2-pyrazinone derivatives for treating diseases or conditions where inhibiting neutrophil elastase activity is useful

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 denotes C1-C6alkyl; W denotes pyrazolyl, triazolyl or imidazolyl; R14 denotes phenyl or a 6-member heteroaromatic ring containing 1-3 nitrogen ring atoms, which is may be substituted with at least one substitute selected from F, Cl, CN and CF3; R3 denotes phenyl, substituted with a trifluoromethyl substitute; R4 denotes hydrogen or C1-C6alkyl; X denotes -C1-C6alkylene-Y-, and Y denotes a single bond, and the alkylene group is a straight or branched C1-C6alkylene, possibly substituted with OH, CO2R66 or C1-C3alkoxy; R5 denotes phenyl or pyridinyl, substituted with -S(O)vR21; or R5 denotes an unsubstituted C3-C6cycloalkyl ring; or R5 can also denote H; R21 denotes hydrogen, C1-C6alkyl or C3-C8cycloalkyl; v equals 1 or 2; and R66 denotes hydrogen or C1-C6alkyl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing said compounds, intermediate compounds and a pharmaceutical composition for treating or reducing the risk of disease or condition, in which inhibiting neutrophil elastase activity based on compounds of formula (I) is useful.

EFFECT: obtaining novel compounds which can be used in medicine to treat or reduce the risk of disease or condition in which inhibiting neutrophil elastase activity is useful.

19 cl, 16 ex

 

The scope of the invention

The present invention relates to derivatives of 2-pyrazinone, methods for their preparation, pharmaceutical compositions containing them and their use in therapy.

Background of the invention

Elastase are perhaps the most destructive enzymes in the body, having the ability to destroy almost all of the components of connective tissue. Uncontrolled proteolytic disintegration under the action of elastases involved in a number of pathological conditions. Human neutrophil elastase (hNE), a member of chymotrypsinogen the superfamily of serine proteases, is a 33-kDa enzyme that is azurophilic granules of neutrophils. Neutrophil concentration NE exceeds 5 mm, and its total cell number, as it is estimated that up to 3 PG. When activated, NE quickly released from the granules into the extracellular space, and some remains associated with the plasma membrane of neutrophils (see Kawabat et al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellular physiological function NE is in the degradation of alien organic molecules absorbed by neutrophils phagocytosis, whereas the main target of extracellular elastase is elastin (Janoffand Scherer, 1968, J. Exp.Med. 128, 1137-1155). In comparison with other proteases (e.g., proteinase 3), NE is unique in that region which gives the ability to destroy almost all extracellular matrix proteins and key plasma proteins (see Kawabat et al., 2002, Eur. J. Pharmacol. 451, 1-10). It destroys a wide range of extracellular matrix proteins such as elastin, collagen type 3 and type 4, laminin, fibronectin, cytokines, etc. (Ohbayashi, N., 2002, Expert Opin. Investig. Drugs, 11, 965-980). NE is the main common mediator of many of the pathological changes seen in chronic lung disease, including the destruction of the epithelium (Stockley, R.A. 1994, Am. J. Resp. Crit. Care Med. 150, 109-113).

The destructive role of NE was established almost 40 years ago, when Laurell and Eriksson reported on the relationship of chronic airway obstruction and emphysema with deficiency of serum α1-antitrypsin (Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140). Subsequently, it was determined that α1-antitripsin is the most important endogenous inhibitor of human NE. The imbalance between the human NE and endogenous antiproteases is believed to be the cause of excess NE in human lung tissue, which is considered the main pathogenic factor in chronic obstructive pulmonary disease (COPD). Excess human NE demonstrates a significant destructive profile and actively participates in the destruction of normal lung structures with subsequent irreversible expansion of the respiratory tract that is mainly seen in emphysema. There is an increase in recruitment of neutrophils into the lungs, which is associated with an increased elastase the second load in the lung and emphysema in mice with deficiency of the inhibitor α 1proteases (Cavarra et al., 1996, Lab. Invest. 75, 273-280). Individuals with higher levels of complex NE-inhibitor α1protease in bronchoalveolar lavage show significantly accelerated deterioration of lung function compared with those who have these levels are lower (Betsuyaku et al. 2000, Respiration, 67, 261-267). Instillation of human NE through the trachea in rats causes pulmonary hemorrhage, accumulation of neutrophils during the acute phase and emphysematous changes during the chronic phase (Karaki et al., 2002, Am. J. Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acute phase of pulmonary emphysema and pulmonary hemorrhage caused by NE in hamsters can be ingibirovany pre-treatment with inhibitors of NE (Fujie et al., 1999, Inflamm. Res. 48, 160-167).

The neutrophil-dominant inflammation of the respiratory tract and mucous obstruction of the respiratory tract are the main pathological features of COPD, including cystic fibrosis and chronic .NE disrupts the production of mucin, which leads to mucous obstruction of the respiratory tract. It is reported that NE enhances the expression of the master gene of respiratory mucin, MUC5AC (Fischer, B.M & Voynow, 2002, Am. J. Respir. Cell Biol., 26, 447-452). Aerosol introduction NE Guinea pigs causes extensive damage to the epithelium within 20 minutes of contact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153, 1405-1411). Moreover, NE reduces the pulse frequency of the cilia man is someone respiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39, 663-667), which is consistent with reduced clearance ciliated epithelium, which is observed in patients with COPD (Currie et al., 1984, Thorax, 42, 126-130). Instillation of NE in the respiratory tract leads to hyperplasia of the mucous glands of hamsters (Lucey et al., 1985, Am. Resp.Crit. Care Med., 132, 362-366). NE also plays a role in mucus hypersecretion in asthma. In a model of acute asthma in sensitized allergen Guinea pigs inhibitor NE prevented degranulation of goblet cells and mucus hypersecretion (Nadel et al., 1999, Eur. Resp. J., 13,190-196).

It was also shown that NE plays a role in the pathogenesis of pulmonary fibrosis. The complex NE-inhibitor α1proteases increased in the serum of patients with pulmonary fibrosis, which correlates with the clinical parameters of these patients (Yamanouchi et al., 1998, Eur. Resp.J. 11, 120-125). In a mouse model of human lung fibrosis NE inhibitor reduces pulmonary fibrosis induced by bleomycin (Taooka et al., 1997, Am. J. Resp.Crit. Care Med., 156, 260-265). Moreover, the researchers showed that mice with a deficiency of NE are resistant to fibrosis of the lungs, induced by bleomycin (Dunsmore et al., 2001, Chest, 120, 35S-36S). The level of NE in the plasma as detected, is increased in patients who developed ARDS (respiratory distress syndrome of adults), which implies the importance of NE in the early pathogenesis of ARDS (Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 428-1433). Antiprotease and NE in complex with antiproteases improve the ENES in the field of lung cancer (Marchandise et al., 1989, Eur. Resp.J. 2, 623-629). Recent studies have shown that polymorphism in the promotor region of the gene NE associated with the development of lung cancer (Taniguchi et al., 2002, Clin. Cancer Res., 8, 1115-1120).

With elevated levels of NE associated acute lung injury induced by endotoxin in experimental animals (Kawabata, et al., 1999, Am. J. Resp.Crit. Care, 161, 2013-2018). As has been shown in acute lung inflammation induced by intratracheal injection of lipopolysaccharide in mice, increased NE activity in bronchoalveolar lavage, which is largely inhibited by the inhibitor of NE (Fujie et al., 1999, Eur. J. Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8, 1293-1299). NE also plays an important role in induced neutrophils increased pulmonary capillary permeability observed in a model of acute lung injury induced by tumor necrosis factor α (TNFa) and phorbol-myristate-acetate (PMA) in isolated perfoirmance rabbit lung (Miyazaki et al., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).

Also suggested that NE plays a role in the compaction of the pulmonary vascular wall induced monocrotaline, and cardiac hypertrophy (Molteni et al., 1989, Biochemical Pharmacol. 38, 2411-2419). Inhibitor of serine elastase reverses pulmonary hypertension induced by monocrotaline, and remodeling in the pulmonary arteries of rats (Cowan et al., 2000, Nature Medicine, 6, 698-702). Recent studies have shown that eranova elastase, that is NE or vascular elastase, play an important role in muscularization small pulmonary arteries caused by cigarette smoke in Guinea pigs (Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000, Brain Research, 858, 55-60), ischemic-reperfusion lung injury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) and myocardial ischemia in heart of rats (Tiefenbacher et al., 1997, Eur. J. Physiol., 433, 563-570). The levels of human NE in plasma significantly increased compared to the norm in inflammatory bowel disease such as Crohn's disease or ulcerative colitis (Adeyemi et al., 1985, Gut, 26, 1306-1311). In addition, it has been suggested that NE is involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collagen-induced arthritis in mice is inhibited by the inhibitor of NE (Kakimoto et al., 1995, Cellular Immunol. 165, 26-32).

Thus, human NE is known as one of the most destructive of serine proteases and she is involved in several inflammatory diseases. Important endogenous inhibitor of human NE is α1-antitripsin. The imbalance between the human NE and antiproteases is believed, causes excess human NE, which may lead to uncontrolled tissue destruction. The balance of protease/antiprotease can be violated reduced the Oh accessibility α 1-antitrypsin deficiency either through inactivation by oxidants, such as cigarette smoke, either as a result of genetic inability to produce adequate serum levels. Human NE involved in the activation or exacerbation of diseases such as pulmonary emphysema, pulmonary fibrosis, respiratory distress syndrome in adults (ARDS), ischemic-reperfusion injury, rheumatoid arthritis and pulmonary hypertension.

DETAILED description of the INVENTION

In accordance with the present invention proposed a compound of formula (I)

where

R1represents hydrogen or C1-C6alkyl;

W represents a 5-membered heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, where at least one of the ring carbon atoms may be replaced by a carbonyl group; and where the heterocyclic ring may substituted by at least one Deputy, selected from halogen, C1-C4of alkyl, C1-C4alkoxy, CN, IT, NO2C1-C3of alkyl, substituted by one or more F atoms, C1-C3alkoxy, substituted by one or more F atoms, groups, NR10R11C≡CR15, CONR16R17CHO, C2-C4alkanoyl, S(O) xR18and OSO2R19;

R14represents phenyl or 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms; and the specified ring possibly substituted by at least one Deputy, selected from halogen, C1-C4of alkyl, C1-C4alkoxy, CN, IT, NO2C1-C3of alkyl, substituted by one or more F atoms, C1-C3alkoxy, substituted by one or more F atoms, groups, NR12R13C≡CR30, CONR31R32CHO, C2-C4alkanoyl, group S(O)pR33and OSO2R34;

R10, R11, R12and R13independently represent H, C1-C6alkyl, formyl or2-C6alkanoyl; or the group-NR10R11or-NR12R13together is a 5-7-membered azollaceae ring, possibly containing one additional heteroatom selected from O, S and NR26;

R15and R30independently represent H, C1-C3alkyl or Si(CH3)3;

R18, R19, R33and R34independently represent N or C1-C3alkyl; with the specified alkyl possibly substituted by one or more F atoms;

R3represents phenyl or five - or six-membered heteroaromatic ring, teramae from 1 to 3 heteroatoms, independently selected from O, S and N; and the specified ring possibly substituted by at least one Deputy, selected from halogen, C1-C6of alkyl, cyano, C1-C6alkoxy, nitro, methylcarbamyl, NR35R36C1-C3of alkyl, substituted by one or more F atoms, or With1-C3alkoxy, substituted by one or more F atoms;

R35and R36independently represent N or C1-C3alkyl; with the specified alkyl may optionally substituted by one or more F atoms;

R4represents hydrogen or C1-C6alkyl, possibly substituted by at least one Deputy, selected from fluorescent, hydroxyl and C1-C6alkoxy;

X represents a simple bond, O, NR24or a group-C1-C6alkylene-Y-, where Y represents a simple bond, oxygen atom, NR24or S(O)w; and the specified alkylen perhaps IT is additionally substituted, halogen, CN, NR37R38With1-C3alkoxy, CONR39R40, CO2R66, SO2R41and SO2NR42R43;

or R4and X are connected together so that the group-NR4X together is a 5-7-membered azollaceae ring, possibly containing one additional heteroatom selected from O, S and NR44; when it is eaten specified ring possibly substituted C 1-C6the alkyl or NR45R46; and the alkyl may optionally replaced IT;

or R5represents a monocyclic ring system selected from the

1) phenoxy,

2) phenyl,

3) 5 - or 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

4) saturated or partially unsaturated With3-C6cycloalkene rings, or

5) saturated or partially unsaturated 4-7 membered heterocyclic ring containing at least one ring heteroatom selected from oxygen, S(O)rand NR20where at least one of the ring carbon atoms may be replaced by a carbonyl group,

or R5represents a bicyclic ring system in which these two rings independently selected from monocyclic ring systems defined in(2), (3), (4) and (5) above, where the two rings or condensed together or are connected directly to each other or separated from each other by linker group selected from oxygen, S(O)tor1-C6alkylene may contain one or more internal or terminal heteroatoms selected from oxygen, sulfur and NR27and possibly substituted by at least one Deputy chosen from hydroxyl, oxo and C1-C6alkoxy,

where monocyclic or bicyclic ring system may be substituted by at least one Deputy, selected from oxygen, CN, IT, C1-C6of alkyl, C1-C6alkoxy, halogen, NR47R48, NO2, OSO2R49, CO2R50C(=NH)NH2C(O)NR51R52C(S)NR53R54, SC(=NH)NH2, NR55C(=NH)NH2, S(O)vR21, SO2NR56R57C1-C3alkoxy, substituted by one or more F atoms, and C1-C3of alkyl, substituted SO2R58or one or more F atoms; and specified With1-C6alkyl may optionally substituted by at least one Deputy, selected from cyano, hydroxyl, C1-C6alkoxy, C1-C6alkylthio and-C(O)NR22R23;

or R5may also represent H;

R20represents hydrogen, C1-C6alkyl, C1-C6alkylaryl or C1-C6alkoxycarbonyl;

R21represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; and the specified alkyl or cycloalkyl group may be additionally substituted by one or more substituents, independently selected from HE, CN, C1-C3alkoxy and CONR59R60;

R 37and R38independently represent H, C1-C6alkyl, formyl or2-C6alkanoyl;

R47and R48independently represent H, C1-C6alkyl, formyl, C2-C6alkanoyl, S(O)qR61or SO2NR62R63and mentioned alkyl group may optionally substituted with halogen, CN, C1-C4alkoxy or CONR64R65;

R41and R61independently represent H, C1-C6alkyl or C3-C6cycloalkyl;

p is 0, 1 or 2;

q is 0, 1 or 2;

r is 0, 1 or 2;

t is 0, 1 or 2;

w is 0, 1 or 2;

x is 0, 1 or 2;

v is 0, 1 or 2;

each of R16, R17, R22, R23, R24, R26, R27, R31, R32, R39, R40, R42, R43, R44, R45, R46, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R62, R63, R64, R65and R66independently represents hydrogen or C1-C6alkyl;

or its pharmaceutically acceptable salt.

