 33-34 received, following the method described in example 32, using the appropriately substituted carbohydrazide.

Example 33

N-{[5-(1,5-dimethyl-1H-pyrazole-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triftorpentan is)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,6 (Shir.s, 1H), 9,29 (t, 1H, J=6 Hz), 7,54 (s, 1H), was 7.36 (t, 2H, J=8 Hz), 7,27 (s, 1H), 6,65 (s, 1H), and 4.8 (d, 2H, J=6 Hz), of 3.78 (s, 3H), 2,31 (s, 3H). LC/MS: m/z=461 (M+H).

Example 34

N-{[5-(2H-1,2,3-triazole-4-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

1H-NMR (d6-DMSO, 500 MHz): δ 12,64 (s, 1H), 9,34 (t, 1H, J=5.4 Hz), 8,87 (Shir.s, 1H), 8,42 (Shir.s, 1H), 7,54 (s, 1H), was 7.36 (t, 2H, J=8 Hz), 7,28 (s, 1H), around 4.85 (d, 2H, J=5.4 Hz). LC/MS: m/z=434 (M+H).

Example 35

N-{[5-(2-oxo-1,2-dihydropyridines-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrol-2-carboxamide

To N-{[5-(2-ethoxypyridine-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide (example 16) (102 mg, 021 mmol) was added 3 ml of 4M hydrogen chloride in 1,4-dioxane and the resulting suspension was stirred at room temperature for 7 hours. The reaction mixture was concentrated. The residue is triturated with dichloromethane in order to get mentioned in the title compound (95 mg).

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), 9.28 are (t, 1H, J=6 Hz), at 8.60 (DD, 1H, J=2 Hz, 8 Hz), 7,73 (s, 1H), 7,52 (s, 1H), 7,35 (t, 2H, J=2 Hz, 8 Hz), 7,27 (s, 1H), of 6.52 (t, 1H, J=7 Hz), 4,82 (d, 2H, J=6 Hz). LC/MS: m/z=460 (M+H).

Example 36

N-{[5-(6-oxo-1,6-dihydropyridines-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Following the method described in example 35, except that the reaction mixture was heated at 70°C for 6 hours, got mentioned in the title compound, using N-{[5-(6-methoxypyridine-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide (example 17) as the source of the connection.

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), to 9.32 (t, 1H, J=6 Hz), of 8.06 (d, 1H, J=3 Hz), of 7.97 (DD, 1H, J=3 Hz:10 Hz), 7,52 (s, 1H), 7,35 (t, 2H, J=8 Hz), 7,27 (s, 1H), 6,45 (d, 1H, J=10 Hz), 4,79 (d, 2H, J=6 Hz). LC/MS: m/z=460(M+H).

Example 37

N-{[5-(6-oxo-1,6-dihydropyridines-2-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Following the method described in example 35, except that the reaction mixture was heated at 100°C for 6 hours mentioned in the title compound was obtained using N-{[5-(6-methoxypyridine-2-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide (example 18) as the parent compound.

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), and 11.2 (Shir.s, 1H), 9,35 (t, 1H, J=6 Hz), 7,81 (t, 1H, J=7 Hz), 7,69 (s, 1H), 7,54 (d, 1H, J=2 Hz), was 7.36 (t, 2H, J=8 Hz), 7,28 (s, 1H), 6,79 (d, 1H, J=8 Hz), 4,82 (d, 2H, J=6 Hz). LC/MS: m/z=460 (M+H).

Example 38

N-{[5-(2-oxo-1,2-dihydropyridines-4-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide

Following the method described in example 35, the and except what the reaction mixture was heated at 100°C for 6 hours mentioned in the title compound was obtained using N-{[5-(2-methoxypyridine-4-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triterpenoid)-1H-pyrrol-2-carboxamide (example 19) as the source of the connection.

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

Example 39

4-(2,4-differentail)-N-[(5-methyl-1,3,4-thiadiazole-2-yl)methyl]-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 1 using intermediate compound 3 instead of intermediate 1.

1H-NMR (CDCl3;500 MHz): δ to 7.93 (s, 1H), 7,73 (t, 1H, J=7 Hz), 6,86 (d, 1H, J=8 Hz), 5,33 (Shir.s, 1H), 4,78 (d, 2H, J=6 Hz), 4.00 points (s, 3H). LC/MS: m/z=363 (M+H).

