(2r)-2-[(4-sulphonyl)aminophenyl]propanamide and pharmaceutical compositions containing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new (2R)-2-phenylpropanamide derivatives of formula (I) or their pharmaceutically acceptable salts having an ability to inhibit CXCL1-induced chemiotaxis of human multiform nuclear leucocytes (PMNs), to a based pharmaceutical composition, to applying them for preparing a drug and a methods for making them. wherein R is specified from H, C1-C5-alkyl, C3-C6-cycloalkyl, thiazol substituted by trifluoromethyl, a residue of formula -CH2-CH2-O-(CH2-CH2O)nR", wherein R" represents H or C1-C5-alkyl, n is equal to an integer within 0 to 2, or R together with an NH-group whereto attached is a radical group of primary amides of natural amino acid such as (2S)-2-aminopropanamide; R' is specified in linear or branched C1-C5-alkyl, C3-C6-cycloalkyl, trifluoromethyl, phenyl, optionally substituted by a group specified in halogen, C1-C5-alkyl, C1-C5-alkoxy and trifluoromethyl; unsubstituted benzyl; thiophen.

EFFECT: preparing the new pharmaceutical composition.

9 cl, 1 tbl

 

BRIEF description of the INVENTION

The present invention relates to new (2R)-2-phenylpropanamide bearing 4-sulfonylamino the substituent in position 4 of the phenyl group and containing pharmaceutical compositions that can be used as inhibitors of chemotaxis polymorph-nuclear and mononuclear cells and which can be used in the treatment of various disorders mediated by chemokine ELR+CXC. In particular, the compounds of this invention can be used in the treatment and control of specific CXCR2-dependent pathologies such as FDS (syndrome obliterating bronchiolitis), COPD (chronic obstructive pulmonary disease), angiogenesis and melanoma.

BACKGROUND of INVENTION

Chemokines constitute a large family of cytokines of chemotaxis, which exert their effects through interaction with receptors belonging to the family of 7TM-GPCRs. The system of chemokines, is crucial for the regulation and control of basal movement of cells during homeostasis and inflammation. Functional consequences of activation of receptors chemokines include moving of cells, degranulation, gene transcription, mitogenic and apoptotic effects. Cells of many types, along with hematopoietic cells Express receptors chemokines; these include endothelial glue the key, smooth muscle cells, stromal cells, neurons and titelmelodie cells. Their activation propagates the effects of activation of receptors chemokines on other aspects of tissue regulation and homeostasis, such as angiogenesis and morphogenetic movements during organogenesis (in addition to the development of cancer and metastasis).

Angiogenesis is characterized by the formation of new blood vessels, is essential for a number of physiological and pathophysiological phenomena such as embryonic development, wound healing, chronic inflammation and the growth of malignant tumors, and chemokines through different mechanisms affect all of these aspects of angiogenesis. First described in 1992, a strong angiogenic a chemokine was CXCL8 (also known as IL-8) [Koch, A.E. et al., Science, 258, 1798, 1992]. From a pathophysiological point of view, regulation of angiogenesis by chemokines is important for the formation and growth of tumors. There are two CXCL8 receptor (CXCR1 and CXCR2); they bind CXCL8 with high affinity. CXCR1 is selective for CXCL8, whereas CXCR2 and interacts with other chemokines as natural ligands. Currently, evidence is accumulating that, for example, CXCL8 plays a pathogenetic role in the development of cutaneous melanoma mediated by CXCR2. It was shown that melanoma samples and cell lines, vydeleny the E. of them, Express several chemokines, including CXCL8 and CXCL1 (and GRO-α). CXCL8 affects the processes of tumor development and metastasis, as it has been shown that he is an autocrine growth factor [Schadendorf D. et al, J. Immunol, 151, 2667, 1993], induces angiogenesis [Strieter R. M. et al., Am. J. Pathol., 141, 1279, 1992] and affects the migration of melanoma cells [Wang J.M. et al., Biochem. Biophys. Res. Commun., 169, 165, 1990] by binding and activation of their receptors. Both of these receptor is expressed in cells of several types (endothelial cells and melanoma cells) and are also involved in the angiogenic response [Addison CL. et al., J. Immunol, 165, 5269, 2000], but in a different way. It was reported [Norgauer J. et al J. Immunol, 156, 1132, 1996]that the low expression of CXCR2 can be detected in normal human melanocytes, but this receptor is stimulated by treatment with factor TNF-α, which is manifested in increased proliferation in response to exposure CXCL8, whereas in the same experiment the expression of CXCR1 is not detected. Well-evaluated the role of CXCL8 as an important angiogenic factor, and it was demonstrated that CXCR2, is the putative angiogenic receptor. Only recently revealed the role of specific receptors CXCR1 and 2 in the development of melanoma [Varney, M. L. et al, Am. J. Clin. Pathol, 125, 209, 2006]. It was demonstrated in vitro, in contrast to CXCR1, which is ubiquitously expressed in malignant human melanomas all the levels Clarke, CXCR2 expressed predominantly in melanoma tumors of higher degrees and that there are significant differences in the levels of CXCR2 expression between thick and thin melanomas, suggesting different roles CXCR2 and CXCR1in vivo. CXCR1 and CXCR2 are involved in the mechanism of the angiogenic response and haptotaxis migration and chemotaxis of melanoma cells. Despite approximately equal affinity for CXCL8 and approximately the same number of these receptors, chemotaxis of neutrophils is mediated mainly by receptor CXCR1 [Quan J.M. et al, Biochem. Biophys. Res. Commun., 219, 405, 1996], and the expression of CXCL8 by endothelial cells stimulates chemotactic response of melanoma cells mediated by receptor CXCR1. As mentioned above, the CXCR2 believe putative receptor, mediating angiogenesis induced chemokine ELR+CXC, what confirms the conclusion about the different roles performed CXCR1 and CXCR2 in the modulation of aggressive malignant phenotype, and that, in the development of melanoma and metastasis expression of CXCL8 correlated with the expression of CXCR2, but not with expression of CXCR1 [Varney, M. L. et al, Am. J. Clin. Pathol, 125, 209, 2006].

Inhibition of the production and/or activity of CXCL8 could be an ideal target (through modulation CXCR2) for effects on malignant melanoma.