In the context of the present description, unless otherwise specified, alkyl, Alchemilla or Alchemilla group Deputy or an alkyl group in the group-the Deputy may be linear eliasville. Similarly, Allenova group can be linear or branched.

In the definition of W, 5-membered heterocyclic ring system may have alicyclic or aromatic properties and can, therefore, be a saturated ring system or partially unsaturated ring system, or fully unsaturated ring system.

R1represents hydrogen or C1-C6alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-pentyl or n-hexyl).

In one embodiment of the invention R1represents a C1-C4- or1-C2alkyl group, particularly methyl group.

W represents a 5-membered heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, where at least one of the ring carbon atoms may be replaced by a carbonyl group; and where the heterocyclic ring may substituted by at least one Deputy, selected from halogen (e.g. fluorine, chlorine, bromine or iodine), With1-C4the alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl or tert-butyl)1-C4alkoxy (e.g. methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy or Tr is t-butoxy), cyano, HE, NO2With1-C3of alkyl, substituted by one or more F atoms (for example, CH2F, CHF2, CF3CH2CH2F, CH2CF3, CF2CF3CH(CF3)2and CH2CH2CF3)1-C3alkoxy, substituted by one or more F atoms (e.g., OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CF3, OCF2CF3, Och(CF3)2and OCH2CH2CF3), NR10R11C≡CR15, -C(O)NR16R17, SNO,2-C4alkanoyl (for example, methylcarbamyl (acetyl), ethylcarbazole, n-propylboronic or ISO-propylboronic), -S(O)xR18and OSO2R19.

In one embodiment the group R14and pyrazinone ring attached to the 5-membered ring W in positions 1, 2.

In one embodiment W is a 5-membered heteroaromatic ring, in particular unsubstituted 5-membered heteroaromatic ring.

Examples of 5-membered heterocyclic ring systems, which can be used and which can be saturated, partially unsaturated, or fully unsaturated, include any of the following: pyrrolidinyl, tetrahydrofuranyl, pyrrolin, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, pyrrolidinyl, imidazolidinyl, oxazolyl, pyrazolyl, thiazolidine is, thienyl, isoxazolyl, isothiazolin, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, imidazolyl, furutani, triazolyl and tetrazolyl.

Preferred ring systems for group W include pyrazolyl, thiazolyl, oxazolyl and imidazolyl.

In one embodiment W is pyrazolyl, triazolyl, thiazolyl, oxazolyl or imidazolyl.

In one embodiment W is pyrazolyl or triazolyl.

R14represents phenyl or 6-membered heteroaromatic ring containing from 1 to 3 (e.g., one, two, or three) ring nitrogen atom; and the specified ring possibly substituted by at least one (e.g. one, two, three or four) Deputy selected from halogen (e.g. fluorine, chlorine, bromine or iodine), With1-C4the alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl or tert-butyl)1-C4alkoxy (e.g. methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy or tert-butoxy), CN, IT, NO2With1-C3of alkyl, substituted by one or more F atoms (for example, CH2F, CHF2, CF3CH2CH2F, CH2CF3, CF2CF3CH(CF3)2and CH2CH2CF3)1-C3alkoxy, substituted by one or more F atoms (e.g., OCH2F, OCHF2, OCF3, OCH2CH F, OCH2CF3, OCF2CF3, Och(CF3)2and OCH2CH2CF3), NR12R13C≡CR30, CONR31R32, SNO,2-C4alkanoyl (for example, methylcarbamyl (acetyl), ethylcarbazole, n-propylboronic or ISO-propylboronic), S(O)pR33and OSO2R34.

Examples of 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preferred ring system is pyridinyl.

In one embodiment, one Deputy on the aromatic ring group, R14must be in 4-(pair)-position relative to group W.

In one embodiment of the invention R14represents phenyl or 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atom; and the specified ring possibly substituted by at least one Deputy, selected from F, Cl, CN and CF3.

In one embodiment of the invention R14represents phenyl or pyridinyl; and the specified ring possibly substituted by at least one Deputy, selected from F, Cl, CN and CF3.

In one embodiment of the invention R14represents phenyl or pyridinyl group, possibly substituted by one or two substituents, independently selected and from F, Cl, CN and CF3.

In one embodiment of the invention R14represents phenyl or pyridinyl; and the specified ring substituted in the 4-(para)position F, Cl or CN, and may be additionally substituted.

In one embodiment of the invention R14represents phenyl or pyridinyl; and the specified ring substituted in the 4-(para)position F, Cl or CN.

R3represents phenyl or five - or six-membered heteroaromatic ring containing from 1 to 3 (e.g., one, two, or three heteroatoms independently selected from O, S and N; and the specified ring possibly substituted by at least one (e.g. one, two, three or four) Deputy selected from halogen (e.g. fluorine, chlorine, bromine or iodine), With1-C6the alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-pentile or n-hexyl), cyano, C1-C6alkoxy (e.g. methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, n-pentoxil or n-hexose), nitro, methylcarbamyl, NR35R36With1-C3of alkyl, substituted by one or more F atoms (for example, CH2F, CHF2, CF3CH2CH2F, CH2CF3, CF2CF3CH(CF3)2and CH2CH2CF3), and C1-C3alkoxy, substituted by one or more atoms is F (for example, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CF3, OCF2CF3, Och(CF3)2and OCH2CH2CF3).

In one embodiment R3represents phenyl or pyridinoline ring, substituted at least one substituent (e.g. one, two or three substituents)independently selected from halogen, cyano, nitro, methyl, trifloromethyl and methylcarbamyl.

In one embodiment R3represents a phenyl group substituted by one or two substituents, independently selected from fluorine, chlorine, cyano, nitro and trifloromethyl.

In another embodiment R3represents a phenyl group substituted by one or two substituents, independently selected from fluorine, chlorine and trifloromethyl.

In another embodiment R3represents a phenyl group, substituted triptorelin substituent (preferably in meta-position).

In another embodiment R3represents a phenyl group substituted in metaprogram Br, Cl, CF3or CN.

R4represents hydrogen or C1-C6alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by at least one substituent (e.g. one or two substituents)independently is selected from fluorescent, hydroxyl and C1-C6alkoxy (e.g. methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, n-pentoxil or n-hexose).

In one embodiment R4represents hydrogen or C1-C4alkyl, possibly substituted by one or two substituents, independently selected from hydroxyl and C1-C4alkoxy.

In another embodiment R4represents hydrogen.

In one embodiment of the invention X represents a simple bond or a group-C1-C6alkylene-Y-, where Y represents a simple bond, oxygen atom, NR24or S(O)w; and the specified alkylen perhaps IT is additionally substituted, halogen, CN, NR37R38With1-C3alkoxy, CONR39R40, CO2R66, SO2R41and SO2NR42R43.

In one embodiment of the invention X represents a simple bond or a group-C1-C6alkylene-Y-, where Y represents a simple bond, oxygen atom, NR24or S(O)w; and the specified alkylen perhaps IT is additionally substituted, halogen, CN, NR37R38With1-C3alkoxy, CONR39R40, SO2R41and SO2NR42R43.

In one embodiment of the invention X represents a group-C1-C6alkylene-Y, and Y represents the th simple link, and Allenova group represents a linear or branched C1-C6-or1-C4-or1-C2alkylen possibly replaced IT, halogen, CN, CO2R66or1-C3alkoxy.

In one embodiment of the invention X represents a group-C1-C6alkylene-Y, and Y represents a simple bond, and Allenova group represents a linear or branched C1-C6-or1-C4-or1-C2alkylen may HE substituted, halogen, CN or C1-C3alkoxy.

In another embodiment of the invention X represents an unsubstituted With1-C2alkylene, in particular methylene.

In another embodiment of the invention X represents a simple bond.

In one embodiment of the invention R4and X are connected together so that the group-NR4X together is a 5-7-membered azollaceae ring, possibly containing one additional heteroatom selected from O, S and NR44; and the specified ring possibly substituted C1-C6the alkyl or NR45R46; and the alkyl may optionally replaced IT.

Examples 5-7-membered usacycling ring, possibly containing one additional heteroatom selected from O, S and NR44include pyrrolidine,piperidine, piperazine, morpholine and peligrosas.

R5represents a monocyclic ring system selected from the

(1) phenoxy,

(2) phenyl,

(3) 5 - or 6-membered heteroaromatic ring containing at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms)independently selected from nitrogen, oxygen and sulphur,

(4) saturated or partially unsaturated With3-C6cycloalkene rings or

(5) a saturated or partially unsaturated 4-7 membered heterocyclic ring containing at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms)independently selected from oxygen, S(O)rand NR20where at least one of the ring carbon atoms may be replaced by a carbonyl group,

or R5represents a bicyclic ring system in which these two rings independently selected from monocyclic ring systems as defined in(2), (3), (4) and (5) above, where the two rings or condensed together or are connected directly to each other or separated from each other by linker group selected from oxygen, S(O)tor1-C6alkylene, possibly containing one or more (e.g. one or two) internal or terminal heteroatom is in, selected from oxygen, sulfur and NR27and possibly substituted by at least one substituent (e.g. one or two substituents)independently selected from hydroxyl, oxo and C1-C6alkoxy (e.g. methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, n-pentoxil or n-hexose);

moreover, this monocyclic or bicyclic ring system may be substituted (ring atom), at least one substituent (e.g. one, two or three substituents)independently selected from oxygen (for example, with the formation of N-oxide), CN, IT,1-C6the alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-pentile or n-hexyl)1-C6alkoxy (e.g. methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, n-pentoxil or n-hexose), halogen (e.g. fluorine, chlorine, bromine or iodine), NR47R48, NO2, OSO2R49, CO2R50C(=NH)NH2C(O)NR51R52C(S)NR53R54, SC(=NH)NH2, NR55C(=NH)NH2, -S(O)vR21, SO2NR56R57With1-C3alkoxy, which is substituted by one or more F atoms (e.g., OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CF3, OCH2CF3, Och(CF3)2and CH 2CH2CF3), and C1-C3of alkyl, which is substituted SO2R58or one or more F atoms (for example, CH2SO2R58CH2CH2SO2R58CH(SO2R58)CH3CH2F, CHF2, CF3CH2CH2F, CH2CF3, CF2CF3CH(CF3)2and CH2CH2CF3); where specified With1-C6alkyl may optionally substituted by at least one Deputy, selected from cyano, hydroxyl, C1-Swilcox (for example, methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, n-pentoxil or n-hexose)1-C6alkylthio (for example, methylthio, ethylthio, n-propylthio, out-propylthio, n-butylthio, out-butylthio, tert-butylthio, n-pentylthio or n-hexylthio) and-C(O)NR22R23;

or R5may also represent hydrogen.

Examples of 5 - or 6-membered heteroaromatic rings include furanyl, thienyl, pyrrolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl. Preferred heteroaromatic rings include isoxazolyl, pyridinyl, imidazolyl and triazolyl.

Unless otherwise stated, the "saturated or partially unsaturated With3-C6cyclo is lilinoe ring" means a 3-6-membered non-aromatic cycloalkyl ring, perhaps one or more double bonds, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. Preferred cycloalkenyl ring is cyclopropyl.

Unless otherwise stated, the "saturated or partially unsaturated 4-7 membered heterocyclic ring", as it is specified above, means 4-7-membered non-aromatic heterocyclic ring may include one or more double bonds and may include a carbonyl group, examples of which include tetrahydrofuranyl, tetramethylsilane, tetrahydropyranyl, 4-oxo-4H-pyranyl (4H-Piran-4-IMT), pyrrolidinyl, 3-pyrroline, imidazolidine, 1,3-DIOXOLANYL (1,3-dioxacyclopentan), piperidinyl, piperazinil, morpholinyl, peligrosamente (hexamethylenimine), pyrrolidinyl and piperidinyl. Preferred saturated or partially unsaturated 4-7 membered heterocyclic ring is pyrrolidinyl.