Example 40

4-(2,6-differentail)-N-[(5-methyl-1,3,4-thiadiazole-2-yl)methyl]-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 1 using intermediate compound 2 instead of intermediate 1.

1H-NMR (CDCl3, 500 MHz): δ 10,7 (s, 1H), 7,88 (t, 1H, J=6 Hz), 7,01 (m, 2H), 5,00 (d, 2H, J=6 Hz), 2,77 (s, 3H). LC/MS: m/z=363 (M+H).

Example 41

4-(2,6-differentail)-N-{[5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 32, using intermediate Obedinenie 2 instead of intermediate 1.

1H-NMR (d6-DMSO, 500 MHz): δ 13,47 (Shir.s, 1H), 12,60 (Shir.s, 1H), to 9.32 (m, 1H), to 7.93 (m, 1H), to 7.61 (m, 1H), 7,45 (s, 1H), 7,25 (m, 3H), 6,86 (s, 1H), to 4.81 (s, 2H). LC/MS: m/z=415(M+H).

Example 42

4-(2,6-debtor-4-methylbenzoyl)-N-{[5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 32, using the intermediate compound 4 instead of intermediate 1.

1H-NMR (d6-DMSO, 500 MHz): δ 13,45 (Shir.s, 1H), 12,58 (Shir.s, 1H), of 9.30 (m, 1H), 7,94 (s, 1H), 7,43 (s, 1H), 7.23 percent (s, 1H), was 7.08 (m, 2H), 6,86 (s, 1H), to 4.81 (s, 2H), is 2.37 (s, 3H). LC/MS: m/z=429(M+H).

Example 43

N-{[5-(2-oxo-1,2-dihydropyridines-3-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triptorelin)-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 35, using the intermediate compound 5 instead of intermediate 1.

1H-NMR (d6-DMSO, 500 MHz): δ of 12.6 (s, 1H), and 11.4 (s, 1H), 8-90 (t, 1H, J=6 Hz), 8,58 (DD, 1H, J=2 Hz, 7 Hz), 7,72 (m, 1H), 7,15 (t, 1H, J=8 Hz), 6,70 (s, 1H), 6,62 (s, 1H), 6,50 (t, 1H, J=6 Hz), 4,74 (d, 2H, J=6 Hz), 3,71 (s, 2H).

Example 44

N-[(5-pyridin-2-yl-1,3,4-thiadiazole-2-yl)methyl]-4-(2,4,6-triptorelin)-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 12, using an intermediate connection is giving 5 instead of intermediate 1.

1H-NMR (CDCl3, 500 MHz): δ which 9.22 (s, 1H), 8,64 (d, 1H, J=5 Hz), a 8.34 (d, 1H, J=5 Hz), 7,87 (m, 1H), 7,41 (m, 1H), 6,84 (s, 1H), 6,67 (t, 2H, J=8 Hz), 6,51 (s, 1H), 5,04 (d, 2H, J=6 Hz), 3,82 (s, 2H).

Example 45

N-{[5-(1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triptorelin)-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 32, using the intermediate compound 5 instead of intermediate 1.

1H-NMR (d6-DMSO, 500 MHz): δ 13,4 (s, 1H), and 11.4 (s, 1H), 8,92 (t, 1H, J=6 Hz), 7,92 (s, 1H), 7,15 (t, 2H, J=8 Hz), at 6.84 (s, 1H), 6,62 (s, 1H), 4,73 (d, 2H, J=6 Hz), 3,32 (s, 2H).

Example 46

N-{[5-(3-methyl-1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-yl]methyl}-4-(2,4,6-triptorelin)-1H-pyrrol-2-carboxamide

Stated in the title compound was obtained following the method described in example 20, using the intermediate compound 5 instead of intermediate 1.

1H-NMR (d6-DMSO, 500 MHz): δ 13,1 (s, 1H), and 11.4 (s, 1H), 8,9 (t, 1H, J=6 Hz), to 7.15 (t, 2H, J=8 Hz), of 6.71 (s, 1H), 6,62 (s, 1H), return of 6.58 (s, 1H), 4.72 in (d, 2H, J=6 Hz), of 3.69 (s, 2H), 2,28 (s, 3H). LC/MS: m/z=433 (M+H).

