Compounds modulating intracellular calcium

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I) or to its pharmaceutically acceptable salt: formula (I) wherein; R1 represents hydrogen; R2 represents phenyl, benzothienyl, benzofuranyl or the group -CH2CH2-phenyl; wherein R2 is optionally substituted by 1 or 2 substitutes optionally specified in F, O, Br, I, -CN, -NO2, -OR8, C1-C6alkyl and -N(R9)2; R4 represents phenyl substituted by 1 or 2 substitutes optionally specified in F, CI, Br, I, -CP3, -OH, -OR8 and C1-C6alkyl; each R8 is optionally specified in C1-C6alkyl; and each R9 is optionally specified in H and C1-C6alkyl. The invention also refers to a pharmaceutical composition for activity modulation of depot-controlled calcium channels (SOC-channels) containing such compounds.

EFFECT: there are produced new compounds and based pharmaceutical compositions which can find application in medicine for treating the diseases or conditions, such as rheumatoid arthritis, psoriasis, inflammatory intestinal disease, asthma and multiple sclerosis.

12 cl, 21 dwg, 1 tbl, 14 ex

 

CROSS-REFERENCE

This application claims the priority of provisional patent application U.S. No. 60/971161 called "Compound that modulates intracellular calcium, filed September 10, 2007, fully incorporated here by reference.

The SCOPE of the INVENTION

There are described compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using these compounds for modulation of the activity depot-operated calcium channels (SOC channels).

PRIOR art

Calcium plays a vital role in the functioning and survival of cells. For example, calcium is a key element in the transduction of signals into and within cells. Initiation of cellular responses to growth factors, neurotransmitters, hormones, and many other signaling molecules occurs through calcium-dependent processes.

Almost all types of cells in some way dependent on the generation of cytoplasmic CA2+signals to regulate cell functions or to run certain answers. Cytosolic CA2+signals controlling a wide range of cellular functions from short-term responses such as contraction and secretion, to long-term regulation of cell growth and proliferation. Typically, these signals include any combination of the release of CA 2+from endocellular depots, such as the endoplasmic reticulum (ER), and the receipt of CA2+across plasma membrane. In one example, the activation of cells begins with the binding of the agonist with surface membrane receptor associated with phospholipase C (PLC) through a mechanism involving G-protein. Activation of PLC leads to the formation of Inositol-1,4,5-triphosphate (IP3), which, in turn, activates the receptor IP3causing the release of CA2+from the ER. Then drop the contents of Ca2+ER is a signal for depot-operated calcium channels (SOC channels in the cytoplasmic membrane.

Depot-operated calcium influx (SOC influx) is a physiological cellular process that controls a variety of functions, such as, without limitation, replenishment of intracellular depot CA2+(Putney et al. Cell, 75, 199-201, 1993), activation of enzyme activity (Fagan et al., J. Biol. Chem. 275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol. 19:497-521, 2001), cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006) and the release of cytokines (Winslow et al., Curr. Opin. Immunol. 15:299-307, 2003). In some newsbody cells such as blood cells, immune cells, blood cells, T-lymphocytes and mast cells, SOC influx occurs through calcium channels activated by release of calcium (CRAC channels), type SOC channel.

This m is the mechanism influx of calcium was called depo-controlled calcium intake (SOCE). Protein molecules stromal interaction (STIM proteins) are an essential component in the functioning of the SOC channels, acting as sensors for detecting decrease in the calcium content in the internal depot and for the activation of SOC channels.

SUMMARY of the INVENTION

There are described compounds of formula (I), (II), (IIA) or (IIB), compositions containing such compounds, and methods of their use for the modulation of intracellular calcium. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) modulate intracellular calcium by inhibiting the activity depot-operated calcium channels. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) modulate intracellular calcium, inhibiting the activity of the activated complexes depot-operated calcium channels. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) inhibit the activation of depo-managed channels. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) inhibit the activation of calcium channels activated by calcium release. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) modulate an activity of, modulate an interaction of, or modulate the level of, or bind to, or interact with at least one protein complex SOC channel. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) modulate an activity of, modulate Simocatta, or modulate the level of, or bind to, or interact with at least one protein complex of the CRAC channel. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) is a selective inhibitor of the activity of SOC channels. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) is a selective inhibitor of the activity of CRAC channels.

In one aspect, there is described a compound of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2represents aryl, benzothiazyl, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8With1-C6of alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R 8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3With1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

For all embodiments, the substituents can be selected from a subgroup of the listed alternatives. For example, in some embodiments, R1represents hydrogen or C1-C6alkyl. In other embodiments, R1represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl or hexyl. In other what their incarnations, R 1represents H, methyl or ethyl. In some embodiments, R1represents N. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic acid.

In some embodiments, R2represents phenyl, naphthyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C1-C6heteroalkyl and C1-C6halogenoalkane.

In some embodiments, R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -N(R9)2, -CO2R9, -C(=O)R8. In some embodiments, R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OCF3, -OMe, -OEt, -OiPr, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, -NH2, -N(Me)2, -CO2H, -CO2Me and - CO2Et.

In some embodiments, R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2HE, -CF3, -OCF3, -OR8C1-C6of alkyl, C1-C6heteroalkyl and C1-C6halogenoalkane. In some embodiments, R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -OH, -CF3, -OCF3, -OMe, methyl, ethyl, isopropyl and tert-butyl. In some embodiments, R2selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; and bestien-2-sludge. In other embodiments, R2selected from phenyl, 3-ftoheia; 4-ftoheia; 4-chlorphenyl; 4-bromophenyl; 4-jodene; 3-methylphenyl; 3-methylphenyl; and bestien-2-yl.

In some embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane. In other embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituent and, selected from F, Cl, Br, I, -CN, -CF3, -OH, -OMe, -OCF3, methyl and ethyl. In other embodiments, R4selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; 2-triptoreline; 3-triptoreline; and 4-trifloromethyl. In some other embodiments, R4selected from phenyl; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 4-bromophenyl; 4-methylphenyl; 3,4-dimetilfenil; and 4-trifloromethyl.

Here we consider any combination of the groups described above for the different variables.

In one aspect, the compound of formula (I) chosen from:

In one aspect, there is described a method of modulating the activity depot-operated calcium channels (SOC channels), comprising bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable with the lute, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug. In one aspect, the bringing into contact occurs in vitro. In another aspect, the bringing into contact occurs in vivo. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one part of a complex depot-controlled calcium channel selected from a family of protein molecules stromal interaction (STIM). In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIM1 or STIM2. In one aspect, the modulation of activity depot-operated calcium channels in the compound of formula (I), (II), (IIA) or (IIB) inhibits depot-driven calcium intake (SOCE). In one aspect of the complex depot-controlled calcium channel is a complex of calcium channel activated by calcium release (CRAC channel). In one aspect, the modulation of the activity of calcium channels activated by release of calcium (CRAC channels), a compound of formula (I), (II), (IIA) or (IIB) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels.

Another AC is the project described here is a method of modulating the activity of calcium channels, activated by the release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one component of the complex calcium channel activated by calcium release (CRAC channel), selected from the family of protein molecules stromal interaction (STIM). In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with STIM1 or STIM2. In one aspect, the modulation of the activity of calcium channels activated by release of calcium (CRAC channels), a compound of formula (I), (II), (IIA) or (IIB) inhibits depot-driven calcium intake (SOCE). In one aspect, the modulation of the activity of calcium channels activated by release of calcium (CRAC channels), a compound of formula (I), (II), (IIA) or (IIB) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) inhibits SOCE with an average and generouse concentration (IC 50less than 10 microns. In yet another aspect, the compound of formula (I), (II), (IIA) or (IIB) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels in a concentration of less than 10 microns.

It also described a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, including the introduction of this mammal the compounds of formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an activity of, modulates an interaction of, or binds to, or interacts with a protein of a mammalian STIM1 or protein of a mammalian STIM2. In one aspect, the disease, disorder or condition in a mammal selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, diseases or disorders of the liver, diseases or disorders of the kidneys, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, ek is him, rejection of the transplanted organ, psoriasis, allogeneic or xenogeneic transplantation, graft rejection, graft versus host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, heavy pseudoparalysis the gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, Sjogren syndrome, cancer and other proliferative diseases and autoimmune diseases or disorders. In one embodiment the disease, disorder or condition is an inflammatory bowel disease. In another embodiment of the inflammatory bowel disease is a nonspecific ulcerative colitis. In yet another embodiment of the inflammatory bowel disease is a Crohn's disease. In one embodiment the disease, disorder or condition is a psoriasis. In one embodiment the disease, disorder or condition is a multiple sclerosis. In one embodiment the disease, disorder or condition is a rheumatoid arthritis. In one embodiment the disease, disorder or condition is a rejection of the transplanted organ. In another one the m aspect, the method further includes the introduction to the mammal a second therapeutic agent. In one aspect, the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, specific inhibitors of cyclooxygenase-2 (Mor-2), Leflunomide, gold-thioglucose, thiomalate gold, ourofino, sulfasalazin, hydroxyarginine, minocycline, agents against tumor necrosis factor-α (TNF-α), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, anti-allergic vaccines, antihistamine agents, antileukotriene agents, beta-agonists, theophylline, and anticholinergic agents. In another aspect, the second therapeutic agent selected from tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate or FTY720, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, beta-methasone, triamcinolone, beclomethasone, acetate fludrocortisone, acetate hypertension, aldosterone, aspirin, salicylic acid, hentaimovi acid, choline salicylate-magnesium, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluoropropene (fluorobiprofen), ibuprofen, Ketoprofen, nabutola (nabutone), Ketorolac, the tromethamine Ketorolac, naproxen, oxaprozin, diclofenac, etodolac, indomethacin is, sulindaka, tolmetin, meclofenamate, meclofenamate sodium, mefenamovoy acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, Leflunomide, gold-thioglucose, thiomalate gold, ourofino, sulfasalazin, hydroxyarginine, minocycline, infliximab, etanercept, adalimumab, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, anti-allergic vaccines, antihistamine agents, antileukotriene agents, beta-agonists, theophylline, and anticholinergic agents.

Also here is a way of inhibition associated with depo-controlled calcium intake (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal, comprising introducing the compound of the formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an interaction of, or modulates the level of, or binds to, or interacts with a protein of a mammalian STIM1 or protein of a mammalian STIM2.

Also here, a method for reducing the expression of cytokines by inhibition associated with depo-managed entrance of calcium activation of NFAT in a mammal, comprising the introduction of the value of the formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs. In one aspect, the compound of formula (I), (II), (IIA) or (IIB) modulates an interaction of, or modulates the level of, or binds to, or interacts with a protein of a mammalian STIM1 or protein of a mammalian STIM2. In one aspect, the cytokine is selected from interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β, IL-1 RA, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemia inhibitory factor (LIF), interferon, gamma-interferon (γ-IFN), B7.1 (CD80), V (70, CD86), tumor necrosis factor-alpha (TNF-α), TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail and factor that inhibits migration (MIF).

In one aspect, there is described the use of the compounds of formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs for the manufacture of drugs for the modulation of the activity depot-operated calcium channels (SOC channels) in a subject or for the treatment of a disease or condition in the subject, in which the useful modulation activity depot-operated calcium the channels (SOC channels). In one aspect, the compound of formula (I), (II), (IIA) or (IIB) inhibits depot-driven calcium intake (SOCE). In another aspect, the activity depot-operated calcium channels represents the activity of calcium channels activated by calcium release.

It also described the product, including packaging material, a compound of formula (I), (II), (IIA) or (IIB) or its composition, or its pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES, which is effective for inhibiting the activity of calcium channels activated by release of calcium (CRAC channels), or to treat, prevent or reduce the intensity of one or more than one symptom of the disease or condition, which is useful in the inhibition of the activity of calcium channels activated by release of calcium (CRAC channels), in the packaging material, and the label, which indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES is used for inhibiting the activity of calcium channels activated by release of calcium (CRAC channels), or to treat, prevent or reduce the intensity of one or more than one symptom or SOS is sustainability, which is useful in the inhibition of the activity of calcium channels activated by release of calcium (CRAC channels). In one aspect, the compound of formula (I), (II), (IIA) or (IIB) inhibits depot-driven calcium intake (SOCE).

In one aspect, there is described a compound of formula (IIA),

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl,1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3 -C8cycloalkyl, phenyl and benzyl.

In one embodiment R1represents hydrogen or C1-C6alkyl. In another aspect, R1represents hydrogen, methyl, ethyl, n-propyl or isopropyl. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic acid.

In another embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3With1-C6of alkyl, C1-C6foralkyl,1-C6heteroalkyl and C1-C6halogenoalkane.

In one embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CF3, -OH, -och3, -OCF3, methyl and ethyl.

In another embodiment the compound of formula (IIA) is a

In one aspect, there is described a compound of formula (IIB),

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, Csub> 1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

In one embodiment R1represents hydrogen or C1-C6alkyl. In yet another aspect, R1represents hydrogen, methyl, ethyl, n-propyl or isopropyl. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic acid.

In another embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3With1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane.

In the bottom of the embodiment R 4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CF3, -OH, -och3, -OCF3, methyl and ethyl.

In another embodiment the compound of formula (IIB) is selected from:

,,,,

Here we consider any combination of the groups described above for the different variables.

In one aspect, there is described a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder and a compound of formula (I), (II), (IIA) or (IIB) or its pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES.

In one aspect, it provides a pharmaceutical composition comprising an effective amount of the compounds proposed here, and pharmaceutically acceptable excipient. In another aspect of the proposed composition, optionally containing a second pharmaceutically active ingredient.

In certain embodiments it provides a pharmaceutical composition comprising: 1) a physiologically acceptable carrier, diluent and/or excipient; 2) one or more than one connection is described here.

In any of the above aspects of other embodiments, including the surrounding single injection of an effective amount of the compounds of formula (I), (II), (IIA) or (IIB), including other embodiments, in which: (1) the compound of formula (I), (II), (IIA) or (IIB) is administered once; (2) the compound of formula (I), (II), (IIA) or (IIB) is administered to the mammal multiple times over a period of time lasting one day; (3) continually; or (4) is constant.

In any of the above aspects are presented in other embodiments, multiple doses of an effective amount of the compounds of formula (I), (II), (IIA) or (IIB), including other embodiments, in which: (1) the compound of formula (I), (II), (IIA) or (IIB) is administered as a single dose; (2) the time between multiple introductions is every 6 hours; (3) the compound of formula (I), (II), (IIA) or (IIB) to impose the mammal every 8 hours. Other or alternative embodiments, the method includes the rest from drugs" (drug holiday), when the introduction of the compounds of formula (I), (II), (IIA) or (IIB) temporarily stop or temporarily decrease the input dose of the compounds of formula (I), (II), (IIA) or (IIB); when the "rest cure" the introduction of the compounds of formula (I), (II), (IIA) or (IIB) resume. The duration of the "vacation from medication can vary from 2 days to 1 year.

In one aspect, the compounds of formula (I), (II), (IIA) or (IIB)described herein is administered to a person. In some embodiments of compounds of formula (I), (II), (IIA) or (IIB)described herein are administered orally.

Connection, pre is defined here used for modulation of intracellular calcium. In one aspect, the compounds proposed here, modulate the activity of SOC channels. In one aspect, the compounds proposed here, modulate the activity of CRAC channels. In another aspect, compounds, proposed here, modulate the activity of proteins STIM. In another aspect, compounds, proposed here, modulate the activity of protein Orai. In another aspect, compounds, proposed here, modulate the functional interactions of proteins STIM protein Orai. In another aspect, compounds proposed here reduces the number of functional SOC channels. In another aspect, compounds proposed here reduces the number of functional CRAC channels. In one aspect, compounds described herein are inhibitors of SOC channels. In one aspect, compounds described herein are blockers CRAC channels.

In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) are selective inhibitors of SOCE. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) are selective inhibitors of the activity of CRAC channels.

Other objectives, features and advantages of the compounds, compositions, methods and uses described herein, will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples describe specific who's incarnation, they are presented only as an illustration, since various changes and modifications within the essence and scope of the invention will be clear to experts in the art from this detailed description.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Figure 1 shows the metabolic pathway of ICRACchannels.

Figure 2 shows that the compound 1 (2-(4-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid) inhibits the initial kinetics of the response associated with CRAC channels in cells RBL-2H3 dependent on concentration.

Figure 3 shows the results of processing cells RBL-2H3 connection 1. The activation of CRAC channels and subsequent effector cells RBL-2H3 induced by thapsigargin (TC)/tetradecanoylphorbol (TRA) and investigated the effects of compound 1 on the degranulation and release of TNF-alpha. Compound 1 inhibited the degranulation with IC50of 2.6 μm and inhibited the release of TNF-alpha with IC50the 3.3 ám.

Figure 4 shows the results of the analysis of degranulation in cells RBL-2H3. Induction TG/TPA for 2 hours in a balanced salt Hanks solution (HBSS) or HBSS+1% serum was preceded by a preliminary treatment with compound 1 for 10 minutes. In the absence of serum compound 1 inhibited the degranulation with an apparent IC50less than approximately 0.3 microns, while in the presence of sivaram and compound 1 inhibited the degranulation with IC 50approximately 1-3 microns.

Figure 5 shows the effects of compound 1 on SOCE, cell proliferation and secretion of IL-2 in T-cells of the rat. Compound 1 inhibited SOCE with IC50approximately 2.4 μm, inhibited cell proliferation with IC50about 4.3 μm and inhibited the secretion of IL-2 with IC50approximately 2.5 microns.

Figure 6 shows the results of inhibition induced concanavalin A (Con A) proliferation of embryonic T-cell human connection 1. Compound 1 inhibited Con A-induced proliferation of fetal T-cells with IC50near 3.7 ám.

7 shows the results of inhibition of the release of IL-2 in T-cells Jurkat connection 1. T-Jurkat cells stimulated by phytohemagglutinin (RNA) and TPA in the presence of compound 1. Compound 1 inhibited the release of IL-2 in T-cells Jurkat with IC50approximately 0.5 micron.

On Fig shows the selectivity profile of compound 1. Compound 1 is a selective inhibitor of SOCE.

Figure 9 shows the selectivity of compound 1 in respect of SOC channels compared to the potential-dependent calcium channels expressed in human cells SH-SY5Y.

Figure 10 shows the additive effects of compounds 1 and cyclosporin a in the inhibition of IL-2 secretion in T-cells Jurkat. T cells stimulated Jurkat using the ON/TPA to induce the secretion of IL-2.

Figure 11 shows the results of oral administration of compound 1 in a rat model of collagen-induced arthritis. In the same analysis of cyclosporine a, administered orally, resulted in reduced liver mass by 9%, while in rats, which were administered compound 1, reducing the weight of the liver were not observed.

On Fig shows the results of oral administration of compound 1 in a murine model of delayed-type hypersensitivity (DTH).

On Fig shows the results of processing cells NECK, sverkhekspressiya STIM1, compound 1 and 2-aminoethoxyethanol (2-ARV). Overexpression of STIM1 in cells NEC enhances the metabolic pathway of entry of Ca2+similar to endogenous SOCE (see Examples). Connection 1 blocks the signal STIM1-dependent entry of CA2+dependent on the concentration of way, and 2-ARV how amplifies this signal (at low concentrations)and inhibits it (in high concentrations).

On Fig shows the results of inhibition-dependent recombinant hOrai1/hSTIM1 entry of CA2+in stable cell connection 1 and connection 2.

On Fig shown that compound 1 and compound 2 inhibited Monster ICRACexpressed in cells stably sverkhekspressiya hOrai1/hSTIM1. Also shown for comparison are the effects of some compounds of the comparison.

On Fig shown that compound 1 inhibits combinatie Ca v1.2 CA2+-channels L-type.

On Fig shown bioavailability and half-life (T1/2) compound 1 in rats by oral administration.

On Fig shows the results of late rejection of skin grafts in Lewis rats, which were administered compound 1.

On Fig shows the results of plasma effects connection 1 within 24 hours after oral administration at a dose of 10 or 50 mg/kg Unless otherwise noted, each point represents the average of three samples.

On Fig shows the results of inhibition of inflammation compound 1 in rat model of ulcerative colitis inflammatory bowel disease (IBD).

On Fig shown bioavailability and T1/2compound 2 (2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid) in rats and the effect of oral input connection 2 in murine DTH model of inflammation.

DETAILED DESCRIPTION

Cellular calcium homeostasis is the result of the addition of the regulatory systems involved in the control of the levels and movements of intracellular calcium. Cellular calcium homeostasis, at least in part, provide the calcium-binding and movement of calcium into the cell and out of the cell through the plasma membrane and within the cell movement of calcium across membranes of intracellular organelles, including the endoplasmic reticulum, sarcoplasmatic reticulum, mitochondria and organelles of endocytosis, including endosome and complementary mechanism.

The movement of calcium across cell membranes is performed by the specialized proteins. For example, the calcium from the extracellular space may enter the cell through different calcium channels and sodium-calcium antiporters, and it is actively removed from the cell calcium pump and sodium-calcium antiporter. It is also possible release of calcium from internal depot through insectivorans and ryanodine receptors, and possible capture these organelles by calcium pumps.

Calcium can enter the cell through any of several General classes of channels, including, without limitation, the potential-dependent calcium channels (VOC channels), depo-operated calcium channels (SOC channels) and sodium-calcium antiporter operating in reverse mode. VOC channels activates membrane depolarization, and they are found in excitable cells such as nerve and muscle, and, for the most part, not found in newsbody cells. In some conditions the CA2+can enter the cells via the Na+-Ca2+-antiporter operating in reverse mode.

Endocytosis is another process by which cells can capture the calcium from the extracellular environment through endosome. In addition the group some cells, for example, exocrine cells, can release calcium through exocytosis.

Calcium concentration in the cytosol is exposed sustainable regulation, the level of calm estimate of about 0.1 μm in mammalian cells, while extracellular calcium concentration is typically about 2 mm. This sustainable regulation contributes to the transduction of signals into and within cells by transient calcium current through the plasma membrane and membranes of intracellular organelles. In the cells there are many intracellular calcium transport and buffer systems, contributing to the formation of intracellular calcium signals and maintaining a low concentration of calcium in the cytoplasm alone. In resting cells the main components involved in maintaining basal levels of calcium are calcium pumps and channels in the endoplasmic reticulum and the plasma membrane. Violation levels of calcium in the cytosol alone can affect the transmission of such signals and give rise to defects of a number of cellular processes. For example, cell proliferation involves a long sequence of calcium signals. Other cellular processes including, without limitation, secretion, signalling and fertilization include calcium with whom ginalization.

Cell surface receptors that activate phospholipase C (PLC), form a cytosolic CA2+signals from intra - and extracellular sources. The initial transient increase in [CA2+]i(intracellular calcium concentration) is the result of release of CA2+from the endoplasmic reticulum (ER)run by the PLC product, Inositol-1,4,5-triphosphate (IP3opening IP3receptors in ER (Streb et al. Nature, 306, 67-69, 1983). Then comes the next phase of a long entrance Sa2+across plasma membrane via specialized depot-operated calcium channels (SOC channels (in the case of immune cells SOC channels are calcium channels activated by release of calcium (CRAC channels)in the plasma membrane. Depot managed entry of CA2+(SOCE) is a process in which the devastation depot CA2+by itself activates CA2+-channels in the plasma membrane, facilitating the replenishment depot (Putney, Cell Calcium, 7, 1-12, 1986; Parekh et al., Physiol.Rev. 757-810; 2005). SOCE is not simply provides CA2+for replenishment depot, but can itself generate long CA2+signals, controlling such essential functions as gene expression, cell metabolism and exocytosis (Parekh and Putney, Physiol. Rev. 85, 757-810 (2005)).

In lymphocytes and mast cells with the Ah receptor activation antigen or Fc-receptors triggers the release of CA 2+from endocellular depots, which in turn leads to the influx of CA2+through CRAC channels in the plasma membrane. The subsequent increase of intracellular CA2+activates calcineurin, phosphatase, regulates the transcription factor NFAT. In resting cells, NFAT is phosphorylated and is located in the cytoplasm, but when dephosphorylating calcineurin NFAT moves into the nucleus and activates various genetic programs, depending on the conditions of stimulation and cell type. In response to infection and during graft rejection NFAT functions together with the transcriptional factor AP-1 (Fos-Jun) in the core of the "effector" T cells, transactivity through this cytokine genes, genes that regulate the proliferation of T-cells, and other genes that control the active immune response (Rao et al., Annu Rev Immunol., 1997; 15:707-47). On the contrary, in T-cells that recognize native antigens, NFAT is activated in the absence of AP-1 and activates a transcriptional program, known as "anergy", inhibiting autoimmune responses (Macian et al., Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002 Jun 14; 109(6):719-31). In a subclass of T cells, known as regulatory T-cells, the vast autoimmunity, mediated by self-reactive effector T cells, NFAT acts together with the transcription factor FOXP3, activating genes suppressor function (Wu et l., Cell, 2006 Jul 28; 126(2):375-87; Rudensky AY, Gavin M, Zheng Y. the Cell. 2006 Jul 28; 126(2):253-256).

The endoplasmic reticulum (ER) provides a set of processes. ER plays a role as a depot, and a drain of the agonist-sensitive CA2+in the lumen occurs folding/protein processing. There are a lot of CA2+-dependent protein chaperones ensure the correct folding of newly synthesized proteins and their direction according to the purpose. ER is also involved in the transport of vesicles, the release of stress signals, regulation of cholesterol metabolism and apoptosis. For many of these processes are needed intraluminal CA2+and violation of the folding of proteins, stress response ER and apoptosis can cause depletion of ER in respect of CA2+over long periods of time. Because of the role of ER as a source of CA2+it is clear that the content of CA2+ER should decrease after stimulation. However, to preserve the functional integrity of the ER, it is vital that the content of CA2+was reduced to too low or remained at a low level. Thus, fill ER CA2+is a Central process in all eukaryotic cells. Because the decrease in the content of CA2+in the ER activates depot-managed CA2+-channels in the plasma membrane believe that the main function of this metal the symbolic value of the entry path of CA 2+is to maintain levels of CA2+ER, necessary for the proper synthesis and folding of proteins. However, depo-managed CA2+-channels have other important functions.

Understanding depot-controlled calcium intake was provided electrophysiological studies, in which it was established that the process of emptying depot activated current CA2+in fat cells called current CA2+activated by release of CA2+or ICRAC. ICRACis not potential-activated, has an inner straightening and highly selective in respect of CA2+. Its found in several types of cells, primarily of hematopoietic origin. ICRACis not the only depot-driven shock, and at the present time it is clear that depo-driven inflow includes the family of CA2+permeable channels with different properties in different cell types. ICRACwas first described depo-controlled current CA2+and remains a popular model for studying depot-driven flow.