Examples of bicyclic ring systems in which two rings or condensed together or are connected directly to each other or separated from each other by linker group include a biphenyl, thienylene, pyrazolidine, phenoxyphenyl, vinylcyclopropyl, naphthyl, indanyl, hinely, tetrahedronal, benzofuranyl, indolyl, (ISO-indolyl, indolinyl, benzofuranyl,benzothiazol, indazoles, benzimidazoles, benzothiazoles, purinol, ISO-chinolin, bromanil, indenyl, chinadoll, Minoxidil, bromanil, RCD-chromanol, 3H-indolyl, 1H-indazole, genocidal, tetrahydronaphthyl, dihydrobenzofuranyl, morpholine-4-ylphenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, 1,3-benzodioxolyl and 3,4-dihydro-ISO-chromanol.

In one embodiment of the invention R5represents a substituted monocyclic ring system as defined above.

In another embodiment of the invention R5represents a substituted bicyclic ring system as defined above.

In another embodiment of the invention R5represents N.

In an additional embodiment of the invention R5represents a monocyclic ring system selected from the

(1) phenoxy,

(2) phenyl,

(3) 5 - or 6-membered heteroaromatic ring containing one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur,

(4) saturated or partially unsaturated With3-C6cycloalkene rings or

(5) a saturated or partially unsaturated 4-7 membered heterocyclic ring containing one or two ring heteroatoms independently selected from oxygen, S(O)rand NR20where at least one of the ring carbon atoms can be good for the military carbonyl group;

or R5represents a bicyclic ring system in which these two rings independently selected from monocyclic ring systems as defined in(2), (3), (4) and (5) above, where the two rings or condensed together or are connected directly to each other or separated from each other by linker group selected from oxygen, methylene, and S(O)t;

moreover, monocyclic or bicyclic ring system substituted by one or two substituents, independently selected from HE, -S(O)vR21and C1-C4the alkyl.

In yet another additional embodiment of the invention R5represents a monocyclic ring system selected from phenyl or 5 - or 6-membered heteroaromatic ring containing one or two ring heteroatoms independently selected from nitrogen and oxygen, which is substituted by one or two substituents, independently selected from HE, -S(O)vR21and C1-C4the alkyl.

In yet another additional embodiment of the invention R5represents phenyl or pyridinyl, substituted-S(O)vR21where v represents the integer 2.

In yet another additional embodiment of the invention R5represents phenyl, substituted with one or two substituents, independently selected from HE, -S(O)vR 21and C1-C4the alkyl.

In yet another additional embodiment of the invention R5represents N.

In yet another additional embodiment of the invention R5represents unsubstituted With3-C6cycloalkyl ring, in particular cyclopropyl.

In one embodiment x is 2.

In one embodiment p is 2.

In one embodiment R10and R11independently represent H, C1-C3alkyl or C2-C3alkylsulphonyl.

In one embodiment R12and R13independently represent H, C1-C3alkyl or C2-C3alkylsulphonyl.

In an additional embodiment, R20represents hydrogen, methyl, ethyl, methylcarbamyl (acetyl), ethylcarboxyl, methoxycarbonyl or etoxycarbonyl.

In one embodiment, v is 2.

R21represents hydrogen, C1-C6alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-pentyl or n-hexyl) or (C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl); and the specified alkyl or cycloalkyl group may be additionally substituted by one or more substituents selected independently from IT, CN, C1-C3alkoxy and CONR59R60.

In still one more is enforced embodiment of the invention R 21represents a C1-C4alkyl or C3-C6cycloalkyl.

In another embodiment R21represents a C1-C3alkyl (in particular methyl, ethyl or ISO-propyl) or cyclopropyl.

In another embodiment R41represents a C1-C3alkyl (in particular methyl, ethyl or ISO-propyl) or cyclopropyl.

In one embodiment of the invention, each of R15, R16, R17, R18, R19, R30, R33, R34, R35, R36, R37, R38, R47, R48, R61, R22, R23, R24, R26, R27, R31, R32, R39, R40, R42, R43, R44, R45, R46, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R62, R63, R64, R65and R66independently represents hydrogen or C1-C3alkyl, in particular methyl, ethyl, 1-propyl or 2-propyl.

In one embodiment of the invention, each of R15, R16, R17, R18, R19, R30, R33, R34, R35, R36, R37, R38, R47, R48, R61, R22, R23, R24, R26, R27, R31, R32, R39, R40, R42, R43, R44, R45, R46, R49, R50R 51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R62, R63, R64, R65and R66independently represents hydrogen or methyl.

In one embodiment of the invention R66represents hydrogen.

In one embodiment of the invention R1represents methyl;

W represents a 5-membered heteroaromatic ring, and R14and 2-pyrazinone ring attached to the 5-membered ring W in the 1,2-positions;

R14represents phenyl or pyridinyl; and the specified ring possibly substituted by at least one Deputy, selected from F, Cl, CN and CF3;

R3represents a phenyl group substituted by one or two substituents, independently selected from fluorine, chlorine, cyano, nitro or trifloromethyl;

R4represents hydrogen;

X represents an unsubstituted With1-C2alkylene, particularly methylene; and

R5represents phenyl, substituted with one or two substituents, independently selected from HE, -S(O)vR21and C1-C4of alkyl, where v is an integer 2.

In one embodiment of the invention

R1represents methyl;

W represents a 5-membered heteroaromatic ring, and R14and 2-the feast of sinonome ring attached to the 5-membered ring W in the 1,2-positions;

R14represents phenyl or pyridinyl; and the specified ring possibly substituted by at least one Deputy, selected from F, Cl, CN and CF3;

R3represents a phenyl group substituted by one or two substituents, independently selected from fluorine, chlorine, cyano, nitro or trifloromethyl;

R4represents hydrogen;

X represents an unsubstituted With1-C2alkylene, particularly methylene; and

R5represents N.

In one embodiment of the invention

R1represents methyl;

W represents pyrazolidine or thiazolidine ring, and R14and 2-pyrazinone ring attached to the 5-membered ring W in the 1,2-positions;

R14represents phenyl or pyridinyl; and the specified ring substituted in the 4-(para)position F, Cl or CN;

R3represents a phenyl group, a substituted meta-position Br, Cl, CF3or CN;

R4represents hydrogen;

X represents a linear or branched C1-C4alkylen may HE substituted, halogen, CN, CO2R66or1-C3alkoxy; and

R5represents N.

Examples of compounds according to the invention include:

6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-Digi operatin-2-carboxylic acid of methylamide;

6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid (5-methanesulfonyl-pyridine-2-ylmethyl)-amide;

6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid ethylamide;

6-[1-(4-cyanophenyl)-1H-1,2,3-triazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carboxamide;

tert-butyl-2-[[6-[2-(4-cyanophenyl)pyrazole-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carbonyl]amino]acetate;

6-[3-(4-chlorophenyl)-3H-[1,2,3]triazole-4-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid of methylamide;

6-[2-(4-chlorophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid of methylamide;

6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N-(2-methoxyethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N-(2-hydroxy-1,1-dimethylethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(6-cyano-3-yl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(triptime the l)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(6-cyano-3-yl)-1H-pyrazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(5-cyano-2-yl)-1H-pyrazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;

6-[1-(5-cyano-2-yl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide and

2-[[6-[2-(4-cyanophenyl)pyrazole-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazin-2-carbonyl]amino]acetic acid;

and pharmaceutically acceptable salts of any of the above.

In the present invention is additionally a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt as defined above, which includes

(a) interactions of the compounds of formula (II)

where L1represents a leaving group (such as halogen or hydroxyl, and R1, R3, R14and W are as defined in formula (I)with the compound of the formula

where X, R4and R5are as defined in formula (I); or

(b) interaction of the compounds of formula (IV)

where Hal represents a halogen atom, and X, R1, R3, R4and R5are as defined in formula (I),

with Amu is Filom R 14-W-M, where R14and W are as defined in formula (I), and M is an ORGANOTIN group, or the group organoboronic acid; or

(C) when W represents thiazolyl or oxazolyl, the interaction of the compounds of formula (V)

where X, R1, R3, R4, R5and R14are as defined in formula (I)with thiourea or wavelengths, respectively;

and, perhaps, after stages (a), (b) or (C) carry one or more of the following stages:

- the transformation of the compounds obtained into another compound according to the invention,

- getting a pharmaceutically acceptable salt of the compound.

In method (a) interactions can easily be carried out in an organic solvent such as dichloromethane or N-methylpyrrolidinone, at a temperature of, for example, in the range from 0°C. to the boiling point of the solvent. If necessary or desirable, may be added to the base and/or agent combinations, such as HATU (O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate), NEAT (1-hydroxy-7-asobancaria), NOT (1-hydroxybenzotriazole hydrate) or DIEA (N,N-diisopropylethylamine).

In method (b) interactions can easily be carried out in an organic solvent, such as DMF, NMP (N-organic or toluene, or mixtures thereof when povyshen the th temperature (i.e. above ambient temperature, 20°C), for example in the range from 50°C to 150°C and in the presence of a suitable catalyst based on transition metal, such as bis(tri-tert-butylphosphine)palladium. If necessary or desirable, may be added a base such as potassium carbonate.

In method (C) the interaction can easily be carried out by a joint heating the two starting compounds in a suitable organic solvent, such as acetonitrile, at a temperature of, for example, in the range from 50°C to 150°C.

Specific methods for obtaining compounds of formula (I) are disclosed in the Examples section of the present description of the invention. Such methods comprise one aspect of the present invention.

The necessary source materials either commercially available or known from the literature or can be obtained using known techniques. Specific methods of obtaining certain key starting compounds disclosed in the Examples section of the present description of the invention, and such methods constitute one aspect of the present invention.

The compounds of formula (I) can be converted into other compounds of formula (I) using standard procedures.

Some intermediate compounds of formula (II), (IV) and (V) are new. These new intermediate compounds are different and the aspect of the invention.

Specialist in the art will understand that the methods of the present invention certain functional groups such as hydroxyl or amino groups, may need to be protected by protective groups. Thus obtaining compounds of formula (I) may include, at an appropriate stage, introducing and/or removing one or more protective groups.

Protect and unprotect functional groups described in "Protective Groups in Organic Chemistry', edited by J.W.F.McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rdedition, T.W.Greene and P.G.M.Wuts, Wiley-lnterscience (1999).

The compounds of formula (I) above may be converted into their pharmaceutically acceptable salt, preferably in salt accession acids, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate or para-toluensulfonate.

The compounds of formula (I) are able to exist in stereoisomeric forms. It is clear that the invention encompasses all geometric and optical isomers (including atropisomers) compounds of formula (I) and mixtures thereof, including racemates. The use of tautomers and their mixtures is also an aspect of the present invention. Especially desirable are enantiomerically pure form.

The compounds of formula (I) and their farmatsevticheskii salts have activity as pharmaceuticals, in particular as modulators of serine proteases, such as proteinase 3 and pancreatic elastase, and especially human neutrophil elastase, and thus may be useful in the treatment or prevention of inflammatory diseases and conditions.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used in the treatment of respiratory diseases such as obstructive airway disease, including asthma, including bronchial, allergic, hereditary, acquired, induced physical stress induced by medications (including induced by aspirin and NSAIDs (non-steroidal anti-inflammatory drugs)and induced dust asthma, both intermittent and persistent and of all degrees of severity, and other cases hyperresponsiveness of the Airways, chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; exogenous allergic alveolitis and related diseases; hypersensitive pneumonitis; pneumovirus, including cryptogenic fibrosis alveolitis, idiopathic interstitial pneumonias, fibrosis, which is a complication of anticancer therapy and the chronic is the first infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculopathy and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the Airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis drug and vasomotor rhinitis; year-round and seasonal allergic rhinitis, including nervous rhinitis (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza virus, coronavirus (including SARS (SARS)and adenovirus.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of bones and joints, such as airtricity associated with osteoarthritis/osteoarthrosis or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis and pain in the lower back or neck area; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, implement the active arthritis and dedifferentiate spondyloarthropathy; septic arthritis and other associated infection arthropathies and bone disease, such as tuberculosis, including Pott disease and arthritis Ponce; acute and chronic induced deposition of crystals synovitis including urate gout, a disease due to deposits of calcium pyrophosphate and inflammation of the tendons, synovial bags and synovial fluid, is associated with Apatite calcium; Behcet's disease; primary and secondary Sjogren syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, a disease of the connective tissue of mixed type and non-differential disease of connective tissues; inflammatory myopathies including dermatomyositis and polymyositis, rheumatic rheumatica; juvenile arthritis including idiopathic inflammatory airtricity joints of any localization and associated syndromes, and rheumatic fever and its systemic complications; vasculitides, including giant cell arteritis diagnostics, Takayasu's arteritis syndrome Jurga-Strauss (Churg-Strauss), polyarteritis Nowotny, microscopic polyarteritis and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulinemia and paraproteins; pain in lower back pain; familial Mediterranean fever syndrome Muqla Wales (Muckle-Wells), semanaiberica fever, disease Kikuchi (Kikuchi); induced by medication arthralgia, skin lesions when tendonitis and myopathy.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of pain and rebuilding of connective tissue in the musculoskeletal disorders due to injury (e.g. sports injuries) or the following diseases: airtricity (for example, rheumatoid arthritis, osteoarthritis, gout or caused by crystal arthropathy), other joint disease (such as degeneration of the intervertebral disc or degeneration of the temporomandibular joint)disease with rebuilding bones (such as osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma, mixed violation of connective tissue, spondyloarthropathies or periodontal disease (such as periodontitis).