Already described possible pathogenetics the I role of CXCL8 in lung disease (lung damage, the acute respiratory distress syndrome, asthma, chronic lung inflammation and fibrosis) and, specifically, in the pathogenesis of COPD (chronic obstructive pulmonary disease) by the way, mediated by CXCR2 [A.T. Hill et al, Am. J. Respir. Crit. Care med., 160, 893, 1999]. COPD is a disease characterized by inflammation of the peripheral Airways, flowing with the participation of many inflammatory cells and mediators. It is associated with increased influx of inflammatory cells, including an increase in the number of macrophages in the Airways and in the tissue. Alveolar macrophages develop from monocytes; they can cause pathological changes characteristic of COPD. It was reported that an increased number of macrophages in COPD is the result of the attraction of monocytes from systemic blood flow. Studies of chemotaxis of mononuclear cells in peripheral blood of patients with COPD show elevated compared with control chemotactic responses towards GRO-α, but not MCP-1, CXCL8 or NAP(ENA)-78 [Traves S. L. et al., J. Leuk. Biol, 76, 441, 2004]. This response is not mediated by differences in the expression of cellular receptors CXCR1 and CXCR2, but in patients with COPD expression of CXCR2 in monocytes is regulated differently: CXCR1 responds to high concentrations of CXCL8 and is responsible for the activation of neutrophils and the allocation of peroxide anions and neutrophil elastase, whereas CXCR2 Rea the range at low concentrations of CXC-chemokines and is involved in chemotactic responses. Currently developed a strong low-molecular inhibitors of CXCR2, such as SB225002, as blockers chemotactic response of neutrophils to CXCL8 and GRO-α. This antagonist has a significant inhibitory effect in relation to a chemotactic response to the sputum of patients with COPD, in which increasing concentrations of GRO-α [Traves SL, et al., Thorax, 57, 590, 2002]. Therefore, CXCR2 antagonists may also lessen the chemotaxis of monocytes and accumulation of macrophages in patients with COPD. These results demonstrate the potential of selective low-molecular-weight antagonists of the CXCR2 (unlike CXCR1) in the treatment of COPD and control lungs.

Recently, there are assumptions about the possible role of chemokines ELR+CXC in the development of the syndrome obliterating bronchiolitis (FDS). FDS is a fibrotic process that leads to a gradual narrowing of the lumen of bronchioles and airway obstruction (difficulty breathing). Usually FDS develops after adenoviral infection or infection with Mycoplasma pneumoniae, but this disease is also associated with chronic rejection of the transplanted lung, especially with chronic rejection of lung allografts. Cumulative frequency FDS to 5 years after lung transplantation is 50-80%, and 5-year graft survival after the start of the FDS is only 30-50% [Douglas, LS. e al., J. Clin. Invest. 115, 1133, 2005]. The PROPERTY is characterized by infiltration peribronchiolar leukocytes that infiltrate in the submucosa membrane, the basement membrane and epithelium of the respiratory tract and destroy them. For tissue damage bronchi, mediated by infiltration and activation of leukocytes, should fibroproliferative and the formation of granulation tissue [Trulock, E. P. Am. J. Respir. Crit Care Med. 155, 789, 1997].

Suppression CXCR2 antibodies that are specific to this receptor, inhibited the early infiltration polymorph-nuclear leukocytes in experimental models OWN in mice [Belperio, J.A., et al., J Clin Invest. 115, 1150, 2005]. Consider also that angiogenesis is a key factor in the development of fibrosis in the PROPERTY and that the ELR chemokines+directly involved in the mechanism of angiogenesis in this disorder. Angiogenic activity in bronchoalveolar lavagno fluid from patients with FDS is a consequence primarily of the presence of the ELR chemokines+CXC. In addition, the studies performed on model FDS in mice also demonstrated increased vascular remodeling that took place in parallel with the expression of chemokines ELR+CXC in the tracheal allograft. Taken together, these data support the hypothesis that the pathophysiological role played by chemokines ELR+CXC in the development of FDS should be twofold: in the first phase, hamaki the s ELR +CXC affect attracting polymorph-nuclear leukocytes (i.e. at the stage of ischemic/reperfusion lesions), and late chronic stage they are involved in vascular remodeling and angiogenesis (i.e. fibroproliferative stage). This means that the blockade activity ELR chemokines+CXC could be an effective therapeutic tool in the treatment of this syndrome.

Molecules that are the subject of this invention represent a new therapeutic agents for the treatment and control of specific diseases associated with CXCL8, especially of pathologies which are well established explicit pathophysiologically key role of CXCR2 (such as FDS, COPD and the development of tumors). It is well known that control movement, activation and differentiation of cells defines a system of cytokines with its main role and host immune responses to invading pathogens. This is confirmed by the fact that viruses induce or encode chemokines, receptors chemokines or proteins that bind chemokines, which variously affect the immune system [Murphy, PM., Nature Immunol., 2, 116, 2001]. It is established that sensitivity to CXCL8 necessary already at a very early stage of the host immune response to infection [McCoIl SR. et al., J. Immunol, 163, 2829, 1999; Moore TA et al. J. Immunol, 164, 908, 2000] and that CXCR1 is the predominant subtype receptors CXCL8, e is pressuremax on human neutrophils. In a recent article [Hess C, et al. Blood, 104, 3463, 2004] receptor CXCR1 described as a system capable of determining a subset of "responsive T-cells (such as T-cells type CD8+)that fill the gap between innate and acquired immune responses, without creating at an early stage vysokotochnuyu antigen-specific effector function, valid in the source of infection before the appearance of new effector cells. Moreover, due to the strict control of the levels of CXCR1 on neutrophils and T-cells type CD8+, an important feature for fine tuning the immune response is different sensitivity to agonists and antagonists of CXCR1. In conclusion, we can hypothesize that in the treatment of chronic diseases with clearly identified the main role of CXCR2 [i.e. cancer (melanoma) and pulmonary (COPD, GSS) disease], does not require blockade of receptor CXCR1 (implemented by the majority of known modulators CXCL8); moreover, due to unnecessary abnormal immune response, resulting from the necessary long-term treatment, such a blockade would be harmful.

Have been recently described new classes "2R-arylpropionate" (WO 02/58858) and 2-arylpropionic acids" (WO 03/043625)that can be used for inhibition of chemotactic activation polymorph-nuclear leukocytes through entries batch which I CXCL8 with CXCR1 and CXCR2. It was stated that the connection of class 2-arylpropionic acids have biological activity against both CXCL8 receptors; in addition, the described compounds with selective activity against CXCR2. Compounds of the class of amides did not show significant selectivity with respect to the subtypes of receptors CXCR1 and CXCR2. Chemical transformation of a subset of the 2-arylpropionic acid amides increased the selectivity to CXCR2 connections, without which this transformation are dual inhibitors CXCR1/2. Marked selectivity and new physico-chemical characteristics make it a subset of amides preferred compounds of this invention, particularly useful for the treatment of specific CXCR2-dependent pathology in Oncology (melanoma) and pulmonology (COPD and FDS).