Depo-managed channels can be activated in any way with the devastation of the depot; apparently, the mechanism of devastation depot doesn't matter, the end result is the activation of depo-managed sign-Sa2+. Physiologically ind the Ktsia devastation depot is by increasing levels of IP 3or other CA2+releasing signals with subsequent release of CA2+from the depot. However, there are several other ways devastation depot. These methods include the following:

1) increased IP3in the cytosol (after stimulation of receptors or dialysis cytosole IP3by itself or related compounds belonging to the same class, such as nematerializiranih analog Ins(2,4,5)P3);

2) application of CA2+-ionophore of ionomycin to increase the permeability of the ER membrane;

3) dialysis of the cytoplasm by high concentrations of chelators CA2+etilenditiodiuksusnoi acid (EGTA) or 1,2-bis-2-aminophenoxyethanol-N,N,N,N-tetraoxane acid (VARTA), chelation of CA2+coming from the depot, preventing, thus, replenishment depot;

4) the effects of inhibitors of CA2+-adenosinetriphosphatase (CA2+-ATPase) sarcoplasmic/endoplasmic reticulum (SERCA), such as thapsigargin, cyclopiazonic acid and di-tert-butylhydroquinone preventing filling depo-ATPase P-type;

5) sensitization of receptors IP3the levels of InsP3alone such agents as thimerosal; and

6) introduction membranophones CA2+-of metal chelators, such as N,N,N,N-tetrakis(2-pyridylmethyl)Ethylenediamine (TPEN), directly to the depot.

what exploits its mass actions TPEN reduces the concentration of free CA 2+in the lumen, without changing the General content of CA2+at the depot so that there is a education signal that is dependent on the depletion of the depot.

These methods devastation depot are not without potential problems. The key property depot-managed sign-Sa2+is that the channels activates the decrease in the content of CA2+in depot, not the subsequent increase in concentration of CA2+in the cytoplasm. However, ionomycin and blockers SERCA pumps in most cases, cause an increase in the concentration of CA2+in the cytoplasm, as a consequence of depletion of the depot, and that the increase of CA2+may lead to the discovery of CA2+-activated cation channels permeable to CA2+. One way of avoiding such problems is to use agents in conditions, when the concentration of CA2+firmly keep to the high concentration of chelator of CA2+such as EGTA or VARTA.

Depo-controlled calcium intake

Reduced concentration of calcium in intracellular depot of calcium, such as the endoplasmic reticulum, resulting in the release of calcium, provides a signal to the influx of calcium from the extracellular environment into the cell. This influx of calcium, providing long "plateau" of increasing calcium concentration in the cytosol, in most cases not due to the potential head of the independent channels of the plasma membrane and does not include activation of calcium channels with calcium. This mechanism influx of calcium called capacitive calcium intake (SSE), the entrance of calcium-activated calcium release, depot-managed sign of calcium or calcium intake that is activated by depletion of the depot. Depo-controlled calcium intake can be written as ion current with special properties. This current is called the ISOC(depo-controlled current) or ICRAC(current-activated calcium release).

Electrophysiological analysis of depot-driven currents or currents activated by calcium release, reveals a special biophysical properties (see, for example, Parekh and Penner (1997) Physiol. Rev. 77:901-930) of these currents. For example, the current can be activated by depletion of intracellular depot of calcium (e.g., non-physiological activators such as thapsigargin, cyclopiazonic acid (CPA), ionomycin and WARTA, and physiological activators such as IP3) and can be selective for divalent cations such as calcium, compared with monovalent ions in physiological fluids or conditions, it can influence changes in the levels of calcium in the cytosol, and it can show a modified selectivity and conductivity at low extracellular concentrations of divalent cations. This current can be blocked or enhanced by 2-ARV (depending on concentration), and block p which means SKF96365 and Gd 3+and in most cases it can be described as calcium current, which is not strictly the potential-dependent.

Studies with fixing the potential on the fat cells and leukemic T-cells Jurkat it was found that the mechanism CRAC input associated with ion channel with special biophysical properties, including high selectivity for CA2+combined with the extremely low conductivity. Moreover, it was shown that CRAC channel meets the strict criteria depot-controllability, that is activated only by a reduction of CA2+in the ER, but not cytosolic CA2+or other intermediaries formed PLC (Prakriya et al., In Molecular and Cellular Insights into Ion Channel Biology (ed. Robert Maue) 121-140 (Elsevier Science, Amsterdam, 2004)).

Regulation depot-managed sign-calcium intracellular depot of calcium

Regulation depot-controlled calcium intake occurs through calcium levels in an intracellular depot of calcium. Intracellular depot of calcium can be characterized by sensitivity to agents that may be physiological or pharmacological triggering calcium release from the depot or inhibiting the supply of calcium in the depot. When describing the intracellular depot of calcium were studied by different cells, and depots were characterized as sensitive to different agents, including without limitation the, IP3and compounds affecting receptor IP3, thapsigargin, ionomycin and/or cyclic adenosine diphosphate-ribose (ADP-ribose, cADPR) (see, for example, Berridge (1993) Nature 361:315-325; Churchill and Louis (1999) Am. J. Physiol. 276:C426-C434; Dargie et al. (1990) Cell Regul. 1:279-290; Gerasimenko et al. (1996) Cell 84:473-480; Gromoda et al. (1995) FEBS Lett. 360:303-306; Guse et al. (1999) Nature 398:70-73).

The accumulation of calcium in the organelles depot, and endoplasmic sarcoplasmatic reticulum (SR; a specialized version of the endoplasmic reticulum in striated muscles), occurs through calcium ATPase sarcoplasmic-endoplasmic reticulum (SERCA), commonly called calcium pumps. When transmitting signals (i.e., upon activation of the channels of the endoplasmic reticulum to ensure the release of calcium from the endoplasmic reticulum into the cytoplasm) replenishment of calcium in the endoplasmic reticulum occurs through SERCA-pump cytoplasmic calcium that entered the cell from the extracellular environment (Yu and Hinkle (2000) J. Biol. Chem. 275:23648-23653; Hofere et al. (1998) EMBO J. 17:1986-1995).

Channels, releasing calcium, associated with the receptor IP3and redonna provide controlled release of calcium from endoplasmic and sarcoplasmic reticulum in the cytoplasm, which leads to transient increases in calcium concentration in the cytoplasm. the launch of calcium release, mediated by receptors IP3results IP3formed during the breakdown of phosphoinositides plasma membrane during the action of phospholipase C activated by the binding of agonist to the receptor plasma membrane associated G-protein. For the launch of calcium release mediated by receptors rudomina, results in the increase of calcium in the cytoplasm, and it is called calcium-induced calcium release (CICR). It is also possible to regulate the activity radonovich receptors (affinity against redonna and caffeine) cyclic ADP-ribose.

Thus, the levels of calcium in the depot and in the cytoplasm of the variable. For example, the free calcium ER may decrease from about 60-400 μm to approximately 1-50 microns in the processing of HeLa cells by histamine agonist associated with PLC histamine receptors (Miyawaki et al. (1997) Nature 388:882-887). Activation depot-controlled calcium intake is lowering the concentration of free calcium in the intracellular depot. Thus, depletion of calcium in the depot, as well as a concomitant increase in the concentration of calcium in the cytosol, can regulate depo-managed entry of calcium into cells.

Cytoplasmic buffer action in relation to calcium

Process activation signaling in cells by agonists can lead to sharp increases of pronic is emoti endoplasmic reticulum for calcium, for example, by opening channels associated with the receptor IP3and plasma membrane through depot-controlled calcium intake. These increases permeability for calcium are associated with increased calcium concentration in the cytosol, which can be divided into two components: the "peak" of calcium release from the endoplasmic reticulum when activated receptor IP3and the plateau phase, which represents the long-term increased levels of calcium, which is the result of the entrance of calcium into the cytoplasm from the extracellular environment. During stimulation of the intracellular concentration of free calcium alone, approximately 100 nm, can generally grow to more than 1 μm. Cell modulates these calcium signals endogenous calcium buffers, including physiological buffer action organelles such as mitochondria, endoplasmic reticulum and the Golgi complex. The capture of calcium by mitochondria through uniporter in the inner membrane due to the highly negative membrane potential of mitochondria and release of calcium occurs slowly through the sodium-dependent and sodium-independent antiporter and, in some cases, pores, causing the transition of the membranes of the mitochondria in a state of high permeability transition pore (PTP)). Thus, mitochondria mo is ut to act as calcium buffers, taking calcium during periods of activation and slowly releasing it later. The supply of calcium in the endoplasmic reticulum regulate the ATPase of the endoplasmic and sarcoplasmic reticulum (SERCA). The intake of calcium in the Golgi complex is mediated calcium transport ATPase, P-type (PMR1/ATP2C1). In addition, there is evidence of removal of a significant amount of calcium released by activation of receptors IP3of cells under the action of the calcium ATPase of the plasma membrane. For example, the calcium ATPase of the plasma membrane provides the main mechanism for the excretion of calcium in human T cells and Jurkat cells, although the excretion of calcium in human T-cells also promotes sodium-calcium exchange. In organelles, which is the depot of calcium, calcium ions can be associated with specialized calcium buffer proteins, such as, for example, calsequestrin, calreticulin and calnexin. In addition, the cytosol contains calcium buffer proteins, modulating calcium peaks and contributing to the redistribution of calcium ions. Thus, proteins and other molecules involved in any of these and other mechanisms through which can be lowered levels of calcium in the cytosol, are proteins involved in participating in and/or obespechivaushyi cytoplasmic buffer action in relation to calcium. Thus, cytoplasmic buffer action in relation to calcium makes it possible prolonged calcium influx through SOC channels. A significant increase in cytoplasmic CA2+or filling depot inactivate SOCE.

Subsequent events-mediated calcium intake

In addition to intracellular changes in calcium depot depot-driven calcium intake has an effect on many events, which is a consequence of or additions to the depot-managed change. For example, the influx of CA2+leads to activation of a large number of calmodulin-dependent enzymes, including serine phosphatase of calcineurin. Activation of calcineurin increased intracellular calcium leads to acute secretory processes, such as degranulation of mast cells. Activated mast cells release pre-formed granules that contain histamine, heparin, TNF-α and enzymes, such as β-hexosaminidase. For some cellular events such as proliferation of b - and T-cells required long calcineurin alarm for which you want prolonged increase in intracellular calcium. Calcineurin regulates several transcription factors, including NFAT (nuclear factor of activated T cells), MEF2 and NFkB. Transcription factors NFAT growthmania role in many types of cells, including immunocompetent cells. In immunocompetent cells NFAT mediates the transcription of a large number of molecules, including cytokines, chemokines and cell surface receptors. Transcriptional elements NFAT were found in the promoters of such cytokines as IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, and tumor necrosis factor-alpha (TNF-α), granulocyte colony-stimulating factor (G-CSF) and gamma-interferon (γ-IFN).

The activity of NFAT proteins regulates the degree of phosphorylation, and it, in turn, regulate as calcineurin and NFAT kinase. Activation of calcineurin by increased levels of intracellular calcium leads to dephosphorylate NFAT and its uptake into the nucleus. Defosfaurilirovnie NFAT masks the nuclear localization sequence NFAT and prevents it from entering the nucleus. Due to the strong dependence of its localization and activity of mediated calcineurin dephosphorylation of NFAT is a sensitive indicator of the levels of intracellular calcium.

Disease, disorder or condition

Clinical studies demonstrate that the CRAC channel is absolutely required for the activation of genes that underlie T-cell response to antigen. Prolonged calcium intake is necessary for lymphocyte activation and adaptive immune response. The entrance of calcium in lymphocytes occurs in the PE the first of all through CRAC channels. The increase of calcium leads to the activation of NFAT and the expression of cytokines necessary for the immune response. Inhibition of depo-managed calcium intake is an effective way of preventing the activation of T cells.

Inhibition of the activity of CRAC channels by the compounds described herein, such as compounds of formula (I), (IIA) and (IIB), provides a method of providing immunosuppressive therapy, as demonstrated by the elimination depo-managed calcium intake, was observed in patients with severe combined immunodeficiency (SCID). T-cells, fibroblasts and, in some cases, cells from patients with T-cell immunodeficiency, or SCID, which is the main defect in the activation of T cells demonstrate a pronounced defect depo-managed calcium intake (Feske et al. (2001) Nature Immunol. 2:316-324; Paratiseti et al. (1994) J. Biol. Chem. 269:32327-32335; and Le Deist et al. (1995) Blood 85:1053-1062). Patients with SCID no adaptive immune response, but without any violations or toxicity to major organs. The phenotype of patients with SCID shows that Inhibition of CRAC channels is an effective way of immunosuppression.

Diseases/disorders involving inflammation, and diseases/disorders associated with the immune system

Diseases or disorders that can be treated or prevented with the use of soy is ineni, compositions and methods proposed here include diseases and disorders involving inflammation and/or related to the immune system. These diseases include, without limitation, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, inflammatory diseases of the nervous system such as multiple sclerosis, and disorders of the immune system.

Activation of neutrophils (PMN) inflammation mediators partly due to the increased concentration of calcium in the cytosol. In particular, suppose that an important role in the activation of PMN plays depot-operated calcium influx. It has been shown that trauma increases depot-operated calcium influx in PMN (Hauser et al. (2000) J. Trauma-Injury Infection and Critical Care 48 (4):592-598), and long-lasting increase in the concentration of calcium in the cytosol due to enhanced depot-driven flow can modify the response to stimuli in combination with chemotaxonomy and to contribute to PMN dysfunction after injury. Thus, modulation of the concentration of cytosolic calcium in PMN through depot-operated calcium channels may be useful in regulation of inflammation-mediated PMN, and to preserve the function of the cardiovascular system after injury, shock or sepsis (Hauser et al. (2001) J. Leukocyte Biology 69 (1):63-68).

Calcium plays an important role in the activation of limpii the RC. Activation of lymphocytes, for example, antigenic stimulation leads to rapid increases in concentrations of free calcium within the cell and activation of transcription factors, including nuclear factor of activated T cells (NFAT), NF-KB, JNK1, MEF2 and CREB. NFAT is a key transcriptional regulator of the gene IL-2 (or other cytokines) (see, for example, Lewis (2001) Annu. Rev. Immunol 19:497-521). Prolonged increase in the level of intracellular calcium is necessary to maintain NFAT in a transcriptionally active state and depends on depo-managed calcium intake. Reduction or blockade of depo-controlled input of calcium in lymphocytes inhibits the calcium-dependent activation of lymphocytes. Thus, modulation of intracellular calcium and, in particular, depo-managed calcium intake (e.g., reduction, elimination depo-controlled input of calcium in lymphocytes may represent a method of treatment of disorders of the immune system or disorders related to the immune system, including, for example, chronic diseases/disorders of the immune system, acute diseases/disorders of the immune system, autoimmune and immunodeficiency diseases/disorders, diseases/disorders involving inflammation, rejection of transplanted organ and graft-versus-host, and changed (for example, hyperic is active) immune the responses. For example, treatment of treatment of autoimmune diseases/disorders may include reduction, blockade or elimination depo-controlled input of calcium in lymphocytes.

Examples of disorders of the immune system include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues), graft rejection, graft versus host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), heavy pseudoparalysis the gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.

Cancer and other proliferative diseases

The compounds of formula (I), (II), (II), (IIA) and (IIB), their compositions and the methods proposed here can be applied in connection with treatment of malignancies, including, without limitation, malignant neoplasms limport the molecular origin, gallbladder cancer, breast cancer, cancer of the colon, endometrial cancer, head and neck cancer, lung cancer, melanoma, ovarian cancer, prostate cancer and colorectal cancer. Depo-controlled calcium intake may play an important role in the proliferation of cancer cells (Weiss et al. (2001) the International Journal of Cancer 92 (6):877-882).

Inhibition of SOCE enough to prevent proliferation of cancer cells. A derivative of pyrazole, BTP-2, direct blocker of ICRACblocks SOCE and proliferation in Jurkat cells (as ZITT et al., J. Biol. Chem., 279, 12427-12437, 2004) and cancer cells of the colon. It was suggested that for long SOCE necessary mitochondrial capture of CA2+(Nunez et al., J. Physiol. 571.1, 57-73, 2006) and that the prevention of mitochondrial capture of CA2+leads to inhibition of SOCE (Hoth et al., P.N.A.S., 97, 10607-10612, 2000; Hoth et al., J. Cell. Biol. 137, 633-648, 1997; Glitsch et al., EMBO J. 21, 6744-6754, 2002). Stimulation of Jurkat cells induces long SOCE and activation of CA2+-dependent phosphatase calcineurin, dephosphorylates NFAT, stimulating expression of interleukin-2 and proliferation. The compounds of formula (I), (II), (IIA) and (IIB) inhibit SOCE and can be applied in the treatment of cancer or other proliferative diseases or conditions.

Diseases and disorders of the liver

Diseases or disorders that can be treated or prevented using the compounds is ormula (I), (II), (IIA) or (IIB), their compositions and methods proposed here include liver diseases and disorders, or diseases and disorders of the liver. These diseases or disorders include, without limitation, damages the liver, for example, due to transplantation, hepatitis and cirrhosis.

It was shown value depot-controlled calcium intake in chronic liver disease (Tao et al. (1999) J. Biol. Chem., 274(34):23761-23769), as well as damage during transplantation after cold preservation - heat of re-oxygenation (Elimadi et al. (2001) J. Am Discrimination, 281(3 Part 1):G809-G815).

Diseases and disorders of the kidney

Diseases or disorders that can be treated or prevented using the methods proposed here include diseases and disorders of the kidneys or kidney diseases and disorders. Hyperplasia mesangial cells is often a key feature of such diseases and disorders. Such diseases and disorders may be due to immunological or other mechanisms of injury, including IgA nephropathy (IgAN), membranosa-proliferative glomerulonephritis or lupus nephritis. Violations of monitoring replication mesangial cells also seems to play a key role in the pathogenesis of progressive renal failure.

Update mesangial cells in the normal adult kidney is slogo very slightly, and the intensity of the pack is less than 1%. An important feature of the diseases of glomeruli/kidney is metangula hyperplasia due to increased intensity of proliferation or reduced loss mesangial cells. The result of stimulating the proliferation mesangial cells without cell loss, for example, due to mitogenic stimulation may be mesangiocapillary glomerulonephritis. The data indicate that the growth regulators mesangial cells, in particular growth factors may act by regulating depot-operated calcium channels (MA et al. (2001) J Am. Soc. of Nephrology, 12:(1) 47-53). Modulators depot-driven influx of calcium may be useful in the treatment of diseases of the glomeruli inhibition of proliferation mesangial cells.

Depo-operated calcium channels

Clinical studies demonstrate that the CRAC channel, the type of SOC channel, which is absolutely required for activation of genes that underlie T-cell response to antigen (Partiseti et al., J Biol. Chem., 269, 32327-32335, 1994; Feske et al., Curr. Biol. 15, 1235-1241, 2005). SOCE can contribute directly to increased levels of CA2+in the cytosol ([CA2+]i), as in T-lymphocytes, where CRAC channels generate long CA2+the signals required to control the expression of genes that underlie the activation of T cells by antigen. Long entrance calcium is required for lymphocyte activation and adaptive immune response. The entrance of calcium in lymphocytes occurs mainly through CRAC channels. Elevated levels of calcium lead to activation of NFAT and the expression of cytokines necessary for the immune response.

CRAC channel has a distinctive biophysical characteristic quantifiable dependence of the depot, and performs an essential function in T-cells. Studies have shown that CRAC channels formed by two protein components that interact with the formation of CRAC channels. In the Assembly of the CRAC channel are two functional component, STIM1 and Orai1. STIM1 (molecule stromal interaction 1) was identified as Sa2+sensor in the ER mammals (Liou, J. et al. Curr. Biol. 15, 1235-1241 (2005); Roos, J. et al. J. Cell Biol. 169, 435-445 (2005); WO 20041078995; US 2007/0031814). Orai1/CRACM1 was identified as a component of the CRAC channel mammals (Feske, S. et al. Nature 441, 179-185 (2006); Vig, M. et al. Science 312, 1220-1223 (2006); Zhang, S. L. et al. Proc. Natl Acad. Sci. USA 103, 9357-9362 (2006)).

STIM1 is Sa2+sensor at the depot CA2+ER, moving in response to the depletion of the depot in the ER departments close to the plasma membrane. Orai1 is a subunit of CRAC channel, forming pores in the plasma membrane. It was shown that each of the two membrane proteins STIM1 and Orai1 is required for the activation of CRAC channels.

The expression of both STIM1 and Orai1 in embryonic cells, human kidney 293 (cells NEC) leads to Voss is yavlenie functional CRAC channels. Expression of Orai1 in itself greatly reduces depot-managed sign-Ca2+in cells NC and CA2+-current activated by release of Ca2+(ICRAC), in cells basophilic leukemia rats. However, when expression simultaneously with depo-sensory protein STIM1 Orai1 causes a strong increase in SOCE, increasing the rate of entry of CA2+to 103 times. This input is fully depot-dependent, since the same coexpressed does not cause measurable depot-independent entry of CA2+. Blocker depo-managed channels, 2-aminoethoxyethanol, completely blocking the entrance. It is known that STIM proteins mediate sensory functions in relation to depot Ca2+and convergence of the membrane of the endoplasmic reticulum and plasma membrane, lacking its own channel properties. Orai1 is part of the channel of the plasma membrane, providing access Sa2+. Inactivation of CRAC channels by overexpression of Orai1 reflects the required stoichiometry STIM1 and Orai1 (Soboloff et al., J. Biol. Chem. Vol.281, no. 30, 20661-20665, 2006).

Protein molecules stromal interaction (STIM)

When screening for RNA interference (RNAi) in S2 cells Drosophila using thapsigargin-activated entry of CA2+as a token depot-operated calcium channels one gene that encodes a protein molecule stromal interaction (tim), led to significantly reduced input of Ca2+(Roos, J. et al. J. Cell Biol. 169, 435-445, 2005). There are also two homologue Stim in mammalian cells, STIM1 and STIM2, each of which, apparently dispersed everywhere (Williams et al., Biochem J. 2001 Aug 1; 357(Pt 3):673-85). STIM1 is Sa2+sensor ER depo-managed sign-Sa2+. STIM1 is a membrane protein type I mass of 77 kDa with several predicted domains of the protein interaction or signaling and is located predominantly in the ER, but also to some extent in the plasma membrane.

STIM1 knockdown by RNAi led to a significant reduction of ICRACin T-cells Jurkat and depo-managed sign-Sa2+in the epithelial cells NECK cells and neuroblastoma SH-SY5Y. However, knockdown of closely related STIM2 had no effect. These results indicate the important role of STIM (Drosophila) and STIM1 (mammals) in the activation mechanism depo-managed channels. It is unlikely that STIM1 was depo-managed channel itself. He doesn't have a pipe-like sequence, and overexpression of the protein is only slightly enhances the entrance of CA2+. STIM1 is located both on the plasma and intracellular membranes such as the ER (Manji et al., Biochim Biophys Acta. 2000 Aug 31; 1481 (1): 147-55. 2000). The sequence of the protein suggests that it permeates the membrane once, when it is his NH 2-end oriented to the ER lumen or extracellular space. NH2the end contains a domain type EF-hand and functions as the CA2+sensor in the ER. Protein contains the domains of interaction between protein-protein, namely the domain helix-helix in the cytoplasm and sterile a motif (SAM) in the ER (or extracellular space), both of which are close to the predicted transmembrane domain. STIM1 is capable of oligomerization, and thus, the protein in the ER and the plasma membrane can interact by linking two molecules (Roos, J. et al. J. Cell Biol. 169, 435-445 (2005)).

When fluorescence total internal reflection (TIRF) and confocal microscopy revealed that STIM1 dispersed throughout the ER with full depot CA2+but with the depletion depot is redistribution at a single point near the plasma membrane. Despite the fact that the redistribution of STIM1 in the connection region ER is slow (Liou, J. et al. Curr. Biol. 15, 1235-1241 (2005); Zhang, S. L. et al. Nature 437, 902-905 (2005), ahead of the opening of CRAC channels for a few seconds (Wu et al., J. Cell Biol. 174, 803-813 (2006)) and, thus, is fast enough to be an important stage in the activation of CRAC channels.

It was suggested that the depletion depot causes the embedding of STIM1 to the plasma membrane, where it can control depo-managed entry of calcium through CRAC channels (Zhang, S.L. et al. Nature 437, 902-905 (2005); Spassova, M. A. et al. Proc. Natl Acad. Sci. USA 103, 4040-4045 (2006)).

A decisive proof that STIM1 is Sa2+sensor for SOCE, is that mutation of the predicted CA2+-binding residues of the structural motif, EF-hand, which is expected to reduce its affinity in respect of Ca2+and, thus, will simulate a state of exhaustion depot, causes spontaneous redistribution of STIM1 a certain point and start constitutive influx of Ca2+through SOC channels, even when filled depot (Spassova, M. A. et al. Proc. Natl Acad. Sci. USA 103, 4040-4045 (2006); Liou, J. et al. Curr. Biol. 15, 1235-1241 (2005)).

Orai proteins

Orai1 (also known as CRACM1) is a widely expressed protein of the plasma membrane by mass of 33 kDa with 4 transmembrane domains and without significant sequence homology with other ion channels (Vig, M. et al. Science 312, 1220-1223 (2006); Zhang, S. L. et al. Proc. Natl Acad. Sci. USA 103, 9357-9362 (2006)).

In studies of T cells from patients-people with the syndrome severe combined immunodeficiency (SCID), where the activation of T-cell receptors or depletion depot does not activate the input Ca2+it was shown that the reason for this is the one point mutation in Orai1 (Feske, S. et al. Nature 441, 179-185 (2006)).

There are other homologues Orai mammals, for example, Orai2 and Orai3, however, their function is not clear. Orai2 and Orai3 can demonstrate SOC-channels with overexpression together with STIM1 in SOME cells (Mercer, J. .et al. J. Biol. Chem. 281, 24979-24990 (2006)).

Evidence that Orai1 is a part of the pores of the CRAC channel were obtained in studies of mutagenesis Orai1. The selectivity of CRAC channel in relation to ions of Ca2+was demonstrated by mutations or Glu 106, or Glu 190, which weakened the ability to bind Ca2+by blocking the permeability in relation to monovalent cations (similar to the mechanisms described for the voltage-dependent CA2+channels) (Yeromin, A. V. et al. Nature 443, 226-229 (2006); Vig, M. et al. Curr. Biol. 16, 2073-2079 (2006); Prakriya, M. et al. Nature 443, 230-233 (2006)).

Neutralization of the charge on a pair of asparagine in the loop I-II (Asp 110 and Asp 112) reduces the blockade Gd3+and the blockade of the output current of extracellular Ca2+, indicating that these negatively charged sites may promote the accumulation of polyvalent cations near the entrance to the pore.