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of skin diseases such as psoriasis, atopic dermatitis, contact dermatitis or other eczematous lesions of the skin and hypersensitivity reactions of the delayed type; phyto - and photodermatitis; seborrheic eczema herpeticum eczema, red flat zoster, sclerotic and atrophic lichen, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, bladderwort, pumpig the ID, congenital bullous bullosa, urticaria, angioneurotic oedema, vasculitides, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern hair loss, sweet syndrome (Sweet), a disease Weber-Christian, multiple erythema, cellulitis, both infectious and non-infectious; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; induced by medication disorders, including drug resistant rash.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of eye diseases such as blepharitis; conjunctivitis, including year-round spring and allergic conjunctivitis; iritic; anterior and posterior uveitis; chorioidea; autoimmune reaction; degenerative or inflammatory disorders affecting the retina; ophthalmia, including sympathetic ophthalmia; sarcoidosis; infections including viral, fungal and bacterial.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the gastrointestinal tract, such as glossitis, gingivitis, periodontitis; oesophagitis, including reflux esophagitis; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritus anus is; coeliac disease, irritable bowel syndrome, diarrhea noninflammatory nature and food allergies that show action, not associated with the gut (for example migraine, rhinitis and eczema).

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of diseases of the cardiovascular system such as atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischemic reperfusion lesion; endocarditis, valvular and aortic, including infective (for example syphilitic); vasculitides; diseases of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be used in the treatment of cancer, for example in the treatment of common types of cancer, including tumors of the prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including leukemia) and lymphoproliferative systems, such as Hodgkin's lymphoma or non-Hodgkin's lymphoma; including the I prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used in the treatment of respiratory distress syndrome in adults (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemic-reperfusion injury, rheumatoid arthritis, syndrome of systemic inflammatory response (SIRS), long-term healing of wounds, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis and damage to the mucosa of the stomach.

In particular, the compounds of formula (I) and their pharmaceutically acceptable salts can be used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and rhinitis.

More specifically, the compounds of formula (I) and their pharmaceutically acceptable salts can be used in the treatment of chronic obstructive pulmonary disease (COPD).

Thus, in the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt as defined here above for use in therapy.

In an additional aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here is higher in the manufacture of a medicinal product for use in therapy.

In an additional aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above, in the manufacture of a medicinal product for the treatment of diseases or conditions of the person, in which useful modulating the activity of neutrophil elastase.

In an additional aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above, in the manufacture of a medicinal product for use in the treatment of inflammatory diseases or conditions.

In an additional aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above, in the manufacture of a medicinal product for use in the treatment of respiratory distress syndrome in adults (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemic-reperfusion injury, rheumatoid arthritis, syndrome of systemic inflammatory response (SIRS), long the e healing wounds, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis and damage to the mucosa of the stomach.

In an additional aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above, in the manufacture of a medicinal product for use in the treatment of chronic obstructive pulmonary disease (COPD).

In the context of the present description, the term "therapy" also includes "prevention", if there is no specific guidance on the opposite. The terms "therapeutic" and "therapeutically" should be understood accordingly.

Prevention is especially suitable for treatment of subjects who have suffered from the previous episode, or otherwise considered as having an increased risk of a given disease or condition. Subjects with the risk of developing a particular disease or condition, usually include those who have a family history of this disease or condition, or those who have been identified by genetic testing or screening as particularly susceptible to developing the disease or condition.

The present invention also a method of treating or reducing the risk of the disease or condition, which is useful in the inhibition of Akti the particular neutrophil elastase, includes introduction to the patient in need, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above.

The present invention also a method of treating or reducing the risk of inflammatory disease or condition comprising administration to a patient in need, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above.

The present invention also a method of treating or reducing the risk of respiratory distress syndrome in adults (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemic-reperfusion injury, rheumatoid arthritis, osteoarthritis, system inflammatory response syndrome (SIRS), long-term healing of wounds, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis and damage of the gastric mucosa, including the introduction to a patient in need in this case, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt as defined the Leno here above.

The present invention also a method of treating or reducing the risk of chronic obstructive pulmonary disease (COPD), comprising the administration to a patient in need, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above.

For these therapeutic applications entered the dosage will, of course, vary depending on the compound, the route of administration, the desired treatment and the disorder. The daily dosage of the compounds according to this invention may be in the range from 0.05 μg/kg to 100 μg/kg

The compounds of formula (I) and their pharmaceutically acceptable salts can be used by themselves, but usually they will enter in the form of pharmaceutical compositions in which the compound/salt of the formula (I) (active ingredient) is in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional methods of selection and fabrication of suitable pharmaceutical compositions are disclosed, for example, in Pharmaceuticals - The Science of Drug Design", M.E.Aulton, Churchill Livingstone, 1988.

Depending on the method of administration, the pharmaceutical composition will preferably contain from 0.05 to 99 wt.% (percent by weight), more preferably from 0.05 to 80 wt.%, even more preferably the t 0.10 to 70 wt.% and, even more preferably, from 0.10 to 50 wt.% the active ingredient, all percentages by weight are calculated on the total weight of the composition.

The present invention also proposed a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt as defined here above, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

This invention is additionally a method to obtain pharmaceutical compositions according to the invention, comprising mixing the compounds of formula (I) or its pharmaceutically acceptable salt as defined here above, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions can be entered locally (e.g., skin or lung and/or Airways) in the form of, for example, creams, solutions, suspensions, heptapteridae (HFA) aerosols and dry powder medications, such as inhaled drugs in the device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral introduction, in the form of solutions or suspensions; or subcutaneous injection; or by rectal introduction in the form of suppositories; or percutaneous route.

Dry powder drugs and HFA-aerosol compounds to posovremeni under pressure can enter therapy in the mouth or nose. Inhalation connection finely milled as desired. Finely ground compound preferably has a mass-average diameter less than 10 microns, and can be suspended in a propellant mixture with the auxiliary dispersing agent, such as8-C20fatty acid or its salt (e.g., oleic acid), salt of the bile acid, phospholipid, alkylchloride, perfluorinated or polyethoxyethanol surfactant, or other pharmaceutically acceptable dispersing agent.

Compounds according to the invention can also be entered via a dry powder inhaler. The inhaler can be a single or mnogorazovyj inhaler and can be triggered by inhalation of the dry powder inhaler.

One possibility is mixing finely ground connection according to the invention with a substance-carrier, for example mono-, di - or polysaccharide, a sugar alcohol or another polyol. Suitable carriers are sugars, such as lactose, glucose, raffinose, melezitose, lactic, ▫ maltitol, trehalose, sucrose, mannitol and starch. Alternatively, finely ground connection can be coated with another substance. The powder mixture can also be distributed in hard gelatin capsules, each containing the desired dose of the active is soedineniya.

Another possibility is to obtain finely ground powder in the areas that are broken during the procedure inhalation. This spheronization powder, you can fill the tank parenteral multi-dose inhaler for medicines, for example, is known as the Turbuhaler®in which a dosing unit measures the desired dose, which then is inhaled by the patient. Using this system, the active ingredient is delivered to the patient with a substance carrier, or without it.

For oral administration the compound according to the invention can be mixed with an adjuvant or a carrier, for example lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin; derivatives of cellulose; a binder, such as gelatin or polyvinylpyrrolidone; and/or a lubricant such as magnesium stearate, calcium stearate, polyethyleneglycol, wax, paraffin and the like, and then pressed into tablets. If you want a tablet shell, kernel, obtained as described above, can be coated with a concentrated sugar solution which may contain, for example, Arabian gum, gelatin, talc and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a volatile organic solvent.

For p is taking the soft gelatin capsules compound according to the invention can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using any of these excipients for tablets. Also hard gelatin capsules can be filled with liquid or semi-solid preparations of the compounds according to the invention.

Liquid preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing the compound according to the invention, and the rest is a sugar and a mixture of ethanol, water, glycerol and propylene glycol. It is possible that such liquid preparations may contain colouring agents, corrigentov, saccharin and/or carboxymethylcellulose as a thickening agent or other excipients known to specialists in this field of technology.

Compounds according to the invention can also type in combination with other compounds used to treat the above conditions.

Thus, the invention additionally relates to combination therapies, where the connection according to the invention or its pharmaceutically acceptable salt or pharmaceutical composition or drug containing the compound according to the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents for the treatment of one or b is more than one of the above listed conditions.

In particular, for the treatment of inflammatory diseases such as (but not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease, the compounds according to the invention can be combined with the agents listed below.

Nonsteroidal anti-inflammatory agents (hereinafter NSAIDs)including non-selective inhibitors of cyclooxygenase MOR-1 and MOR-2, applied both topically and systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, such as mefenamovaya acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective inhibitors MOR-2 (such as meloxicam, celecoxib, rofecoksib, valdecoxib, lumiracoxib, parecoxib, etoricoxib); inhibiting cyclooxygenase donors of nitric oxide (CINOD); glucocorticosteroids (input, both local and oral, intramuscular, intravenous or intra-articular path); methotrexate; Leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular medications, such as derivatives of hyaluronic acid; and food d is the additives, such as glucosamine.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt together with a cytokine or agonist or antagonist function of cytokines (including agents which act on cytokine signalling pathways such as modulators system suppressors of cytokine signaling pathways, SOCS), including alpha-, beta - and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL)including IL1-23, and antagonists or inhibitors interleukins, such as anakinra; inhibitors of tumor necrosis factor alpha (TNF-α), such as monoclonal antibodies against TNF (e.g., infliximab, adalimumab, and CDP-870) and antagonists of TNF receptors, including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxifylline.

In addition, this invention relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt with a monoclonal antibody directed by b-lymphocytes (such as CD20 (rituximab)), MRA-alLI6R, or T-lymphocytes (CTLA4-Ig, HuMax II-15).

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a modulator of the function of receptors chemokines, such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR, CCR7, CCR8, CCR9, CCR10 and CCR11 (for a family of S-C); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for a family of C-X-C) and CX3CR1 for a family of C-X3-S.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt inhibitor of the matrix metalloprotease (DFID), i.e. stromelysins, collagenases and gelatinase and aggrecanases; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11 and MMP-9 and MMP-12, including such agents, as doxycycline.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a leukotriene biosynthesis inhibitor, inhibitor of 5-lipoxygenase (5-LO) or an antagonist of a protein that activates 5-lipoxygenase (FLAP), such as: zileuton; ABT-761; Finlayson; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenol-hydrazones; methoxyethylamine, such as Zeneca ZD-2138; the compound SB-210661; a connection represents a pyridinyl-substituted 2-cyanonaphthalene, such as L-739010; Union representing 2-cyanohydrin, such as L-746530; or an indole or quinoline compound such as MK-591, MK-886, and BAY×1005.

The present invention additionally relates to comb the Nations of the compounds according to the invention or its pharmaceutically acceptable salt with a leukotriene receptor antagonist (LT) B4, LTC4, LTD4 and LTE4 selected from the group consisting of phenothiazines-3-1, such as L-651392; ajdinovic compounds such as CGS-25019C; benzoxazepine, such as ontazolast; benzoquinoneimine, such as BIIL 284/260; and of compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY×7195.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with an inhibitor of phosphodiesterase (PDE), such as the methylxanthines including theophylline and aminophylline; selective inhibitor of PDE isoenzyme, including PDE4 inhibitor, an inhibitor of the isoform PDE4D, or a PDE5 inhibitor.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with an antagonist of histamine receptor type 1, such as cetirizine, loratadine, desloratadine, Fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine or mizolastine applied orally, topically or parenterally.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a proton pump inhibitor (such as omeprazole) or gastroprotective histamine antagonist cocktail recipes. is s type 2.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with an antagonist of histamine receptor type 4.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a vasoconstrictor sympathomimetic, which represents an agonist of adrenergic alpha-1/alpha-2, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, nafazolina hydrochloride, Oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazoline hydrochloride, tramazoline hydrochloride or Ethylmorphine hydrochloride.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with anticholinergic agents, including an antagonist of muscarinic receptor (M1, M2 and M3), such as atropine, hyoscin, glycopyrrolate, ipratropium bromide, Tiotropium bromide, oxytrope bromide, pirenzepine or telenzepine.

The present invention also relates to combinations of compounds according to the invention or its pharmaceutically acceptable salt and agonist beta adrenergic receptors (including beta-receptor subtypes 1-4), such as izoprenalin, salbutamol, formoterol, salmeterol, terbutaline, ortsiprenalin of bitolterol mesilate or pirbuterol, or chiral enantiomer.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt chromosom, such as cromoglycate sodium or nedocromil sodium.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with an agent that modulates nuclear hormone receptors, such as receptors, activated proliferation peroxisome (PPAR).

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt together with immunoglobulin (Ig) or Ig drug or an antagonist or antibody modulating the functioning of the Ig, such as anti-IgE (e.g. omalizumab).