An alternative method of obtaining a sample 32

Stage 1. The Friedel-crafts

Method: This method was performed with two portions and both were treated equally.

50 l mnogogolovy round bottom flask in a steam ban is, equipped with verhneprivodnaya stirrer, thermocouple probe, and addition funnel with the inlet of the nitrogen, top-loaded 2,4,6-triptoreline acid, dichloromethane and DMF. An inlet for nitrogen was combined with NaOH separator. Oxalicacid was loaded into the addition funnel and added over 15 minutes, and during this time the temperature dropped to 10°C with evolution of gas. The reaction mixture was stirred for 1 hour, heating to 17°C. After three hours at room temperature the sample was checked by HPLC for completion of the reaction. Sample extinguished in methanol.

75 l mnogogolovy round bottom flask in a steam bath, equipped with verhneprivodnaya stirrer, thermocouple probe and inlet for nitrogen, top-loaded aluminium chloride, suspended in dichloromethane. To this suspension was added a solution of carboxylic acid for 5 minutes with a concomitant rise in temperature from 17°C to 22°C. the Mixture was stirred at room temperature for 45 minutes. Pyrrole-2-carboxylic acid was added in several portions over 40 minutes with vigorous evolution of gas after each download. The temperature rose to 23°C. After 30 minutes at room temperature selected sample and checked for completeness of reaction HPLC. The reaction mixture was stirred for additional 2 hours n the ed location in the ice and put it on top of dry ice for cooling during the night. 100 l mnogogolovy round bottom flask in a steam bath, equipped with verhneprivodnaya stirrer, thermocouple probe and inlet for nitrogen top, download, HCl and placed in ice to cool it during the night.

To the cooled HCl solution was added to the reaction mixture for 1 3/4 hours, raising the temperature to 24°C. the resulting suspension was kept for 1 hour at room temperature and then filtered. The filter residue was washed by a large amount of HCl, followed by rinsing with water.

The filter residue was dried in the vessel with nitrogen during the night. Then wet the filter residue was dried in a vacuum oven at 55°C with a nitrogen purge during the weekend. To the resulting solid residue in 100 l mnogogolos round bottom flask in a steam bath, equipped with verhneprivodnaya stirrer, thermocouple probe, and addition funnel with the inlet of the nitrogen, top-loaded crude product anilinophenol terracarbon acid and methanol. This suspension was heated at 48°C for dissolution of the product in which it is cooled. After reaching 30°C through the addition funnel was added water for 1 hour.

The suspension was cooled to 5°C and maintained for 2 hours. Then the suspension was filtered at 5°C and the filter residue was washed with cold mixture (5°C) methanol:water. VL is iny solid product was checked on the ratio of regioisomers HPLC. The filter residue was dried in the vessel with nitrogen during the night before packing.

NMR:

1H (DMSO, 400 MHz) δ 12,92 (Shir.s, 1H), 12,70 (Shir.s, 1H), 7,58 (DD, 1H, J=3,4, 1.5 Hz), 7,31 (DD, 2H, J=9,4, 7.9 Hz),? 7.04 baby mortality (t, 1H, J=2.0 Hz).

13C (DMSO, 100 MHz) δ 180,8, 162,8 (dt, JCF=249,41, 15,72 Hz), 161,4, 159,2 (DDD,JCF=248,60, 15,76, of 11.15 Hz), 130,2, 125,9, 125,9, 114,7 (TD, JCF=18,75, 4,71 Hz), 114,3, 101,4 (TD, JCF=23,98, 3,01 Hz).

19F (DMSO, 376 MHz) δ -105,26, -105,28, -105,29, -111,11,-111,13.

HRMS:[M-H]-C12H5O3NF3-designed 268,0222; found 268,0228; error: 2,2 m D.

2,4,6-Triptoreline acid:

NMR:

1H (DMSO, 400 MHz) δ 13,89 (Shir.s, 1H), 7,27 (m, 2H).

13C (DMSO, 100 MHz) δ 163,28 (dt, JCF=250,9, 16.0 Hz), 161,5, 160,3 (DDD, JCF=253,6, 15,8, 9.7 Hz), 109,0 (TD, JCF=19,5, a 4.7 Hz), 101,5 (TD, JCF=26,8, 3.5 Hz).

19F (DMSO, 376 MHz) δ -103,6, -103,6, -103,7, -108,3, -108,3.