The currents observed in overexpression of Orai1 very similar to the ICRAC. and considering the fact that Orai1 may form multimeric (Yeromin, A. V. et al. Nature 443, 226-229 (2006); Vig, M. et al. Curr. Biol. 16, 2073-2079 (2006); Prakriya, M. et al. Nature 443, 230-233 (2006)), it is likely that native CRAC channel is either of multimer Orai1 alone or in combination with closely related subunits Orai2 and/or Orai3.

Functional depo-operated calcium channels

Description SOC channels was largely obtained through one type of the SOC channel, CRAC channel. The activity of CRAC channels stimulates the reduction of CA2+in the lumen of the ER, which is combined with the opening of CRAC channels in the plasma membrane through the action of STIM1 and Orai1. STIM1 detects the depletion of Ca2+causing its accumulation in the transitional ER near the plasma membrane. The study is based on TIRF CA2+imaging to determine the location of open CRAC channels was observed that increasing [CA2+]ilocalized in the same place and point STIM1, directly indicating that the opening of CRAC channels occurs only in the immediate vicinity of these places (Luik et al, J. Cell Biol. 174, 815-825 (2006)).

In cells with simultaneous expression of both STIM1 and Orai1 exhaustion depo causes the transition of Orai1 by itself dispersed from distribution to accumulation in the plasma membrane STIM1 directly opposite, allowing STIM1 to activate the channel (Luik et al., J. Cell Biol. 174, 815-825 (2006); Xu, P. et al. Biochem. Biophys. Res. Commun. 350, 969-976 (2006)). Thus, CRAC channels are formed opposed to clusters of STIM1 in the ER and Orai1 in the plasma membrane, separated by a narrow gap of cytosole. Connecting the gap (approximately 10-25 nm) can be quite small for protein-protein interaction. This supports the fact that the possibility of simultaneous thus sverhagressivnym STIM1 and Orai1 (Yeromin, A. V. et al. Nature 443, 226-229 (2006);Vig, M. et al. Curr. Biol. 16, 2073-2079 (2006)).

Thus, STIM1 and Orai1 interact, either directly or as members of a complex of several proteins. Confirmation of this was observed in one study, when the expression of cytosolic part of STIM1 in itself was enough to activate CRAC channels (Huang, G. N. et al. Nature Cell Biol. 8, 1003-1010 (2006)), and the effects of removing the ERM/spiral-spiral and other C-terminal domains suggest the value in the formation of STIM1 clusters and activation of SOC channels (Baba, Y. et al. Proc. Natl Acad. Sci. USA 103, 16704-16709 (2006)). On the luminal side of STIM1 deleting Sa2+in vitro selection EF-SAM forms dimers and multimer higher order, indicating that oligomerization of STIM1 may be early stage depot-driven calcium activation (Stathopulos et al., J. Biol. Chem. 281, 35855-35862 (2006)).

The compounds of formula (I), (II), (IIA) and (IIB)described herein modulate intracellular calcium, such as inhibition or reduction of SOCE and/or ICRAC. Modulation by compounds of formula (I), (II), (IIA) and (IIB) can lead to many effects, such as, without limitation, protein binding, interaction with the protein, or modulation of interactions, activities, levels or any physical, structural or other property of a protein involved in the modulation of intracellular calcium (e.g., STIM protein and/or an Orai protein).

For example, how about Enki binding or interaction of the investigational agent with the protein, involved in the modulation of intracellular calcium include nuclear magnetic resonance (NMR), mass spectroscopy, fluorescence spectroscopy, scintillation analyses of convergence, analysis of surface plasma resonance and others. Examples of ways to assess the modulation of interactions, activities, levels or any physical, structural or other property of a protein involved in the modulation of intracellular calcium include, without limitation, analyses resonance energy transfer fluorescence (FRET-analyses to estimate the effects of the interaction of proteins, NMR, x-ray crystallography and circular dichroism to assess effects on protein interactions and on the physical and structural properties of the protein, and assays of activity that are appropriate to assess the specific activity of the protein.

The monitoring or assessment of effects on intracellular calcium

When monitoring or assessing the effect of the compounds of formula (I), (II), (IIA) or (IIB) on intracellular calcium in any of the methods of screening/identification described herein or known in the art, may be made a direct or indirect evaluation or measurement of cellular calcium (including cytosolic calcium and calcium intracellular organelles or compartments) and/or move it ions into, within or out of the cell, organelles, depot calc what I or part thereof (for example, membrane). Described here and/or in the art known for the many ways of assessing the levels of calcium and displacement or ion current. Specific applicable method and conditions used can depend on what specific aspect of intracellular calcium monitorium or appreciate. For example, as described herein, are known and can be used reagents and conditions to assess exactly depot-controlled calcium intake, levels of calcium in the cytosol alone, buffer action in relation to calcium and levels of calcium in intracellular organelles and depot of calcium, capture them, and calcium fluxes from them. The effect of the compounds of formula (I), (II), (IIA) or (IIB) on intracellular calcium can be monitored or assessed using, for example, cells, intracellular organelles or compartments depot calcium, membranes (including, for example, areas separated membrane and the lipid bilayer) or free cell analysis system (for example, membrane vesicles from normal location of the lipid layers). In most cases, some aspect of intracellular calcium monitorium or appreciate in the presence of an investigational agent and compared to a control, such as intracellular calcium in the absence of an investigational agent.

Methods of modulating intracellular calcium

Modulation inside the cellular calcium can represent any change or correction of intracellular calcium, including, without limitation, changes in the concentration or level of calcium in the cytoplasm and/or intracellular organelles depot of calcium, for example, the endoplasmic reticulum, the change in the movement of calcium inside, from and within cells or intracellular depot of calcium or organelles, change the location of calcium within cells and the change in the kinetics or other properties of calcium currents inside, from and within cells. In certain embodiments, the modulation of intracellular calcium may include a change or correction of, for example, reduction or inhibition, depo-managed sign-calcium buffer action against cytosolic calcium, movement of calcium inside, out of or within an intracellular depot of calcium or organelles, or levels of calcium in them, and/or basal levels of calcium in the cytosol, or levels of calcium in the cytosol alone. In some embodiments, the modulation of intracellular calcium may include a change or correction receptor-mediated movement of ions (e.g. calcium), movement of ions (e.g. calcium), managed by the second intermediary, the influx of calcium into the cell or its outflow from the cell and/or capture of ions (e.g. calcium) or their release from intracellular compartments, including, for example, endosome and complementary mechanism.

In one aspect, compounds description is installed here modulate intracellular calcium, such as, without limitation, modulation (e.g., decreasing or inhibiting) the activity of SOC channels, such as inhibition of the activity of CRAC channels (e.g., inhibition of ICRACthe inhibition of SOCE), in the cell of the immune system (e.g., a lymphocyte, a white blood cell, T-cell, B-cell), fibroblast (or cell that has the origin from fibroblast) or the cell of the epidermis, dermis, or skin (e.g., keratinocytes). Phase modulation of one or more than one protein involved in the modulation of intracellular calcium (e.g., STIM protein and/or protein Orai), may include, for example, reduce the expression, activity, function and/or molecular interactions of protein. For example, if the cell shows increased levels of calcium or lack of regulation aspect modulation of intracellular calcium, such as depo-managed calcium intake, the modulation may include a lower level of expression, activity or function, or molecular interactions of protein, such as STIM protein and/or protein Orai.

Treatment

Here, a method of modulation of the activity depot-operated calcium channels (SOC channels), comprising bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I) or its pharmaceutical preparations is automatic acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2represents aryl, benzothiazyl, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C3-C6cycloalkyl,1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl, C2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl,1-C6heteroalkyl,1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O) N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

In one embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where the bringing into contact occurs in vitro.

In one embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where the bringing into contact occurs in vivo.

In yet another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part with the connection forms of the crystals (I), where the compound of formula (I) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one part of a complex depot-controlled calcium channel selected from a family of protein molecules stromal interaction (STIM).

In another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I)where the compound of formula (I) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIM1 or STIM2.

In another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where modulation of the activity depot-operated calcium channels in the compound of formula (I) inhibits depot-driven calcium intake (SOCE).

In yet another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where complexType-controlled calcium channel is a complex calcium channel, activated by the release of calcium (CRAC channel).

In another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where modulation of the activity of calcium channels activated by release of calcium (CRAC channels), a compound of formula (I) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels.

In yet another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where R1represents hydrogen or C1-C6alkyl.

In one embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where R4selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; 2-triptoreline; 3-triptoreline; and 4-trifloromethyl.

In another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where R2selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; and bestien-2-Il.

In yet another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where R2represents hydrogen, methyl, ethyl, n-propyl or isopropyl.

In another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where 2selected from phenyl, 3-ftoheia; 4-ftoheia; 4-chlorphenyl; 4-bromophenyl; 4-jodene; 3-methylphenyl; 3-methylphenyl; and bestien-2-yl.

In yet another embodiment, a method of modulation of the activity depot-operated calcium channels, comprising the bringing into contact of the complex depot-controlled calcium channel (SOC-channel) or part thereof with a compound of formula (I), where R4selected from phenyl; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 4-bromophenyl; 4-methylphenyl; 3,4-dimetilfenil; and 4-trifloromethyl.

Also here, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2represents aryl, benzothiazyl, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C3 -C6cycloalkyl,1-C6heteroalkyl,1-C6halogenoalkane, tetrazolyl, C2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8 cycloalkyl, phenyl and benzyl.

In one embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs where the compound of formula (I) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one component of the complex calcium channel activated by calcium release (CRAC channel), selected from the family of protein molecules stromal interaction (STIM).

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs where the compound of formula (I) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with STIM1 or STIM2.

In yet another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, including the surrounding introduction of the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where modulation of the activity of calcium channels activated by release of calcium (CRAC channels), a compound of formula (I) inhibits depot-driven calcium intake (SOCE).

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where modulation of the activity of calcium channels activated by release of calcium (CRAC channels), a compound of formula (I) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels.

In yet another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs where the compound of formula (I) inhibits SOCE with IC50less than 10 microns.

In another embodiment, a method of modulating the activity of calcium channels activated by release of Kal the Oia (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs where the compound of formula (I) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels in a concentration of less than 10 microns.

In yet another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane.

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R1represents the waters of the genus or C 1-C6alkyl.

In one embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C1-C6heteroalkyl and C1-C6halogenoalkane.

In yet another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R1represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, m-pentyl or hexyl.

In one embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutical preparations is automatic acceptable MES or pharmaceutically acceptable prodrugs, where R1represents H, methyl or ethyl.

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -CF3, -OH, -OMe, -OCF3, methyl and ethyl.

In yet another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -OH, -CF3, -OCF3, -OMe, methyl and ethyl.

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES is or pharmaceutically acceptable prodrugs, where R4selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; 2-triptoreline; 3-triptoreline; and 4-trifloromethyl.

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; and bestien-2-Il.

In yet another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising an introduction soybean is inane formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2selected from phenyl, 3-ftoheia; 4-ftoheia; 4-chlorphenyl; 4-bromophenyl; 4-jodene; 3-methylphenyl; 3-methylphenyl; and bestien-2-yl.

In another embodiment, a method of modulating the activity of calcium channels activated by release of calcium (CRAC channels), in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R4selected from phenyl; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 4-bromophenyl; 4-methylphenyl; 3,4-dimetilfenil; and 4-trifloromethyl.

In one aspect, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2is the Wallpaper aryl, sensational, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl, C2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected the C C 1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

In one embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs where the compound of formula (I) modulates an activity of, modulates an interaction of, or binds to, or interacts with a protein of a mammalian STIM1 or protein of a mammalian STIM2.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the disease, disorder or condition in a mammal selected from diseases/disorders involving inflammation, g is Aerolineas, uveitis, diseases or disorders of the liver, diseases or disorders of the kidneys, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, rejection of transplanted organ, allogeneic or xenogeneic transplantation, graft rejection, graft versus host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, heavy pseudoparalysis the gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, multiple sclerosis, Sjogren syndrome, and autoimmune diseases or disorders.

In yet another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the disease, disorder or condition is s represents rheumatoid arthritis.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the disease, disorder or condition is a psoriasis.

In one embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the disease, disorder or condition is an inflammatory bowel disease.

In another embodiment of the inflammatory bowel disease is a nonspecific ulcerative colitis.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or f is matemticas acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the disease, disorder or condition is a rejection of the transplanted organ.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the disease, disorder or condition is a multiple sclerosis.

In yet another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, optionally including the introduction to the mammal a second therapeutic agent.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium CA is Alov, includes introduction to the mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, specific inhibitors SOH-2, Leflunomide, gold-thioglucose, thiomalate gold, ourofino, sulfasalazin, hydroxyarginine, minocycline, agents against TNF-α, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, anti-allergic vaccines, antihistamine agents, antileukotriene agents, beta-agonists, theophylline, and anticholinergic agents.

In yet another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the second therapeutic agent selected from tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate or FTY720, prednisone, cortisone acetate, prednisolone, methylprednisolone is, dexamethasone, betamethasone, triamcinolone, beclomethasone, acetate fludrocortisone, acetate hypertension, aldosterone, aspirin, salicylic acid, hentaimovi acid, choline salicylate-magnesium, choline salicylate, choline salicylate-magnesium, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluoropropene, ibuprofen, Ketoprofen, nabutola (nabutone), Ketorolac, tromethamine Ketorolac, naproxen, oxaprozin, diclofenac, etodolac, indometacin, sulindaka, tolmetin, meclofenamate, meclofenamate sodium, mefenamovoy acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, Leflunomide, gold-thioglucose, thiomalate gold, ourofino, sulfasalazin, hydroxyarginine, minocycline, infliximab, etanercept, adalimumab, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, anti-allergic vaccines, antihistamine agents, antileukotriene agents, beta-agonists, theophylline, and anticholinergic agents.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, including centuries the decline in the mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R1represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl or hexyl.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R1represents H, methyl or ethyl.

In one embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -CF3, -OH, -OMe, -OCF3, methyl and ethyl.

In yet another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of AK is Yunosti depot-operated calcium channels, includes introduction to the mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -OH, -CF3, -OCF3, -OMe, methyl and ethyl.

In one embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R4selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; 2-triptoreline; 3-triptoreline; and 4-trifloromethyl.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, wherein polizeirevier activity depot-operated calcium channels, includes introduction to the mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; and bestien-2-Il.

In another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, comprising the administration to a mammal the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R2selected from phenyl, 3 - ftoheia; 4-ftoheia; 4-chlorphenyl; 4-bromophenyl; 4-jodene; 3-methylphenyl; 3-methylphenyl; and bestien-2-yl.

In yet another embodiment, a method of treatment of disease, disorder or condition in a mammal, which is useful in the inhibition of the activity depot-operated calcium channels, including the introduction of melicope the surrounding of the compounds of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where R4selected from phenyl; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 4-bromophenyl; 4-methylphenyl; 3,4-dimetilfenil; and 4-trifloromethyl.

Also here is a way of inhibition associated with depo-controlled calcium intake (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2represents aryl, benzothiazyl, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C3-C6cycloalkyl,1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl, C2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R , -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

In one embodiment, a method for inhibition associated with depo-controlled calcium intake (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal, comprising introducing the compound of the formula (I) or it is pharmaceutically acceptable salts, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs where the compound of formula (I) modulates an interaction of, or modulates the level of, or binds to, or interacts with a protein of a mammalian STIM1 or protein of a mammalian STIM2.

In another aspect, a method for reducing the expression of cytokines by inhibition associated with depo-managed entrance of calcium activation of NFAT in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2represents aryl, benzothiazyl, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl, C2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8 , -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl,1-C6foralkyl,1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

In another embodiment, a method for reducing the expression of cytokines by inhibition associated with depo-managed entrance of calcium activation of NFAT in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically PR is integral to the MES or pharmaceutically acceptable prodrugs, where the compound of formula (I) modulates an interaction of, or modulates the level of, or binds to, or interacts with a protein of a mammalian STIM1 or protein of a mammalian STIM2.

In yet another embodiment, a method for reducing the expression of cytokines by inhibition associated with depo-managed entrance of calcium activation of NFAT in a mammal, comprising introducing the compound of the formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs, where the cytokine is selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β, IL-1 RA, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemia inhibitory factor (LIF), interferon, gamma-interferon (γ-IFN), V (CD80), V (70, CD86), TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, ligand CD27, CD30 ligand, 4-1BBL, Trail and factor that inhibits migration (MIF).

Connections

Compounds described herein modulate intracellular calcium, and can be used in the treatment of diseases or conditions where modulation of extracellular calcium has a beneficial effect. In one embodiment of the compounds described herein modulate depot-driven calcium intake. In one embodiment of compounds of formula (I), (I), (IIA) or (IIB) interrupt the Assembly of SOCE units. In another embodiment of the compounds of formula (I), (II), (IIA) or (IIB) alter the functional interactions of proteins that form complexes depot-operated calcium channels. In one embodiment of compounds of formula (I), (II), (IIA) or (IIB) alter the functional interactions of STIM1 and Orai1. In other embodiments of compounds of formula (I), (II), (IIA) or (IIB) are blockers then SOC channels. In other embodiments of compounds of formula (I), (II), (IIA) or (IIB) are blockers then CRAC channels.

In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) inhibits electrophysiological current (Isoc)directly associated with activated SOC channels. In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) inhibits electrophysiological current (ICRAC)directly associated with activated CRAC channels.

Diseases and disorders which may be useful for modulation of intracellular calcium include, without limitation, a disease associated with the immune system (e.g., autoimmune disease), a disease or disorder involving inflammation (e.g. asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, inflammatory diseases of the nervous system, multiple sclerosis and Rosstroy the VA immune system), cancer and other proliferative diseases, kidney disease and liver disease. In one aspect, compounds described herein may be used as immunosuppressants to prevent rejection of the transplant, rejection in allogenic or xenogenic transplantation (organ, bone marrow, stem cells, other cells and tissues), graft versus host. Rejection of transplanted organ can be the result of the transplantation of tissues or organs. Graft-versus-host may be the result of bone marrow transplantation or stem cells.

Compounds described herein modulate the activity or modulate an interaction of, or bind to, or interact with at least one part of a protein complex depot-controlled calcium channel. In one embodiment of the compounds described herein modulate the activity or modulate an interaction of, or bind to, or interact with at least one part of a protein complex calcium channel activated by calcium release. In one aspect, compounds described herein reduce the level of functional complexes depot-operated calcium channels. In one aspect, compounds described herein reduce the level of activated complexes depot-managed calcavecchia. In one aspect of the complexes depot-operated calcium channels are complexes of calcium channels activated by calcium release.

The compounds described herein for treating a disease or disorder, when administered to a subject with a disease or disorder effectively reduce, alleviate or eliminate a symptom manifestations of the disease or disorder. Compounds described herein can also enter the subject, Prednisolonum to the disease or disorder that has no symptoms symptom of the disease or disorder, and thus they prevent or delay the development of symptoms. The agent may have such effects by itself or in combination with other agents or can function, enhancing therapeutic effect of another agent.

Compounds described herein, their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvate modulate intracellular calcium and can be used to treat patients in whom modulation of extracellular calcium provides a useful effect.

In one aspect, there is described a compound of formula (I) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug,

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R2represents aryl, benzothiazyl, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -CON(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl,1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8/sup> , -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl.

For all embodiments, the substituents can be selected from a subgroup of the listed alternatives. For example, in some embodiments, R1represents hydrogen or C1-C6alkyl. In other embodiments, R1represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl or hexyl. In other embodiments, R1represents H, methyl or ethyl. In some embodiments, R1represents N. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic acid.

In some embodiments, R2represents phenyl, naphthyl or benzothiazyl, where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8With1-C6of alkyl, C1-C6heteroalkyl and C1-C6halogeno the Qila.

In some embodiments, R2possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C1-C6halogenoalkane, tetrazolyl,1-C6geterotsiklicheskie, phenyl, -N(R9)2, -CO2R9, -C(=O)R8. In some embodiments, R2possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OCF3, -OMe, -OEt, -OiPr, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, -NH2, -N(Me)2, -CO2H, -CO2Me and-CO2Et. In other embodiments, R2possibly substituted by 1 or 2 substituents selected from-NH(CO)CH3, propyl, -CF3, methyl, ethyl, -SO2CH3, -CN, or-och3.

In some embodiments, R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8C1-C6of alkyl, C1-C6heteroalkyl and C1-C6halogenoalkane. In some embodiments, R2represents phenyl or sensational; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -OH, -CF3, -OCF3, -OMe, methyl, ethyl, isopropyl and tert-butyl. In some the embodiments, R 2selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimetilfenil; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; and bestien-2-sludge. In other embodiments, R2selected from phenyl, 3-ftoheia; 4-ftoheia; 4-chlorphenyl; 4-bromophenyl; 4-jodene; 3-methylphenyl; 3-methylphenyl; and bestien-2-yl.

In some embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane. In other embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -CF3, -OH, -OMe, -OCF3, methyl and ethyl. In other embodiments, R4selected from phenyl; 2-ftoheia; 3-ftoheia; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-jodene; 3-jodene; 4-jodene; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-d is methylphenyl; 2,3-dimetilfenil; 3,4-dimetilfenil; 3,5-dimetilfenil; 2-triptoreline; 3-triptoreline; and 4-trifloromethyl. In some other embodiments, R4selected from phenyl; 4-ftoheia; 2-chlorphenyl; 3-chlorphenyl; 4-chlorphenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 4-bromophenyl; 4-methylphenyl; 3,4-dimetilfenil; and 4-trifloromethyl.

In one embodiment of the proposed compound of formula (I), where R4represents 4-chlorophenyl, R1represents hydrogen, and R2represents a group CH2CH2is phenyl. In another embodiment of the proposed compound of formula (I), where R4represents 3,4-dichlorophenyl, R1represents hydrogen, and R2represents a group CH2CH2is phenyl. In another embodiment of the proposed compound of formula (I), where R4represents a 3,5-dichlorophenyl, R1represents hydrogen, and R2represents a group CH2CH2is phenyl.

Here we consider any combination of the groups described above for the different variables.

In one aspect, the compound of formula (I) chosen from:

2-(4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid is;

2-(4-perbenzoic)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(2-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(phenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(4-were)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-jogesuido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-were)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3,5-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-were)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-were)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(phenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-were)thiophene-3-carboxylic what Islami;

2-(bestien-2-ylamino)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-were)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(phenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-forfinal)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

methyl-2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylate;

ethyl-2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylate;

2-(4-jogesuido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

4-(2,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(3,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(3,5-dichlorophenyl)-2-(3-dryers is propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(3-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(2-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(2-chloro-4-perbenzoic)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3,4-differentaite)thiophene-3-carboxylic acid;

2-(2-chloro-4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(2-perbenzoic)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-fluoro-4-methoxybenzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-methylbenzamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(4-cyanobenzoyl)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-ethylbenzamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-(trifluoromethyl)benzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(2,4-differenl)propanamide)type the-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamide)thiophene-3-carboxylic acid; and

4-(4-chlorophenyl)-2-(3-(4-chlorophenyl)propanamide)thiophene-3-carboxylic acid; or pharmaceutically acceptable salts, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs.

In one aspect, the compound of formula (I) chosen from:

2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-perforprovide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-chlorophenylpiperazine)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(2-chloro-4-perbenzoic)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3,4-differentaite)thiophene-3-carboxylic acid;

2-(2-chloro-4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(2-perbenzoic)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-fluoro-4-methoxybenzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-methylbenzamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(4-cyanobenzoyl)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-ethylbenzamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-4-(trifluoromethyl)benzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamide)thiophene-3-carboxylic acid; and

4-(4-chlorophenyl)-2-(3-(4-chlorophenyl)propanamide)thiophene-3-carboxylic acid; or pharmaceutically acceptable salts, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs.

In yet another aspect, the compound of formula (I) chosen from:

2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamide)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-harfe who yl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-jogesuido)-4-(4-bromophenyl)thiophene-3-carboxylic acid; or pharmaceutically acceptable salts, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs.

In another aspect of the proposed compound of formula (I)chosen from:

or their pharmaceutically acceptable salts, pharmaceutically acceptable MES or pharmaceutically acceptable prodrugs.

In one aspect, there is described a compound of the formula (II)

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9/sup> , -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug.

For all embodiments, the substituents can be selected from a subgroup of the listed alternatives. For example, in some embodiments, R1represents hydrogen or C1-C6alkyl. In other embodiments, R1represents hydrogen, methyl, ethyl, n-propyl or isopropyl. In other embodiments, R1represents tert-butyl. In other embodiments, R1represents hydrogen. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic acid.

In some embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3With1-C6of alkyl, C1-C6foralkyl, C1-C6GE is aralkyl and C 1-C6halogenoalkane. In other embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CF3, -OH, -och3, -OCF3, methyl and ethyl.

Other embodiments of the compounds described herein include, without limitation, the compounds in Table 1.