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with other systemic or topically applied anti-inflammatory agent such as thalidomide or its PR is izvozna, retinoid, dithranol or calcipotriol.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a combination of aminosalicylates and sulfapiridina, such as sulfasalazin, mesalazine, balsalazide and olsalazine; and immunomodulatory agents such as thiopurine, and corticosteroids, such as budesonide.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt together with an antibacterial agent such as a derivative of penicillin, tetracycline, macrolide, beta-lactam, a fluoroquinolone, metronidazole, inhalation of aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors, such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside inhibitor of reverse transcriptase, such as nevirapine or efavirenz.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with a cardiovascular agent such as block the tor calcium channels, blocker beta-adrenergic receptors, angiotensin-converting enzyme (ACE), antagonist of angiotensin receptor-2; agent, lipid-lowering, such as a statin or fibrate; modulator morphology of blood cells, such as pentoxifylline; thrombolytic or anticoagulant, such as an inhibitor of platelet aggregation.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with an agent acting on the Central nervous system, such as an antidepressant (such as sertraline), a drug against Parkinson's disease (such as deprenyl, L-DOPA, ropinirole, pramipexol, an inhibitor of monoamine oxidase B (IAIA), such as selgin, rasagiline, the inhibitor compounds R (comP), such as tasmar, inhibitor-2, an inhibitor of the reuptake of dopamine antagonist N-methyl-D-aspartate (NMDA), a nicotinic agonist, a dopamine agonist or inhibitor synthase neuronal nitric oxide), or a drug against Alzheimer's disease, such as donepezil, rivastigmine, taken, inhibitor SOH-2, propentofylline or metrifonate.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt with an agent for the treatment of acute or chronic pain, such as the current Central or peripheral is Ki analgesic (for example, opioid or its derivative), carbamazepine, phenytoin, sodium valproate, amitryptiline or other antidepressants, paracetamol or non-steroidal anti-inflammatory agent.

The present invention additionally relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt together with parenterally or topically applied (including inhalation) a local anesthetic agent, such as lignocaine or its derivative. The compound of the present invention or its pharmaceutically acceptable salt can also be used in combination with an agent against osteoporosis, including hormonal agent such as raloxifene or biphosphonate, such as alendronate.

The present invention further relates to the combination of compounds according to the invention or its pharmaceutically acceptable salt together with: (1) a tryptase inhibitor; (2) an antagonist of platelet activating factor (PAF); (3) the inhibitor of the interleukin converting enzyme (ICE); (4) the inhibitor insertunorderedlist IMPDH; (5) an inhibitor of adhesion molecules, including antagonists of VLA-4 (very late antigen); (6) a cathepsin; (7) a kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example, gefitinib or of imatinib mesilate), serine/trionychinae (such as an inhibitor of mitogen-activated p is otentikasi (MAP-kinase), such as R, JNK, protein kinase a, b or C, or a kinase inhibitor kinase (IKK)), or a kinase involved in cell cycle regulation (such as the cyclin-dependent kinase); (8) an inhibitor of glucose-6-phosphate-dehydrogenase; (9) receptor antagonist kinin-B1or - In2; (10) a remedy against gout, such as colchicine; (11) an inhibitor of xanthine oxidase, e.g., allopurinol; (12) by means of facilitating the excretion of uric acid, for example, probenecid, sulfinpirazonom or benzbromarone; (13) a stimulator of growth hormone secretion; (14) transforming growth factor (TGFβ); (15) platelet-derived growth factor (PDGF); (16) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (17) granulocyte-macrophage colony-stimulating factor (GM-CSF); (18) capsaicinoid cream; (19) receptor antagonist tachykinin NK1or NK3selected from the group consisting of NKP-608C, SB-233412 (talnetant) or D-4418; (20) an elastase inhibitor selected from the group consisting of UT-77 or ZD-0892; (21) inhibitor THF-alpha converting enzyme (TACE); (22) an inhibitor of the inducible synthase nitric oxide (iNOS); (23) receptor-homologous molecule for chemoattractant located on T cells (such as a CRTH2 antagonist); (24) inhibitor R; (25) the agent to modulate the functioning of Toll-like receptor the (TLR); (26) agent modulating the activity of purinergic receptors such as RH; (27) inhibitor factor activation of transcription, such as NF-κ, API, or STATS.

The connection according to the invention or its pharmaceutically acceptable salt can also be used in combination with existing therapeutic agent for the treatment of cancer, and suitable agents include, for example:

(1) antiproliferative/antineoplastic drug or combination of them, used in medical Oncology, such as alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan or nitrosoanatabine); an antimetabolite (for example, antifolate, such as ftorpirimidinu, such as 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); antitumor antibiotics (for example, anthracycline, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubitsin, mitomycin-C, dactinomycin or mithramycin); antimitoticescoe agent (for example, Vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or taxoid, such as Taxol or Taxotere); or a topoisomerase inhibitor (e.g., epipodophyllotoxins, such as etoposide, teniposide, amsacrine, topotecan or camptothecin;

(2) cytotoxic agent, such as an antiestrogen (e.g., tamoxifen, toremifene, raloxifene, droloxifene or idoxifene), feedback regulator of estrogen receptor (for example fulvestrant), an antiandrogen (for example, bikalutamid, flutamide, nilutamide or ciproteron acetate), an antagonist of LHRH (luteinizing hormone-growth hormone, or LHRH agonist (for example goserelin, leuprorelin or buserelin), progestogen (for example, Maestrale acetate), aromatase inhibitor (for example, anastrozole, letrozole, varsol or exemestane) or inhibitor bureaucracy, such as finasteride;

(3) an agent that inhibits the invasion of cancer cells (for example, the inhibitor metalloproteinase, such as marimastat, or the inhibitor of receptor functioning urokinase plasminogen activator);

(4) the inhibitor of the functioning of growth factors, for example: antibody to rostovomu factor (for example the anti-erbb2 antibody trastuzumab or the anti-erbb1 antibody cetuximab [S]), inhibitor farnesyltransferase, the inhibitor tyrosinekinase or inhibitor of serine/trainingin, inhibitor family of epidermal growth factors (for example, the inhibitor of the EGFR family tyrosinekinase, such asN-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) or 6-acrylamide-<> N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)-hinzelin-4-amine (CI 1033)), an inhibitor of a family of growth factors platelet-derived origin or inhibitor of a family of growth factors hepatocites origin;

(5) an antiangiogenic agent such as an agent that inhibits the effects of vascular endothelial growth factor (for example, an antibody against vascular endothelial cell growth factor bevacizumab, a compound described in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example, linomide, inhibitor functioning of integrin αvβ3 or angiostatin);

(6) an agent that affects the blood vessels, such as combretastatin A4, or a compound described in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(7) an agent used in antisense therapy, for example, the agent aimed at one of the targets listed above, such as ISIS 2503, an anti-ras antisense agent;

(8) an agent used in the methodology of gene therapy, for example in the approach, consisting in the replacement of aberrant genes, such as the approaches in relation to aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (focused on genes enzyme proletarienne therapy), such as approaches using sitoindosides, timedancing or bacterial azoreductase, and approaches consisting in increasing the resilience of the human patient to chemotherapy or radiotherapy, such as gene therapy multidrug resistance; or

(9) an agent used in the immunotherapy approach, for example ex-vivo and in-vivo methods for increasing the immunogenicity of tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, methods of reducing dullness T cells, methods of using transfected immune cells such as cytokine-transfetsirovannyh dendritic cells, methods of using cytokine-transfected tumour cell lines and methods of using antiidiotypic antibodies.

In particular, the compounds according to the invention can be introduced in combination with a second active ingredient which is selected from:

(a) a PDE4 inhibitor including an inhibitor of the isoform PDE4D;

(b) agonist (β-adrenergic receptors, such as metaproterenol, isoproterenol, izoprenalin, albuterol, salbutamol, formoterol, salmeterol, terbutaline, ortsiprenalin, bitolterol mesilate, pirbuterol or indacaterol;

(C) an antagonist of muscarinic receptors (e.g., M1, M2 or M3 antagonist, such as a selective M3 antagonist)such as ipratropium bromide, Tiotropium bromide, oxytrope bromide, pirenzepine, telenzepine;

(d) modulator functioning chemokine receptor(such as a CCR1 antagonist or CCRS-receptor);

(d) an inhibitor of functioning kinase;

(e) the agonist of the steroid receptor of glucocorticoid;

(g) the agonist of the steroid receptor glucocorticoid; and

(C) protease inhibitors (such as MMR or MMR inhibitor).

The present invention hereinafter will be further illustrated by the following representative examples.

General methods

1H-NMR and13C-NMR spectra were recorded on the instrument Varian Inova 400 MHz or Varian Mercury-VX 300 MHz. The Central peaks of chloroform-d (δH7,27 ppm), DMSO-d6Hof 2.50 ppm), acetonitrile-d3H1,95 ppm) or methanol-d4Hand 3.31 ppm) were used as internal standards. Column chromatography was performed using silica gel (0,040-0,063 mm, Merck). Unless otherwise indicated, the starting materials were commercially available. All solvents and commercial reagents were of laboratory quality and were used as they were received.

The following method was used for analysis of liquid chromatography/mass spectrometry (LC/MS).

The instrument Agilent 1100; column Waters Symmetry of 2.1×30 mm; mass spectrometry with chemical ionization at atmospheric pressure (APCI); flow rate 0.7 ml/min; wavelength 254 nm; solvent A: water + 0.1% of triperoxonane acid (TFA); solvent B: acetonitrile + 0.1% of TFA; gradient: 15-95%B/W 8 mi is, 95% B for 1 minute

Analytical chromatography was performed on a column of Symmetry With18and 2.1×30 mm, particle size 3.5 µm. Mobile phase acetonitrile/water/0.1% of triperoxonane acid in a gradient from 5% to 95% acetonitrile for 8 minutes at a current of 0.7 ml/min

Abbreviations or terms used in the examples have the following meanings:

THF:Tetrahydrofuran
DCM:Dichloromethane
DME:Dimethoxyethan
DMF:N,N-Dimethylformamide
EtOAc:The ethyl acetate
DMSO:The sulfoxide
YVES:The original substance
Etc.:Example
KT:Room temperature

Example 1

6-[2-(4-Cyano-phenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-Cryptor-methyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid of methylamide

6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (IV, 0.05 g, 0,128 mmol), 1-(4-cyanophenyl)-1 is-pyrazole-5-Bronevoy acid (IV, 0,062 g, 0,256 mmol), Cs2CO3(0.125 g, 0.384 mmol) and DME (3 ml) was added to a glass test tube for synthesis using microwave radiation. The mixture was degirolami nitrogen was added Pd(PBut3)2(0,010 g). The tube was sealed and heated with stirring at 110°C (150 W) in a microwave oven for 10 minutes. The mixture was diluted with EtOAc (5 ml) and filtered. The solution was concentrated in vacuo and purified by chromatography on silica with getting enough pure material, which was further purified by preparative HPLC (high performance liquid chromatography) to obtain 0,012 g (20%) specified in the title compound as a white solid.

1H NMR (400 MHz, DMSO-D6) δ 8.70 (m, 1H), 7.97-7.84 (m, 6H), 7.77 (d, J=7.8 Hz, 1H), 7.67 (d, J=8,8 Hz, 2H), 6.76 (d, J=1.8 Hz, 1H), 2.72 (d, J=4,8 Hz, 3H), 1.86 (s, 3H);

APCI-MSm/z: 479,3 [MH+].

Examples 2 and 3

Analogously to Example 1 were synthesized the following compounds.

Etc.Connection1H NMRm/zYVES
26-[2-(4-Cyano-phenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazin-2-carboxylic to the slots (5-methanol-radioactive-pyridine-2-yl-methyl)-amide 1H NMR (400 MHz, DMSO-D6) δ 9.52 (t, J=6.0 Hz, 1H), 8.98 (bs, 1H), 8.27 (d, J=8,2 Hz, 1H), 8.00-7.85 (m, 6H), 7.81 (d, J=8,3 Hz, 1H), 7.69 (d, J=8,3 Hz, 2H), 7.49 (d, J=8,3 Hz, 1H), 6.79 (s, 1H), 4.63 (d, J=6.0 Hz, 2H), 3.29 (s,, 3H), 1.91 (s, 3H).634,0IV
IV
36-[2-(4-Cyano-phenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazin-2-carboxylic acid ethylamide1H NMR (400 MHz, DMSO-D6) δ 8.69 (t, J=5.7 Hz, 1H), 7.98-7.84 (m, 6H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (d, J=8,8 Hz, 2H), 6.77 (d, J=1.8 Hz, 1H), 3.24-3.16 (m, 2H), 1.87 (s, 3H), 1.02 (t, J=7.2 Hz, 3H).493,1IV

Example 4

6-[1-(4-Cyano-phenyl)-1H-1,2,3-triazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trichromatic)-phenyl]-3,4-dihydropyrazine-2-carboxamide

a) 4-[1,2,3]Triazole-1-yl-benzonitrile

4-Perbenzoate (0,847 g, 7 mmol), 1H-[1,2,3]triazole (0,483 g, 7 mmol), Cs2CO3of 2.27 g, 7 mmol) and DMF (8 ml), and magnetic stirrer was placed in a vessel. The mixture was heated with stirring for 3 h at 80°C. Extractive processing (EtOAc/H2O) and subsequent drying (Na2SO4) gave the crude product, which was purified on silica to obtain 0.55 g (46%) specified in the header of the intermediate connection.

1H NMR (400 MHz, DMSO-D6) δ 9.00 (d, J=1.2 Hz, 1H), 8.18 (d, J=8,8 Hz, 2H), 8.11 (d, J=8,8 Hz, 2H), 8.05 (d, J=1.2 Hz, 1H).

b) 4-(5-Tributylstannyl-G1,2.31 triazole-1-yl)-benzonitrile

4-[1,2,3]Triazole-1-yl-benzonitrile (0,105 g, 0.6 mmol) and dry THF (6 ml)and a magnetic stirrer were placed in a flask. The flask was filled with argon and kept in an inert atmosphere and cooled to -78°C. At this temperature, was added dropwise tert-BuLi (0,36 ml, 1.7 M, 0.6 mmol) in 1-2 minutes. The mixture was stirred at this temperature for 15 minutes and within 1 minute was added Bu3SnCl (0,19 g, 0.6 mmol), then the mixture was let to rise slowly to CT. The crude mixture was directly purified on silica (heptane:EtOAc, 4:1) to give 0.12 g (43%) specified in the header of stannane.