DISCLOSURE of INVENTIONS

The present invention describes a new class of (2R)-2-phenylpropanamide bearing 4-sulfonylamino the substituent in position 4 of the phenyl group and containing pharmaceutical compositions which can be used as inhibitors of chemotaxis polymorph-nuclear and mononuclear cells and which can be used for treatment of various diseases mediated by chemokines ELR+CXC similar acute inflammatory diseases, such as COPD, or angiogenesis, Oper the target-ELR chemokines +CXC, which can lead to tumorigenesis, as in malignant melanoma. These compounds are characterized by good solubility in water due to chemical differences R'-substituent in the ring, irrespective of the nature of the residue R. Examples of such substituents are alkylsulfonamides, arylsulfonamides and heteroatomcontaining. Some of these amides are derivatives already described 2-arylpropionic acids, showing good specificity to GROα-induced chemotaxis. It was unexpectedly found that chemical modification of these acids into amides allowed to obtain new connections, not shown activity against receptor CXCR1, but with increased activity against CXCR2. The new selectivity described amides against CXCR2 has been evaluated in experiments on the inhibition of migration of transfectants CXCR1/L1.2 and CXCR2 - /L1.2 in response to the impact of CXCL8. The data in Table 1 show that these compounds are strong inhibitors CXCL1-induced chemotaxis of human polymorph-nuclear leukocytes with IC50about 10-8M. In contrast, the same compounds at a concentration of 10-7M does not have a significant inhibitory effect against CXCL8-induced chemotaxis of human polymorph-nuclear l is nocito. These results are consistent with a major role played CXCR1 in stimulation of chemotaxis induced CXCL8. At the same time, research selectivity showed that these compounds do not show significant inhibitory activity against migration of transfectants CXCR1/L1.2 in response to the impact of CXCL8 in concentrations of up to 10-6M. moreover, compounds of this class was confirmed by the complete absence of activity cyclooxygenase way. On the basis of the material described above in the introduction, the obvious potential role of this new class of compounds in the treatment of CXCR2-dependent pathologies in the field of Oncology (specifically, melanoma) and in the field of pulmonology (COPD, SOB).

DETAILED description of the INVENTION

Now discovered a new class of (2R)-2-phenylpropanamide as inhibitors of chemotaxis polymorph-nuclear and monuclear cells. In particular, the compounds of this invention are powerful inhibitors of the chemotaxis of neutrophils induced CXCL1, with improved pharmacokinetic and pharmacological activity. Thus, the present invention provides (2R)-2-phenylpropanamide derivatives of the formula (I):

and their pharmaceutically acceptable salt,

where R is selected from the

Is H, OH, C1-C5-alkyl, C3-C6-cycloalkyl, Csub> 2-C5-alkenyl, C1-C5-alkoxygroup and phenyl;

- heteroaryl group selected from substituted and unsubstituted pyrrole, thiophene, furan, indole, imidazole, thiazole, oxazole, pyridine and pyrimidine;

- residue of the formula-CH2-CH2-O-(CH2-CH2O)nR", where R" is H or C1-C5-alkyl, n is an integer from 0 to 2;

or R, together with the NH-group to which it is attached, is a group of radicals of the primary amides of natural amino acids, such as (2S)-2-aminopropane, (2S)-2-amino-3-phenylpropanamide, (2S)-2-amino-3-hydroxypropanoic, (2S)-2-amino-3-carboxypropanoyl, (2S)-2,6-diaminohexanoic. NH-group, mentioned above, as part of a group of radical primary amides natural amino acid is an amino group of a natural amino acid.

R' is selected from

- linear or branched C1-C5-alkyl, C3-C6-cycloalkyl, C2-C5-alkenyl and trifloromethyl;

substituted or unsubstituted phenyl;

substituted or unsubstituted benzyl;

- heteroaryl group selected from substituted and unsubstituted pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole and oxazole.

Further, the present invention provides compounds of formula (I) for use as medicines. In particular, such l the drug funds are inhibitors CXCL1-induced chemotaxis polymorph-nuclear and mononuclear cells.

Compounds of the present invention belong to the chemical class of (2R)-2-(4-sulfonyl)aminophenylacetamido. The compounds of formula (I) are inherently included in the General formula of the compounds described above in WO 01/58852, but their characteristics differ from the preferred compounds of the above invention significant advantages.

It was unexpectedly found that this class of compounds has a high selectivity to the receptor CXCR2, as shown in determining activity against receptor CXCR1 in the study of chemotaxis, which allows the use of this class of compounds as medicines for the treatment of various chronic or acute CXCR2-dependent pathological conditions, especially neoplastic disorders such as melanoma. In fact, it was demonstrated that CXCR2 is expressed predominantly melanoma tumors and metastases high degree and that there are significant differences in the levels of CXCR2 expression between thick and thin melanomas, which implies a different role for CXCR2 and CXCR1 alsoin vivo[Varney, M. L. et al, Am. J. Clin. Pathol, 125, 209, 2006]. In addition, CXCR2 antagonists are especially useful therapeutic application in the treatment of important pulmonary diseases such as COPD [Hay, D.W.P. et al., Current Opinion in Pharmacology, 1, 242, 2001].

Preferred R-gr is pami are:

H, C1-C5-alkyl, C3-C6-cycloalkyl, L-2-amino-1-methyl-2-oxoethyl; heteroaryl group selected from substituted and unsubstituted thiazole, oxazole, pyridine.

Preferred R'groups are:

linear or branched C1-C5-alkyl, C3-C6-cycloalkyl, trifluoromethyl, benzyl; phenyl, unsubstituted or substituted by a group selected from halogen, C1-C4-alkyl, C1-C4-alkoxygroup, trifloromethyl, thiophene.

Particularly preferred compounds of this invention are:

1 - (2R)-2-{4-[(isopropylphenyl]amino}phenyl)propanamide;

2 - (2R)-2-{4-[(isopropylphenyl]amino}phenyl)propanamide, sodium salt;

3 - (2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl) propanamide;

4 - (2R)-2-{4-{[(2,6-dichlorophenyl)sulfonyl]amino}phenyl) propanamide;

5 - (2R)-2-{4-[(methylsulphonyl)amino]phenyl}propanamide;

6 - (2R)-2-{4-[(phenylsulfonyl)amino]phenyl}propanamide;

7 - (2R)-2-{4-{[(4-were)sulfonyl]amino}phenyl) propanamide;

8 - (2R)-2-{4-{[(4-methoxyphenyl)sulfonyl]amino}phenyl) propanamide;

9 - (2R)-2-(4-[(benzylmethyl]amino}phenyl)propanamide;

10 - (2R)-2-(4-{[(4-chlorophenyl)sulfonyl]amino}phenyl) propanamide;

11 - (2R)-2-(4-{[(4-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]propanamide;

12 - (2R)-2-{4-[(Tien-2-ylsulphonyl)amino]phenyl}propanamide;

13 - (2R)-2-{4-[(cyclopentylacetyl is)amino]phenyl} propanamide;

14 - (2R)-2-(4-{[(trifluoromethyl)sulfonyl]amino} phenyl)propanamide;

15 - (2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-methylpropanamide;

16 - (2R)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-{4-[(isopropylphenyl]amino}phenyl)propanamide;

17 - (2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide;

18 - (2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl] propanamide;

19 - (2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-[2-(2-hydroxyethoxy)ethyl] propanamide;

20 - (2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-cyclopropylamine.

The most preferred compound in this list is the connection 1 and the corresponding sodium salt.

The compounds of this invention are powerful inhibitors of chemotaxis of human polymorph-nuclear leukocytes induced CXCL1. The compounds of this invention of formula (I) are usually isolated in the form of additive salts with organic and inorganic pharmaceutically acceptable bases.

Examples of such bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, (D,L)-lysine, L-lysine, tromethamine.