Pyrrole-2-carboxylic acid:

NMR:

1H (DMSO, 400 MHz) δ 12,16 (Shir.s, 1H), 11,68 (Shir.s, 1H), 5,70 (m, 1H), of 6.71 (m, 1H), 6,13 (m, 1H).

13C (DMSO, 100 MHz) δ 161,9, 123,4, 122,9, 114,7, 109,3.

Stage 2. Education acylhydrazides

Experiment:

Into a reaction vessel were loaded methyl ester (140 g, 1110 mmol), hydrazinehydrate (94 ml, 1554 mmol) and methanol (700 ml), and then boiled under reflux.

LC results: 45 min: 72% conversion; 1.25 hours: 85% conversion.

The reaction to shift the ü maintained for an additional 2.5 hours, then was stirred at room temperature overnight, after which LC analysis showed completion of the reaction. The resulting suspension was cooled to 3°C, the solid residue was filtered and washed with 200 ml of water, then dried in a stream of nitrogen, to obtain 120 g (86% yield) acylhydrazides.

Stage 3. Chlorotyrosine

Experiment:

Reagent 1 (100 g, 793 mmol) suspended in ethyl acetate (1000 ml) in a 3 l 3-necked RBF with verhneprivodnaya stirring and treated with potassium bicarbonate (600 ml, 1800 mmol). Then the reaction mixture was cooled to 5°C, after which was added for 7 minutes chlorocatechol (76 ml, 952 mmol). Observed temperatures up to 16°C. LC analysis after 15 minutes showed complete reaction. Added 100 ml of 6N HCl, then add another 15 ml of 12N HCl to bring the pH to 4.6. The solid residue was filtered and washed with 150 ml of cold water and dried overnight in a stream of nitrogen, to get 143,7 g (89%) of the desired product.

Stage 4. Cyclization

Experiment:

Suspended reagent 1 (75 g, 370 mmol) and reagent Lawesson (150 g, 370 mmol) in THF (1500 ml), and then boiled under reflux in nitrogen atmosphere for 2.5 hours. Then the reaction was cooled to room temperature and concentrated. The resulting OST is OK was dissolved in 250 ml EtOAc, was treated with 300 g of silica gel, then filtered. The residue on the filter was washed 3×500 ml EtOAc. The first fraction was passed through a layer of silica gel again and fractions with product were concentrated and re-dissolved in DCM, chromatographically on silica gel, 1.5 kg column, suirable EtOAc/heptane 50-60%. Selected fractions from the substance in order to obtain 41 g of the solid residue (55,2 %).

Stage 5. The substitution of sodium azide

Experiment:

Dissolved reagent 1 (38 g, 189 mmol) in DMF (160 ml) at room temperature. Was added sodium azide (12,93 g, 199 mmol)was stirred at ambient temperature. The mixture became orange after a few minutes began to fall precipitate.

After stirring the reaction mixture during the weekend, LC analysis showed completion of the reaction. Added 250 ml of water (slightly exothermic), which resulted in a homogeneous solution, and then started to crystallize the precipitate. The suspension was cooled to 5°C, filtered, washed with 2×100 ml cold water and dried to obtain 36,6 g (92%) of product.

Stage 6. Recovery azide

Experiment:

Suspended reagent 1 (32,0 g, 154 mmol) in THF (160 ml)was added water (8,01 g, 445 mmol). Was added dropwise within one hour of trimethylol the Institute of 1.0 M in THF (170 ml, 170 mmol). Analysis after 2 hours showed the absence of starting material. The solution was concentrated and the resulting residue was treated with 160 ml of 2N HCl and stirred at room temperature overnight.

Then the solution was podslushivaet 60 ml of 5N NaOH. Added 160 ml of 1N NaHCO3and was used directly in the next end the condensation reaction.

Stage 7a. Activation

Experiment:

Dissolved reagent 1 (41.5 g, 154 mmol) in THF (415 ml)was added 0.25 ml of DMF, was then added oxalicacid (14,15 ml, 162 mmol). The solution was stirred at room temperature for 1 hour, then concentrated. The resulting residue was diluted with 200 ml of 2-MeTHF and used directly in the final stage of condensation.