APCI-MSm/z: 460 [MN+].

C) 6-[1-(4-Cyano-phenyl)-1H-1,2 .3-triazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-crenel]-3,4-dihydropyrazine-2-carboxamide

4-(5-Tributylstannyl-[1,2,3]triazole-1-yl)-benzonitrile (0.15 g, 0.32 mmol), 6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (IV, 0,054 g, 0.14 mmol), Pd(PBut3)2(10 mg) and DME (2 ml) were placed in a test tube for synthesis using microwave radiation. The mixture was degirolami and heated in a microwave reactor for synthesis (SEM) at 100°C (max 150 W) for 10 minutes. The solvent was removed in vacuum to obtain crude product, which was purified on silica and then further purified by preparation the tive HPLC. Pure fractions were freeze dried to obtain 27 mg (41%) specified in the connection header.

1H NMR (400 MHz, DMSO-D6) δ 8.64-8.57 (m, 1H), 8.18 (s, 1H), 8.02 (d, J=8,4 Hz, 2H), 7.98-7.92 (m, 2H), 7.88 (t, J=8.0 Hz, 1H), 7.83 (d, J=8,4 Hz, 2H), 7.77 (d, J=8.0 Hz, 1H), 2.70 (d, J=4.9 Hz, 3H), 1.94 (s, 3H).

APCI-MSm/z: 480,0 [MH+].

Examples 5-9

Analogously to Example 4 were synthesized the following compounds.

Etc.Connection1H NMRm/zYVES
5tert-Butyl-2-[[6-[2-(4-cyanophenyl)pyrazole-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazin-2-carbonyl]amino]acetate1H NMR (400 MHz, DMSO-D6) δ 9.17 (t, J=5.7 Hz, 1H), 7.96 (d, J=6,7 Hz, 2H), 7.94 (d, J=1.8 Hz, 1H), 7.92 - 7.85 (m, 3H), 7.80 (d, J=7.8 Hz, 1H), 7.68 (d, J=8,8 Hz, 2H), 6.78 (d, J=1.8 Hz, 1H), 3.89 (d, J=5.8 Hz, 2H), 1.90 (s, 3H), 1.39 (s, 9H).579,4
66-[3-(4-Chloro-phenyl)-3H-[1,2,3]triazole-4-yl]-5-methyl-3-oxo-4-(3-tri-vermeil-phenyl)-3,4-dihydro-pyrazin-2-carboxylic acid of methylamide1H NMR (400 MHz, DMSO-D6) δ 8.65-8.57 (m, 1H), 8.13 (s, 1H), 7.98-7.91 (m, 2H), 7.87 (t, J=7.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.65 (d, J=8,9 Hz, 2H), 7.59 (d, J=8,9 is C, 2H), 2.72 (d, J=4,7 Hz, 3H), 1.89 (s, 3H).489,3IV
76-[2-(4-Chloro-phenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-Cryptor-methyl-phenyl)-3,4-dihydro-pyrazin-2-carboxylic acid of methylamide1H NMR (400 MHz, DMSO-D6) δ 8.74-8.65 (m, 1H), 8.01-7.68 (m, 6H), 7.62-7.44 (m, 3H), 7.60 (d, J=1.8 Hz, 1H), 2.73 (d, J=4,8 Hz, 3H), 1.80 (s, 3H).488,0IV

Etc.Connection1H NMRm/zYVES
86-[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]-N-(2-methoxyethyl)-5-methyl-3-oxo-4-[3-(trifter-methyl)phenyl]-3,4-dihydropyrazine-2-carboxamide1H NMR (400 MHz, CD3CN) δ 9.01 (s, 1H), 7.90 (d, J=7,3 Hz, 1H), 7.80 (m, 4H), 7.63 (m, 4H), 6.68 (d, J=1.8 Hz, 1H), 3.47 (m, 2H), 3.31 (d, J=9.7 Hz, 5H), 1.86 (s, 3H).523,0
96-[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-pyrazin-2-carboxamide1H NMR (400 CD3CN) δ 8.98 (s, 1H),7.90 (d, J=8.0 Hz, 1H), 7.84 (d, J=16 Hz, 2H), 7.79 (s, 2H), 7.61 (t, J=8.7 Hz, 4H), 6.68 (d, J=1.6 Hz, 1H), 3.49 (s, 2H), 1.86 (s, 3H), 1.27 (d, J=10,6 Hz, 6H).537,1

Example 10

6-[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

a) 5-Methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylic acid

NaOH (1 M, 6 ml) was added to methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0,60 g, 1.92 mmol)dissolved in EtOH (12 ml) and the mixture was stirred for 15 minutes. The aqueous phase was neutralized by addition of HCl (1 M, 7 ml) to pH 6 to 7 and were extracted with ethyl acetate (3×15 ml). The organic phase was dried (MgSO4), filtered and evaporated. No further purification was not performed.

APCI-MS m/g: 299,0 [MN+].

b) N,N,5-Trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

A mixture of 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylic acid (0.21 g, 0.7 mmol), HATU (0,266 g, 0.7 mmol) and Et3N (0,293 g, 2.9 mmol) in DMF (2 ml) was subjected to interaction with dimethylamine HCl. After 2 h the reaction mixture was diluted with water and extracted with ethyl acetate (3×5 ml). The organic phase was dried (MgSO4), filtered and evaporated. No further purification was not performed.

APCI-MS m/z: of 326.0 [MH+].

b) 6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)f the Nile]-3,4-dihydropyrazine-2-carboxamide

N,N,5-Trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.14 g, 0.43 mmol) in a vial was dissolved under argon in DMF (2 ml). Was added N-bromosuccinimide (0,089 g, 0.5 mmol). The vial was sealed and was carried out by stirring for 30 minuter mixture was purified by preparative HPLC to obtain 0,100 g (57%) indicated in the title compound in the form of a solid substance.

APCI-MS m/z: 403,9 [MH+].

g) 6-(3,3-Diethoxypropane-1-inyl)-N,N,5-trimethyl-3-oxo-4-[3-(trifter-methyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.10 g, 0,247 mmol), diethylacetal propargilovyh aldehyde (0,48 mg, 0,370 mmol), copper iodide(I) (0,001 mg of 0.005 mmol) and Et3N (1 ml) in THF (1 ml) were placed in a glass test tube for microwave synthesis. The mixture was degirolami argon was added Pd(Cl2) (PPh3)2(0,007 g). The tube was sealed and heated with stirring at 60°C. (150 W) in a microwave oven for 20 minutes. The mixture was diluted with EtOAc (5 ml) and filtered. The solution was concentrated in vacuo and then purified on silica to obtain specified in the title compound (28 mg, 25%).

d) 6-[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

6-(3,3-Diethoxypropane-1-inyl)-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-di is itoperates-2-carboxamide (0,028 g, 0,062 mmol) was dissolved in DMF (1 ml) in a vessel for microwave synthesis. Added 4-cyanophenylacetic hydrochloride (0,013 g 0,074 mmol). The vessel was sealed and heated with stirring to 120°C for 5 minuter mixture was purified by preparative HPLC to obtain 9 mg (29%) indicated in the title compound as a white solid.

1H NMR (399,99 MHz, CD3CN) δ 7.88 (d, J=7.8 Hz, 1H), 7.79 (m, 5H), 7.64 (m, 3H), 6.64 (d, J=1.8 Hz, 1H), 2.90 (d, J=8,8 Hz, 3H), 2.70 (s, 3H), 1.97 (s, 3H).

APCI-MSm/z: 493,0 [MH+].

Example 11

Analogously to Example 10 was synthesized following the connection.

Etc.Connection1H NMRm/z
116-[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifter-methyl)phenyl]-3,4-dihydropyrazine-2-carboxamide1H NMR (400 MHz, CD3CN) δ 8.80 (s, 1H), of 7.97 (d, 1H), 7.93-7.86 (m, 4H), 7.72 (t, 3H), 7.67 (s, 1H), 6.76 (d, J=1.8 Hz, 1H), 2.93 (dq, J=7,3, and 3.7 Hz, 1H), 1.95 (s, 3H), 0.83 (dd, J=7,0, 1.7 Hz, 2H), 0.59 (dd, J=10,6, 5.0 Hz, 2H).505,0

Example 12

6-[1-(6-Cyano-3-yl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

a) Methyl-6-iodine-5-methyl-3-OK, what about the-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate

Methyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (described in the synthesis IV, 1.5 g, 4.8 mmol), dry DCM (7.0 ml), triperoxonane acid (3.0 ml) and N-iodosuccinimide (1.0 g, 4.5 mmol) were mixed and stirred at RT in the dark (the flask was covered with aluminum foil). After 5 h was added water (5 ml) and the mixture was concentrated using a rotary evaporator. Was added water (3 ml) and the mixture was concentrated as described above. The resulting mixture was diluted with acetonitrile to a total volume of 50 ml Purification by preparative HPLC with a mixture of acetonitrile-water as eluent (neutral eluent) gave 0,905 g (yield 46%) indicated in the title compound as a yellow crystalline solid.

1H NMR (400 MHz, DMSO-D6) δ 7.93 (brs, 1H), 7.92 (d, J=7,6 Hz, 1H), 7.84 (t, J=7,6 Hz, 1H), 7.75 (d, J=7,6 Hz, 1H), 3.82 (s, 3H), 2.14 (s, 3H).

APCI-MS m/z 438,8 (MH+).

b) Methyl-6-(3,3-diethoxypropane-1-inyl)-5-methyl-3-oxo-4-[3-(trifter-methyl)phenyl]-3,4-dihydropyrazine-2-carboxylate

Methyl-6-iodine-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (1.2 g, 2.8 mmol), dimer allylpalladium(II)chloride (0,0072 g), 10% by weight of three(tert-butyl)phosphine in hexane (2.1 ml) and anhydrous DMF (3.0 ml) was stirred to obtain a clear solution. Added diethylacetal propargilovyh aldehyde (of 0.44 ml, 3.1 mmol) in anhydrous DMF (2.3 ml), then small amounts of 1,4-di is sabillo[2.2.2]octane (0,63 g, 5.6 mmol). The red solution was purged with dry argon for 5 minutes and then stirred under argon at KT. After 4 h the solvent is evaporated using an oil pump. The residue was transferred in acetonitrile (10 ml), filtered through glass wool and then concentrated with silica. Chromatography on silica with ethyl acetate mixtures-heptane (1:10 and 1:2) as eluents gave 0,46 g (37%) indicated in the title compound as a yellow oil.

1H NMR (400 MHz, CD2Cl2) δ 7.84 (d, J=8,8 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.49 (brs, 1H), 7.43 (d, J=8,4 Hz, 1H), 5.47 (s, 1H), 3.92 (s, 3H), 3.80-3.71 (m, 2H), 3.68-3.58 (m, 2H), 2.20 (s, 3H), 1.23 (t, J=7.2 Hz, 6N).

APCI-MS m/z 439 (MH+), 393 (M-45).

C) Methyl-6-[1-(6-cyano-3-yl)-1H-pyrazole-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate

Methyl-6-(3,3-diethoxypropane-1-inyl)-5-methyl-3-oxo-4-[3-(trifter-methyl)-phenyl]-3,4-dihydropyrazine-2-carboxylate (0,073 g, 0,17 mmol) and 5-hydrazinopyridazine-2-carbonitril triptorelin (0,050 g, 0.20 mmol) in dioxane (3 ml) was placed in a vessel. Added 2 M HCl (0,188 ml) and the mixture was stirred at 55°C for 15 minutes. After cooling, was added NaHCO3(0,048 g) and the mixture was extracted with DCM and water. The combined organic phases are washed with water, brine, dried (Na2SO4) and evaporated. The residue was dissolved in acetic acid (10 ml) and the vessel was sealed. Rast is the PR was stirred at 90°C for 10 hours After evaporation the residue was purified by preparative HPLC to obtain 0,023 g (28%) specified in the connection header.

APCI-MS m/z: 481,0 [MH+].

g) 6-[1-(6-Cyano-3-yl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

Methyl-6-[1-(6-cyano-3-yl)-1H-pyrazole-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0,026 g, 0,054 mmol) in acetonitrile (0.33 ml) and ethanol (0,074 ml) was placed in a vessel. Added cyclopropylamine (of 0.14 ml, 2.0 mmol), the vessel was sealed and stirred at 60°C for 10 h After evaporation the residue was purified by preparative HPLC to obtain 0,010 g (37%) specified in the connection header.

1H NMR (400 MHz, DMSO-D6) δ 8.89 (d, J=2.3 Hz, 1H), 8.69 (d, J=4.5 Hz, 1H), 8.18-8.09 (m, 2H), 8.01-7.93 (m, 3H), 7.88 (t, J=8.0 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 2.79-2.69 (m, 1H), 2.03 (s, 3H), 0.71-0.62 (m, 2H), 0.45-0.36 (m, 2H).

APCI-MSm/z: 506,0 [MH+].

Examples 13-15

Analogously to Example 12 were synthesized the following compounds.