Table 1
Typical compounds of formula (I) and formula (II)
No. of connectionsR2-R1-R4
14-forfinal-H4-bromophenyl
24-forfinal-H4-chlorophenyl
34-forfinal-H3,4-dichlorophenyl
44-forfinal-H4-triptoreline
54-forfinal-H2-bromophenyl
64-forfinal-H3,4-dimetilfenil
74-forfinal-H2-chlorophenyl
84-forfinal-H2,4-dichlorophenyl

94-forfinal-Hphenyl
104-forfinal-H4-were
113-forfinal-H4-bromophenyl
124-chlorophenyl-H4-bromophenyl
134 jogesuido-H2,4-dichlorophenyl
14bestien-2-yl-H4-bromophenyl
153-were-H4-bromophenyl
164-bromophenyl-H4-were
174-bromophenyl-H4-chlorophenyl
184-bromophenyl-H4-bromophenyl
194-bromophenyl-H3,5-dichlorophenyl
204-bromophenyl-H3-chlorophenyl
214-bromophenyl-H3,4-dimetilfenil
224-bromophenyl-H4-triptoreline
23 4-bromophenyl-H3,4-dichlorophenyl
244-bromophenyl-H2-bromophenyl
253-forfinal-H4-chlorophenyl
263-forfinal-H2,4-dichlorophenyl
273-forfinal-H3,4-dimetilfenil
283-forfinal-H3-chlorophenyl
293-forfinal-H4-were
303-forfinal-H3,4-dichlorophenyl
313-forfinal-H2-bromophenyl
323-forfinal -H4-triptoreline
334-chlorophenyl-H4-chlorophenyl
344-chlorophenyl-H4-were
354-chlorophenyl-H2,4-dichlorophenyl
364-chlorophenyl-H4-forfinal
374-chlorophenyl-H3,4-dichlorophenyl
384-chlorophenyl-H3,4-dimetilfenil
394-chlorophenyl-H4-triptoreline
404-chlorophenyl-Hphenyl
414-chlorophenyl-H 2-bromophenyl

td align="center"> 4-bromophenyl
424-chlorophenyl-H3-chlorophenyl
43bestien-2-yl-H4-chlorophenyl
44bestien-2-yl-H4-were
45bestien-2-yl-H2,4-dichlorophenyl
46bestien-2-yl-H3-chlorophenyl
47bestien-2-yl-H4-triptoreline
48bestien-2-yl-H2-bromophenyl
49bestien-2-yl-H3,4-dimetilfenil
503-were -H4-chlorophenyl
513-were-H4-were
523-were-Hphenyl
533-were-H2-bromophenyl
543-were-H4-forfinal
553-were-H3-chlorophenyl
563-were-H4-triptoreline
573-were-H2,4-dichlorophenyl
583-were-H3,4-dimetilfenil
594-chlorophenyl-Me4-forfe the Il
604-chlorophenyl-Et4-forfinal
614 jogesuido-H4-bromophenyl
62CH2CH2-phenyl-H2,4-dichlorophenyl
63CH2CH2-phenyl-H3,4-dichlorophenyl
64CH2CH2-phenyl-H3,5-dichlorophenyl
65CH2CH2-phenyl-H4-chlorophenyl
66CH2CH2-phenyl-H3-chlorophenyl
67CH2CH2-phenyl-H2-chlorophenyl
682-chloro-4-forfinal-H
693,4-differenl-H4-bromophenyl
702-chloro-4-forfinal-H4-chlorophenyl
712-forfinal-H4-bromophenyl
723-fluoro-4-methoxyphenyl-H4-bromophenyl
734-were-H4-chlorophenyl
744-cyanophenyl-H4-bromophenyl

754-ethylphenyl-H4-chlorophenyl
764-triptoreline-H4-chlorophenyl
77CH2CH2(3-forfinal) -H4-chlorophenyl
78CH2CH2(3-forfinal)-H4-bromophenyl
79CH2CH2-(2,4-differenl)-H4-chlorophenyl
80CH2CH2-phenyl-H4-bromophenyl
81CH2CH2(4-forfinal)-H4-bromophenyl
82CH2CH2-(3,4-differenl)-H4-chlorophenyl
83CH2CH2-(2,4-differenl)-H4-bromophenyl
84CH2CH2-(3,4-differenl)-H4-bromophenyl
85CH2CH2(4-forfinal)-H 4-chlorophenyl
86CH2CH2(3-chlorophenyl)-H4-chlorophenyl
87CH2CH2(4-chlorophenyl)-H4-chlorophenyl

Compounds in Table 1 are named:

2-(4-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(2-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(phenyl)thiophene-3-carboxylic acid;

2-(4-perbenzoic)-4-(4-were)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-jogesuido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(3-methylben the amido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-were)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3,5-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-bromobenzene)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-were)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(3-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-were)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carbon is the first acid;

2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(phenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(4-chlorobenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-were)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(bestien-2-ylamino)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-were)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(phenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(2-bromophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-forfinal)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(3-chlorophenyl)thio is EN-3-carboxylic acid;

2-(3-methylbenzamide)-4-(4-triptoreline)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;

2-(3-methylbenzamide)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;

methyl-2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylate;

ethyl-2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylate;

2-(4-jogesuido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;

4-(2,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(3,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(3,5-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(3-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(2-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(2-chloro-4-perbenzoic)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3,4-differentaite)thiophene-3-carboxylic acid;

2-(2-chloro-4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(2-perbenzoic)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-fluoro-4-methoxybenzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-methylbenzamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(4-cyanobenzoyl)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-this is benzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(4-(trifluoromethyl)benzamido)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-bromophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;

4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamide)thiophene-3-carboxylic acid; and

4-(4-chlorophenyl)-2-(3-(4-chlorophenyl)propanamide)thiophene-3-carboxylic acid.

In one aspect, there is described a compound of the formula (II)

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1/sub> -C6foralkyl,1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug.

For all embodiments, the substituents can be selected from a subgroup of the listed alternatives. For example, in some embodiments, R1represents hydrogen or C1-C6alkyl. In other embodiments, R1represents hydrogen, methyl, ethyl, n-propyl or isopropyl. In other embodiments, R1represents hydrogen. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic key is lots.

In some embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane. In other embodiments, R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CF3,-OH, -och3, -OCF3, methyl and ethyl.

In one embodiment R1represents hydrogen or C1-C6alkyl. In yet another aspect, R1represents hydrogen, methyl, ethyl, n-propyl or isopropyl.

In another embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3With1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane.

In one embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CF3, -OH, -och3, -OCF3, methyl and ethyl.

In another embodiment the compound of formula (IIA) is a

.

In one aspect, there is described a compound of formula (IIB),

where R1represents hydrogen, C1-C6alkyl, C1-C6halogenoalkane or benzyl;

R4represents aryl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO3, -CF3, -OH, -OR8, -OCF3C1-C6of alkyl, C3-C6cycloalkyl, C1-C6foralkyl, C1-C6heteroalkyl, C1-C6halogenoalkane, tetrazolyl,2-C6geterotsiklicheskie, phenyl, -NHS(=O)2R8, -S(=O)2N(R9)2-C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R9, -N(R9)2, -N(R9)C(=O)R8, -CO2R9, -C(=O)R8, -OC(=O)R8, -C(=O)N(R9)2, -SR8, -S(=O)R8and-S(=O)2R8;

each R8independently selected from C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

each R9independently selected from H, C1-C6of alkyl, C1-C6halogenoalkane,3-C8cycloalkyl, phenyl and benzyl;

or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug.

In one embodiment R1represents hydrogen or C1-C6alkyl. In yet another aspect, R1is own the th hydrogen, methyl, ethyl, n-propyl or isopropyl. In one embodiment of the carboxyl group thiophene nucleus is replaced by bioisosteres carboxylic acid.

In another embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3With1-C6of alkyl, C1-C6foralkyl, C1-C6heteroalkyl and C1-C6halogenoalkane.

In one embodiment R4represents phenyl, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, -CF3, -OH, -och3, -OCF3, methyl and ethyl.

In another embodiment the compound of formula (IIB) is selected from:

,,and.

In this description of the group and their alternates may be selected by the person skilled in the art machinery to ensure stable groups and connections.

Other forms of connections

Compounds described herein may in some cases exist in the form of diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all of diastereomeric, enantiomeric and epimeria forms, as well as their suitable mixtures. Separation of stereoisomers can be carried out by the HRO what ecografia or by formation and separation of diastereomers by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, included in this description by reference). Stereoisomers can be obtained by stereoselective synthesis.

In some situations, the compounds can exist in the form of tautomers. All tautomers are included in the formulas described here.

The methods and compositions described herein include the use of an amorphous form and crystalline forms (also known as polymorphs). Compounds described herein may be presented in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are also included in the scope of the present description. In addition, the compounds described herein may exist in resolutional, as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Solvated forms of the compounds represented here also seen as disclosed here.

In some embodiments of the compounds described herein may be obtained in the form of prodrugs. "Prodrug" refers to an agent into the original drug in vivo. Prodrugs are often useful because, in some situations they may be easier to introduce than the source the drug. They can, for instance, be bioavailable by oral administration, while the original drug is not bioavailable when administered orally. The prodrug may also have improved solubility in pharmaceutical compositions compared to the original drug. A non-limiting example of a prodrug may be a compound described herein, input in the form of ester (the"prodrug") to facilitate the transfer through the cell membrane where water solubility detrimental to mobility but which then undergoes metabolic hydrolysis with the formation of carboxylic acid, the active substance enters the cell, where the solubility in water is useful. Another example of a prodrug may be a short peptide (polyaminoamide)associated with the acid group in the metabolism of which is the release of the active group. In certain embodiments, when the introduction of the prodrug in vivo subjected to chemical conversion to the biologically, pharmaceutically or therapeutically active form of connection. In certain embodiments, the prodrug is exposed to enzymatic metabolism in one or more than one stage or process with the formation of the biologically, pharmaceutically or therapeutically active form of the connection.

For prolec is rstv pharmaceutically active compound modify so the active connection will be restored when introduced in vivo. The prodrug can be designed to change the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the taste and smell of medicines or to change other characteristics or properties of the drug. On the basis of knowledge of pharmacodynamic processes and drug metabolism in vivo, specialists in the art, knowing the pharmaceutically active compound, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drag Design and Drag Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985; Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Miller et al., J. Med. Chem. Vol.46, no. 24, 5097-5116, 2003; Aesop Cho, "Recent Advances in Oral Prodrug Discovery", Annual Reports in Medicinal Chemistry, Vol.41, 395-407, 2006).

Proletarienne forms of the compounds described herein, where the prodrug is subject to metabolism in vivo to form compounds of formula (I), (II), (IIA) or (IIB)as described here is included in the scope of the claims. In some cases, some of the compounds described herein can be a prodrug for another derivative or active connection.

Prodrugs are often p is Lesny, because in some situations they can be easier to introduce than the original drug. They can, for instance, be bioavailable by oral administration, while the original drug is not bioavailable when administered orally. The prodrug may also have improved solubility in pharmaceutical compositions compared to the original drug. Prodrugs can be designed as a reversible derived medicines for use as modifiers to enhance the transport of drugs in the site-specific tissue. In some embodiments development of prodrugs increases the effective solubility in water. See, for example, Fedorak et al., Am. J. Physiol, 269:G210)-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all included in this description).

Sites on the aromatic ring portion of the compounds described herein may be susceptible to various metabolic reactions, therefore, the introduction of suitable substituents in the aromatic ring structures, such as, exclusively in ka is este example, Halogens can reduce, minimize or eliminate this metabolic pathway.

Compounds described herein may be in the state of isotopes (e.g. with a radioisotope) or by other means, including, without limitation, the use of chromophores or fluorescent groups, bioluminescent labels, photoactive, or chemiluminescent labels.

Compounds described herein, include labeled with isotopes connection, identical to the compounds set forth in the various formulas and structures presented here, except for the fact that one or more than one atom is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N18O,17O,35S18F,36Cl respectively. Certain labeled with isotopes of the compounds described herein, for example, those that include radioactive isotopes, as3H and14With, useful in the analysis of the distribution of drugs and/or substrates in tissues. In addition, the replacement of such isotopes like deuterium, that is,2H, can be done in the possible certain therapeutic advantages, resulting from greater metabolic stability, such as increased half-life in vivo or reduced requirements of the doses.

In additional or other embodiments of the compounds described herein are subject to metabolism in the organism in need of this, for the formation of the metabolite, which are then used to provide the desired effect, including the desired therapeutic effect.

Compounds described herein may be received and/or to be used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, without limitation: (1) salt accession acids, formed by the interaction between the compounds in free base form with a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or organic acid, such as, for example, acetic acid, propionic acid, Capraia acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, triperoxonane acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzo is ina acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, toluensulfonate acid, 2-naphthalenesulfonate acid, 4-methylbicyclo-[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 4,4'-methylenbis-(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid, butyric acid, phenylacetic acid, fenilalanina acid, valproic acid and the like; (2) salts formed when replacing the acidic proton present in the original compound, a metal ion, for example an alkali metal ion (e.g. lithium, sodium, potassium), alkali earth metal ion (e.g. magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein may form coordination compounds with organic base, such as, without limitation, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, Tris(hydroxymethyl)methylamine. In other cases, the compounds described herein may form a salt with aminoxy the lots, such as, without limitation, arginine, lysine and the like. Acceptable inorganic bases used for the formation of salts with compounds containing acidic proton, include, without limitation, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

It should be understood that the reference to the pharmaceutically acceptable salt includes her form with the accession of solvent or crystalline form, in particular a solvate or polymorph. The solvate contain either stoichiometric or non-stoichiometric amount of solvent and can be formed in the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol and the like. When water is the solvent, the formation of hydrates, or when the solvent is alcohol, there is a formation of the alcoholate. The solvate of the compounds described herein can easily be obtained or formed in the way described here. In addition, connections, proposed here, can exist in resolutiony, as well as solvated forms. In most cases, to compounds and methods proposed here, the solvated forms are considered as equivalent nonsolvated forms.

In some embodiments of the compounds described is here such as the compounds of formula (I), (II), (IIA) and (IIB), presented in various forms, including, without limitation, amorphous forms, milled forms and shapes of the nanoparticles. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include various configurations of packing of crystals of the same elemental composition of compounds. Polymorphs usually have different patterns of x-ray diffraction, melting point, density, hardness, crystal form, optical properties, stability and solubility. Various factors, such as solvent for recrystallization, crystallization rate and temperature of storage, can lead to the dominance of one crystalline form.

Screening and description of pharmaceutically acceptable salts, polymorphs and/or solvate can be conducted using a variety of techniques, including, without limitation, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Methods of thermal analysis focused on thermochemical degradation and thermophysical processes, including, without limitation, polymorphic transformation, and such methods are used to analyze the relationship of the various polymorphic forms, to determine mass loss, to determine the glass transition temperature or IP who studies the compatibility of the excipients. Such methods include, without limitation, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA) and thermogravimetric analysis and infrared spectroscopy (TG/IR). Methods x-ray diffraction include, without limitation, diffractometers on the single crystal and powder diffractometers and synchrotron radiation sources. Various used spectroscopic techniques include, without limitation, spectroscopy Raman scattering, infrared spectroscopy based on the Fourier transform (FTIR)spectroscopy in the visible and ultraviolet spectrum (UV-VIS-spectroscopy and nuclear magnetic resonance (NMR) (liquid and solid). Various microscopic techniques include, without limitation, microscopy in polarized light, scanning electron microscopy (SEM) with energy dissipating x-ray analysis (EDX), scanning electron microscopy in the "natural environment" with EDX (in the gas atmosphere or an atmosphere of water vapor), infrared microscopy (IR-microscopy and microscopy with Raman scattering.

In this description of the group and their alternates may be selected by the person skilled in the art machinery to ensure stable groups and connections.

<> The synthesis of compounds

In some embodiments the synthesis of compounds described herein are carried out using the methods described in the chemical literature, using methods described herein, or their combination. In addition, solvents, temperatures and other reaction conditions presented here can be modified by experts in the field of technology.

In other embodiments of the source materials and reagents used for the synthesis of compounds described herein are synthesized or obtained from commercial sources, such as, without limitation, Sigma Aldrich, FischerScientific (Fischer Chemicals) and AcrosOrganics.

In other embodiments of the compounds described herein, and other related compounds with other substituents are synthesized using methods and products described herein and known in the art, such as described, for example, in Fieser and Fieser''s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd''s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock''s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and (Plenum 2000, 2001), and Green and Wuts, Protective groups in Organic Synthesis 3rdEd., (Wiley 1999) (all included in this description by reference). General methods for obtaining compounds as disclosed herein may be derived from, and is known in the art reactions, and the reaction can be modified with the use of appropriate reagents and conditions, as will be clear to a person skilled in the art for the introduction of various groups found in formulas as presented here. As a guide can be applied to the following synthesis methods.

The formation of covalent bonds by reaction of electrophile and nucleophile

Compounds described herein may be modified using various electrophiles and/or nucleophiles to form new functional groups or substituents. In Table 2, entitled "Examples of covalent linkages and precursors", lists non-limiting examples of covalent linkages and functional groups of the precursor, forming covalent bonds. Table 2 can be used as a guide to many available combinations of electrophiles and nucleophiles, providing covalent bonds. Functional group precursor is shown as an electrophilic group and a nucleophilic group.

Table 2
Examples of covalent linkages and precursors
Product covalent binding The electrophileNucleophile
CarboxamideActivated estersAmines/anilines
CarboxamideArylazideAmines/anilines
CarboxamideAcylhomoserineAmines/anilines
EstersAcylhomoserineAlcohols/phenols
EstersAllnutriAlcohols/phenols
CarboxamideAllnutriAmines/anilines
EminiAldehydesAmines/anilines
The bonds alkylaminesAlkylhalogenideAmines/anilines
EstersAlkylhalogenideCarboxylic acids
The thioethersAlkylhalogenide Thiols
EthersAlkylhalogenideAlcohols/phenols
The thioethersThe alkyl sulphonatesThiols

EstersAnhydridesAlcohols/phenols
CarboxamideAnhydridesAmines/anilines
ThiophenolThe aryl halidesThiols
ArylamineThe aryl halidesAmines
The thioethersAzedineThiols
CarboxamideCarboxylic acidsAmines/anilines
EstersCarboxylic acidsAlcohols
HydrazinesThe hydrazidesCarboxylic acids
N-acylceramide or anhydridesCarbodiimideCarboxylic acids
EstersDiazoalkanesCarboxylic acids
The thioethersEpoxidesThiols
The thioethersHalogenoacetylThiols
UreaIsocyanatesAmines/anilines
UrethanesIsocyanatesAlcohols/phenols
ThiocarbamideIsothiocyanatesAmines/anilines
The thioethersMaleimideThiols
The bonds alkylaminesSulphonate estersAmines/anilines
The thioethersSulphonate estersThiols
SulfonamidesSulfonylmethane the Amines/anilines
Sulphonate estersSulphonylchloridePhenols/alcohols

The use of protective groups

In the described reactions may be necessary to protect reactive functional groups, for example hydroxyl groups, amino groups, aminogroup, tigroup or carboxyl groups, preferably their presence in the final product, to avoid their unwanted participation in the reactions. The protecting groups used to block some or all of the reactive groups and to prevent the involvement of such groups in chemical reactions until the removal of the protective group. Preferably, each of the protective group can be removed is different from the other protective groups by the way. Protective group, otsepleniya in completely disparate reaction conditions, to satisfy the requirement of differential removal.

The protective group can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis) and/or oxidative conditions. Groups such as triphenylmethyl, dimethoxytrityl, acetal and tert-butyldimethylsilyl, acid-volatile and can be used to protect reactive carboxyl and Hydra is xilinix groups in the presence of amino groups, protected carbobenzoxy (Cbz group), removed by hydrogenolysis, and fluorenylmethoxycarbonyl group (Fmoc group), unstable grounds. Reactive groups of carboxylic acids and hydroxyl groups can be blocked groups unstable to the grounds, such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked groups unstable to acids, such as tert-BUTYLCARBAMATE, or carbamates, as resistant to acids and bases, but removed by hydrolysis.

Reactive groups of carboxylic acids and hydroxyl groups can also be blocked by protective groups removed by hydrolysis, such as benzyl group, while the amino group capable of attaching the hydrogen from acids, you can block groups unstable to the grounds, such as Fmoc-group. Reactive groups of carboxylic acids can be protected by conversion into simple ester compounds, examples of which are shown here, including the transformation in alkalemia esters, or you can lock the protective groups are removed by oxidation, such as 2,4-dimethoxybenzyl, while co-existing amino groups can be blocked volatile fluorides by siliconsamurai.

Allyl block the dominant group is applicable in the presence of the protective groups of acids and bases, because the former are stable and can be subsequently removed metal or pi-acid catalysts. For example, protection is blocked by allyl carboxylic acids can be removed Pd0-catalyzed reaction in the presence of unstable to acid tert-BUTYLCARBAMATE or unstable to the grounds acetate protective groups are amines. Another form of protective group is a resin which can be connected connection or intermediate product. Because the residue is attached to the resin, the functional group is blocked and cannot communicate. Upon release from the resin functional group is available for interaction.

Typical blocking/protective groups can be chosen from:

Other protective groups and a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, included in this description by reference).

Total synthesis

Obtaining compounds of formula (I), (II), (IIA) and (IIB)described herein may be carried out by methods known in the art, such as described in Koebel et al., J. Med. Chem. 1975, vol 18, no 2, 192-194; Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966, 99, 94-100; Sabnis, R. W. Sulfur Rep. 1994, 16, 1-17; Sbnis, R. W. et al., J. Heterocyclic Chem. 1999, 36, 333; Gemot A. Eller, Wolfgang Holzer Molecules 2006, 11, 371-376; Michael G. et al., J. Med. Chem.; 1999; 42(26) pp 5437 - 5447; all included here by reference.

In one embodiment of the compounds described herein, receive sequence depicted in Scheme A.

Scheme A. a non-limiting example of the synthesis of compounds of formula (I), (II), (IIA) or (IIB)

Condensation of Knoevenagel between ketones of structure a-1 and cyanoacetate structure a-2 leads to the formation of Schiff bases of structure a-3. For example, ketones of structure a-1 is subjected to interaction with cyanoacetate structure a-2 in the presence of an amine, such as morpholine, in a solvent such as toluene, under conditions of dehydration, such as in the presence of 4 Å molecular sieves, with the formation of Schiff's base structure a-3. Schiff's base structure a-3 is subjected to interaction in the reaction conditions of Gavalda (sulfur (S8), morpholine in a solvent such as ethanol and toluene) with the formation of teofanov patterns a-4. Tifany patterns a-4 then subjected to operation with a variety of carboxylic acid anhydrides with obtaining compounds of formula (I). In another embodiment of tifany patterns a-4 can be combined with carboxylic acids in the presence of the agent combinations, such as, for example, dicyclohexylcarbodiimide (DCC), diisopropylamide the imide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N-hydroxybenzotriazole (NOVT), N-hydroxysuccinimide (HOSu), 4-NITROPHENOL, pentafluorophenol, tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (TBTU), hexaflurophosphate O-benzotriazole-N,N,N, N'-tetramethyluronium (HBTU), hexaflurophosphate benzotriazol-1-yl-oxy-Tris-(dimethylamino)-phosphonium (THIEF), hexaflurophosphate benzotriazol-1-yl-oxy-Tris-pyrrolidinone, hexaflurophosphate bromo-Tris-pyrrolidinone, tetrafluoroborate 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium (TNTU), tetrafluoroborate O-(N-Succinimidyl)-1,1,3,3-tetramethyluronium (TSTU), hexaflurophosphate tetramethylpiperidine and the like, to obtain the compounds of formula (I).

In another embodiment of the compounds of formula (I), (II), (IIA) and (IIB) are obtained by the following method, shown in Scheme B.

Scheme b non-limiting example of the synthesis of compounds of formula (I), (II), (IIA) or (IIB)

Ketones of structure a-1, cyanoacetate structure A-2, elemental sulfur, morpholine and ethanol mixed together and stirred at room temperature with the formation of teofanov patterns A-4. Tifany patterns A-4 then subjected to interaction with activated carboxylic acids, such as acid chlorides, with the formation of amides of structure A-5. Hydrolysis of the ester functional group of the amides is structure A-5 results of the corresponding carboxylic acids.

The schemes presented here are only illustrative of some methods that can be synthesized compounds described herein, and in these schemes can be made various changes, and they will be offered to the specialist in the art with reference to this description.

In this description of the group and their alternates may be selected by the person skilled in the art machinery to ensure stable groups and connections.

The exact terminology

If not defined otherwise, all technical and scientific terms used herein have the same meaning, as they are commonly understood by the specialist in the field of technology to which the claimed subject matter of the invention. If used herein, the terms have multiple definitions, are the main definition of this section. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g. sequences available in GenBank or other databases)mentioned herein incorporated by reference. Where reference is made to a URL or other such identifier or address, imply that such identifiers can change and particular information on the Internet can come and go, but equivalent information can be found by searching the Internet. Ssy is ka on them is evidence of availability and public distribution of such information.

It should be understood that the foregoing General description and following detailed description are merely an example and explanation and do not limit none of the stated objects of the invention. In this application the use of the singular includes the use of the plural, unless specifically stated otherwise. It should be noted that when used in this description and the attached claims forms in the singular, indicating an indefinite number include plural referents unless the context clearly dictated otherwise. In this application the use of "or" means "and/or"unless stated otherwise. In addition, the use of the term "includes" or "including", as well as other forms, such as "include", "includes" and "included"is not limiting.

The section headings used herein are given only for organizational purposes, and should not be interpreted as limiting the described object of the invention.

The definition of standard chemical terms can be found in the works to which reference is made, including, without limitation, Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and (2001), Plenum Press, New York. Unless otherwise stated, apply conventional methods of mass spectroscopy, nuclear magnetic resonance, high performance liquid chromatography (HPLC), chemistry Belko is, biochemistry, methods of recombinant DNA and pharmacological methods known to experts in this field of technology.

If not given special definitions described herein laboratory methods and techniques of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry, and the nomenclature used in connection with them are well-known specialists in this field of technology. For chemical synthesis, chemical analysis, acquisition, production and delivery of pharmaceuticals and treatment of patients can be used standard methods. For recombinant DNA, synthesis of oligonucleotides and cultivation and transformation of tissues can be used standard methods (e.g., electroporation, lipofection). Reactions and methods of purification can be carried out, for example, using sets of descriptions of the manufacturer, or as is usually done in the art or as described herein. The foregoing techniques and methods, can in most cases be carried out by conventional means known in the art, and as described in various General and more specific references that are listed and discussed in the present description.

It should be understood that the methods and compositions described herein are not limited to the particular methodologies, protocols, to locname lines, constructs, and reagents described herein and may be changed by themselves. Also it should be understood that the terminology used here is given only for the purpose of describing particular embodiments, and imply that it does not restrict the scope of the methods, compounds, compositions, are described here.

When you use here C1-Cxincludes C1-C2C1-C3... C1-Cx. C1-Cxrefers to the number of carbon atoms constituting the referent group (except for possible substitutes).

"Alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group can include or not include unsaturated units. The alkyl group may be a "saturated alkyl" group, which means it does not contain unsaturated units (i.e. double carbon-carbon links or triple carbon-carbon bond). The alkyl group can also be an "unsaturated alkyl" group, which means that it contains at least one unsaturated unit. Alkyl group, saturated or unsaturated, can be an alkyl group branched-chain, non-branched chain or cyclic alkyl group.

"Alkyl" group may have from 1 to 6 atoms is of Pereda (when it appears anywhere here numerical range, as for example, from "1 to 6", refers to each integer in the given range; for example, from 1 to 6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on up to 6 carbon atoms, inclusive, however, this definition also includes the existence of the term "alkyl" without specifying a numerical range). The alkyl group of the compounds described herein may be designated as "C1-C6alkyl" or similar designations. Solely as an example, "C1-C6alkyl" indicates that the alkyl chain contains from one to six carbon atoms, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentile, isopentyl, neopentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure of the alkyl group may be panoramically or diradicals (i.e. alkalinous group).

The term "alkoxy" refers to the group-O-alkyl, where alkyl is an alkyl, as defined here.