Stage 7b. The final condensation

Experiment:

A solution of the crude acid chloride of the acid and amine were mixed and stirred at room temperature for 2 hours. After completion of the reaction (LC analysis), the solution was concentrated to remove organic solvents and the resulting aqueous suspension was filtered, the solid residue was washed with water (100 ml, 150 ml), then 150 ml of acetonitrile and dried with suction to obtain 72 g of a pale-green solid residue.

Recrystallization

Download 71,8 g of the solid residue in a 22 l round bottom flask and was added to 7.0 ml of acetonitrile and 3.5 l of water, then heated to 77°C. Filter the hot mixture through a Buchner funnel to remove insoluble compounds. (The filtrate was slightly turbid.) Pumped filtrate (61°C) in a clean 22 l round bottom flask through 5 MK linear filter in order to obtain a clear yellow solution. Slowly cooled to 30°C and then cooled to 5°C. Filtered the solid residue and washed his 250 ml of a 2/1 mixture of acetonitrile/water, dried in vacuum over night to get 44,65 g (67% yield on stage 2 and recrystallization) of the final product.

1. The connection represented by the chemical formula (I)

where:
L is chosen from the group consisting of:
(a) -C(O)-,
(e) -CH2-;
Ar1does not necessarily represent mono-, di - or tizamidine phenyl ring, where the substituents independently selected from the group consisting of:
(a) halogen and
(b)- (C1-4of alkyl;
Ar2represents an optionally substituted thiadiazole ring where the Deputy represents-C1-4alkyl, -C3-5cycloalkyl-methylcyclopropyl, phenyl or 5 - or 6-membered monocyclic heteroaromatic ring or the bicyclic heteroaromatic ring with 9 or 10 the volumes, moreover, the aforementioned heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl or the heteroaromatic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:
(a) halogen,
(b) -C1-6the alkyl, optionally substituted by 1 to 4 fluorine atoms,
(c) -O-C1-6of alkyl,
(d) -CF3and
(1) oxo.

2. Connection on p. 1, where L is chosen from the group consisting of:
(a) -C(O)- and
(b) -CH2-.

3. Connection on p. 2, where L represents-C(O)-.

4. Connection on p. 1, where
Ar1represents optionally mono-, di - or tizamidine phenyl ring, where the substituents independently selected from the group consisting of:
(a) halogen,
(b)- (C1-4the alkyl and
(c) -O-C1-4the alkyl.

5. Connection on p. 4, where
Ar1represents optionally mono-, di - or tizamidine phenyl, where the substituents independently selected from the group consisting of
(a) fluorine,
(b) chlorine and
(C) -CH3.

6. Connection on p. 1, where
Ar2represents an optionally substituted thiadiazolyl.

7. Connection on p. 6, where the Deputy represents - C1-4alkyl, -C3-5cycloalkyl-methylcyclopropyl, phenyl or 5 - or 6-membered monocyclic heteroaromatic ring or bicyclic the civil heteroaromatic ring with 9 or 10 atoms, moreover, the aforementioned heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl or the heteroaromatic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:
(a) halogen,
(b)- (C1-6the alkyl, optionally substituted CF3,
(c) -O-C1-4of alkyl,
(d) -CF3and
(e) C3-6cycloalkyl.

8. Connection on p. 7, where the Deputy is a phenyl or 5 - or 6-membered monocyclic heteroaromatic ring, and mentioned heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl or the heteroaromatic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:
(a) halogen,
(b)- (C1-6the alkyl, optionally substituted CF3,
(c) -O-C1-4of alkyl;
(d) -CF3and
(e) C3-6cycloalkyl.

9. Connection on p. 1 of the formula I

where
L represents-C(O)-;
Ar1represents optionally mono-, di - or tizamidine phenyl, where the substituents independently selected from the group consisting of:
(a) F,
(b) Cl and
(c) -C1-4of alkyl;
Ar2is an optional for ewenny thiadiazolyl, and Deputy represents phenyl or 5 - or 6-membered monocyclic heteroaromatic ring, and mentioned heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl or the heteroaromatic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:
(a) halogen,
(b)- (C1-4of alkyl,
(c) -O-C1-4of alkyl,
(d) -CF3,
(e) C3-6cycloalkyl.