The compounds of this invention of formula I were evaluated byin vitroin relation to their ability to inhibit chemotaxis polymorph-nuclear leukocytes (hereinafter referred to as PMNs) and monocytes, indutsirovannymi IL-8 and GRO-α. For this purpose, to highlight PMNs from heparinization human blood obtained from healthy adult volunteers, removed mononuclear cells (sedimentation on the dextran according to the procedure disclosed in WJ. Ming et al., J. Immunol, 138, 1469, 1987) and red blood cells (hypotonic solution). Cell viability was calculated as the exception Trypanosoma blue, and the ratio of circulating polymorph-nuclear cells was evaluated in centrifugate after dyeing dye Diff Quick.

In the study of CXCL8-induced chemotaxis used recombinant human CXCL8 (Pepro Tech) as a stimulant in the chemotaxis experiments: liofilizovannye protein was dissolved in a volume of HBSS containing 0.2% of bovine serum albumin (BSA)to get a backup solution with a concentration of 10-5M, which was diluted in HBSS to a concentration of 10-8M, which was used in the study of chemotaxis.

Inhibition of chemotaxis induced GRO-α, has been evaluated in similar tests.

In experiments on the chemotaxis of PMNs incubated with the compounds of this invention having formula (I), for 15 min at 37°C in atmosphere containing 5% CO2.

During the test on chemotaxis [W. Falket et al., J. Immunol. Methods, 33, 239, 1980] used filters without PVP with 5-μm pores and microcamera suitable for replication.

Soy is inane of this invention, having the formula (I), was tested at a concentration in the range between 10-6and 10-10M; that is, they were added in this concentration to the bottom and top then microcamera. The ability of compounds of this invention having formula (I), to inhibit the chemotaxis of human monocytes was evaluated according to the opened method [Van Damme J. et al.,Eur. J. Immunol, 19, 2367, 1989].

The compounds of formula (I) were tested to evaluate their selectivity in the migration test using L1.2 cells, transfected with CXCR1 and CXCR2. Analysis was performed using Transwell filters with a pore size of 5 μm and following the described procedure [T. Imai et al., J. Biol. Chem, 273, 1764, 1998]. L1.2 cells - this mouse pre-T cells, transfected with a vector (pc-DNA-CXCR1 or CXCR2), containing the gene encoding a particular protein (CXCR1 or CXCR2). In tests conducted byex vivowith whole blood according to the procedure disclosed Patrignani et al., in J. Pharmacol. .. Ther., 271, 1705, 1994, it was found that the compounds of formula (I) is completely ineffective as inhibitors of the enzyme cyclooxygenase (COX).

In most cases, the compounds of formula (I) in concentrations of 10-5-10-7M do not interfere with the production of PGE2, induced in murine macrophages by stimulation with lipopolysaccharide (LPS, 1 μg/ml). Inhibition of the production of PGE2you can register, in most cases, is at the limit of the statistical the first importance, often below 15-20% of the basal values. Reduced efficiency of inhibition of COX is advantageous for therapeutic use the compounds of this invention, since the inhibition of prostaglandin synthesis stimulates macrophages to increase the synthesis of TNF-α (induced by LPS or hydrogen peroxide), which is a critical mediator of the activation of neutrophils and stimulates the production of such cytokines as interleukin-8.

Inhibitors of activation of CXCR2 find useful application as detailed above, especially in the treatment of chronic inflammatory pathologies in which it is assumed that CXCL8 receptors and GRO-α plays a key pathophysiological role in the development of the disease. Specifically, assume that the activation of CXCR2 is significant when the mediating angiogenic activity of chemokines ELR+CXC-mediated CXCL8 proliferation of epidermal cells, angiogenesis and melanoma in animal models [Keane M. P. et al. J. Immunol, 172, 2853, 2004] and in patients with different levels of malignant melanoma [Varney, M. L. et al, Am. J. Clin. Pathol, 2006, 125, 209].

In addition, CXCR2 antagonists are especially useful therapeutic use in the treatment of such important pulmonary diseases such as chronic obstructive pulmonary disease (COPD) (D. WP Hay and H.M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247) and syndrome oblite youseo of bronchiolitis (FDS) [Trulock, E. P. Am. J. Respir. Crit Care Med. 155, 789, 1997].

Therefore, the next subject of the present invention is the creation of connections for use in the treatment of angiogenesis, melanoma, chronic obstructive pulmonary disease (COPD) and syndrome of obliterating bronchiolitis (FDS), and the use of such compounds in the manufacture of medicaments and for the treatment of the above diseases.

In the scope of the present invention also includes pharmaceutical compositions comprising a compound of the invention and a suitable carrier.

The compounds of this invention, together with traditionally used adjuvant, carrier, diluent or excipient, you can actually put in the form of pharmaceutical compositions and unit dosage forms, and in this form they can be applied in solid form, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with these liquids, or in a form intended for oral administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms may include the ingredients in conventional proportions, together with additional active soy is inanami or factors or without them, and such unit dosage forms may contain any valid effective amount of the active ingredient commensurate with the intended range of the applied daily dose.

When used as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. Such compositions can be prepared in a form well known in the pharmaceutical industry and includes at least one active connection. Typically, compounds of this invention administered in pharmaceutically effective amounts. The real number of input connections is usually defined on the basis of the essential facts, including the pathological condition being treated, the chosen route of administration, the nature of the introduced compound, the age, body weight and response of the individual patient, the severity of the symptoms in this patient, etc.

The pharmaceutical compositions of this invention can be administered in a number of ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, these compounds are prepared preferably in the form of injectable or oral compositions. Compositions for oral administration can take the form of bulk liquid solutions or suspen is s or bulk powders. However, more typically, these compositions provide in the form of ready-made forms packaged in a single dose, to facilitate accurate dosing when taken. The term "unit dosage forms" refers to physically discrete units, applicable as single doses to humans and other animals, each unit contains a predetermined quantity of active material calculated to create the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled and pre-measured vials or syringes with liquid compositions or, in the case of solid compositions, pills, tablets, capsules, etc. In the compositions of the acid compound is usually a smaller amount of component (comprising from about 0.1 to about 50% by weight or, preferably, from about 1 to about 40% by weight), and the remaining amount consists of various fillers or carriers with tools that facilitate technological processing and formation of the desired finished shape.

Liquid forms applicable for oral administration can include acceptable aqueous or non-aqueous media with a buffer substances, suspendresume and dispersing agents, dyes, on dochkami etc. Liquid formulations, including injectable compositions described herein below, always keep in the dark to avoid catalytic effect of light, such as the formation of hydroperoxide or peroxide. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragakant or gelatin; excipients, such as starch or lactose; a disintegrator such as alginic acid, primogel or corn starch; lubricating substance, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring, such as peppermint, mint, methylsalicylate or orange flavoring.

Injectable compositions are usually based on injectable sterile physiological salt solution, or physiological salt solution with phosphate buffer or other injecting carriers known in this field. As indicated above, the acid derivative of formula (I) in such compositions is typically a smaller number of component, often comprising 0.05 to 10% by weight, and the remaining amount falls on the injectable carrier and the like, the Average daily dose will depend on various factors such as the seriousness of the disease and the patient's condition (in trust, gender and body weight). The usual dose ranges from 1 mg or more mg to 1500 mg of the compounds of formula (I) per day, not necessarily, divided into multiple doses. Due to the low toxicity of the compounds of this invention can also enter higher doses for extended periods of time.