The term "alkenyl" refers to the type of alkyl groups, where the first two atoms of alkyl group is brisout double bond, not part of the aromatic group. That is, in the beginning alkenylphenol groups are atoms C(R)=CR2where R refers to the remaining parts alkenylphenol group, which may be the same or different. Non-limiting examples alkenylphenol groups include-CH=CH2- (CH3)=CH2, -CH=SNSN3, -CH=C(CH3)2and- (CH3)=SNSN3. Alchemilla group can be an alkyl group branched-chain, non-branched chain or cyclic alkenylphenol grouping (in this case, it can also be known as "cycloalkenyl" group). Alkeneamine group can have from 2 to 6 carbon atoms. Alkeneamine groups can be substituted or unsubstituted. Depending on the structure Alchemilla group may be panoramically or diradicals (i.e. alkenylamine group).

The term "quinil" refers to the type of alkyl groups, where the first two atom alkyl groups form a triple bond. That is, in the beginning alkenylphenol groups are atomswhere R refers to the remaining parts alkenylphenol group. Non-limiting examples alkenylphenol groups includeandPart of the "R" alkenylphenol groupies who ovci may be branched, unbranched or cyclic. Alchemilla group can have from 2 to 6 carbon atoms. Alkyline groups can be substituted or unsubstituted. Depending on the structure Alchemilla group may be panoramically or diradicals (i.e. alkynylamino group).

"Amino" refers to the group-NH2.

The term "alkylamino" or "alkylamino" refers to the group-N(alkyl)xHywhere alkyl is an alkyl, as defined here, and the x-and y is selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen atom to which they are attached, can possibly form a cyclic ring system. "Dialkylamino" refers to the group-N(alkyl)2where alkyl is an alkyl, as defined here.

The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. The aromatic ring can be formed from five, six, seven, eight, nine or more than nine atoms. Aromatic structures may be substituted. The term "aromatic" includes aryl groups (e.g. phenyl, naphthalenyl), and heteroaryl groups (for example, pyridinyl, chinoline).

When used herein, the term "aryl" refers to aromatize the who to ring, in which each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine or more than nine carbon atoms. Aryl groups may possibly be substituted. Aryl groups include, without limitation, phenyl and naphthalenyl. Depending on the structure of the aryl group may be panoramically or diradicals (i.e. Allenova group).

"Carboxyl" refers to-CO2H. In some embodiments of the carboxyl groups may be replaced by "bioisosteres carboxylic acid", which refers to the functional group or grouping, demonstrating similar to the carboxylic acid group of physical and/or chemical properties. Bioisostere carboxylic acid is similar to the group of carboxylic acids of biological properties. Connection with the carboxylic acid group may be a carboxylic acid group, substituted bioisostere carboxylic acid, and have similar physical and/or biological properties when compared with a compound containing carboxylic acid. For example, in one embodiment of bioisostere carboxylic acid is ionized at physiological pH to approximately the same extent as the group of carboxylic acids. Examples of bioisosteres carboxylic acids in luchot, without limitation,

,,,,,,,,

and the like.

The term "cycloalkyl" refers to monocyclic or polycyclic nonaromatic the radical, where each of the atoms forming the ring (that is, atoms of the skeleton), represents a carbon atom. Cycloalkyl can be saturated or partially unsaturated. Cycloalkyl may be condensed with an aromatic ring (in this case, cycloalkyl connected through a carbon atom, which is not a atom of the aromatic ring). Cycloalkyl groups include groups having from 3 to 10 atoms in the ring. Illustrative examples cycloalkyl groups include, without limitation, the following groups:

,,,,,,,,,,,

and the like.

The term "heteroaryl" or alternatively, "heteroaromatic"refers to aryl g is the SCP, containing in the ring one or more than one heteroatom selected from nitrogen, oxygen and sulfur. Nitrogen-containing "heteroaromatic" or "heteroaryl" group refers to an aromatic group, where at least one of the atoms of the skeleton of the ring is a nitrogen atom. Polycyclic heteroaryl group may be condensed or unfused. Illustrative examples of heteroaryl groups include the following groups:

,,,,,

,,,,,,,,,

,,,,,,,,

and the like.

"Heterocytolysine" group or "heteroalicyclic" group refers to cycloalkyl group, where at least one atom of the skeleton ring is heteroa the Ohm, selected from nitrogen, oxygen and sulfur. Radicals can be condensed with aryl or heteroaryl. Illustrative examples geterotsiklicheskikh groups, also called non-aromatic heterocycles include;

,,,,,,,

,,,,,,,,,

,,,,,,,,,,,,,

and things like that. The term heteroalicyclic also includes all ring forms of carbohydrates, including, without limitation, monosaccharides, disaccharides and oligosaccharides. Unless otherwise stated, heterocicluri have a ring from 2 to 10 carbon atoms. It is clear, is that when the number of carbon atoms in heteroseksualci the number of carbon atoms in this heteroseksualci not equal to the total number of atoms (including heteroatoms), the components of heteroseksualci (i.e. atoms of the skeleton ring geterotsiklicheskie).

The term "halogen", or alternative "halogen"denotes the fluorescent, chloro, bromo and iodide.

The term "halogenated" refers to an alkyl group substituted by one or more than one halogen. The Halogens may be the same or they can be different. Non-limiting examples of halogenoalkanes include-CH2Cl-CF3, -CHF2, -CH2CF3, -CF3CF3, -CF(CH3)3and the like.

The terms "foralkyl and feralcode" include alkyl and alkoxygroup, respectively, substituted by one or more than one fluorine atom. Non-limiting examples of foralkyl include-CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3and things like that. Non-limiting examples of forelcosure include-OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2and the like.

The term "heteroalkyl" refers to the alkyl radical, where one or more than one atom of the skeleton chain selected from an atom other than carbon atom, such as oxygen atom, nitrogen, sulfur, phosphorus, silicon or combinations thereof. Heteroatom (heteroatoms) can be located in any domestic who eat the position heteroalkyl group. Examples include, without limitation, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-och3and-CH=CH-N(CH3)-CH3. In addition to two heteroatoms may be arranged in series, as for example,- CH2-NH-co3and CH2-O-Si(CH3)3. With the exception of the number of heteroatoms, heteroalkyl can have from 1 to 6 carbon atoms.

The term "communication" or "single bond" refers to a chemical bond between two atoms, or two groups, where the atoms are connected by a link and consider them as part of a larger substructure.

The term "group" refers to a particular segment or functional group of the molecule. Chemical groups are often recognized chemical groups included in or attached to a molecule.

When you use here Deputy "R" when it appears by itself and without the numerical designation refers to the Deputy selected from alkyl, Galaga is valkila, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (linked through an atom ring) and geterotsiklicheskie.

The term "possibly substituted" or "substituted" means that the corresponding group may be substituted by one or more than one additional group (s)individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, geterotsiklicheskie, HE, alkoxygroup, alloctype, allylthiourea, aristocraty, alkylsulfonate group, arylsulfonate group, alkylsulfonate group, arylsulfonate group, -CN, halogeno, acyl, alloctype, -CO2N", group-CO2-alkyl, nitro, halogenoalkane, foralkyl and amino, including mono - and disubstituted amino group (for example, -NN2, -Other, -N(R)2), and their protected derivatives. As an example, possible substituents may represent a group LsRswhere each Lsindependently selected from-O-, -S(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(C1-alkyl)- or -(C2-C6alkenyl)-; and each Rsindependently selected from H, (C1-C6the alkyl), (C3-C8cycloalkyl), aryl, heteroaryl, geterotsiklicheskie and C1-C6heteroalkyl. The protective group that can form a protected derivative of these to enter the deputies, presented in such sources as Greene and Wuts, above.

The methods and compositions described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of formula (I), (II), (IIA) or (IIB), as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds can exist in the form of tautomers. All tautomers are included in the scope of the compounds represented here. In addition, the compounds described herein may exist in resolutional, as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Solvated forms of the compounds represented here also seen as disclosed here.

The terms "set and "product" are used as synonyms.

The term "subject" or "patient" includes mammals and animals that are not mammals. Examples of mammals include, without limitation, any member of the class of Mammals: humans, primates, non-humans, such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory vividly the data including rodents, such as rats, mice and Guinea pigs, and the like. Examples of animals that are not mammals include, without limitation, birds, fish and the like. In one embodiment of the methods and compositions presented herein, the mammal is a human.

The terms "treat" or "treating" when used here includes facilitating, weaken or reduce the intensity of symptoms of the disease or condition, preventing additional symptoms, improvement, or prevention of the causes underlying the symptoms, suppression of the disease or condition, such as the termination of development of the disease or condition, relieving the disease or condition, the induction of regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, prophylactically and/or therapeutically.

When used here "protein-target" refers to a protein or part protein, which can be linked compound described herein, or may interact with a compound described herein, such as the compound of formula (I), (II), (IIA) or (IIB). In certain embodiments the protein target is a protein STIM. In certain embodiments the protein target is a protein Orai.

When used here "TIM protein" includes, without limitation, STIM-1 mammals, such as STIM-1 of human and rodent (e.g. mouse), D-STIM Drosophila melanogaster, C-STIM .elegans, STIM Anopheles gambiae and STIM-2 mammals, such as STIM-2 of human and rodent (e.g., mouse) (see [0211]-[0270] US 2007/0031814 and Table 3 US 2007/0031814 included here by reference). As described herein, it was found that these proteins are involved in, participate in, and/or provide depot-managed sign of calcium or modulation of cytoplasmic buffer action in relation to calcium and/or modulation of the levels of calcium in, or movement of calcium into, within or from the intracellular depot of calcium (e.g., endoplasmic reticulum).

When used here "Orai protein" includes Orai1 (SEQ ID NO: 1, as described in WO 07/081804), Orai2 (SEQ ID NO: 2 as described in WO 07/081804) or Orai3 (SEQ ID NO: 3 as described in WO 07/081804). The sequence of the nucleic acid Orai1 corresponds to GenBank access number NM_032790, the sequence of the nucleic acid Orai2 corresponds to GenBank access number BC069270, and the sequence of the nucleic acid Orai3 corresponds to GenBank access number NM_152288. When you use here Orai refers to one or more than one gene Orai, for example, Orai1, Orai2, Orai3 (see Table I WO 07/081804). As described herein, it was found that these proteins are involved in, participate in, and/or provide depot-driven calcium intake or it is modulation, cytoplasmic buffer action in relation to calcium and/or modulation of the levels of calcium in or movement of calcium into, within or from the intracellular depot of calcium (e.g., endoplasmic reticulum).

The term "fragment" or "derived", referring to a protein (e.g., STIM, Orai), refers to proteins or polypeptides that retain essentially the same biological function or activity as the native protein (proteins), in at least one assay. For example, fragments or derivatives of the corresponding protein retains at least about 50% activity of native proteins, at least about 75%, at least about 95% activity of native protein as determined, for example, the analysis of the inflow of calcium.

When used here, the reduction in intensity of symptoms of a particular disease, disorder or condition by the introduction of a compound or pharmaceutical composition refers to any reduction in the severity of, delaying the emergence of, slowing the progression or reduce the duration, permanent or temporary, lasting or transient that can be attributed or associated with the introduction of the compound or composition.

When used herein, the term "modulate" means to interact with the protein target or not is orestano, or indirectly, so that the activity of the protein target is changed, including, solely as an example, the inhibition of the activity of the target or the limitation or reduction of activity of the target.

When used herein, the term "modulator" refers to a compound that alters the activity of the target. For example, the modulator may increase or decrease the intensity of a specific activity targets compared with the intensity of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor, which reduces the intensity of one or more than one activity of the target. In certain embodiments the inhibitor completely prevents one or more than one activity of the target.

When used here "modulation"related to intracellular calcium, refers to any change or correction of intracellular calcium, including, without limitation, changes in the concentration of calcium in the cytoplasm and/or intracellular organelles depot of calcium, such as endoplasmic reticulum, changing the kinetics of calcium currents inside, from and within cells. In one aspect, the modulation refers to the reduction.

When used herein, the term "target activity" refers to biological activity that can be modulated by the modulator. Some typical target activity and include, without limitation, affinity binding, signal transduction, enzyme activity, tumor growth, inflammation or processes associated with inflammation, and decrease the intensity of one or more than one symptom associated with the disease or condition.

The terms "inhibit", "inhibiting" or "inhibitor" activity SOC channels or CRAC channels when used here relate to the inhibition of the activity depot-operated calcium channels or activity of calcium channels activated by calcium release.

The term "acceptable" in relation to the preparation, composition or ingredient when used here means no persistent adverse effect on the General health condition of the subject undergoing treatment.

"Pharmaceutically acceptable" when used here refers to a substance, such as a carrier or diluent that does not eliminate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the substance can be administered to the individual without causing undesirable biological effects or harmful interactions with any of the components of the composition containing a specified substance.

The term "pharmaceutical combination" when used here refers to the product resulting from the mixing or combination of the I more than one active ingredient and includes both fixed, and non-fixed combinations of the active ingredients. The term "fixed combination" means that one active ingredient, e.g. a compound of formula (I), (II), (IIA) or (IIB), and the collateral agent is administered to the patient together in the form of a single entity or dosage. The term "non-fixed combination" means that one active ingredient, e.g. a compound of formula (I), (II), (IIA) or (IIB), and the collateral agent is administered to a patient as separate objects, or together, either simultaneously or sequentially with no specific limitations on the periods of time where this introduction provides effective levels of the two compounds in the body of the patient. The latter also applies to the mixed therapy, for example the introduction of three or more active ingredients.

The term "pharmaceutical composition" refers to a mixture of compounds of formula (I), (II), (IIA) or (IIB)described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspendresume agents, thickeners and/or excipients. The pharmaceutical composition facilitates administration of a medicinal product in the body. In the art there are many methods of introducing compounds, including, without limitation, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and local BB is Denia.

The terms "effective amount" or "therapeutically effective amount" when used here refer to the number of input agent or compound, sufficient to facilitate, to some extent, one or more than one symptom of the disease or condition about which treatment. The result can be reduction and/or alleviation of the signs, symptoms or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition containing the compound of formula (I), (II), (IIA) or (IIB)described herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in each individual case can be determined using techniques such as the study with higher doses.

The terms "enhance" or "enhancing" when used here refers to the increase or extension of the desired effect, either in strength or duration. Thus, in relation to enhance the effect of therapeutic agents, the term "amplification" refers to the ability to increase or prolong the effect of other therapeutic agents in the system, either in strength or duration. "Enhancing the effective number is the number" when used here refers to the number, adequate to enhance the effect of another therapeutic agent to the desired system.

I believe that the terms "co-administration" or the like when used here include the introduction of the selected therapeutic agents to a single patient, and imply that they include treatment regimens in which the agents enter the same or different routes of administration or at the same time or at different times.

The term "carrier" when used here refers to a relatively non-toxic chemical compounds or agents that facilitate the introduction of compounds into cells or tissues.

The term "diluent" refers to chemical compounds that are used for cultivation of the considered connection before delivery. Diluents may also be used to stabilize compounds, because they can provide a more stable environment. In the art as diluents use salts dissolved in buffered solutions (which can also provide control or maintain pH), including, without limitation, phosphate buffered saline solution.

"Metabolite" of the compounds disclosed here, is a derivative of this compound, formed during the metabolism of compounds. The term "active metabolite" refers to a biologically active derivative connect the tion, formed during the metabolism of compounds. The term "metabolism" when used here refers to the set of processes (including, without limitation, hydrolysis and reactions catalyzed by enzymes), through which the body changes a certain substance. Thus, enzymes can lead to certain structural changes to the connection. For example, cytochrome P450 catalyzes the many oxidation and reduction reactions, while uridinediphosphoglycosyltransferase kataliziruet transfer of the activated molecules of glucuronic acid to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. More information about the metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein may be identified either by the introduction of compounds to the owner and analysis of tissue samples from the host, or by incubation of compounds with liver cells in vitro and analysis of the obtained compounds. Both methods are well known in the art.

"Bioavailability" refers to the percentage weight of the compounds described herein (e.g. compounds of formula (I), (II), (IIA) or (IIB)), delivered at the overall flow of the studied animal or human. The total exposure (AUC (0-∞)) of a drug is the means when administered intravenously is usually defined as 100% bioavailability (F%). "Bioavailability by oral administration" refers to the extent to which the connection described here, is absorbed into the General bloodstream after oral administration of the pharmaceutical composition compared to intravenous injection.

"Concentration in plasma" refers to the concentration of the compound of formula (I), (II), (IIA) or (IIB), unveiled here, in the plasma component of blood of a subject. It should be understood that the concentration of these compounds in plasma can vary significantly between subjects, due to variability in relation to metabolism and/or possible interactions with other therapeutic agents. According to one embodiment, opened here, the concentration disclosed here compounds in plasma can vary from subject to subject. Similarly, such values as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the curve plasma concentration (AUC (0-∞))may vary from subject to subject. Because of this variability, the amount necessary to constitute "a therapeutically effective amount" of the compounds may vary from subject to subject.

When used here "calcium homeostasis" refers to maintaining the overall balance of intracellular levels and n is ramadani calcium, including calcium signaling within cells.

When used here "intracellular calcium" refers to calcium, which is located in the cell, without specifying a specific location in the cell. On the contrary, "cytosolic" or "cytoplasmic" in terms of calcium is calcium, which is located in the cytoplasm of a cell.

When using the effect on intracellular calcium is any change to any aspect of intracellular calcium, including, without limitation, changing levels and locations of intracellular calcium and movement of calcium inside of and within cells or intracellular depot of calcium, or organelles. For example, the effect on intracellular calcium can be a change in properties, such as, for example, kinetics, sensitivity, speed, amplitude and electrophysiological characteristics of the calcium current or movement occurring in the cell or portion thereof. The effect on intracellular calcium can be a change of any process that modulates intracellular calcium, depo-managed entrance of calcium, cytosolic buffer action in respect of the calcium, and the levels of calcium in or movement of calcium inside, out of or within an intracellular depot of calcium. Any of these aspects can be assessed in a variety of ways, including the traveler, without limitation, increased levels of calcium or other ion (particularly cation), the movement of calcium or other ion (particularly cation), changes in the levels of calcium or other ion (particularly cation), the kinetics of the currents of calcium or other ion (particularly cation) and/or the transport of calcium or other ion (particularly cation) through the membrane. Change can represent any such change, which is statistically significant. Thus, for example, if they say that intracellular calcium in the test cell and the control cell differ, this difference may represent a statistically significant difference.

When used here "involved" in regard to the relationship of protein and aspect of intracellular calcium and the regulation of intracellular calcium means that if you reduce, modify or eliminate the expression or activity of the protein in the cell is related or associated to the reduction, modification or elimination of one or more than one aspect of intracellular calcium and the regulation of intracellular calcium. Such a change or decrease in the expression or activity can occur via changes in the expression of the gene encoding the protein, or changes in the levels of protein. Thus, a protein involved in the aspect of intracellular calcium, that is definitely, for example, depo-controlled calcium intake may be a protein, providing or participating in the aspect of intracellular calcium and the regulation of intracellular calcium. For example, protein, providing depot-driven calcium intake, may be a STIM protein and/or protein Orai.

When using here a protein that is a component of the calcium channel is a protein involved in mnogovekovom complex, forming a channel.

When used here "basal" or "at rest" in relation to levels of calcium in the cytosol refers to the concentration of calcium in the cytoplasm of a cell, such as, for example, nstimerevent cell that was not exposed to conditions that cause the movement of calcium into or out of cells or within cells. The basal level of calcium in the cytosol or the level of calcium in the cytosol alone can represent the concentration of free calcium (calcium is not associated with the cellular substance that binds calcium in the cytoplasm of a cell, such as, for example, nstimerevent cell that was not exposed to conditions that cause the movement of calcium into or out of the cell.

When using "move" in relation to ions, including cations, such as calcium, refers to the movement or change of location is of, such as, for example, the flow of ions inside, out of or within a cell. Thus, movement of ions can represent, for example, the movement of ions from the extracellular environment into the cell, from the cell into the extracellular environment from intracellular organelles or site-depot in the cytosol, from cytosol in intracellular organelle or website-depot, from one intracellular organelles or site-depot to another intracellular organelle or website-depot from the extracellular environment in intracellular organelle or website-depot from intracellular organelles or site-depot in the extracellular environment or from one location to another within the cytoplasm of the cell.

When used here "sign cations" or "the entrance of calcium into the cell refers to the entrance of cations, such as calcium, intracellular location, such as the cytoplasm of a cell, or into the lumen of intracellular organelles or site-depot. Thus, the input of the cations may represent, for example, the movement of cations into the cytoplasm from the extracellular environment or from intracellular organelles, or site, depot, or the movement of cations in intracellular organelle or website-depot from the cytoplasm or the extracellular environment. The movement of calcium into the cytoplasm from intracellular organelles or site-depot also called "calcium release from organelles or site-depot.

P and use here "protein modulating intracellular calcium" refers to any cellular protein involved in the regulation, control and/or changes in intracellular calcium. For example, such a protein may be involved in the change or correction of intracellular calcium in several ways, including, without limitation, by maintaining basal levels of calcium in the cytoplasm or levels of calcium in the cytoplasm alone or through participation in the cellular response to the signal transmitted into the cell through a mechanism involving the deviation of intracellular calcium from the basal state or state of rest. In the context of protein, modulating intracellular calcium", "cellular" protein is a protein associated with the cell, such as, for example, a cytoplasmic protein, a protein associated with the plasma membrane or intracellular protein membrane. Proteins, modulating intracellular calcium include, without limitation, proteins, transport of ions, proteins, calcium-binding and regulatory proteins that regulate ion transport proteins.

When used here "improvement" refers to the improvement of the disease or condition or at least partial relief of symptoms associated with the disease or condition.

When used here "cellular response" refers to any cellular response, privatise is the movement of ions into and out of the cell or within the cell. The cellular response can be associated with any cellular activity based at least in part, on ions, such as calcium. Such activity may include, for example, cell activation, gene expression, endocytosis, exocytosis, cell migration and cell death by apoptosis.

When used here "immune cells" include cells of the immune system, performing the function or activity in the immune response, such as, without limitation, T-cells, b-cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, white blood cells, antigen-presenting cells and natural killer cells.

When used here "cytokine" refers to small soluble proteins, secretively cells are able to change the behavior or properties secreting cells or other cells. Cytokines bind receptors cytokines and stimulate behavior or property of the cells, such as proliferation, death or differentiation of cells. Typical cytokines include, without limitation, interleukins (e.g. interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β and IL-1 RA), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin M, ERI is repeatin, leukemia inhibitory factor (LIF), interferons, V (also known as CD80), V (also known as 70, CD86), members of the family of tumor necrosis factor (TNF) (TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail) and factor inhibiting migration (MIF).

"Depo-managed sign-calcium" or "SOCE" refers to the coordination mechanism of release of calcium ions from intracellular depots and the flow of ions across plasma membrane.

"Selective inhibitor activity SOC channels" means that the inhibitor is selective in respect of SOC channels and essentially does not affect the activity of other types of ion channels.

"Selective inhibitor of the activity of CRAC channels" means that the inhibitor is selective in respect of CRAC channels and essentially does not affect the activity of other types of ion channels and/or other SOC channels.

Examples of pharmaceutical compositions and routes of administration

The pharmaceutical compositions can be manufactured in conventional manner using one or more than one physiologically acceptable carrier, including excipients and auxiliaries that facilitate processing of the active compounds to obtain compositions which can be used pharmaceutically. A suitable composition depends on the selected route of administration. Any of the well known methods, media and the excipients may be applied as appropriate and as is known in the art. A brief description of the pharmaceutical compositions described herein can be detected, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), included in this description by reference.

The pharmaceutical composition when used here refers to a mixture of the compounds of formula (I), (II), (IIA) or (IIB)described herein, and other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspendresume agents, thickeners and/or excipients. The pharmaceutical composition facilitates the introduction of the compound into the body. When applying the methods of treatment and uses prepositional here, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or condition to be treated. In some embodiments the mammal is a human. therapeutically effective amount can vary depending on the severity of the disease, the age and relative health of the subject, the activity of the used connections and other factors. The compounds of formula (I), (II), (IIA) or (IIB) is t to be used by themselves or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy).

The pharmaceutical compositions described herein may be administered to the subject by several routes of administration, including, without limitation, oral, parenteral (e.g. intravenous, subcutaneous, intramuscular), intranasal, transbukkalno, local, rectal, or transdermal route of administration. Moreover, the pharmaceutical compositions described herein containing the compound of formula (I), (II), (IIA) or (IIB)described herein may be manufactured in any suitable dosage form, including, without limitation, aqueous dispersions for oral administration, liquids, gels, syrups, elixirs, suspensions, suspensions, aerosols, compositions with controlled release, instant composition, effervescent compositions, lyophilized compositions, tablets, powders, pills, coated tablets, capsules, and compositions with delayed release, song, slow release, compositions with intermittent release composition consisting of a set of particles, and mixed compositions of immediate-release and controlled release.

Compounds and/or compositions can enter a local rather than systemic manner, for example by injection of the compound directly into the organ or tissue, often in a depot preparation or composition with prolonged release. Such dlitelnodeystvuyuschie compositions the AI can be introduced by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. In addition, the drug can be entered in the system for targeted delivery of drugs, for example, in a liposome coated with organ-specific antibody. Liposomes will be focused on the body and selectively captured in it. In addition, the drug may be in the form of compositions with quick release, in the form of a composition with a slow release or in the form of a composition with an intermediate release.

Pharmaceutical compositions containing a compound described herein may be manufactured in a conventional way, such as, solely as an example, by conventional methods of mixing, dissolving, granulating, production drops, grinding into powder, emulsification, encapsulation, capture or pressing.

The pharmaceutical compositions will contain at least one compound of formula (I), (II), (IIA) or (IIB)described herein as an active ingredient in the form of free acid or free base or in the form of pharmaceutically acceptable salts. In addition, the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type and the activity. In some situations, the compounds can exist in the form of tautomers. All tautomers are included in the scope of the compounds represented here. In addition, the compounds described herein may exist in resolutional, as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Solvated forms of the compounds represented here also seen as disclosed here.

In certain embodiments of the compositions presented herein may also contain one or more than one preservative to inhibit microbial activity. Suitable preservatives include Quaternary ammonium compounds such as benzalkonium chloride, bromide, cetyltrimethylammonium and chloride of cetylpyridinium.

Pharmaceutical compositions for oral administration can be obtained by mixing one or more than one solid excipient with one or more than one compound described herein (e.g. compound of formula (I), (II), (IIA) or (IIB), grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets, pills or capsules. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; the courthouse square cellulose, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hypromellose, carboxymethylcellulose sodium; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desirable, can be added leavening agents, such as cross-stitched croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

The dragee cores provide suitable coatings. This purpose can be used in concentrated solutions of sugars, which may possibly contain the Arabian gum, talc, polyvinylpyrrolidone, carboloy gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In coatings for tablets or pills may be added dyes or pigments for identification or distinction of different combinations of doses of active compounds.