10. Connection on p. 1 of formula (II)

(II)
where
Ar2represents an optionally substituted thiadiazolyl where the Deputy is a phenyl or 5 - or 6-membered monocyclic heteroaromatic ring, and mentioned heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from the group consisting of S, O and N, where mentioned phenyl or the heteroaromatic ring is optionally mono - or disubstituted by substituents independently selected from the group consisting of:
(a) halogen,
(b)- (C2-6of alkyl,
(c) -O-C1-4the alkyl and
(d) -CF3.

11. Connection on p. 1, selected from the group consisting of:

1
2
3
4

5
6
7
8
9
10

11
12
13
14
15
16

17
18
19
20
21

22
23
24
25
26

29
27
28
30
31

32
33
34
35
36
37

38
39
40
41
42
43

44
45
46

12. Pharmaceutical composition for prevention or treatment of disease, disorder or condition mediated by cytokine containing an inert carrier and an effective amount of the compounds under item 1.

13. The use of compounds on p. 1 to obtain drugs for treatment or prevention of asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondilitis, osteoarthritis or gout arthritis.

14. The compound having the following structure:

15. Pharmaceutical composition for prevention or treatment of disease, disorder or condition mediated by cytokine containing an inert carrier and an effective amount of the compounds under item 14.

16. The use of compounds on p. 14 for obtaining a medicinal product for the treatment or prevention of asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondilitis, osteoarthritis Il is gouty arthritis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, denoted by Form B, characterised by X-ray powder diffraction at reflected angles of 2θ: 14.902, 18.123, 18.87, 20.204, 20.883, 21.79, 24.186, 26.947. The invention relates to a fungicidal composition containing a crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, denoted by Form B, in an effective amount and at least one additional component selected from a group consisting of a surfactant and a liquid carrier. The invention relates to a method of controlling plant diseases caused by fungal plant pathogens, which includes applying a fungicidally effective amount of said polymorph on a plant or part thereof or seeds. The invention also relates to methods of obtaining said crystalline polymorph.

EFFECT: crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, having a higher melting point and which is less soluble.

12 cl, 13 tbl, 2 dwg, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to traumatology and orthopaedics, and can be used for treating patients with epicondylitis. That is ensured by applying a complex of measures, in particular a restraint of motions in the involved segment, physiotherapy and drug treatment. A pain syndrome is pre-evaluated by a visual analogue scale (VAS). A proximal forearm is immobilised with an epicondylic bandage in the daytime for 7-10 days in sportsmen, and for 2-3 weeks in common patients. Therapeutic exercises (TE) are prescribed from the first day of treatment. The first part of TE consisting of isometric and static exercises aiming at strengthening arm muscles is done before noon. The second part of TE comprising relaxing exercises is performed in the late afternoon or after any physical loads. The patient continues with the therapeutic exercises after the bandage is removed and to be used for professional or sports loads only. Electric stimulation is conducted daily for 7-10 days with using TENS apparatus or its analogues generating electrical signals covering the enthesis and the involved forearm muscles. Arthrofoon is administered with underlying electric stimulation. If the pain syndrome value according to the VAS is less than 4 points, the preparation is administered as a monotherapy in a dose of 4 weeks a day for three months. If the pain syndrome according to the VAS is more than 4 points, Arthrofoon is administered in a dose of 8 tablets a day in a combination with a selective non-steroid anti-inflammatory preparation in a therapeutic dose for no more than 10 days. The therapeutic regimen also contains Sirdalud 2-4 mg one hour before bedtime for 2 weeks. There are also administered vasodilators improving microcirculation of the involved segment, intramuscularly for 10 days. The therapeutic complex is also added with Milgamma B 2 ml, 5 injections, and another 5 injections triduan. Wobenzyme is administered for 3-4 weeks. Calcemine or Calcemine-advance, the preparations of calcium are administered for six months. The therapeutic course according to the presented regimen is repeated half a year later. The physical exercising for the arm muscles strengthening are to be further done two or three times a week on the average for min. 30 minutes for the life term if suffering high loads or doing any top-class sports for the purpose of maintaining the forearm tonus. The segment of interest is fixed with an orthesis when suffering a load. The therapy with the TENS or similar apparatus of the forearm muscles of interest and the enthesis follow a pronounced load 2-3 hours before bedtime and shall be accompanied with a session of relaxing exercises.

EFFECT: method provides the evident and stable clinical effect characterised by the complete recurrence-free recovery by the physical restoration of the tissue structure within the inflammation with the high quality of life and a surgical intervention avoided.

1 dwg, 2 ex

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