The above-described components for oral input or injectable compositions are only typical examples. Additional materials, as well as technological methods, etc. described in Part 8 of the monograph "Remington''s Pharmaceutical Sciences Handbook", 18thEdition, 1990, Mack Publishing Company, Easton, Pennsylvania, which is incorporated here by reference. The compounds of this invention can also enter in forms with prolonged release or drug-delivery systems with prolonged release. Description of typical materials with prolonged release can also be found in the materials included in the manual Remington, above.

The present invention is illustrated in the following examples, which should not be construed as limiting the scope of this invention.

EXAMPLES

Alkyl and arylsulfonate used as reagents in the synthesis of compounds of formula (I)are known products, usually available commercially, or they can be prepared FPIC is the means described in the literature.

(2R)-2-(4-AMINOPHENYL)propanamide

(2R)-2-(4-Nitrophenyl)propanoic acid (6 g, of 30.6 mmol) was dissolved in dry CH2Cl2(80 ml) was added 1,1-carbonyldiimidazole (5,58 g, 34,41 mmol) and the resulting solution was 2 hours and stirred at room temperature. Through this solution was barbotirovany gaseous ammonia until the complete disappearance of the intermediate product, a specific IR-analysis (8 hours). The organic solution was added a saturated solution of NH4Cl (20 ml) and was divided in two phases. The organic phase is again washed with water (2×25 ml), dried over Na2SO4was filtered, evaporated under vacuum and obtained (2R)-2-(4-nitrophenyl)propanamide in the form of a white solid (5.1 g, 26,15 mmol).

(2R)-2-(4-Nitrophenyl)propanamide (4.9 g, to 25.2 mmol) was dissolved in a mixture of THF (30 ml) and CH3OH (30 ml) and the resulting solution was cooled to T=0-5°C. was Added ammonium formate (8 g, 126 mmol), and then portions was carefully added 10% Pd/C (1.6 g). The resulting mixture was allowed to mix at room temperature over night, until complete disappearance of starting material (according to TLC). After filtration under vacuum through a layer of celite and removal of the solvent under reduced pressure was isolated pure (2R)-2-(4-AMINOPHENYL)propanamide in the form of a white powder (4 g, 24,24 mmol). The yield of 96.2%. TPL 110-112°C; [α]D25(c=0,6, CH3O): -1,9°C; 1H-NMR (CDCl3) δ 7,10 (d, 2H, J=7 Hz), of 6.65 (d, 2H, J=7 Hz), 5,35 (users, 2H, CONH2), 3,52 (m, 1H), 1,50 (d, 3H, J=7 Hz).

(2R)-2-{4-[(Isopropylphenyl]amino}phenyl)propanamide (1)

(2R)-2-(4-AMINOPHENYL)propanamide (0.5 g, was 3.05 mmol) was dissolved in pyridine (2 ml) was added 2-propanesulfonate (of 0.53 ml, 3,66 mmol). The resulting solution of 4 h was heated under reflux and left overnight at room temperature. After complete disappearance of the original amide solution was diluted with Et2O (10 ml) and the organic layer washed with 1 n HCl (2×5 ml) and H2O (2×5 ml), dried over Na2SO4was filtered, evaporated under vacuum and obtained (2R)-2-{(4-[(isopropylphenyl) amino]phenyl}propanamide in the form of a pale yellow solid (667 mg, 2,47 mmol). Yield 81%, TPL 125-127°C; [α]D25(c=0.3, and CH3OH): is-12.7°;1H-NMR (DMSO-d6) δ 9,65 (users, 1H, SO2NH), 7,40 (users, 1H, CONH2), to 7.25 (d, 2H, J=7 Hz), 7,12 (d, 2H, J=7 Hz), 6,80 (users, 1H, CONH2), 3,52 (kV, 1H, J=7 Hz), 3.15 in (m, 1H), 1,22 (d, 3H, J=7 Hz ), of 1.18 (d, 6H, J=7 Hz).

Following the above procedure and on the basis of relevant sulphonylchloride, has prepared the following amides:

(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)propanamide (2); waxy solid; [α]D25(c=0.5, CH3OH): -8,3°C;1H-NMR (CDCl3) δ 8,10 (d, 1H, J=7 Hz), 7,52 was 7.45 (m, 2H,+NH), 7,32-7,27 (m, 1H), 7,13 (d, 2H, J=7 Hz), 7,05 (d, 2H, J=7 Hz), 5,55 (users, H, CONH2), 5,28 (users, 1H, CONH2), of 3.48 (q, 1H, J=7 Hz), of 1.42 (d, 3H, J=7 Hz).

(2R)-2-{4-{[(2,6-dichlorophenyl)sulfonyl]amino}phenyl) propanamide (3); waxy solid; [α]D25(c=0.5, CH3OH): -10°;1H-NMR (CDCl3) δ 7,52 (users, 1H, NH), 7,35-7,20 (m, 3H), 7,13 (d, 2H, J=7 Hz), 7,05 (d, 2H, J=7 Hz), 5,55 (users, 1H, CONH2), 5,28 (users, 1H, CONH2), of 3.48 (q, 1H, J=7 Hz), of 1.42 (d, 3H, J=7 Hz).

(2R)-2-{4-[(methylsulphonyl)amino]phenyl}propanamide (4); waxy solid; [α]D25(C=0.5, CH3OH): is 12.5°;1H-NMR (DMSO-d6) δ 9,65 (users, 1H, NH), 7,40 (users, 1H, CONH2), to 7.25 (d, 2H, J=7 Hz), 7,12 (d, 2H, J=7 Hz), 6,80 (users, 1H, CONH2), 3,64 (c, 3H), 3,52 (kV, 1H, J=7 Hz), 1,22 (d, 3H, J=7 Hz).

(2R)-2-{4-[(phenylsulfonyl)amino]phenyl}propanamide (5); white powder; TPL 152-153°C; [α]D25(c=0.5, CH3OH): -13,5°C;1H-NMR (DMSO-d6) δ a 7.92 (m, 2H), 7,74 to 7.62 (m, 3H+NH), 7,40 (users, 1H, CONH2), 7,30 (d, 2H, J=7 Hz), to 7.15 (d, 2H, J=7 Hz), 6,88 (users, 1H, CONH2), 3,60 (kV, 1H, J=7 Hz), of 1.40 (d, 3H, J=7 Hz).

(2R)-2-{4-{[(4-were)sulfonyl]amino}phenyl)propanamide (6); white powder; TPL 138-140°C; [α]D25(c=0,2, CH3OH): 7.1°C;1H-NMR (CDCl3) δ the 7.65 (d, 2H, J=7 Hz), 7,28-to 7.15 (m, 4H), 7,05 (d, 2H, J=7 Hz), 6,45 (users, 1H, NH), 5.25-inch (users, 1H, CONH2), 3,52 (kV, 1H, J=7 Hz), 2,38 (c, 3H), of 1.47 (d, 3H, J=7 Hz).