Pharmaceutical compositions that can be used orally include a tight push-fit capsules made of gelatin, and also soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tight push-fit capsules can contain the active ing eventy mixed with a filler, such as lactose, binders, such as starches, and/or lubricating agents such as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as non-volatile oils, liquid paraffin, or liquid polyethylene glycols. In addition, it is possible to add stabilizers.

In some embodiments, solid dosage forms disclosed herein may be presented in the form of tablets (including a suspension tablet, dissolving tablet, the tablet-grinding, rapidly decaying tablet, effervescent tablet or pill in the form of capsules, pills, powders (including sterile packaged powder, a powder for a single use or effervescent powder), capsules (including soft or hard capsules, for example capsules made of gelatin of animal origin or hydroxyethylmethylcellulose (receiver array) of vegetable origin, or capsules coated particles" ("sprinkle capsules")), solid dispersion, solid solution, dosage form, susceptible to biological degradation, compositions, controlled release dosage forms with intermittent release dosage forms, consisting of many particles, beads, granules or spray. In the other embodiments the pharmaceutical composition is in the form of powder. In other embodiments the pharmaceutical composition is presented in the form of tablets, including, without limitation, quick-dissolving tablet. In addition, the pharmaceutical compositions of the compounds described herein can be entered as separate capsules or dosage form consisting of a set of capsules, In some embodiments the pharmaceutical composition is administered as two or three, or four capsules or tablets.

In some embodiments, solid dosage forms such as tablets, effervescent tablets, and capsules, are made by mixing particles of compounds of formula (I), (II), (IIA) or (IIB)described herein, with one or more pharmaceutical excipients with the formation of the composition in the form of bulk mixture. When these compositions are in the form of a volumetric mixture is called homogeneous, implying that the particles of the compounds of formula (I), (II), (IIA) or (IIB)described herein are evenly distributed on the composition so that the composition can be easily divided into equally effective standard dosage forms, such as tablets, pills and capsules. Single doses may also include film coatings, collapsing when ingested or in contact with the diluent. These compositions can be manufactured by conventional pharmacological methods.

Solid pharmaceutical is karstenia form, described herein may contain a compound of the formula (I), (II), (IIA) or (IIB)described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, a binding agent, filler, suspendisse agent, corrigent, sweetener, baking powder, dispersing agent, surfactant, lubricant agent, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, a substance that promotes penetration, wetting agent, defoamer, an antioxidant, preservative, or one or more than one combination. In other aspects, using standard coating methods such as described in Remington''s Pharmaceutical Sciences, 20th Edition (2000)provide a film coating around the composition of the compounds described herein. In one embodiment, some or all of the particles of the compounds described herein, are coated. In another embodiment, some or all of the particles of the compounds described herein, are enclosed in microcapsules. In yet another embodiment, the particles of the compounds described herein, are not enclosed in microcapsules and do not have coverage.

Suitable carrier materials for use in the solid dosage forms described herein include, without limitation, Arabian gum, gelatin, colloidal silicon dioxide, glycerol calcium, calcium lactate, multidex is Rin, glycerin, magnesium silicate, sodium Caseinate, soy lecithin, sodium chloride, calcium phosphate, potassium phosphate, stearylamine sodium, carragenin, monoglyceride, diglyceride, pregelatinized starch, hypromellose acetate-stearate of hydroxypropylmethylcellulose, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

Suitable fillers for use in the solid dosage forms described herein include, without limitation, lactose, calcium carbonate, calcium phosphate, calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrine, dextran, starches, pregelatinized starch, hypromellose (receiver array), the phthalate of hydroxypropylmethylcellulose, acetate-stearate of hydroxypropylmethylcellulose (HPMCAS), sucrose, xylitol, lactic, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

For the maximum possible effective release of the compounds of formula (I), (II), (IIA) or (IIB) from a matrix of solid dosage forms, composition is often used leavening agents, especially when the dosage form is pressed with a binder. Leavening agents are contributing to the destruction of the matrix dosage forms by swelling or capillary action upon absorption of moisture in Lekarstvo the th form. Suitable leavening agents for use in the solid dosage forms described herein include, without limitation, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, microcrystalline cellulose, e.g. Avicel®, Avicel® PH101, Avicel® PH 102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, or croscarmellose cross-stitched cellulose, such as cross-crosslinked carboxymethylcellulose sodium (Ac-Di-Sol®), cross-crosslinked carboxymethylcellulose, cross-stitched crosscarmellose, cross-cross-linked starch such as sodium starch glycolate, cross-cross-linked polymer such as crosspovidone, cross-crosslinked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, clay such as Veegum® HV (magnesium silicate-aluminum), a gum such as agar, guar gum, fruit of the carob tree, Karaya, pectin, or tragacanth gum, starch glycolate sodium bentonite, natural sponge, a surfactant, a resin, such as cation-exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

Connect the surrounding substances, which impart to the compositions in the form of solid dosage forms for oral administration cohesive ability: for the composition in the form of a capsule, filled with powder, they contribute to the formation of the tube, which can be filled capsules with hard or soft shell, and to compositions in the form of tablets, they provide the stability of the pellet after pressing, and help to ensure homogeneity of the mixture at the stage of molding or filling. Substances suitable for use as bonding agents in solid dosage forms described herein include, without limitation, carboxymethyl cellulose, methylcellulose (e.g., Methocel®), hypromellose (e.g., Hypromellose USP Pharmacoat-603), acetate-stearate of hydroxypropylmethylcellulose (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®) and microcrystalline cellulose (such as Avicel®), microcrystalline dextrose, amylose silicate of magnesium-aluminum, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crosspovidone, povidone, starch, pregelatinized starch, tragakant, dextrin, sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (for example, Xylitab®), lactose, natural or synthetic gum such as Arabian gum, tragacanth gum, ghatti-gum, mucilage of husk isapol, starch, polyvinylpyrrolidone (e.g. Povidone® CL, Kollidon® CL, Polyplasdone® XL-10 and Povidone® K-12), erbogachan larch wood, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

In most cases, the in compositions in the form of gelatin capsules filled with powder, use levels binder 20-70%. The level of binder used in the compositions in the form of tablets varies depending on the use of direct compression, wet granulation, compaction roller or the use of other excipients, such as fillers, which themselves can act as moderately effective linking agents. Specialists in the manufacture of dosage forms can determine the level of binder compositions, but in compositions in the form of tablets usually use a level of binding of the substance to 70%.

Suitable lubricants or sliding substances for use in the solid dosage forms described herein include, without limitation, stearic acid, calcium hydroxide, talc, corn starch, sodium fumarate, and salts of alkaline and alkaline-earth metals such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polietilenglikol is or methoxypolyethyleneglycol, such as Carbowax™polyethylene glycol-400 (PEG 4000), PEG 5000, PEG 6000, propylene glycol, sodium oleate, glycerinated, glycerylmonostearate, glycerinated, valium magnesium or sodium, and the like.

Suitable diluents for use in the solid dosage forms described herein include, without limitation, sugars (including lactose, sucrose and dextrose), polysaccharides (including dexterity and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins and the like.

Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glycerylmonostearate, servicemanual, orbitalmaneuvers, triethanolamine oleate, monoether of polyoxyethylenesorbitan and oleic acid, monoether of polyoxyethylenesorbitan and lauric acid, Quaternary ammonium compounds (for example, Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusinate, triacetin, vitamin E, D-alpha tocopherylacetate-1000-succinate (TPGS), and the like.

Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, servicemanual, monoether of polyoxyethylenesorbitan and oleic acid, Polysorbate, poloxamer, bile acids, glitzer monostearate, copolymers of ethylene oxide and of propylene oxide, for example, Pluronic® (BASF), and the like.

Suitable suspendresume agents for use in the solid dosage forms described herein include, without limitation, polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone R17, polyvinylpyrrolidone K or polyvinylpyrrolidone K, polyethylene glycol, such as polyethylene glycol can have a molecular weight from about 300 to about 6000, or from about 3350 to about 4000, or from about 5400 to about 7000, copolymer of vinylpyrrolidone/vinyl acetate (S630), carboxymethylcellulose sodium, methylcellulose, hypromellose, Polysorbate-80, hydroxyethylmethylcellulose, sodium alginate, gums, such as, for example, tragacanth gum and Arabic gum, xantana, including xanthan gum, sugars, cellulose polymers, such as, for example, carboxymethylcellulose sodium, methylcellulose, carboxymethylcellulose sodium, hypromellose, hydroxyethylmethylcellulose, Polysorbate-80, sodium alginate, polyethoxysiloxane sorbitanoleat, polyethoxysiloxane sorbitanoleat, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described herein include, for example, boutilier the p hydroxytoluene (EIT), sodium ascorbate and tocopherol.

It should be understood that the additives used in the solid dosage forms described herein are substantially the same. Thus, the above additives should be considered solely as non-limiting examples of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein. Specialist in the art can easily determine the amount of these additives in accordance with specific desired properties.

In other embodiments, one or more than one layer of the pharmaceutical composition plasticized. As a clarification, the plasticizer in most cases is a solid or a liquid with a high boiling point. Suitable plasticizers can be added in amounts of from about 0.01% to about 50% by weight (wt./mass.) covering songs. Plasticizers include, without limitation, diethylphthalate, esters of citric acid, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylenglycol, polyethylene glycol, triethylcitrate, dibutylsebacate, stearic acid, Sterol, stearate and castor oil.

Molded tablets are solid dosage forms manufactured by pressing surround MESI compositions described above. In various embodiments of the pressed tablets are designed to dissolve in the oral cavity, will include one or more than one corrigent. In other embodiments pressed tablets will include film surrounding the final compressed tablet. In some embodiments of the film coating can provide a delayed release of the compounds of formula (I), (II), (IIA) or (IIB)described herein, of the composition. In other embodiments of the film coating adherence of the patient to treatment (e.g. coating Opadry® or sugar coating). Film coatings, including Opadry®, typically comprise from about 1% to about 3% by weight of the tablet. In other embodiments pressed tablets contain one or more than one excipient.

The capsule can be manufactured, for example, the space volume of the mixture compositions of the compounds described here, inside the capsule. In some embodiments of the composition (non-aqueous suspensions and solutions) placed in a soft gelatin capsule. In other embodiments the composition is placed in a standard gelatin capsules or regulative capsules, such as capsules, containing a receiver array. In other embodiments the composition is placed in a capsule covered with particles (sprinkle capsule), which can be ingested as a whole or open it and sprinkle the contents on food is before a meal. In some embodiments, therapeutic dose is divided into several (for example two, three or four) capsules. In some embodiments the entire dose of the composition is delivered in the form of a capsule.

In various embodiments, the particles of the compounds of formula (I), (II), (IIA) or (IIB)described herein and one or more than one excipient subjected to dry mixing and pressing with mass formation, such as a tablet, having sufficient hardness to provide a pharmaceutical composition which disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration releasing thus the composition of the contents of the gastrointestinal tract.

In another aspect, the dosage form may contain the composition enclosed in microcapsules. In some embodiments the substance to be concluded in the microcapsules is present one or more other compatible material. Typical substances include, without limitation, pH modifiers, enhancers destruction, defoamers, antioxidants, corrigentov and substance-media, such as binders, suspendresume agents, disintegrating agents, fillers, surface is Resto-active substances, soljubilizatory, stabilizers, lubricants, wetting agents, and diluents.

Substances that are applicable for the conclusion in the microcapsules described herein, include substances that are compatible with the compounds described herein, effectively isolating the compound from other incompatible excipients. Substances that are compatible with the compounds of formula (I), (II), (IIA) or (IIB)described herein, are substances that slow the release of the compounds of formula (I), (II), (IIA) or (IIB) in vivo.

Typical substances for encapsulation in microcapsules that are applicable to slow release compositions containing the compounds described herein include, without limitation, esters of hydroxypropylcellulose (LDCs)such as Klucel® or Nisso LDCs, esters nitrosamines hydroxypropylcellulose (L-HPC), esters of hydroxypropylmethylcellulose (receiver array), such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, polymers, methylcellulose, such as Methocel®-A, acetate-stearate of hydroxypropylmethylcellulose Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof E, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA)such as Opadry AMB, hydroxyethyl cellulose, such as Natrosol®, carboxymethylcellulose and salts carboxymetilcellulose (CMC), such as Aqualon®-CMC, polyvinyl alcohol and copolymers of polyethylene glycol, such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KX), the polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, acetate-phthalate cellulose, whips Sepifilm, as for example a mixture of a receiver array and stearic acid, cyclodextrins, and mixtures of these substances.

In other embodiments, the plasticizers such as glycols, for example polyethylene glycol-300 (PEG 300), PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid and triacetin included in the substance to be concluded in the microcapsules. In other embodiments, the substance to be concluded in the microcapsules, is applicable for the delayed release pharmaceutical compositions, is a substance of the Pharmacopoeia of the United States (USP) or National formulary (NF). In other embodiments, the substance to be concluded in the microcapsules is a Klucel. In other embodiments, the substance to be concluded in the microcapsules is a methylcellulose.

Enclosed in the microcapsules of the compounds of formula (I), (II), (IIA) or (IIB)described herein may be manufactured by methods known to the person skilled in the art. Such known methods include, for example, the methods of spray drying methods with BP is mausima disk and the solvent (spinning disk-solvent processes), methods of melting, the ways in spray cooling, fluidized bed, electrostatic deposition, compaction by centrifugation, rotational suspension dispersion, polymerization at the interface liquid - gas or solid - gas, extrusion pressure, bath or spray solvent extraction (spraying solvent extraction bath). In addition to these, can also be applied to some chemical methods, such as complex coacervation, evaporation of the solvent, the incommensurability of polymers, polymerization at the interface of phases in a liquid medium, in situ polymerization, drying in a liquid medium and desolately in a liquid medium. In addition, can also be applied in other ways, such as the compaction roller, the pressing/spheronization, coacervation or coated nanoparticles.

In other embodiments also produce effervescent powders according to the present description. Effervescent salts were used for the dispersion of drugs in water prior to oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture usually composed of sodium bicarbonate, citric acid and/or tartaric acid. By dissolving these salts in water is the interaction of acids and bases from vysvobozhdenijah carbon dioxide what causes "hiss". Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Instead of the combination of sodium bicarbonate and citric and tartaric acids can be used any combination of acids and bases, resulting in the release of carbon dioxide, provided that the ingredients are suitable for pharmaceutical applications and lead to a pH of about 6.0 or higher.

In other embodiments of the compositions described herein containing compound described herein are solid dispersion. Methods for such solid dispersions known in the art and include, without limitation, for example, U.S. patents№№4343789, 5340591, 5456923, 5700485, 5723269 and publication of U.S. patent No. 2004/0013734. In other embodiments of the compositions described herein are solid solutions. Such solutions contain a substance together with the active agent and other excipients such a way that heating of the mixture leads to the dissolution of the medicinal product, and the resulting composition is then cooled to obtain a solid mixture, which can then be processed or directly added to the capsule, or extruded to obtain pellets. Methods for such solid solutions of the local in the art and include, without limitation, for example, U.S. patent No. 4151273, 5281420 and 6083518.

The pharmaceutical solid dosage forms, including compositions described herein containing the compound of formula (I), (II), (IIA) or (IIB)described herein, can then be processed to provide a controlled release of the compounds of formula (I), (II), (IIA) or (IIB). Controlled release refers to the release of the compounds of formula (I), (II), (IIA) or (IIB)described herein containing dosage forms in accordance with the desired profile over an extended period of time. Profiles of controlled release include, for example, profiles prolonged release, sustained release, intermittent release and delayed release. In contrast to the compositions immediate-release compositions with controlled release make possible the delivery agent to a subject over an extended period of time in accordance with a predetermined profile. Such speed of release can provide therapeutically effective levels of the agent over an extended period of time and, through this, to provide a longer period of pharmacological response, minimizing, at the same time, the side effects compared to conventional dosage forms with quick release is. Such long periods of response provide many of the benefits inherent in such compositions, unattainable appropriate short-acting preparations immediate-release.

In some embodiments, solid dosage forms described herein may be made in the form of dosage forms for oral dosage forms with delayed release, enteric-coated surface, in the form of dosage forms of the pharmaceutical compositions as described herein for oral administration, which used enteric coated to effect the release in the small intestine of the gastrointestinal tract. Dosage form with an enteric coating can be an extruded or molded, or extruded tablet form (coated or uncoated)containing granules, powder, beads, granules or particles of the active ingredient and/or other components of the composition, which themselves have a coating or no coating. Dosage form for oral administration with the enteric coating may also be a capsule (coated or uncoated)containing pellets, grains or granules of the solid carrier or composition, which themselves are coated or have no coverage.

When used herein, the term "C the slow release" refers to such delivery, that release can be carried out in a in most cases predictable place intestine, distal, than it could be implemented in the absence of changes, resulting in slow release. In some embodiments of the method of slow release coating. Any coating should be applied with sufficient thickness such that the entire coating does not dissolve in the fluids of the gastrointestinal tract at pH below about 5, but at pH of about 5 and above. Coatings can be made of the following substances.

Acrylic polymers. Properties of acrylic polymers (especially their solubility in biological fluids) can vary depending on the degree and type of substitution. Examples of substituted acrylic polymers include copolymers of methacrylic acid and copolymers of methacrylate ammonium. Available series Eudragit E, L, S, RL, RS and NE (Rohm Pharma) as solubilization in an organic solvent, aqueous dispersion or dry powders. Series Eudragit RL, NE and RS insoluble in the gastrointestinal tract, but permeable, and they are used mainly for delivery to the colon. Series Eudragit E is dissolved in the stomach. Series Eudragit L, L-30D and S is insoluble in the stomach and dissolve in the intestine.

Derivatives of cellulose. Examples of suitable derivatives of the cellulite, tighten the PS are ethylcellulose, the reaction mixture partial acetate of cellulose esters and anhydride and phthalic acid. Properties can vary depending on the degree and type of substitution. Acetate-cellulose phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water system and are dried by spray drying SAR-pseudolarix with particles <1 μm. Other components Aquateric may include pluronic (pluronics), varieties of Tween and acetylated monoglycerides. Other suitable cellulose derivatives include: acetate-trimellitate cellulose (Eastman); methylcellulose (Pharmacoat, Methocel); phthalate of hydroxypropylmethylcellulose (NRSR); succinate of hydroxypropylmethylcellulose (HPMCS); and acetate-succinate of hydroxypropylmethylcellulose (for example, AQOAT (Shin Etsu)). Properties can vary depending on the degree and type of substitution. For example, NRMS, such as brand HP-50, HP-55, HP-55S, HP-55F, is appropriate. Properties can vary depending on the degree and type of substitution. For example, suitable marks acetate-succinate of hydroxypropylmethylcellulose include, without limitation, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), soluble at higher pH. These polymers are presented in the form of granules or fine powders for aqueous dispersions.

The polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH>5 that is, it is much less permeable to water vapor and gastric juice.

In some embodiments, the coating can contain, and usually contains a plasticizer and, optionally, other excipients to cover, such as dyes, talc and/or magnesium stearate, well known in the art. Suitable plasticizers include triethylcitrate (Citroflex 2), triacetin (glyceryltrinitrate), acetylcarnitine (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethylphthalate, tributyltin, acetylated monoglycerides, glycerol esters of fatty acids, propylene glycol, and dibutyl phthalate. In particular, anionic polymers of acrylic acid will usually contain 10-25% by weight of plasticizer, mainly, dibutyl phthalate, polyethylene glycol, triethylcitrate and triacetin. Coating used conventional methods of coating, such as spray coating or the application shell. The shell thickness must be sufficient to ensure the intact status of the dosage form for oral administration to achieve the desired area local delivery in the intestine.

In addition to the plasticizers in the coatings can be added dyes, substances that reduce the stickiness, surfactants, defoamers, lubricants (for example, Carnauba wax or PEG) for solubilization or dispersion of the substance of the coating and to improve the coating properties and the aircraft is on the product.

In other embodiments, the delivery compositions described herein containing the compound of formula (I), (II), (IIA) or (IIB)described herein is performed with the use of the dosage form with intermittent release. Dosage form with intermittent release can provide one or more than one pulse for immediate release at a predetermined time after a controlled delay period or in certain places. Dosage forms with intermittent release can be entered using a variety of compositions with intermittent release, known in the art. For example, such compositions include, without limitation, the compositions described in U.S. patents№№5011692; 5017381; 5229135; 5840329; 4871549; 5260068; 5260069; 5508040; 5567441 and 5837284.

Many types of systems controlled release are suitable for use with the compositions described herein. Examples of such delivery systems include, for example, systems based on polymers such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrix system, not based on polymers constituting lipids, including sterols such as cholesterol esters cholesterol and fatty acids or neutral fats such as mono-, di - and triglycerides; hydrogel system release; forces konoye system; system-based peptides; wax coatings, pharmaceutical form, susceptible to biological degradation, compressed tablets using conventional bonding agents and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2nd Ed., Vol.1, pp.209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.751-753 (2002); U.S. patent№№4327725; 4624848; 4968509; 5461140; 5456923; 5516527; 5622721; 5686105; 5700410; 5977175; 6465014; and 6932983.

In some embodiments of the proposed pharmaceutical composition containing particles of the compounds described herein, e.g. compounds of formula (I), (II), (IIA) or (IIB), and at least one dispersing agent or suspendisse agent, for oral administration to a subject. The composition can be a powder and/or granules for suspension, and when mixed with water, get essentially homogeneous suspension.

Liquid dosage forms of the compositions for oral administration can be an aqueous slurry selected from the group including, without limitation, pharmaceutically acceptable aqueous dispersions, emulsions, solutions, elixirs, gels and syrups for oral administration. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757 (2002).

Aqueous suspensions and dispersions described herein may maintain a homogeneous state, as defined in the USP (edition 2005, Chapter 905), at least for 4 hours. D the heterogeneity distorts should be determined by the method of sampling, the relevant definition of homogeneity of the entire composition. In one embodiment the aqueous slurry can be resuspendable with the formation of a homogeneous suspension of physical mixing duration less than 1 minute. In another embodiment the aqueous slurry can be resuspendable with the formation of a homogeneous suspension of physical mixing less than 45 seconds. In yet another embodiment the aqueous slurry can be resuspendable with the formation of a homogeneous suspension of physical mixing duration less than 30 seconds. In yet another embodiment, the stirring is not necessary to maintain a homogeneous aqueous dispersion.

The pharmaceutical compositions described herein may include sweeteners, such as, without limitation, syrup Arabian gum, Acesulfame K, alitum, anise, Apple, aspartame, banana, fruit, milk jelly with whipped cream, berries, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, Cola, chilled cherry, cool citrus, cyclamate, CIEMAT (cyclamate), dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, syrup of licorice (liquorice), grape, grapefruit, honey, isomalt, lemon, lime, lemon CR is m, the glycyrrhizinate of monoamine (MagnaSweet®), maltol, mannitol, maple, marsh mallow, menthol, mint cream, berry blend, neohesperidin DC, NOTAM, orange, pear, peach, peppermint, cream peppermint, Prosweet® Powder, raspberry fizzy drink from the roots, rum, saccharin, safrole, sorbitol, spearmint, mint cream curly, strawberry, strawberry cream, Peconic krapivinsky, Sucralose, sucrose, saccharin sodium, saccharin, aspartame, Acesulfame potassium, mannitol, Talin, Sucralose, sorbitol, Swiss cream, tagatose, Mandarin, thaumatin, candied fruits, vanilla, walnut, watermelon, cherry, gaultheria, xylitol, or any combination of these corrigentov, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

In some embodiments the pharmaceutical compositions described herein may be a self emulsifiable system drug delivery (SEDDS). Emulsion is a dispersion of one immiscible phase to another, usually in the form of drops. In most cases, the emulsion receive intensive mechanical dispersion. SEDDS, unlike emulsions or microemulsions spontaneously form an emulsion when added to excess water, without any external mechanical dispersion the treatment or mixing. The advantage of SEDDS is that for the distribution of the drops in the solution should only mild agitation. In addition, the water or aqueous phase may be added directly to the introduction, which provides stability unstable or hydrophobic active ingredient. Thus, SEDDS provides an effective delivery system for oral or parenteral delivery of hydrophobic active ingredients. SEDDS can improve the bioavailability of hydrophobic active ingredients. Methods of making self emulsifiable dosage forms known in the art and include, without limitation, for example, U.S. patent No. 5858401, 6667048 and 6960563.

It should be understood that the above-listed additives used in the aqueous dispersions or suspensions described here overlap, since different experts in this field of technology are often various classifications specific additive or the additive usually used for any of several different functions. Thus, the above additives should be considered solely as non-limiting examples of the types of additives that can be included in the compositions described herein. Specialist in the art can easily determine the amount of these additives in accordance with the specific desire is considered the property.

In the art known compositions for intranasal, and they are described, for example, in U.S. patent No. 4476116, 5116817 and 6391452. The compositions containing the compound described here, manufactured in accordance with these and other techniques well known in the art, are made in the form of solutions in saline solution using benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, N. S. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and preparations made using suitable non-toxic pharmaceutically acceptable ingredients. These ingredients are known to specialists in the manufacture of dosage forms for nasal administration, and some of them can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, which is the standard reference in this field of technology. The selection of appropriate media largely depends on the nature of the desired nasal dosage forms, for example, solutions, suspensions, ointments or gels. Nasal dosage forms in most cases contain significant amounts of water in addition to the active ingredient. May also be present small the number of other ingredients, such as pH correctors, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents or buffer or other stabilizing and solubilizing agents. Preferably nasal dosage form should be isotonic nazalnam secrets.

For administration by inhalation the compounds described herein may be presented in the form of an aerosol, mist or powder. Delivery of the pharmaceutical compositions described herein are suitably carried out in the form of getting sprayed aerosol from the package under pressure or a nebulizer with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure, the unit dose can be determined by valve for delivering metered quantities. Can be made capsules and cartridges of, such as, only as an example, gelatin for use in an inhaler or insufflator containing a powder mix of the compound described herein and a suitable base powder, such as lactose or starch.