Etc.Connection1H NMRm/zYVES
136-[1-(6-Cyano-3-yl)-1H-pyrazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trif ormetal)phenyl]-3,4-dihydropyrazine-2-carboxamide 1H NMR (400 MHz, DMSO-D6) δ 8.91 (d, J=2.3 Hz, 1H), 8.76-8.68 (m, 1H), 8.20-8.09 (m, 2H), 8.02-7.93 (m, 3H), 7.89 (t, J=7.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 6.82 (d, J=1.7 Hz, 1H), 2.70 (d, J=4,6 Hz, 3H), 2.02 (s, 3H).480,0
146-[1-(5-Cyano-2-yl)-1H-pyrazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide1H NMR (400 MHz, DMSO-D6) δ 8.88-8.81 (m, 2H), 8.45 (dd, J=8,6, 2.2 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.99-7.94 (m, 2H), 7.89 (t, J=8,1 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 6.80 (d, J=1.6 Hz, 1H), 2.73 (d, J=the 4.7 Hz, 3H), 1.84 (s, 3H).480,0

AveConnection1H NMRm/zYVES
156-[1-(5-Cyano-2-yl)-1H-pyrazole-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(triptime-Tyl)phenyl]-3,4-dihydropyrazine-2-carboxamide1H NMR (400 MHz, DMSO-D6) δ 8.95 (d, J=4.4 Hz, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.45 (dd, J=8,7, and 2.1 Hz, 1H), 8.07 (d, J=8,9 Hz, 1H), 8.02( d, J=1.6 Hz, 1H), 7.99-7.94 (m, 2H), 7.88 (t, J=8,1 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 6.80 (d,, J=1.6 Hz, 1H), 2.84-2.75 (m, 1H), 1.85(s, 3H), 0.72-0.65 (m, 2H), 0.49-0.43 (m, 2H).506,0

Example 16

2-[[6-[2-(4-Cyanophenyl)pyrazole-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazin-2-carbonyl]amino]acetic acid

Specified in the title compound was obtained from the compound of Example 5 after acid cleavage of the tert-butyl methyl ether and purification by HPLC.

1H NMR (400 MHz, DMSO-D6) δ 12.71 (s, 1H), 9.25 (t, J=5.6 Hz, 1H), 7.96 (d, J=6.2 Hz, 2H), 7.94 (d, J=1.8 Hz, 1H), 7.92-7.85 (m, 3H), 7.80 (d, J=8.0 Hz, 1H), 7.68 (d, J=9,3 Hz, 2H), 6.78 (d, J=1.8 Hz, 1H), 3.94 (d, J=5.5 Hz, 2H,), 1.88 (s, 3H).

APCI-MSm/z: 523,3 [MH+].

Obtaining initial substances

Source materials for the above examples are either commercially available or easily obtained by standard methods from known compounds. For example, the following relationships are non-limiting illustrations of some of the original substances.

The original substance IV

3-Bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-he

3-Triptorelin (5.0 g, 31 mmol) and triethylamine (3.54 in g, 35 mmol) was dissolved in DCM (60 ml, dried). The mixture was cooled on ice and stir the solution was added dropwise a solution of ETHYLACETYLENE (4,36 g, 32 mmol) in DCM (15 ml). After complete addition, the reaction mixture was left to stand for 10 minutes. The reaction mixture was washed with water (50 ml), then washed with brine (30 ml) and the organic phase was dried over Na2 SO4. After filtration and evaporation was received of 8.04 g (99%) of ethyl oxo{[3-(trifluoromethyl)phenyl]amino}acetate as a white solid.

1H NMR (300 MHz, DMSO-D6) δ 11.09 (s, 1H), 8.19 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.61 (t, J=8,1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 4.32 (q, J=7.5 Hz, 2H), 1.32 (t=7.0 Hz, 3H);

APCI-MSm/z: 262,0 [MN+].

The ethyl oxo{[3-(trifluoromethyl)-phenyl]amino}acetate (8,04 g, 30.7 mmol) was dissolved in ethanol (50 ml, 99.5%pure). To the stirred solution in one portion was added 1-amino-2-propanol (racemic, 2,32 g, 31 mmol) and the mixture was heated to the temperature of reflux distilled within 90 minutes. The mixture was allowed to cool and evaporated to dryness, obtaining 8,80 g (99%) of N-(2-hydroxypropyl)-N'-[3-(trifluoromethyl)-phenyl]academic in the form of a white solid.

1H NMR (300 MHz, DMSO-D6) δ 10.99 (bs, 1H), 8.77 (t, J=6.3 Hz, 1H), 8.29 (s, 1H), 8.11 (d, J=8,2 Hz, 1H), 7.60 (t, J=8,1 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 4.91 (d, J=4.9 Hz, 1H), 3.78 (p, J=5.7 Hz, 1H), 3.20-3.12 (m, 2H), 1.05 (d,, J=6.3 Hz, 3H);

APCI-MSm/z: 273,1 [MH+].

N-(2-Hydroxypropyl)-N'-[3-(trifluoromethyl)phenyl]-academic (2.2 g, 7,58 mmol) was dissolved in CH3CN (50 ml) and water (7 ml). To the stirred solution was added NaBrO3(1,15 g, 7,58 mmol) and a solution of RuCl3×H2O in CH3CN (3 ml). The mixture was stirred for 1 h and the reaction was monitored by LC-MS (combination of liquid chromatography and mass spectrometry) and TLC (thin layer chromatography). Organic process is Itel was removed in vacuum and the residue was distributed between DCM (200 ml) and water (200 ml). The organic phase was dried with Na2SO4after filtration and evaporation was obtained 2.0 g (91%) of N-(2-oxopropyl)-N'-[3-(trifluoromethyl)phenyl]-Academica as off-white solid.

1H NMR (300 MHz, DMSO-D6) δ 11.04 (s, 1H), 9.08 (t, J=6.0 Hz, 1H), 8.29 (s, 1H), 8.12 (d,J=8,1 Hz, 1H), 7.61 (t, J=8,1 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 4.09 (d, J=6.0 Hz, 2H), 2.14 (s, 3H).

N-(2-Oxopropyl)-N'-[3-(trifluoromethyl)phenyl]academic (1.6 g, 5.5 mmol) and glacial acetic acid (15 ml) was placed in a vessel (20 ml). To this solution was added concentrated sulfuric acid (40 drops) and the flask was sealed and heated with stirring to 100°C for 90 minutes. Was added 40 drops of sulfuric acid and the reaction was allowed to proceed for 90 minutes. The reaction mixture was allowed to cool and acetic acid was removed in vacuum. The residue was distributed between EtOAc (60 ml) and water (40 ml). The aqueous phase was neutralized with NaOH solution to pH 6-7. The organic phase was dried and after filtration and evaporation was obtained the crude product, which was purified on silica to obtain 1.1 g (74%) of 6-methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione as yellowish solid.

1H NMR (400 MHz, DMSO-D6) δ 11.24 (bs, 1H), 7.87-7.81 (m, 2H), 7.77 (t, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 6.30 (d, J=5,2 Hz, 1H), 1.61 (d, J=1.1 Hz, 3H);

APCl-MSm/z: 271,0 [MH+].

6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridin-,3-dione (0.52 g, 1.92 mmol) and 1,2-dichloroethane (10 ml) was placed in a vessel (20 ml). To the resulting suspension was carefully added oxalipatin (of 0.53 ml, 1.24 g, of 5.75 mmol). In the process of adding a formed foam, and once the foam has subsided, began stirring. Was added DMF (3 drops) and the vessel was sealed and the mixture was stirred over night. Added another portion of oxalylamino (0.2 ml, and 0.46 g of 2.23 mmol) and DMF (3 drops) and the reaction was carried out for 24 h the Mixture was distributed between DCM (20 ml) and water (20 ml) and the organic phase was dried. In the filtration and evaporation was obtained the crude product, which was purified on silica, getting 0,59 g (93%) of 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-it.

1H NMR (400 MHz, DMSO-D6) δ 7.96 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.27 (s, 1H), 1.84 (s, 3H);

APCI-MSm/z: 232,9 and 234,9 [MH+].

The original substance IV

6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trichromatic)phenyl]-3,4-dihydro-pyrazin-2-carboxamide

The steel reactor pressure vessels (Parr) with a supply of gaseous loaded WITH 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]-pyrazin-2(1H)-he (EV, 0.25 g, 0.75 mmol), Pd(OAc)2(0.015 g, 0,067 mmol), PPh3(0,030 g, 0.11 mmol) and methanol (25 ml). To this mixture was added triethylamine (0.5 ml, 0.36 g, 3.6 mmol) and a magnetic stirrer. The reactor was purged WITH and in the system created a pressure equal to 6 atmospheres (approx. 600 to the as). The reactor was heated with stirring to 90°C., the mixture was intensively mixed and the reaction was allowed to proceed for 4 hours Volatiles were removed in vacuum and the crude product was purified on silica to obtain 0.11 g (47%) of methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carboxylate in the form of solids.

1H NMR (400 MHz, DMSO-D6) δ 7.97 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.52 (s, 1 H), 3.80 (s, 3H), 1.94 (s, 3H);

APCI-MSm/z: 310,0 [MN+].

Methyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.11 g, 0.35 mmol) was dissolved in a solution of methylamine (33% in ethanol, 5 ml) in a vessel. The vessel was sealed and heated with stirring at 50°C for 30 minutes. Volatiles were removed in vacuum to obtain crude product, which was purified for analytical purposes by preparative HPLC to obtain 0,079 g (73%) of N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide in the form of solids.

1H NMR (400 MHz, DMSO-D6) δ 8.95 (m, 1H), 7.98-7.90 (m, 2H), 7.84 (t, J=7.7 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.64 (s, 1H), 2.78 (d, J=4,7 Hz, 3H), 1.98 (s, 3H);

APCI-MSm/z: 312,0 [MN+].

N,5-Dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0,079 g, 0.25 mmol) was dissolved in DMF (1.5 ml) in a vessel. Was added N-bromosuccinimide (of 0.066 g, 0.38 mmol). The vessel was sealed and heated with paramasivan the m to 50°C for 90 minutes. The crude mixture was added dropwise to water (20 ml) under stirring with a magnetic stirrer. The precipitate was separated by filtration to obtain 0,078 g (80%) 6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide in the form of solids.

1H NMR (400 MHz, DMSO-D6) δ 8.96 (m, 1H), 7.98-7.91 (m, 2H), 7.86 (t, J=8,2 Hz, 1H), 7.77 (d, J=8,2 Hz, 1H), 2.79 (d, J=4,8 Hz, 3H), 2.12 (s, 3H);

APCI-MSm/z: 389,9 and 391,9 [MH+].

The original substance IV

6-Bromo-5-methyl-N-{[5-(methylsulphonyl)pyridine-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

The steel reactor pressure vessels (Parr) with a supply of gaseous loaded WITH 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]-pyrazin-2(1H)-he (IV, of 0.30 g, 0.89 mmol), Pd(OAc)2(0.035 g, 0.16 mmol), PPh3(0,070 g, 0.26 mmol) and 5-methanesulfonyl-pyridine-2-ylamine (0,46 g, to 1.79 mmol) in methanol (25 ml). To this mixture was added triethylamine (1.5 ml, of 1.09 g, 10 mmol) and a magnetic stirrer. The reactor was purged WITH and in the system created a pressure equal to 6 atmospheres (approx. 600 kPa). The reactor was heated to 90°C., the mixture was intensively mixed and the reaction was allowed to proceed for 4 h, then allowed to cool. Volatile impurities were removed in vacuum and the crude product was purified by preparative HPLC, which gave 0,22 g (53%) of 5-methyl-N-{[5-(methylsulphonyl)-pyridine-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carbox the foreign Ministry in the form of a white solid after freeze drying the pure fractions.

1H NMR (400 MHz, DMSO-D6) δ 9.81 (t, J=5.8 Hz, 1H), 8.99 (d, J=2,15 Hz, 1H), 8.29 (dd, J=8.3 and 2.3 Hz, 1H), 7.98 (s, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=8,2 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 3.29 (s, 3H), 2.01 (s, 3H);

APCI-MSm/z: 467,0 [MH+].

5-Methyl-N-{[5-(methylsulphonyl)-pyridine-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0,097 g, 0.21 mmol) was dissolved in DMF (2 ml) in a vessel. To this mixture was added N-bromosuccinimide (by 0.055 g, 0.31 mmol), the vessel was sealed and the mixture was heated at 50°C With stirring for 1 h the Crude mixture was added dropwise to water (40 ml) under stirring with a magnetic stirrer. The precipitate was separated by filtration to obtain 0,105 g (92%) of 6-bromo-5-methyl-N-{[5-(methylsulphonyl)pyridine-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide in the form of solids.

1H NMR (400 MHz, DMSO-D6) δ 9.80 (t, J=6.0 Hz, 1H), 8.99 (d, J=2.10 Hz, 1H), 8.29 (dd, J=8,2 and 2.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.88 (t, J=8,3 Hz, 1H), 7.79 (d, J=8,3 Hz, 1H), 7.61 (d, J=8,3 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 3.30 (s,, 3H), 2.15 (s, 3H);

APCI-MSm/z: 544,9 and 546,9 [MN+].