(2R)-2-{4-{[(4-methoxyphenyl)sulfonyl]amino}phenyl) propanamide (7); white powder; TPL 118-120°C; [α]D25(c=0,2,CH 3OH): -3,6°C;1H-NMR (CDCl3) δ of 7.70 (d, 2H, J=7 Hz), 7,22 (d, 2H, J=7 Hz), 7,05 (d, 2H, J=7 Hz), 6.90 to (d, 2H, J=7 Hz), 6,52 (users, 1H, NH), 5.25-inch (users, 2H, CONH2), 3,85 (c, 3H), 3,55 (kV, 1H, J=7 Hz), a 1.45 (d, 3H, J=7 Hz).

(2R)-2-(4-[(benzylmethyl]amino}phenyl)propanamide (8); white powder; TPL 68-70°C; [αD25(c=0,2, CH3OH): -2,5°C;1H-NMR (CDCl3) δ7,40-7,35 (m, 3H), 7,30-7,25 (m, 4H), to 7.15 (d, 2H, J=7 Hz), 6,21 (users, 1H, NH), 5,31 (users, 2H, CONH2), 4,35 (c, 2H), to 3.58 (q, 1H, J=7 Hz), 1.57 in (d, 3H, J=7 Hz).

(2R)-2-(4-{[(4-chlorophenyl)sulfonyl]amino}phenyl)propanamide (9); white powder; TPL 150-153°C; [α]D25(c=0,2, CH3OH): -3,6°C;1H-NMR (CDCl3) δ of 7.75 (d, 2H, J=7 Hz), was 7.45 (d, 2H, J=7 Hz), 7,25 (d, 2H, J=7 Hz), 7,05 (d, 2H, J=7 Hz), 6,68 (users, 1H, NH), 5,28 (users, 2H, CONH2), 3,55 (kV, 1H, J=7 Hz), 1.50 in (d, 3H, J=7 Hz).

(2R)-2-(4-{[(4-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl] propanamide (10); white powder; TPL 178-180°C; [α]D25(c=0,2, CH3OH): -2,5°C;1H-NMR (CDCl3) δ 9,20 (users, 1H, NH), of 7.90 (d, 2H, J=7 Hz), to 7.68 (d, 2H, J=7 Hz), to 7.15 (d, 2H, J=7 Hz), 7,05 (d, 2H, J=7 Hz), the 5.45 and 5.30 (users, 2H, CONH2), of 3.48 (q, 1H, J=7 Hz), a 1.45 (d, 3H, J=7 Hz).

(2R)-2-{4-[(Tien-2-ylsulphonyl)amino]phenyl}propanamide (11); white powder; TPL 58-60°C; [α]D25(c=0,2, CH3OH): is 3.5°;1H-NMR (CDCl3) δ 7,58 (d, 1H, J=2 Hz ), 7,52 (d, 1H, J=2 Hz), 7,25 (d, 2H, J=7 Hz), 7,10 (d, 2H, J=7 Hz), 7,05 (d, 1H, J=2 Hz, 6,75 (users, 1H, NH), 5,35 (users, 2H, CONH2), to 3.58 (q, 1H, J=7 Hz), to 1.48 (d, 3H, J=7 Hz).

(2R)-2-{4-[(cyclopentyl sulfonyl)amino]phenyl}propanamide (12) ; waxy solid; [α]D25(C=0.5, CH3OH): -10,2°C;1H-NMR (DMSO-d6) δ7,75 (users, 1H, NH), 7,40 (users, 1H, CONH2), 7,30 (d, 2H, J=7 Hz), to 7.15 (d, 2H, J=7 Hz), 6,88 (users, 1H, CONH2), 3,60 (kV, 1H, J=7 Hz), to 3.34 (m, 1H), 2,08-of 1.97 (m, 2H), 1.85 to about 1.75 (m, 2H), 1.60-to 1,50 (m, 4H), of 1.40 (d, 3H, J=7 Hz).

(2R)-2-(4-{[(trifluoromethyl)sulfonyl]amino}phenyl)propanamide (13); waxy solid; [α]D25(c=0.5, CH3OH): -24,5°;1H-NMR (DMSO-d6) δ 9,60 (users, 1H, NH), the 7.65 (d, 2H, J=7 Hz), 7,40 (users, 1H, CONH2), 7,12 (d, 2H, J=7 Hz), 6,85 (users, 1H, CONH2), 3,52 (kV, 1H, J=7 Hz), of 1.40 (d, 3H, J=7 Hz).

(2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-methylpropanamide (14)

(2R)-2-{[4-(isopropylacetanilide)phenyl]}propanoic acid, prepared as described in WO 03/042625, (0.65 g, 2.4 mmol) was dissolved in CH2Cl2(8 ml)was added the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (WSC) (0,46 g, 2.4 mmol) and 1-hydroxybenzotriazole (HOBT) (0,324 g, 2.4 mmol) and the resulting mixture was allowed to mix at room temperature for 30 minutes and Then was added dropwise a mixture of methylamine hydrochloride (0,155 g, 2,43 mmol) and triethylamine (0.33 ml, 2.4 mmol) in CH2Cl2(2 ml) and the resulting mixture was left overnight at room temperature. This mixture was diluted with CH2Cl2(10 ml) and the organic layer washed with 1 N. HCl (2×10 ml) and H2O (2×10 ml), dried over Na2SO was filtered, evaporated under vacuum and obtained (2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-methylpropanamide in the form of a waxy solid (0,63 g of 2.23 mmol). Yield 93%. [α]D25(c=1, CH3CH2OH): are-20.5°;1H-NMR (CDCl3) δ 9,65 (users, 1H, SO2NH), 7,25 (d, 2H, J=7 Hz), 7,12 (d, 2H, J=7 Hz), and 5.30 (users, 1H, NH), 3,52 (kV, 1H, J=7 Hz), 3.15 in (m, 1H), 2,78 (d, 3H, J=3 Hz)to 1.22 (d, 3H, J=7 Hz ), of 1.18 (d, 6H, J=7 Hz).

Following the above procedure, and based on appropriate commercial hydrochloride amines and propanoic acids of the formula (II)

where R' is defined above, has prepared the following amides:

(2R)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-{4-[(isopropylphenyl]amino}phenyl)propanamide (15); white powder; TPL 132-135°C; [α]D25(c=1, CH3OH): -22,5°;1H-NMR (DMSO-d6) δ 9,65 (users, 1H, SO2NH), 8,35 (users, 1H, NH), of 7.70 (d, 2H, J=7 Hz), a 7.62 (d, 2H, J=7 Hz), 7,50-7,35 (users, 1H, CONH2), 7,15-7,05 (users, 1H, CONH2), 4,45-4,32 (m, 1H), of 4.05 (q, 1H, J=7 Hz), 3.15 in (m, 1H), 1.55V (d, 3H, J=7 Hz), of 1.35 (d, 3H, J=7 Hz), of 1.18 (d, 6H, J=7 Hz).

(2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide (16); glassy solid; [α]D25(c=0.5, CH3OH): -8,4°C;1H-NMR (CDCl3) δ 9,65 (users, 1H, SO2NH), 8,75 (users, 1H, NH), was 7.45 (d, 2H, J=7 Hz), 7,30 (d, 2H, J=7 Hz), 7,25 (c, 1H), 3,82 (kV, 1H, J=7 Hz), 3.15 in (m, 1H), 1,24 (d, 3H, J=7 Hz )and 1.15 (d, 6H, J=7 Hz).