Compositions for transbukkalno introduction, containing compounds described herein may be introduced using a variety of compositions known in the art. For example, the hat song include, without limitation, U.S. patent No. 4229447, 4596795, 4755386 and 5739136. In addition, dosage forms for transbukkalno introduction, described herein, can optionally contain susceptible to biological degradation (hydrolyzable) polymeric carrier, which also contributes to the adhesion of the dosage form to the mucosal lining of the cheeks. Dosage form for transbukkalno introduction is made so that it gradually fell apart within a predefined period of time, the delivery connection is provided over essentially the entire specified period. As will be clear to experts in the field of technology, transbukkalno the drug delivery avoids the disadvantages associated with oral drug delivery, for example, slow suction, destruction of the active agent of the fluids present in the gastrointestinal tract, and/or inactivation during the first passage through the liver. Against susceptible to biological degradation (hydrolyzable) polymeric carrier, it should be understood that it may be used for virtually any such carrier, provided that it does not harm the desired release profile of the medicinal product and that the media is compatible with the compound of the formula (I), (II), (IIA) or (IIB)described herein, and any is mi other components, which may be present in a unit dose for transbukkalno introduction. In most cases, the polymeric carrier contains a hydrophilic (water-soluble and swellable in water) polymers, adgesiruta to wet the surface of the buccal mucosa. Examples of polymeric carriers, are applicable here, include polymers and copolymers of acrylic acid, for example, known as "carbomer" (one such polymer is Carbopol®, which can be obtained from B.F. Goodrich). In dosage forms for transbukkalno introduction, described herein, may also include other components, including, without limitation, disintegrating agents, diluents, binders, lubricants, corrigentov, dyes, preservatives, and the like. For transbukkalno or sublingual injection composition can be in the form of tablets, pellets or gels, made in the usual way.

Composition for transdermal administration, described here, can be entered using a variety of devices described in the art. For example, such devices include, without limitation, U.S. patent№№3598122, 3598123, 3710795, 3731683, 3742951, 3814097, 3921636, 3972995, 3993072, 3993073, 3996934, 4031894, 4060084, 4069307, 4077407, 4201211, 4230105, 4292299, 4292303, 5336168, 5665378, 5837280, 5869090, 6923983, 6929801 and 6946144.

Dosage forms for transdermal administration, described here, can counter the AMB certain pharmaceutically acceptable excipients, conventional in the art. In one embodiment of the composition for transdermal administration, described herein include at least three components: (1) the composition of compounds of formula (I), (II), (IIA) or (IIB); (2) a substance that promotes penetration; and (3) an aqueous adjuvant. In addition, the composition for transdermal administration, described herein may include additional components, such as, without limitation, gelling agents, fundamentals of creams and ointments and the like. In some embodiments, the composition for transdermal injection can optionally include a tissue or netchenawoe the basis for stronger suction and prevent removal of the composition for the transdermal injection of the skin. In other embodiments of the composition for transdermal administration, described here, is able to maintain a saturated or supersaturated state to stimulate diffusion into the skin.

In the compositions suitable for transdermal administration of compounds described herein may be used in devices for transdermal delivery and plasters for transdermal delivery, and these songs can be a lipophilic emulsions or tebufelone aqueous solutions, dissolved and/or dispersed in the polymer or binding substance. Such patches can be designed for continuous, Prieur what vistas delivery of pharmaceutical agents or delivery of pharmaceutical agents on demand. Moreover, transdermal delivery of the compounds described herein can be implemented by ionophoretically patches and the like. In addition, the TRANS-dermal patches can provide controlled release of the compounds of formula (I), (II), (IIA) or (IIB)described herein. The absorption rate can be reduced with the use of rate-controlling membranes or by capture compound in a polymer matrix or gel. On the contrary, to increase the suction can be used amplifiers suction. Power suction or media may contain absorbable pharmaceutically acceptable solvents to facilitate the passage through the skin. For example, devices for transdermal injection presented in the form of a bandage containing a base, a reservoir containing the compound, possibly with the media, perhaps the rate-controlling barrier to deliver the compound into the skin of the host with a controlled predetermined rate over an extended period of time and a means of attaching the device to the skin.

Composition suitable for intramuscular, subcutaneous or intravenous injection may contain pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for the recovery of sterilized the solutions or dispersions for injection. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, cremophor (cremophor), and the like) suitable mixture, vegetable oils (such as olive oil) and organic esters for injection, such as etiloleat. Proper fluidity can be maintained, for example, by applying a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The composition is suitable for subcutaneous injection, may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. Preventing the growth of microorganisms can provide various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Also, it may be desirable inclusion isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of dosage forms for injection may be due to the use of agents delaying absorption, such as aluminum monostearate and gelatin.

For intravenous injection of the compounds described herein may be prepared in aqueous solutions, preferably in physiologist who Cesky compatible buffers, such as Hanks solution, ringer's solution or saline. For insertion through the mucous membranes in the composition is the use of substances that promote penetration, suitable for overcoming the barrier. In most cases, these substances promoting the penetration, known in the art. For other parenteral injections, appropriate composition may include an aqueous or non-aqueous solutions, preferably physiologically compatible buffers or excipients. Such excipients in most cases known in this technical field.

Parenteral injection may include bolus injection or continuous infusion. Compositions for injection can be presented in a standard dosage form such as capsules or containers for a few doses, with added preservative. The pharmaceutical composition described herein, can be represented in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous fillers and may contain agents for the manufacture of dosage forms, such as suspendresume agents, stabilizers and/or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In opalanie, suspensions of the active compounds can be produced in a form suitable oil suspensions for injection. Suitable lipophilic solvents or fillers include non-volatile oils such as sesame oil, or synthetic esters of fatty acids, such as etiloleat, or triglycerides, or liposomes. Aqueous suspension for injection may contain substances which increase the viscosity of the suspension, such as carboxymethylcellulose sodium, sorbitol, or dextran. Perhaps the suspension may also contain suitable stabilizers or agents which increase the solubility of compounds in order to make possible the preparation of highly concentrated solutions. Alternatively, the active ingredient can be provided in powder form for reconstitution in a suitable filler, such as sterile pyrogen-free water, before use.

In certain embodiments can be used in the delivery of pharmaceutical compounds, such as, for example, liposomes and emulsions. In certain embodiments of the compositions, proposed here, can also contain mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (polymer of acrylic acid), poly(methylmethacrylate), polyacrylamide, polycarbophil, copolymer of acrylic acid and butyl acrylate, the sodium alginate is dextran.

In some embodiments of the compounds described herein may be introduced locally and can be made in the form of a variety of compositions for local administration, such as solutions, suspensions, lotions, gels, pastes, medicated spatulas, balms, creams or ointments. Such pharmaceutical compositions may contain soljubilizatory, stabilizers, agents that increase toychest, buffers and preservatives.

Compounds described herein may also be made in the form of compositions for rectal administration, such as enemas, gel for rectal administration, foam for rectal administration, aerosols for rectal administration, suppositories, gel suppositories or retention enemas, containing conventional suppozitornoj bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In the form of compositions in the form of suppositories first melting a low-melting wax, such as, without limitation, a mixture of glycerides of fatty acids, possibly in combination with cocoa butter.

In most cases the agent, such as a compound of formula (I), (II), (IIA) or (IIB), is injected in a quantity effective to improve the disease or disorder or prevent the development of symptoms (that is therapeutically effective amount). In affect, the, therapeutically effective amount may be an amount capable of at least partially preventing a disease or disorder or to reverse it. The dose required to achieve effective amount can vary depending on the agent, composition, disease or disorder, and the individual who administered the agent.

Determination of effective amounts may also include in vitro, in which different doses of the agent is introduced into cells in culture and determine the concentration of the agent, effective to improve some or all of the symptoms, to calculate the concentration required in vivo. The effective amount may also be based on animal studies in vivo.

The agent can be introduced before, during or after the onset of symptoms or disorders. In some embodiments the agent is administered to a subject with a family history of the disease or disorder, or with the phenotype, which may indicate a predisposition to the disease or disorder or having the genotype, because of which the subject is predisposed to the disease or disorder.

The delivery system may depend on a number of factors, including, for example, the estimated target and route of administration, such as local or systemic. Targets for delivery can in order to predstavljati certain cells, which is the cause of the disease or disorder or contributing to the disease or disorder, including, for example, cells with altered intracellular calcium or impaired regulation of calcium or disturbed calcium homeostasis, and cells that do not have altered intracellular calcium, but which may have some changes, defect or failure, which can be, at least partially, offset, offset, exposed to reverse the development or weakened by changes in intracellular calcium cells. Specific cells include, for example, immune cells (e.g. lymphocytes, T-cells, b-cells, leukocytes, fibroblasts or cells, originating from fibroblast)cells of the epidermis, the cells of the dermis or skin (e.g., keratinocytes), blood cells, kidney cells or kidney cells (e.g., mesangial cells), muscle cells (e.g., smooth muscle cell, such as smooth muscle cell of the respiratory tract (trachea or bronchi)), excretory or secretory cells (e.g. cells of the salivary glands, including cells of the parotid salivary gland the cells of the acini and cells of the submandibular salivary gland). For example, the cell-target can be a resident or infiltrating cells of the lungs or respiratory tract, contributing to asthma, re identne or infiltrating cells of the nervous system, contributing to neurological, neurodegenerative or demyelinizing disease or disorder, resident or infiltrating cells involved in graft rejection kidney, transplanted cells, activation of which leads to graft versus host, resident or infiltrating cells involved in graft rejection kidney, resident or infiltrating cells, activation of which contributes to inflammation, for example, arthritis, resident or infiltrating cells of the kidney or urinary system (for example, mesangial cells)involved in neuropathy and glomerulonephritis, and the resident or infiltrating cells of the exocrine glands (e.g., salivary and lacrimal glands), involved in autoimmune disorders (e.g., sjögren's disease). The introduction of the agent can be directed to one or more than one type of cells or a subset of cell types by methods known to experts in this field of technology. For example, the agent may be associated with an antibody, ligand receptor on the cell surface or toxin, or may be enclosed in the particle selectively captured by the cells, such as liposomes or virus in which the viral receptor-specific binds a specific cell type or virus particle without viral nucleic acid, ilimage to be introduced locally.

Examples of routes of administration and treatment regimens for

Compounds described herein may be used in the compositions of drugs for the modulation of intracellular calcium or treatment of diseases or conditions in which it will be useful, at least in part, modulation of intracellular calcium. In addition, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment, involves the introduction of a specified subject pharmaceutical compositions containing at least one compound described herein, or its pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES in therapeutically effective amounts.

The compositions containing the connection (connection)described herein can be entered for prophylactic and/or therapeutic treatment. In therapeutic applications, compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partial suppression of the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's condition, body weight and response to drug means the and opinion of the treating physician.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to a specific disease, disorder or condition, or, otherwise, the patient with the risk of such disease, disorder or condition. This number is defined as a "prophylactically effective amount or dose". In such applications the exact amount also depends on the state of health of the patient, body weight and the like. When applying the patient an effective amount for such use, will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's condition, body weight and response to medications and opinions of the treating physician.

In the absence of improvement of the patient at the discretion of the physician possibly prolonged use of compounds, that is, over a long period of time, including the application throughout the life of the patient, to improve or otherwise control or limit the symptoms of the disease or condition in a patient.

In case of improving the condition of the patient at the discretion of the physician possible permanent connections; alternatively, the dose of the drug may be temporarily lowered or the medicine may be temporarily pre is grown for a specific period of time (i.e. "stay away from drugs"). The duration of the "vacation from medication can vary from 2 days to 1 year, including, solely as an example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. The dose reduction during a break from drugs" can be from about 10% to about 100%, including, solely as an example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100%.

While improving the health of the patient enter a maintenance dose if needed. Then, the dose and frequency of administration, or both, can be reduced as a function of the symptoms, to a level which maintains the improved disease, disorder or condition. However, when the recurrence of symptoms for the patient may be necessary intermittent treatment on a long term basis.

The number of times a given agent that will correspond to such an amount will vary depending on the specific compound, disease or condition and its severity, the individual parameters (e.g. body weight) of the subject or host in need of treatment, but, nevertheless, can be determined by a method known in the art, in accordance with the specific circumstances of the case, including, for example, a particular input agent, route of administration, the condition, about which treatment, and the subject or host being treated. In most cases, however, the doses used for the treatment of adult will normally be from about 0.02 to about 5000 mg per day, in some embodiments from about 1 to about 1500 mg per day. The desired dose may appropriately be represented in the form of a single dose or in divided doses administered simultaneously (or over a short period of time) or with suitable intervals, for example, in the form of two, three, four or more doses per day.

The pharmaceutical composition described herein may be presented in a standard dosage forms suitable for single administration of certain doses. In a standard dosage form, the composition is divided into standard doses containing appropriate quantities of one or more connections. The standard dose may be in the form of packaging, steriade the discrete quantity of the composition. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Compositions in the form of aqueous suspensions can be Packed in beyond re-sealing containers per dose. Alternatively, it may be used preventable re-sealing the containers in multiple doses, in which case the composition typically includes a preservative. Solely as an example, compositions for parenteral injection may be presented in a standard dosage form, including, without limitation, ampoules or containers in multiple doses with added preservative.

Described here daily dose, appropriate for the compounds described herein are from about 0.01 mg/kg to about 20 mg/kg In one embodiment, the daily dose is from about 0.1 mg/kg to about 10 mg/kg of the Indicated daily dose large mammal, including, without limitation, humans, is from about 0.5 mg to about 1000 mg, and appropriately administered in the form of a single dose or in divided doses, including, without limitation, up to four times per day, or in the form of slow release. Suitable standard dosage forms for oral administration contain from about 1 to about 500 mg Akti is the main ingredient. In one embodiment, the standard dose is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. of the above ranges are only approximate, because the number of variables in relation to individual schemes of treatment is high, and significant deviations from these recommended values are not unusual. Such doses may be changed depending on several variables, including, without limitation, the activity of the used compound, disease or condition about which treatment, route of administration, the requirements of the individual subject, the severity of the disease or condition about which treatment, and the opinion of the practitioner.

Toxicity and therapeutic efficacy of such regimens can be determined by standard pharmaceutical methods in cell cultures or experimental animals, including, without limitation, the determination of the median lethal dose (LD50) (the dose lethal to 50% of the population) and the mean effective dose (ED50) (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is a tera is efticiency index and can be expressed as the ratio between LD 50and ED50. Preferred compounds demonstrating high therapeutic indices. The data obtained in the tests on cell cultures and animal studies, can be applied in the determination of the dose range for use in humans. The dosage of such compounds is usually in the range of concentrations in circulating blood, including ED50with minimal toxicity. The dosage may vary within this range depending on the dosage form and the applicable route of administration.

Combined treatment

The compounds of formula (I), (II), (IIA) or (IIB) and their compositions can also be applied in combination with other well known therapeutic agents that are selected for their therapeutic value for the condition to be treated. In most cases there is no need to introduce the compositions described herein, and, in embodiments, which used a combination therapy with other agents in the same pharmaceutical composition, and, because of different physical and chemical properties, it may be necessary to enter them in different ways. Determination of the route of administration and the advisability of introducing in the same pharmaceutical composition, where possible included in the scope of knowledge of a qualified practitioner. First weeniedom to be carried out according to established protocols known in the art, and then, on the basis of the observed effects, a qualified practicing doctor may change the dose, route of administration and time of administration.

In some cases it may be appropriate to introduce at least one compound of formula (I), (II), (IIA) or (IIB)described herein in combination with another therapeutic agent. Solely as an example, if one of the side effects which are experienced by the patient during introduction of the compounds described herein, such as the compound of formula (I), (II), (IIA) or (IIB), is nausea, then it may be appropriate introduction agent from nausea in combination with the first therapeutic agent. Or, solely as an example, therapeutic efficacy of the compounds described herein can be increased by the introduction of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is increased). Or, solely as an example, the benefits provided to the patient, may be increased by the introduction of one of the compounds described herein with another therapeutic agent (which also includes the treatment regimen)that also has a useful therapeutic effect. In any case, regardless of the disease, RA the disorder or condition, about which treatment, the overall beneficial effect on the patient, may simply be an additive effect of the two therapeutic agents or the patient may be provided a synergistic beneficial effect.

The specific choice of the used compounds will depend on the diagnosis of the attending physicians and their opinions about the state of the patient and the appropriate treatment Protocol. The compounds can be administered simultaneously (e.g., simultaneously, essentially simultaneously or within the same treatment Protocol) or sequentially, depending on the nature of the disease, disorder or condition, the patient's condition and the actual choice of the used compounds. Determination of the order of introduction and the number of re-introductions of each therapeutic agent for the treatment Protocol included in the scope of knowledge of a qualified physician after evaluation of the disease, about which treatment, and the patient's condition.

A therapeutically effective dose may vary with the use of drugs in the treatment combinations. Methods of experimental determination of therapeutically effective doses of drugs and other agents for use in the circuits of the combined treatment described in the literature. For example, in the literature actively describe the application of regular is sirovaniya, that is, providing more frequent introduction of smaller doses to minimize toxic side effects. Combinational treatment additionally includes periodic courses of treatment, starting and ending at different times, contributing to the treatment of the patient.

For the combined treatment described here, the dose jointly commissioned compounds will of course vary depending on the type used in conjunction input medicines from specific applicable medicines from a disease or condition about which treatment, and so forth. In addition, when the joint introduction of one or more than one biologically active agent connection suggested here, may be administered either simultaneously with the biologically active agent (agents), or sequentially. The sequential introduction of the treating physician will determine the appropriate sequence of introduction of the protein in combination with a biologically active agent (agents).

In any case, the multiple therapeutic agents (one of which is a compound of formula (I), (II), (IIA) or (IIB)described herein) may be entered in any order or even simultaneously. With the simultaneous introduction of multiple therapeutic agents may be presented in one single form or the short form (for example, either in the form of one pill, or in the form of two separate pills). One of therapeutic agents can be entered in multiple doses, or both can be entered in multiple doses. Non-simultaneous with the introduction of time between multiple doses can vary from more than zero weeks to less than four weeks. In addition, combination methods, compositions and preparations should not be restricted to the use of only two agents; they also involve the use of multiple therapeutic combinations.

It is clear that the regimen of medicines for the treatment, prevention or improvement of a state (States), the relief of which is directed admission medication may be changed in accordance with many factors. These factors include the disorder or condition that affects the entity, as well as the age, body weight, gender, nutrition and health status of the subject. Thus, in fact, used regimen medicines can vary within wide limits and, therefore, may differ from the diagrams of medication provided here.

Pharmaceutical agents comprising the combination therapy disclosed herein may be a combined dosage form or be presented in a separate dosage forms, p is jednoznacnih for essentially simultaneous administration.

Pharmaceutical agents comprising the combination therapy may also be introduced consistently with any therapeutic compound, administered according to the scheme, requiring two-stage injection. The scheme of two-stage injection may require sequential introduction of active agents or separate introduction of a separate active agents. The period of time between multiple stages of injection can vary from several minutes to several hours, depending on the properties of each pharmaceutical agent, such as activity, solubility, bioavailability, half-life in plasma and kinetic profile of the pharmaceutical agent. Diurnal variations in the concentration of a target molecule can also determine the optimal interval between doses.

In addition, the compounds described herein may also be applied in combination with the methods, which can provide the patient with additive or synergistic beneficial effect. Solely as an example, expect that the methods described here, patients will receive therapeutic and/or prophylactic beneficial effect, where the pharmaceutical composition of the compounds disclosed here, and/or combination with other therapeutic agents combined with a genetic study to determine whether individuelles mutant gene, for known correlation with certain diseases and disorders.

Compounds described herein, and combined treatment can be applied before, during or after the onset of illness or condition, and time of introduction of the composition containing a compound can vary. Thus, for example, the compounds can be applied as a preventive, and can be extended to introduce subjects with a propensity to develop conditions or diseases to prevent disease or condition. Compounds and compositions can be administered to the subject if symptoms occur or as soon as possible after symptoms appear. Introduction connections can be initiated within the first 48 hours from the time of onset of symptoms, preferably within the first 48 hours from the time symptoms appear, more preferably within the first 6 hours of the onset of symptoms, and most preferably within the first 3 hours after onset of symptoms. The first injection can be carried out in any feasible way of introduction, such as, for example, intravenous injection, bolus injection, infusion over approximately 5 minutes to about 5 hours, a pill, capsule, patch for transdermal administration, transbukkalno shipping and the like, or the combination. The compound is preferably administered as soon as possible after detection or occurrence of the suspected onset of the disease or condition and within the time required for the treatment of diseases, as for example from 1 day to about 3 months. The duration of treatment may vary for each subject, and the duration may be determined using known criteria. For example, the compound or composition containing the compound, you can enter for at least 2 weeks, preferably from about 1 month to about 5 years.

Inhibitors of SOCE

In one aspect, the compounds of formula (I), (II), (IIA) or (IIB) can be introduced or applied in combination with other known inhibitors of SOCE. In one aspect, the known inhibitors of SOCE are non-selective inhibitors. In one aspect, the known inhibitors of SOCE are selective inhibitors.

It has been described many inhibitors of SOCE. Known inhibitors of SOCE include:

a) cations, including cations of the lanthanides, such as, for example, Gd3+La3+;

b) inhibitors of P-450, including econazole, miconazole, clotrimazole, ketoconazole;

C) cyclo-oxygenase inhibitors, including niflumova acid, flufenamic acid, tenidap;

g) inhibitors of lipoxygenase, including nordihydroguaiaretic acid, akosut trenova acid;

e) compounds, which are blockers of channels, including SK&F 96365, SC38249, LU52396, L-651,582, tetrandrine, 2-aminoethoxyethanol (2-ARV);

e) compounds that inhibit SOCE, not acting on SOC channels themselves, including U73122 (an inhibitor of phospholipase C), wortmannin (inhibitor phosphatidylinositides).

Some of these known inhibitors of SOCE have non-specific effects and/or multiple mechanisms of action that contribute to inhibition of SOCE, including the blockage of pores SOC channel (channel blockers), inhibition of mitochondrial synthesis of adenosine triphosphate (ATP), apparently contributing to SOCE (Gamberucci et al., J Biol. Chem., 269, 23597-23602, 1994; Marriott et al., Am. J. Physiol., 269, C766-C774, 1995), changes in cytoplasmic pH (Muallem et al., Am. J. Physiol., 257, G917-G924, 1989), and inhibition of the activation of SOC channels.

Immunosuppressants

In one embodiment of compounds of formula (I), (II), (IIA) or (IIB) is administered as a single agent with immunosuppressive therapy to reduce, inhibit or prevent activity of the immune system. In clinical practice immunosuppressive therapy is used to: prevent rejection of transplanted organs and tissues (e.g. bone marrow, heart, kidney, liver); the treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., the roar of atomnogo arthritis, heavy pseudoparallelism gravis, systemic lupus erythematosus, Crohn's disease and ulcerative colitis); and treatment of some other pautakan inflammatory diseases (e.g., long-term control of allergic asthma).

In some embodiments of compounds of formula (I), (II), (IIA) or (IIB) can be entered with other immunosuppressive agents selected from: calcineurin inhibitors (such as, without limitation, cyclosporine, tacrolimus); inhibitors of the target of rapamycin mammalian (mTOR) (such as, without limitation, sirolimus, everolimus); anti-proliferative drugs (such as, without limitation, azathioprine, mycofenolate acid); corticosteroids (such as, without limitation, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, acetate fludrocortisone, acetate hypertension, aldosterone, hydrocortisone); antibodies (such as, without limitation, monoclonal antibodies against recetor IL-2Rα (basiliximab, daclizumab), polyclonal antibodies against T cells (antithymocyte globulin (ATG), antilimfocitarnyi globulin (ALG))).

Other immunosuppressants include, without limitation: glucocorticoids (alclometasone, aldosterone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, KLO is Amazon, clocortolone, cloprednol, cortisone, cortisol, deflazacort, hypertension, desonide, desoximetasone, detoxication, dexamethasone, diflorasone, diflucortolone, difluprednate, fluchloralin, fludrocortisone, fludroxycortide, flumetazon, flunisolide, acetonide fluoqinolona, fluocinonide, fluocortin, fluocortolone, formation, flaperon, flupredniden, fluticasone, farmacita, halcinonide, halobetasol, hydrocortisone/cortisol, aceponate hydrocortisone, balarat hydrocortisone, hydrocortisone butyrate, loteprednol, Madison, meprednisone, methylprednisolone, aceponate methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisone, prednisolone, prednisone, rimexolone, tixocortol, triamcinolon, WebEasy), cyclophosphamide, nitrosamine, cisplatin, carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogues, inhibitors of protein synthesis, methotrexate, azathioprine, mercaptopurine, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, Atgam(R), Thymoglobuline®, OKT3®, basiliximab, daclizumab, cyclosporine, tacrolimus, sirolimus, interferons (IFN-β, IFN-γ), opioids, TNF-binding proteins (infliximab, etanercept, adalimumab, golimumab), mycophenolate acid, mycophenolate mofetil, FTY720 and also listed in the US 7060697.

Agents for the treatment of autoimmune diseases, Pospolita the data

diseases

Where the subject suffers from or has the risk of suffering an autoimmune disease, disorder or condition, or an inflammatory disease, disorder or condition, the compound of formula (I), (II), (IIA) or (IIB) may be entered in any combination with one or more of the following therapeutic agents: immunosuppressants (eg, tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, microphenomena or FTY720), glucocorticoids (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, acetate fludrocortisone, acetate hypertension, aldosterone), nonsteroidal anti-inflammatory drugs (e.g. salicylates, arylalkenes acid, 2-arylpropionic acids, N-allantaylor acids, oxycam, coxibs or sulfonanilide), specific inhibitors of cyclooxygenase-2 (SOH-2) (for example, valdecoxib, etoricoxib, lumiracoxib, celecoxib or rofecoxib), Leflunomide, gold-thioglucose, gold-thiomalate, ourofino, sulfasalazin, hydroxyarginine, minocycline, TNF-α-binding proteins (e.g., infliximab, etanercept or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, and is of telenational, theophylline or anticholinergic agents.

In one embodiment of compounds of formula (I), (II), (IIA) or (IIB)described herein can be introduced in combination with inhibitors of NFAT-calcineurin way. In one embodiment the inhibitors of NFAT-calcineurin pathways include, without limitation, cyclosporin A (CsA) and tacrolimus (FK506).

In one embodiment the compound of formula (I), (II), (IIA) or (IIB), or compositions and medicaments containing a compound of the formula (I), (II), (IIA) or (IIB)can be administered to the patient in combination with an anti-inflammatory agent, including, without limitation, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).

NSAIDs include, without limitation, aspirin, salicylic acid, entityname acid, choline salicylate-magnesium, choline salicylate, choline salicylate-magnesium, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluoroborate, ibuprofen, Ketoprofen, nauton (nabutone), Ketorolac, tromethamine Ketorolac, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamico acid, piroxicam, meloxicam, specific inhibitors MOR-2 (such as, without limitation, celecoxib, rofecoksib, valdecoxib, parecoxib, etoricoxib, lumira is xib, CS-502, JTE-522, L-745,337 and NS398).

Here the considered combination with NSAID representing selective inhibitors SOH-2. Such compounds include, without limitation, disclosed in U.S. patent No. 5474995; U.S. patent No. 5861419; U.S. patent No. 6001843; U.S. patent No. 6020343; U.S. patent No. 5409944; U.S. patent No. 5436265; U.S. patent No. 5536752; U.S. patent No. 5550142; U.S. patent No. 5604260; U.S. patent No. 5698584; U.S. patent No. 5710140; WO 94/15932; U.S. patent No. 5344991; U.S. patent No. 5134142; U.S. patent No. 5380738; U.S. patent No. 5393790; U.S. patent No. 5466823; U.S. patent No. 5633272; U.S. patent No. 5932598 and 6313138; all included here by reference.