The original substance IV

[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]baronova acid

4-(1H-Pyrazole-1-yl)benzonitrile (Eur. J. Org. Chem. 2004, 695-709) (1.5 g, 8,87 mmol) in dry THF (50 ml) under argon was stirred at -78°C, while for 20 minutes was added diisopropylamide lithium (1.8 M solution in a mixture of THF/hexane/ethyl benzene; 5,2 ml, to 9.32 mmol). Lane is smeshivanie and cooling was continued for 1 h, dropwise within 30 minutes was added triisopropylsilyl (8 ml, 34.5 mmol) and then the temperature was allowed to rise during the night to CT. The pH value of the reaction mixture is brought to 5 with 1 M HCl and the mixture is then concentrated to a minimum volume and extracted with ethyl acetate (200 ml) and brine (3×100 ml). The organic phase was collected, dried (Na2SO4), filtered and evaporated to a brown solid (1,32 g), which was used in the next stage without additional purification.

APCI-MSm/z: 214,1 [MN+].

Analysis of human neutrophile Lactasoy using energy transfer fading fluorescence resonance (Quenched-FRET)

In the analysis of human use the neutrophilic elastase (HNE), purified from the serum (Calbiochem art. 324681; Ref. Baugh, R.J. et al., 1976, Biochemistry. 15, 836-841). HNE was stored in 50 mm sodium acetate (NaOAc), 200 mm sodium chloride (NaCl), pH 5.5, with the addition of 30% glycerol at -20°C. was Used proteiny substrate Elastase Substrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref. Castillo, M.J. et al., 1979, Anal. Biochem. 99, 53-64). The substrate was kept in dimethyl sulfoxide (DMSO) at -20°C. Add in the analysis were carried out as follows: the test compounds and controls were added in black 96-well tablets with a flat bottom (Greiner 655076), 1 ál of 100% DMSO, then 30 μl of HNE in sample buffer with 0.01% of Triton (trademark) X-100 detergent. The composition OPYTNO the buffer: 100 mm Tris(hydroxymethyl)aminomethane (TRIS) (pH 7.5) and 500 mm NaCl. Enzyme and compounds were incubated at room temperature for 15 minutes. Then add 30 ál of the substrate in the experimental buffer. Experienced the mixture incubated for 30 minutes at room temperature. The concentration of the enzyme HNE and substrate during incubation was 1.7 nm and 100 μm, respectively. The analysis is then stopped by adding 60 μl of a solution to stop (140 mm acetic acid, 200 mm monochloracetate sodium, 60 mm sodium acetate, pH of 4.3). Measured fluorescence instrument Wallac 1420 Victor 2 in the following settings: excitation 380 nm, emission 460 nm. The values of the IC50(50%inhibitory concentration) was determined using a curve approximation XIfit using the model 205.

When testing using the above screening, the compounds of the Examples showed values IC50in respect of inhibiting the activity of human neutrophil elastase less than 30 microns (micromoles), which indicates that the compounds according to the invention are believed to possess useful therapeutic properties. Specific results are presented in the following Table.

ConnectionInhibition of human neutrophil elastase, IC50(micromoles, µm)
Example 1 0,00033
Example 20,00032
Example 120,0010
Example 160,00061

1. The compound of formula (I)

where R1represents a C1-C6alkyl;
W represents pyrazolyl, triazolyl or imidazolyl;
R14represents phenyl or 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms, which may be substituted by at least one Deputy, selected from F, Cl, CN and CF3;
R3represents phenyl, substituted triptorelin Deputy;
R4represents hydrogen or C1-C6alkyl;
X represents a group-C1-C6alkylene-Y, and Y represents a simple bond, and Allenova group represents a linear or branched C1-C6alkylen may HE substituted, CO2R66or C1-C3alkoxy;
R5represents phenyl or pyridinyl, substituted-S(O)vR21; or
R5represents unsubstituted With3-C6cycloalkyl ring;
or R5may also represent H;
R21represents hydrogen, C 1-C6alkyl or C3-C8cycloalkyl;
v is 1 or 2; and
R66represents hydrogen or C1-C6alkyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R14and pyrazinone the ring is connected to the 5-membered ring W in positions 1, 2.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where R14represents phenyl or pyridinyl group, possibly substituted by one or two substituents, independently selected from F, CL, SP and CF3.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where X represents an unsubstituted With1-C2alkylen.

5. The compound according to claim 1 or its pharmaceutically acceptable salt, where R5represents N.

6. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1represents methyl;
W represents pyrazolidine or thiazolidine ring, and R14and 2-pyrazinone ring attached to the 5-membered ring W in 1, 2 positions;
R14represents phenyl or pyridinyl; and the specified ring substituted in the 4-(para)position F, Cl or CN;
R3represents a phenyl group substituted in the meta-position CF3;
R4represents hydrogen;
X present is employed, a linear or branched C 1-C4alkylen may HE substituted, CO2R66or1-C3alkoxy;
R66represents hydrogen or methyl; and
R5represents N.

7. The compound of formula (I) according to claim 1, chosen from:
6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid methylamide;
6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid (5-methanesulfonyl-pyridine-2-ylmethyl)-amide;
6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid ethylamide;
6-[1-(4-cyanophenyl)-1H-1,2,3-triazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carboxamide;
tert-butyl-2-[[6-[2-(4-cyanophenyl)pyrazole-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazin-2-carbonyl]amino]acetate;
6-[3-(4-chloro-phenyl)-3H-[1,2,3]triazole-4-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl)-phenyl)-3,4-dihydropyrazine-2-carboxylic acid methylamide;
6-[2-(4-chlorophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid methylamide;
6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N-(2-methoxyethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;
6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N-(2-hydroxy-1,1-dimethylethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)f the Nile]-3,4-dihydropyrazine-2-carboxamide;
6-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;
6-[1-(6-cyano-3-yl)-1H-pyrazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;
6-[1-(5-cyano-2-yl)-1H-pyrazole-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide; and
2-[[6-[2-(4-cyanophenyl)pyrazole-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazin-2-carbonyl]amino]acetic acid;
and pharmaceutically acceptable salts of any of the above.

8. The compound of formula (I) according to claim 1, which is 6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid of methylamide, or its pharmaceutically acceptable salt.

9. The compound of formula (I) according to claim 1, which is 6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid (5-methanesulfonyl-pyridine-2-ylmethyl)-amide, or its pharmaceutically acceptable salt.

10. The compound of formula (I) according to claim 1, which is 6-[2-(4-cyanophenyl)-2H-pyrazole-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydropyrazine-2-carboxylic acid ethylamide, or its pharmaceutically acceptable salt.

11. The compound of formula (I) according to claim 1, which is 6-[1-(4-cyanophenyl)-1H-1,2,3-triazo the-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carboxamide, or its pharmaceutically acceptable salt.

12. The method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt according to claim 1, which includes (a) the interaction of the compounds of formula (II)

where L1represents a leaving group (such as halogen or hydroxyl, and R1, R3, R14and W are as defined in formula (I),
with the compound of the formula

where X, R4and R5are as defined in formula (I); or (b) the interaction of the compounds of formula (IV)

where Hal represents a halogen atom, and X, R1, R3, R4and R5are as defined in formula (I),
with the nucleophile R14-W-M, where R14and W are as defined in formula (I), and M is an ORGANOTIN group, or the group organoboronic acid;
and, perhaps, after stages (a) or (b) carrying out one or more of the following stages:
- the transformation of the compounds obtained into another compound according to the invention,
- getting a pharmaceutically acceptable salt of the compound.

13. The intermediate compound of formula (IV)

where Hal represents a halogen atom, and X, R1, R3, R4and R5are as defined in claim 1.

14. Pharmaceutical composition for treating or reducing the risk of the disease or condition, which is useful in the inhibition of the activity of neutrophil elastase, containing the compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 11, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

15. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 11 for use in therapy.

16. A method of treating or reducing the risk of the disease or condition, which is useful in the inhibition of the activity of neutrophil elastase, comprising the administration to a patient in need, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 11.

17. The method according to clause 16, where the disease or condition is a respiratory distress syndrome in adults (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis including chronic bronchitis, bronchiectasis, pulmonary hypertension, asthma including refractive asthma, rhinitis, psoriasis, ischemic-reperfusion injury, rheumatoid arthritis, osteoarthritis, system inflammatory response syndrome (SIRS), nonhealing wound, cancer, atherosclerosis, peptic ulcers, Crohn's disease, ulcerative colitis or damage to the mucous Obolo the qi of the stomach.

18. The method according to 17, where the disease or condition is a cystic fibrosis.

19. The method according to 17, where the disease or condition is a bronchiectasis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing optically pure voriconazole via: a) coupling reaction of 1-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-yl)ethanone with 4-(1-bromoethyl)-6-(4-chlorophenylsulphanyl)-5-fluoropyrimidine in Reformatsky reaction conditions to obtain the desired (2R,3S)/(2S,3R) enantiomeric pair, b) splitting the thiol fragment from the enantiomer to obtain racemic voriconazole; and c) extracting the desired optically pure voriconazole via optical separation of the enantiomer using an optically active acid.

EFFECT: improved method.

4 cl, 7 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (1) in free form or in form of a salt. In formula (1): X1 and X2 all independently denote halogen; A denotes a radical of formula where (R1)1-2 denotes 1-2 identical or different substitutes selected from a group comprising C1-C4-alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, R2R3N-C1-C4-alkyl, halogen, hydroxy group, C1-C4-alkoxy group, halogen-C1-C4-alkoxy group, C1-C4-alkylthio group, C1-C4-alkanoyl, C1-C4-alkanoylamino group, C1-C4-alkylsulphonylamino group, C1-C4-alkylsulphonyl, C1-C4-alkylthionyl, NR2R3 and morpholinyl; or A denotes a radical of formula where ring (a) denotes a 5-member heterocyclic ring containing 1 or 2 heteroatoms selected from a group comprising O and N, which can further be substituted with C1-C4-alkyl, and which is annelated in positions 3 and 4; and R2 and R3 all independently denote hydrogen or C1-C4-alkyl. The invention also relates to a parasite control composition containing said compounds, a parasite control method on warm-blooded animals and use of compounds of formula (1) to prepare a parasite control composition.

EFFECT: high efficiency of using said compounds.

11 cl, 7 ex, 2 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the area of chemistry, chemical and pharmaceutical industry and medicine and refers to compounds of formula (1) that can be useful as antipsychotic drugs. Described compounds of formula (1) are the derivatives of 5H-dibenzo[b, e][1, 4]diazepine or its pharmacologically acceptable salts with acid and application of the compounds. Compounds of formula (1) possess higher activity compared to clozapine.

EFFECT: improved antipsychotic effect.

8 cl, 23 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound 4-(1-(4-(4-methoxyphenylthio)-2,5-dioxo-2,5-dihydro-1H-pyrro-3-yl)-1H-indol-3-yl)butyl carbamimidothioate (the compound "ЛХТА-1833") which can be used in therapy of colon cancer, breast cancer, melanoma, leucosis.

EFFECT: preparing the new compounds for treating cancer.

2 cl, 2 tbl, 3 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1H-quinazoline-2,4-diones of formula and to their pharmaceutically acceptable salts where R1 and R2 have the values specified in cl. 1 of the patent claim. The specified compounds exhibit antagonistic activity with respect to the AMPA receptor.

EFFECT: reception of a pharmaceutical composition for preparing a preparation used for treating a condition mediated by the AMPA receptor and first of all for treating epilepsy or schizophrenia.

8 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole derivatives of formula any isomers thereof or any mixture of isomers thereof or a pharmaceutically acceptable salt, where R is -(CR'R")n-Rc, where Rc is C1-6-alkyl, R' is hydrogen or C1-6-alkyl, and R" is hydroxy; n equals 1; X is N; and Y, Z and W is CRd, where each Rd is hydrogen; Ro is halogen. The invention also relates to a pharmaceutical composition containing a compound of formula I, use of the compound of formula I and a GABAA-receptor complex modulating method.

EFFECT: obtaining novel benzimidazole derivatives which are sensitive to GABAA-receptor complex modulation.

8 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2,6-substituted-4-monosubstituted aminopyrimidines of formula (I) or pharmaceutically acceptable salts thereof, which have prostaglandin D2 receptor antagonist properties. In formula R1 is 2,4-dichlorophenyl or 4-trifluoromethoxyphenyl, and when R1 is 2,4-dichlorophenyl, R2 is 3-carboxypyrrolidinyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperdin-1-yl, 4-aminopiperidin-1-yl, 4-acetamidepiperidin-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylsulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminosulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-thiomorpholin-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonyl-1-methylethyl)phenyl, 3-carboxymethylpiperidin-1-yl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 3-ethylsulphonylaminocarbonylpiperidin-1-yl, 3-tert-butylsulphonylaminocarbonylpiperidin-1-yl, 3-trifluoromethylsulphonylaminocarbonylpiperidin-1-yl, 3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidin-1-yl, 3-aminocarbonylpiperidin-1-yl, 3-dimethylaminocarbonylpiperidin-1-yl, 3-dimethylaminosulphonylaminocarbonylpiperidin-1-yl or 2-carboxy-2,3-dihydrobenzofuran-5-yl, and when R1 is 4-trifluoromethoxyphenyl, R2 is 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypiperidinyl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 5-carboxythiophen-2-yl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: high efficiency of using said compounds.

3 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: method is realised by reacting 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)benzimidazole with a compound of formula

, in which Z denotes a leaving group. The compound obtained this way undergoes suitable treatment if necessary. The cyano group of the obtained 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl]biphenyl of formula

is then converted to an acid functional group through hydrolysis at temperature ranging from 140°C to 200°C in the presence of a base in a system of high-boiling solvents, and the obtained telmisartan is converted to a hydrochloride during processing if necessary.

EFFECT: easy processing, treatment and extraction of telmisartan.

12 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

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