(2R)-2-{4{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide (17) ; waxy solid; [α]D25(c=0.5, CH3OH): -5,5°C;1H-NMR (CDCl3) δ 9,50 (users, 1H, SO2NH), 8,72 (users, 1H, NH), 8,10 (d, 1H, J=7 Hz), 7,50-of 7.48 (m, 2H), 7,32-7,27 (m, 1H), 7,20 (c, 1H), 7,13 (d, 2H, J=7 Hz), 7,05 (d, 2H, J=7 Hz), 3,48 (kV, 1H, J=7 Hz), of 1.42 (d, 3H, J=7 Hz).

(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide (18); colorless oil; [α]D25(c=0.5, CH3OH): -4,5°;1H-NMR (CDCl3) δ 9,50 (users, 1H, SO2NH), 8,10 (d, 1H, J=7 Hz), 7,50-of 7.48 (m, 2H), 7,32-7,27 (m, 1H), 7,15 (d, 2H, J=7 Hz), was 7.08 (d, 2H, J=7 Hz), 6,10 (users, 1H, NH), 3,70-of 3.60 (m, 3H), 3,55 is 3.40 (m, 6H), 2.05 is (users, 1H, OH), of 1.52 (d, 3H, J=7 Hz).

(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-cyclopropylamine (19); colorless oil; [α]D25(c=0.5, CH3OH): -11,5°C;1H-NMR (CDCl3) δ 9,50 (users, 1H, SO2NH), 8,10 (d, 1H, J=7 Hz), 7,50-of 7.48 (m, 2H), 7,32-7,27 (m, 1H), 7,15 (d, 2H, J=7 Hz), was 7.08 (d, 2H, J=7 Hz), 5,45 (users, 1H, NH), 3,50 (kV, 1H, J=7 Hz), 2,75-2,62 (m, 1H), of 1.52 (d, 3H, J=7 Hz), 0,8 (m, 2H), 0,42 (m, 2H).

(2R)-2-{4-[(Isopropylphenyl]amino}phenyl)propanamide, sodium salt

(2R)-2-{(4-[(Isopropylphenyl)amino]phenyl}propanamide (1) (500 mg, of 1.85 mmol) was dissolved in CH3OH (15 ml). Was added dropwise NORMEX 1 n NaOH (1,85 ml of 1.85 mmol) and the resulting solution was allowed to mix at room temperature for 2 hours After evaporation of the solvent was added water (3 ml) and the clear solution was frozen, was liofilizovane and got soda is ewww salt of (2R)-2-{4-[(isopropylphenyl]amino}phenyl) propanamide (541 mg, of 1.85 mmol) as pale yellow powder. Quantitative output. [α]D25(c=0.4, CH3OH): -11,75°;1H-NMR (D2O) δ to 7.32 (d, 2H, J=7 Hz), to 7.15 (d, 2H, J=7 Hz), 3,82 (kV, 1H, J=7 Hz), at 3.35 (m, 1H), and 1.54 (d, 3H, J=7 Hz ), of 1.35 (d, 6H, J=7 Hz).

Sodium salt compounds 2-19 were prepared according to the same above procedure.

The table contains data on the biological activity of typical compounds of the present invention

NameStructureCXCL1 (% inhibi simulation when
10-8M)
CXCL8 (% inhibi simulation when
10-7M)
(2R)-2-{4-
[(isopropylphenyl]amino}phenyl)
propanamide
(1)
67±77±18
(2R)-2-{4-{[(2-
chlorophenyl)sulfonyl]amino}phenyl)
propanamide
(2)
41±719±5
(2R)-2-{4-{[(2,6-
dichlorophenyl)sulfonyl]amino}phenyl)
propanamide
(3)
39±1014±5
75±710±7
(2R)-2-{4-
[(phenylsulfonyl)amino]phenyl}
propanamide
(5)
44±915±10
(2R)-2-{4-{[(4-
were)sulfonyl]amino}phenyl)
propanamide
(6)
65±412±10

(2R)-2-{4-{[(4-
methoxyphenyl)sulfonyl]amino}phenyl)
propanamide (7)
71±119±7
(2R)-2-(4-
[(benzylmethyl]amino}phenyl)
propanamide
(8)
58±614±9
(2R)-2-(4-{[(4-
chlorophenyl)sulfonyl]amino}phenyl)
propanamide
(9)
53±1220±4
(2R)-2-(4-{[(4-
trifluoromethyl)phenyl]sulfonyl}amino)
phenyl]propanamide
(10)
69±515±7
(2R)-2-{4-[(Tien-2-ylsulphonyl)
amino]phenyl}propanamide
(11)
50±217±4
(2R)-2-{4-[(cyclopentylacetyl)
amino]phenyl}propanamide
(12)
67±721±10
(2R)-2-(4-{[(trifluoromethyl)sulfonyl]
amino}phenyl)propanamide
(13)
75±1124±7
(2R)-2-{4-[(isopropylphenyl]
amino}phenyl)-N-methylpropanamide
(14)
64±88±9
(2R)-N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-2-{4-[(isopropylphenyl]amino}
phenyl)propanamide (15)
58±210±8
(2R)-2-{4-
[(isopropylphenyl]amino}phenyl)-N-
[4-(trifluoromethyl)-1,3-ti is evil-2-yl]
propanamide
(16)
49±1011±7
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]
amino}phenyl)-N-[4-(trifluoromethyl)-
1,3-thiazol-2-yl]propanamide
(17)
40±1214±11
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-
N-[2-(2-hydroxyethoxy)ethyl]
propanamide
(18)
59±56±7
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]
amino}phenyl)-N-cyclopropylamine
(19)
60±819±4

1. (2R)-2-phenylpropanamide derivatives of the formula (I):

and their pharmaceutically acceptable salts,
in which
R is selected from
- H, C1-C5-alkyl and C3-C6-cycloalkyl;
- thiazole, substituted by trifluoromethyl;
- residue of the formula-CH2-CH2-O-(CH2-CH2O)nR"where R" is H or C1-C5-alkyl, n is an integer from 0 to 2;
or R together with the NH-group to which it is attached is a group of radicals of the primary amides of natural amino acids, such as (2S)-2-aminopropane;
R' is selected from
- linear or branched C1-C5-alkyl, C3-C6-cycloalkyl and trifloromethyl;
is phenyl, optionally substituted by a group selected from halogen, C1-C5-alkyl, C1-C5-alkoxy and trifloromethyl;
- unsubstituted benzyl;
- thiophene.

2. Compounds according to claim 1, in which
R is selected from
H, C1-C5-alkyl, C3-C6-cycloalkyl, L-2-amino-1-methyl-2-oxoethyl; thiazole, substituted by trifluoromethyl; R' is selected from
linear or branched C1-C5-alkyl, C3-C6-cycloalkyl, trifloromethyl, benzyl; phenyl, unsubstituted or substituted by a group selected from halogen, C1-C4-alkyl and trifloromethyl; thiophene.

3. Compounds according to claim 1, chosen from:
(2R)-2-{4-[(isopropylphenyl]amino}phenyl)propanamide;
sodium salt of (2R)-2-{4-[(isopropylphenyl]amino}
phenyl)propanamide;
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)propanamide;
(2R)-2-{4-{[(2,6-dichlorophenyl)sulfonyl]amino}phenyl)propanamide;
(2R)-2-{4-[(methylsulphonyl)amino]phenyl}propanamide;
(2R)-2-{4-[(phenylsulfonyl)amino]phenyl}propanamide;
(2R)-2-{4-{[(4-were)sulfonyl]amino}phenyl)propanamide;
(2R)-2-{4-{[(4-methoxyphenyl)sulfonyl]amino}phenyl)propanamide;
(2R)-2-(4-[(benzylmethyl]amino}phenyl)propanamide;
2R)-2-(4-{[(4-chlorophenyl)sulfonyl]amino}phenyl)propanamide;
(2R)-2-(4-{[(4-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]propanamide;
(2R)-2-{4-[(Tien-2-ylsulphonyl)amino]phenyl}propanamide;
(2R)-2-{4-[(cyclopentylacetyl)amino]phenyl}propanamide;
(2R)-2-(4-{[(trifluoromethyl)sulfonyl]amino}phenyl)propanamide;
(2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-methylpropanamide;
(2R)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-(4-[(isopropylphenyl]amino}phenyl)propanamide;
(2R)-2-{4-[(isopropylphenyl]amino}phenyl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide;
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide;
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide;
(2R)-2-{4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-N-cyclopropylamine.

4. Compounds according to claim 1, which is (2R)-2-{4-[(isopropylphenyl]amino}phenyl)propanamide and its sodium salt.

5. Compounds according to any one of claims 1 to 4, intended for use as a drug that inhibits CXCL1-induced chemotaxis of human polymorph-nuclear leukocytes (PMNs).

6. The use of compounds according to any one of claims 1 to 4 for preparing a medicinal product for the treatment of diseases involving induced CXCL1 chemotaxis of human PMNs, where these diseases selected from melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD) and the syndrome is obliterating bronchiolitis (FDS).

7. Pharmaceutical compositions that inhibit induced CXCL1 chemotaxis of human PMNs, comprising pharmaceutically effective amount of a compound according to any one of claims 1 to 4 in a mixture with appropriate media.

8. The method of obtaining compounds of formula (I) according to claim 1, including the interaction of the compounds of formula (II)
in which R' has the meaning given in claim 1, with an amine of the formula other, in which R has the meaning given in claim 1.

9. The method of obtaining compounds of formula (I) according to claim 1, including the interaction of (2R)-2-(4-AMINOPHENYL)propanamide with sulphonylchloride formula R SO2Cl, in which R' has the meaning given in claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

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FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to fluorine and trifluoralkyl-containing heterocyclic sulfonamides of general formula I , where T - CHO, COR8 and C(OH)R1R2; R1 and R2 -hydrogen, C1-6alkyl; R3 -hydrogen; R4 - (CF3)nalkyl, (CF3)nalkylphenyl, and (F)ncycloalkyl; N equals 1-2; R5 - hydrogen, halogen, dien, condensed with Y, when Y stands for C, and dien, condensed with Y, when Y stands for C and substituted with halogen; W, Y and Z - C, CR6 and N, on condition that at least one of W or Y, or Z must be C; R6 -hydrogen halogen or C1-6alkyl; X - S and NR7; R7 - C1-6alkyl; and R8 - C1-6alkyl. Also described are method of obtaining compounds I, pharmaceutical composition and application of compounds, intermediate compounds, used in synthesis.

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48 cl, 5 tbl, 42 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of formulas (Ip3) or (Ip4) wherein R1P3 means unsubstituted or substituted phenyl or thienyl wherein substitutes represent halogen atom, (C1-C6)-alkyl, (C1-C4)-halogenalkyl, nitro group, (C1-C4)-alkoxy group; R16P3 and R17P3 in common with carbon atom to which they are bound mean a bridge-bound saturated (C5-C12)-ring system that is substituted with (C4-C12)-alkyl, (C1-C6)-alkoxycarbonylamino group, for example, tert.-butoxycarbonylamino group; R18P3 means hydrogen atom; R1P4 means unsubstituted or substituted phenyl or thienyl wherein substitutes represent halogen atom, (C1-C6)-alkyl, (C1-C4)-halogenalkyl, nitro group, (C1-C4)-alkoxy group; R16P4 and R17P4 in common with carbon atom to which they are bound mean a substituted bridge-bound saturated (C5-C12)-cycloalkyl ring system, substituted piperidine or substituted bridge-bound piperidine wherein substitutes mean (C1-C6)-alkoxyoxycarbonyl, (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with (C4-C12)-alkyl, (C1-C4)-halogenalkyl, nitro group, aminocarbonyl; R18P4 means hydrogen atom or hydroxyl but hydrogen atom preferably; mP4 means 1. Compounds of formulas (Ip3) and (Ip4) inhibit activity of steroid sulfatase that allows their using as components of pharmaceutical composition.

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

7 cl, 13 tbl, 386 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

The invention relates to N-substituted aminotetralin formula 1

< / BR>
where R1independently selected from the group consisting of hydrogen; hydroxy; halogen; C1-8-alkoxy; substituted C1-8-alkoxy, where the Deputy is a halogen; n is 0-2; Y is methylene; m is 0-3;1means hydrogen;2means hydrogen; R2selected from the group consisting of hydrogen; hydroxy; C1-6-alkyl, C1-6-alkenyl; phenyl; substituted phenyl where the Deputy is chosen from halogen, C1-6-alkyl, C1-6-alkoxy, trifter-C1-6-alkyl, nitro; naphthyl and pyridyl; L is chosen from the group consisting of C1-8-alkylene; C1-4-alkylen-C3-7-cycloalkyl-C1-4-alkylene; C1-4-alkylen-aryl-C1-4-alkylene; R3selected from phenyl; substituted phenyl where the Deputy is chosen from halogen, nitro, C1-8-alkoxy, trifloromethyl and amino-C1-8-alkyl; naphthyl; and tanila and their enantiomers, diastereoisomers and pharmaceutically acceptable salts

The invention relates to new derivatives of nitromethylene General formula 1 in which R represents the radical (I), (II) or (III)

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts showing an ability to inhibit sphingosine kinase, to a based pharmaceutical composition, to a method of inhibiting sphingosine kinase and a method of treating diseases specified in breast cancer, diabetic retinopathy, arthritis and colitis. , wherein X represents -C(R3,R4)N(R5)-, -C(O)N(R4)-; R1 represents phenyl unsubstituted or substituted by 1 or 2 halogens. The values of R2, R3, R4, R5 substitutes are such as specified in the patent claim.

EFFECT: preparation of new compounds.

17 cl, 24 dwg, 9 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: medicine.

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

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

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in a medicinal agent for treating lower urinary tract symptoms.

6 cl, 56 tbl, 231 ex

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