Compounds described as selective inhibitors of MOR-2, and therefore applicable in the methods or pharmaceutical compositions described herein include, without limitation, celecoxib, rofecoksib, lumiracoxib, etoricoxib, valdecoxib, parecoxib, or their pharmaceutically acceptable salts.

Corticosteroids include, without limitation: betamethasone, prednisone, alclometasone, aldosterone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, clotrimazol, deflazacort, hypertension, desonide, desoximetasone, detoxication, dexamethasone, diflorasone, diflucortolone, difluprednate, fluchloralin, fludrocortisone, fludroxycortide, flumetazon, flunisolide, acetonide fluoqinolona fluocinonide, fluocortin, fluocortolone, formation, flaperon, flupredniden, fluticasone, farmacita, halcinonide, halobetasol, hydrocortisone/cortisol, aceponate hydrocortisone, balarat hydrocortisone, hydrocortisone butyrate, loteprednol, Madison, meprednisone, methylprednisolone, aceponate methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisone/prednisolone, prednisone, rimexolone, tixocortol, triamcinolone and lobetta.

Other agents used as anti-inflammatory drugs include disclosed in published U.S. patent 2005/0227929 included here by reference.

Some commercially available anti-inflammatory drugs include, without limitation, Arthrotec® (diclofenac and misoprostol), Asacol® (5-aminosalicylic acid), Salofalk® (5-aminosalicylic acid), Auralgan® (antipyrine and benzocaine), Azulfidine® (sulfasalazin), Daypro® (oxaprozin), Lodine® (etodolac), Ponstan® (marennikova acid), Solumedrol® (methylprednisolone), Voeg® (aspirin), Bufferin® (aspirin), Indocin® (indomethacin), Vioxx® (rofecoksib), Celebrex® (celecoxib), Bextra® (valdecoxib), Arcoxia® (etoricoxib), Prexige® (lumiracoxib), Advil®, Motrin® (ibuprofen), Voltaren® (diclofenac), Orudis® (Ketoprofen), Mobic® (meloxicam), Relafen® (nabumetone), Aleve®, Naprosyn® (naproxen), Feldene® (piroxicam).

In one embodiment of compounds of formula (I), (II), (IIA) or (IIB) in which W ill result in combination with leukotriene receptor antagonists, including, without limitation, BAY u9773 (see EP 00791576; published 27 August 1997), DUO-LT (Tsuji et al., Org. Biomol. Chem., 1, 3139-3141, 2003), zafirlukast (Accolate®), montelukast (Singulair®), pancoast (Onon®) and their derivatives or analogues.

Sets/products

It also described the kits and products for use in therapeutic applications described herein. Such kits can include the media, packaging, or container divided into compartments for one or more than one container, such as vials, tubes and the like, each of which contains one of the individual elements for use in the method described here. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers can be made from many materials such as glass or plastic.

The products offered here include packaging materials. Packaging materials for use in pharmaceutical packaging products include, for example, U.S. patent No. 5323907, 5052558 and 5033252. Examples of pharmaceutical packaging materials include, without limitation, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected pharmaceutical composition and the intended route of administration and treatment. Assume a wide range of compositions is soedinenii and compositions proposed here, as well as many methods of treatment for any disease, disorder, or condition, which will be useful in the inhibition of the activity of CRAC channels.

For example, the container (s) may contain one or more than one compound described herein may, in a composition or in combination with another agent as disclosed here. The container (s)may be sterile inlet (for example, the container may be a bag or bottle of intravenous solution with tube, sharp needle for subcutaneous injection). Such kits may contain a connection with an identifying description or label or instructions relating to its use in the methods described here.

The kit will typically include one or more than one additional container, each of which contains one or more than one of the different materials (such as reagents, it is possible, in a concentrated form, and/or devices)desirable from a commercial point of view and from the point of view of the user, for the use of the compounds described herein. Non-limiting examples of such materials include, without limitation, buffers, diluents, filters, needles, syringes; media, packaging, container, bottle and/or label the tubes with the transfer of content and/or the regulations for use, and leaflets and package inserts with instructions for use. Also typically will include a set of instructions.

The label may be on the container or may be associated with it. The label can be on a container when letters, numbers or other characters forming the label attached, press out or engraved on the container; a label can be attached to the container when it is present in the reservoir or carrier, which is also a container, for example, in the form of leaflets to the package insert. The label can be used to indicate that the content should be used for specific therapeutic applications. The label can also be briey indicated how to use content, such as in the ways described here.

In certain embodiments the pharmaceutical compositions can be presented in a pack or dispensera device, which may contain one or more than one standard dosage form, containing the connection suggested here. Packaging, for example, may contain a metal or plastic foil, such as blister packaging. Packing or dispensarie device can be provided with instructions for implementation. The pack or dispenser may also be provided with a notification associated santanera, in the form prescribed by a governmental Agency regulating the manufacture, use or sale of pharmaceutical goods, specified in this notice reflects the resolution of this institution in the form of a medicinal product for use in human or in veterinary medicine. Such notice, for example, may be a marking approved by the Management under the control over products and medicines of the USA for drugs, prescription, or approved liner for the product. Can also be made of a composition containing the compound, proposed here, is made in a compatible pharmaceutical carrier, and they can be placed in an appropriate container and labeled for treatment of the specified condition.

Tests

To assess depo-managed calcium intake and calcium signaling in cells can be applied several techniques. Such techniques include, without limitation, the electrophysiology of fixation capacity (measurement of calcium ions and other ions on opposite sides of cell membranes such as the plasma membrane), measure of electrical capacity (allow you to monitor exocytosis at the level of individual cells), visualization of calcium using fluorescent dyes allows you to track the patterns of movement ka is ice within the cytoplasm, resonance energy transfer fluorescence (FRET) allows to evaluate the interaction between protein - protein, and molecular biological methods allow you to manipulate the levels of expression of proteins of interest.

To study the modulation of intracellular calcium by compounds of formula (I), (II), (IIA) and (IIB) can be used with a wide range of methods of analysis. Such assays include cell-based assays in vitro as well as animal models in vivo. Can be applied to any analysis that identifies, monitorium or measure the effect on intracellular calcium, including events, mediated by calcium intake. Such assays include, without limitation, assays that monitorium, measure and/or detect the levels of intracellular calcium modulation of the levels of calcium and movement of calcium inside, out of or within a cell and intracellular organelles. Tests may also include monitoring, measurement and/or detection of events, mediated by calcium intake, and molecules involved in events that are mediated by calcium intake, such as, without limitation, molecules of signal transduction, transcription factors, secreted molecules and other molecules that are affected by changes in calcium homeostasis. Analyses include, without limitation described herein and described in published U.S. patent No. 2007/0031814 and WO 07/08104, included here by reference.

Cells and cell models

For in vitro studies of the modulation of intracellular calcium by compounds of formula (I), (II), (IIA) and (IIB) are available with a wide range of cell types for such assays. In a specific embodiment the cell is a cell in which there is a depot-driven calcium intake, or cell, which can be manipulated in such a way, that it occurred depot-driven calcium intake. In a specific embodiment, the cell contains one or more proteins involved in the modulation of intracellular calcium (and, in particular, involved in participating in and/or providing depot-driven calcium intake, movement of calcium inside, out of or within an intracellular organelle or depot of calcium, modulation of the levels of calcium in the intracellular organelle or depot of calcium (e.g., endoplasmic reticulum) and/or a buffer action in terms of calcium), as for example proposed here. In certain embodiments, the protein (proteins) includes STIM proteins (including protein STIM1, STIM2, DSTIM and CSTIM) and/or Orai proteins (Orai1, Orai2, Orai3). The cell can Express the protein (proteins) endogenous or to Express the protein (proteins) recombinante.

Cells for use in these methods can be derived from any species. In one embodiment, the cells may constitute e kriticheskie cells. In one embodiment, the cell can be a yeast, insect (e.g., Drosophila or Anopheles) or mammals. Mammalian cells include, without limitation, cells of the rodent (e.g. mouse, rat and hamster, Primate, monkey, dog, ox, rabbit and man. In these methods can be used in many types of cells, including, for example, nerve cells, cells of the nervous system, brain, immune system, such as T-lymphocytes and b-cells, embryonic stem cells, blood cells and gemopoeticescoe cells, stromal cells, myeloid cells, lymphoid cells, and many tumor and cancer cells. Specific cells include cells of Drosophila Schneider 2 or S2, embryonic kidney cells human (NEC), cells basophilic leukemia rats (RBL-2H3), Jurkat cells, epithelial cells, rhabdomyosarcoma cells, rabdosia cells, retinoblastoma cells, cell ependymomas, neuroblastoma cells, osteosarcoma cells, fibroblasts, stromal cells, bone marrow cells erythroleucus and lymphocytic cells. Other cell lines include SOME of 293 and T, Cho (Chinese hamster ovary) (including Cho-K1), LTK-, N2A, H6 and HGB. Many such cells and cell lines are available through the Depository cells, such as, for example, the American type culture collection (American Type Culture Collection (ATCC, Manassas, Va.)). Embryonic cell may be obtained by isolation from tissue sources. The receipt, maintenance and use of such cells and cell lines is well known.

Can be used by cells known cell lines, such as neuroblastoma cells SH-SY5Y cells, pheochromocytoma RS, neuroblastoma cells SK-N-BE(2)C or SK-N-SH cells ependymomas human SK-N-MC cells, SMS-KCNR cells, human neuroblastoma LAN-5 neuroblastoma cells human GI-CA-N cells human neuroblastoma GOTO cells of mouse neuroblastoma Neuro 2a (N2A) and/or cells human neuroblastoma IMR 32 cells of chronic myeloid leukemia (e.g., human cells C)cells , promyelocytic leukemia (e.g., HL60 cells) and cells histiocytomas lymphoma (e.g., U937 cells), cells of Burkitt lymphoma (e.g., cells SE), b cells (for example, NALM6), cell acute lymphoblastic leukemia (for example, MOLT4 cells), T cells (e.g., Jurkat cells) and early T cells-ALL (for example, cells DU528).

The choice of cells for use in in vitro assays to study the modulation of intracellular calcium by compounds of formula (I), (II), (IIA) and (IIB) may include multiple conditions, including, for example, a particular protein used in the method, and the specific aspect of the activity modulation of intracellular calcium, monitored or estimated in the way.

In one embodiment the modulation of intracellular calcium compound of the formula (I), (II), (IIA) and (IIB) the research is t the monitoring or evaluation of the effect on depo-controlled calcium intake. Cells typically used in such ways, demonstrate depot-driven calcium intake either naturally or through manipulation of cells. Cells, endogenous showing depo-managed entrance of calcium include some excitable cells and most newsbody cells and can be identified using methods described herein and/or known in the art.

In one embodiment it may be desirable to use the cage, including the components of the alarm system and mediators that affect the release of calcium from intracellular stores. For example, cells comprising system components of receptor-mediated activation of phospholipase C (PLC), can be used for physiological activation (through education IP3) depletion depot to facilitate monitoring depo-managed calcium intake. Receptor-mediated PLC activation occurs through specific binding mechanisms: activation of PLC-β receptors associated with G protein-coupled (GPCR) and activation of PLC-γ tyrosinekinase receptors and preceptoring tyrosine kinases. Thus, the cells, including the receptor-mediated activation of PLC can be monitored or assessed for depot-controlled input of calcium upon activation by the agonist of one or more than the underwater receptor, aware that he participates in this system. (See, for example, Bouron (2000) FEBS Lett 470:269-272; Millar et al. (1995) J. Exp.Biol. 198:1843-1850; Yagodin et al. (1998) Cell Calcium 23:219-228; Yagodin et al. (1999) Cell Calcium 25:429-438; and Patterson et al. (2002) Cell 111:1-20).

Assessment of intracellular calcium after treatment with the compound of formula (I), (II), (IIA) and (IIB) may be carried out in numerous conditions. Conditions can be selected to evaluate the effect of the investigational agent on a particular aspect of intracellular calcium. For example, are known and can be used reagents and conditions for assessment depot-controlled calcium intake, levels of calcium in the cytosol alone, buffer action in relation to calcium and levels of calcium in intracellular organelles, capture them, and calcium fluxes from them. The levels of calcium in the cytosol alone, the levels of calcium in intracellular organelles and the movement of cations can be estimated using any of the methods described herein or known in the art. Such methods of assessing the modulation of intracellular calcium include, without limitation, calcium-sensitive indicator measurements, such as fluo-3, mag-fura 2 and ER-intended acorin, measurement on the basis of labeled calcium (such as45Ca2+) and electrophysiological measurements. Specific aspects of the ion current that can be measured include, without limitation, VK is UCA reduction (including eliminating) the magnitude of the ion current, modified biophysical properties of the ion current and the changed sensitivity of the current-to-activators or inhibitors processes calcium current, such as, for example, depo-controlled calcium intake. Also available reagents and conditions for use in the evaluation of receptor-mediated movement of calcium and move calcium, managed by the two mediators.

Assessment of depot-controlled calcium intake

In one aspect, the compounds of formula (I), (II), (IIA) and (IIB) are added to cells under conditions that allow depo-controlled calcium intake, to assess the effects of compounds of the formula (I), (II), (IIA) and (IIB) for depo-controlled calcium intake. Such conditions are described herein and known in the art.

For example, in one method, cells can be treated to reduce the levels of calcium in intracellular depot and then analyzed for signs of the influx of ions (such as calcium) in response to the presence of the compounds of formula (I), (II), (IIA) and (IIB). Methods of reducing the levels of calcium in intracellular depot and analysis of cells for signs of the influx of ions (e.g. calcium) are known in the art and are described here.

Other ways to detect or monitor the current through the depot-operated channels (e.g., ISOC, ICRACin the presence of compounds of formula (I), (II), (IIA) and (IIB) can the be applied electrophysiological analysis of the currents through the plot of the plasma membrane, separate from cells or membrane vesicles from normal location of the lipid layers.

Evaluation of events, mediated by calcium intake

There are several molecules involved in regulated calcium metabolic pathways. Evaluation of molecules involved in events that are mediated by calcium intake, may be used to monitor intracellular calcium and may be applied, for example, in screening assays described herein to monitor the effects of compounds of the formula (I), (II), (IIA) and (IIB). Examples of assays include, without limitation, assays that detect, determine the presence, levels, changes in the levels, education, modification (such as phosphorylation and dephosphorylation), displacement, degradation and activity of molecules involved in events that are mediated by calcium intake (see, for example, Trevillyan et al. (2001) J. Biol. Chem. 276:48118-26). The analyses described here can be applied to cells that were treated or contacted with the compound of the formula (I), (II), (IIA) and (IIB), or expressing the modified number of studied molecules (such as protein, involved in the regulation of calcium, including protein STIM, Orai protein), or with control cells. Analyses can also be performed with cells that were stimulated physiological or non-physiological activator, or in restimulating the cells. The following is a representative assays for molecules involved in events that are mediated by calcium intake, and imply that these are only examples. In any method of screening and/or modulation described here can also be applied to other tests for these molecules and analyses for other molecules involved in events that are mediated by calcium intake.

The release of β-hexosaminidase

In the fat cells influx of CA2+leads to degranulation and release of inflammatory mediators, such as heparin, histamine, and enzymes, such as β-hexosaminidase. Detecting and/or measuring the release of such molecules can thus be used to monitor intracellular calcium. For example, the environment from the fat cells can be collected. Then may be added a suitable substrate for β-hexosaminidase (for example, p-nitrophenylacetylene), and the optical density of the mixture can be estimated to measure the relative value of the activity of β-hexosaminidase samples (Funaba et al. (2003) Cell Biol. International 27:879-85).

Calcium/calmodulin-dependent fosfataza activity CaN

Phosphatase of calcineurin (CaN) dephosphorylate different proteins, affecting their activity and localization. Activity can be assessed by incubating purified CaN and a substrate CaN, for example, radioactively mechen the th peptide, the corresponding sequence subunit RII-dependent cyclic adenosine monophosphate (camp-dependent) kinase, or with the compound of the formula (I), (II), (IIA) and (IIB)or without it (see, Trevillyan et al. (2001) J. Biol. Chem 276:48118-26). Level radioactively labelled peptide and/or the amount of released free of inorganic phosphate can be measured to assess dephosphorylate activity CaN.

The transcriptional activity of NFAT

The transcription factor NFAT (nuclear factor of activated T cells) regulates several genes in response to levels of intracellular calcium. For example, NFAT proteins regulate the transcription of cytokine genes involved in the immune response. The promoters from the genes regulated by NFAT and/or regulatory regions and elements from these genes can be used to monitor expression regulated NFAT, and, through this, monitoring of intracellular calcium. Can be designed merged designs reporter gene and promoters regulated NFAT, or items of regulated NFAT, functionally associated with a reporter gene such as luciferase, β-galactosidase, green fluorescent protein (GFP) or any other reporter, known in the art (see, for example, published patent application U.S. No. 2002-0034728). The number or activity of the reporter protein by yavlyaetsya activity of NFAT.

Phosphorylation of NFAT

Regulation of NFAT activation occurs through, mainly, its phosphorylation, which, in turn, regulates its subcellular localization. In unstimulated cells, NFAT is a hyperphosphorilated cytosolic protein. The increase in intracellular Ca2+induced by multiple mechanisms, increases the activity of CA2+-calmodulin-dependent phosphatase calcineurin. Activated of calcineurin dephosphorylates several serine residues in the regulatory region of the molecule NFAT. Defosfaurilirovnie NFAT occurs in response to reduced levels of CA2+or inhibition CaN.

The state of phosphorylation of NFAT can be monitored, for example, expression in cells provided with a detectable label NFAT protein, such as His6-tagged NFAT. Labeled NFAT can be purified from cells using chromatography with Ni2+and subjected to electrophoresis in a gel and staining or Western-blotting. Forms of NFAT with a greater degree of phosphorylation can be distinguished by their slower movement. The state of phosphorylation of NFAT can be used as a measure of activation of NFAT (see, Trevillyan et al. (2001) J. Biol. Chem 276:48118-26).

Nuclear localization of NFAT

Localization of NFAT between the cytoplasm and the nucleus regulates the phosphorylation of NFAT. Phosphorylation of NFAT, pragotrade the nuclear localization masking the nuclear localization sequence. Nuclear localization of NFAT can be monitored, for example, expression in cells fluorescently labeled NFAT, for example GFP-NFAT. For monitoring nuclear localization labeled NFAT can be applied confocal microscopy (see, Trevillyan et al. (2001) J. Biol. Chem 276:48118-26).

Secretion of cytokines

The secretion of cytokines, such as secretion of IL-2, can be monitored using the analysis detection of proteins. For example, can be collected supernatant from immunocompetent cells. Enzyme-linked immunosorbent assay (ELISA) or other suitable format with antibodies to IL-2 can be applied for detecting and/or measuring the amount of secreted IL-2 compared with control cells. The secretion of other cytokines, such as TNF-α, can also be defined in similar analyses.

Expression of cytokines

The expression of cytokines, such as, without limitation, IL-2, cells can be assessed either direct or indirect ways. For example, in indirect methods, the promoter of IL-2 may be functionally associated with a reporter gene such as luciferase or β-galactosidase, and the reporter construct can be introduced into cells. The reporter gene expression can be monitored and compared with gene expression in the control cells (see, Trevillyan et al. (2001) J. Biol. Chem 276:48118-26). Altern is effective, it is possible to evaluate the expression of mRNA or protein of endogenous or recombinant IL-2.

The proliferation of T-cells

Such cytokines as IL-2 is required for the proliferation of T-cells in response to mitogenic or alloantigen stimulation, and thus, changes in the expression or secretion of cytokines lead to changes in the proliferation of T-cells. T cells can be induced, such as by concanavalin or alloreactive lymphocytes and proliferation of T cells can be measured, for example, subjecting the cells to a pulse3H-thymidine and measurement include3H-thymidine (see, Trevillyan et al. (2001) J. Biol. Chem 276:48118-26).

The modulation (e.g. inhibition or reduction) SOCE compounds of formula (I), (II), (IIA) and (IIB) can be determined by evaluation of any of the following criteria:

a) there is direct inhibition of increased [Ca2+]ias measured by the calcium indicator;

b) there is direct inhibition of ISOCor ICRACas measured by the method of fixation capacity;

C) there is a subsequent inhibition of the signaling functions, such as calcineurin activity, subcellular localization of NFAT, phosphorylation of NFAT and/or production of cytokines, such as IL-2; or

g) there are changes caused by the activation of cell proliferation, cell differentiation and/or signaling pathways of apoptosis.

Fashion and animals

Model animals, which can be used in embodiments of the methods further include animals such as, without limitation, animals are not people who have, at least in some of their cells, modification or defect, or aberrant functioning of cellular process based or regulated by intracellular calcium. Cellular processes based or regulated by intracellular calcium include, for example, activation of cells, gene expression, cell migration and apoptosis. Diseases/disorders that can be at least partially offset by the modulation of intracellular calcium include, without limitation, autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, Sjogren syndrome (cytokines associated with invasion of lymphocytes in the epithelial cells of the salivary glands, are able to reduce the mobilization of calcium in the cells of the parotid salivary gland; also activate T-cells, including the activation of transcription factors, gene expression of cytokines and cell proliferation depends on the long-term increase of the level of intracellular calcium provided depot-controlled calcium intake), asthma (depo-controlled calcium intake may play an important role in mediating contraction and proliferation Gladkaya the s cells of the bronchi), glomerulonephritis, inflammation of the renal glomeruli (changes in intracellular calcium, as for example due to depo-controlled calcium intake, as a signal for adhesion of monocytes in joint cultural models of inflammation of the renal glomeruli).

Types of animal models include, without limitation, animals are not people, such as invertebrates and vertebrates, are not people, and mammals are not humans, rodents (e.g., mouse, rat, and hamster), cows, chicken, pigs, goats, dogs, sheep, insects, Drosophila, nematodes, worms, .elegans, monkeys, gorillas and other primates.

Models of transgenic animals include and nereshennyh animals. One example of such a model animal, which can be used in certain embodiments of the methods is the model hyperresponsiveness of the Airways (AHR), a characteristic symptom of asthma, on the rodents. This model can be obtained, for example, sensitization by immunization with ovalbumin with subsequent exposure to an aerosol of ovalbumin provocation of cholinergic stimulation (for example, the introduction of methacholine or acetylcholine) (see, for example, Xu et al. (2002) J. Appl. Physiol. 93:1833-1840; Humbles et al. (2002) Proc. Natl. Acad. Sci. 99:1479-1484). Hyper-reactivity of the Airways (which can be assessed using methods known in this area of the equipment, for example, using barometric plethysmography combined for recording curves of the respiratory pressure and measurement of pulmonary parameters such as the conductivity of the lungs and lung compliance) can be evaluated and compared in animals treated and not treated with the compound of formula (I), (II), (IIA) and (IIB). Another example of an animal model that can be used in certain embodiments of the methods is the model mezangioproliferativnom glomerulonephritis in rodents, which can be obtained, for example, the introduction of antibodies against Thy1.1 (see, for example, Jefferson and Johnson (1999) J. Nephrol. 12:297-307). Any number of parameters, indicating glomerulonephritis and renal dysfunction (e.g., proliferation mesangial cells, blood pressure, protein excretion with urine, creatinine clearance, the glomerulosclerosis index and other parameters) can be evaluated and compared in animals treated and not treated with investigational agent. Mouse with diabetes in non-obese (NOD), inbred line of mice, which spontaneously develop autoimmune diabetes, have many similar immunogenetic characteristics with diabetes mellitus type 1, is another example of an animal model that can be used in a particular embodiment ways. These mice also manifested many signs of AU is ommanney ecoclimate (such as Sjogren syndrome), including reduced secretory function of exocrine tissue (see, for example, Humphreys-Beher and Peck (1999) Arch. Oral Biol. 44 Suppl 1:S21-25 and Brayer et al. (2000) J. Rheumatol. 27:1896-1904). The features related to Sjogren syndrome (e.g., lymphocytic infiltrates in exocrine glands (e.g., salivary and lacrimal glands), the presence of dendritic cells and macrophages in the submandibular salivary glands, the absence of differences in the measurement of basal and stimulated secretion of tears from the lacrimal glands, the speed of the current of saliva and amylase activity) can be evaluated and compared in animals treated and not treated with the compound of formula (I), (II), (IIA) and (IIB). In certain embodiments of the methods may also be used in a model of autoimmune disease in animals (e.g. rodents). Such animals include rat model, available through the National Institutes of Health (NIH) Autoimmune Rat Model Repository and Development Center (Bethesda, Md.; available at www.ors.od.nih.gov/dirs/vrp/ratcenter). One rat model of rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases is a model of collagen-induced arthritis (CIA) (see, for example, Griffiths and Remmers (2001) Immunol. Rev. 184:172-183). Typical phenotypes of autoimmune disease (e.g., altered levels of immune reactivity against native antigens, chronic inflammation of expresser the participating autoantigens target organs and activation and participation of infiltrating mononuclear cells and tissue fibroblasts in damage to the body) can be evaluated and compared in animals treated and not treated with the compound of formula (I), (II), (IIA) and (IIB). In a specific embodiment of the methods can also be used a model of neuropathic or inflammatory pain in animals (e.g. rodents). For example, a rat model of neuropathic pain includes the development of tactile-allodynia (too strong answer harmless in other circumstances, incentives) after ligation of lumbar spinal nerves (see, for example, Chaplan et al. (1994) J. Neurosci. Methods 53:55 to 63 and Luo et al. (2001) J. Neurosci. 21:1868-1875). Tactile allodynia, one of the hallmarks of neuropathic pain, can be estimated (for example, rating threshold otdergivanija paws in response to the application of pressure) and compared in animals treated and not treated with the compound of formula (I), (II), (IIA) and (IIB).

EXAMPLES

These examples are given solely for illustrative purposes and without limiting the scope of the claims presented here. Source materials and reagents used for the synthesis of compounds described herein may be synthesized or may be purchased from commercial sources, such as, without limitation, Sigma-Aldrich, Acros Organics, Fluka and Fischer Scientific.

Example 1: 2-(4-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid (compound 1)

Elemental sulfur (10 mmol), ethylcyanoacrylate is (10 mmol) and p-bromoacetophenone (10 mmol), ethanol (2 ml) and morpholine (2 ml) mixed together and stirred at room temperature for about 20 hours. The reaction mixture was poured into 20 ml of methylene chloride and 25 ml of brine. The layers are separated and the aqueous layer was extracted with 2× 15 ml of methylene chloride. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue is purified on a flash chromatography to obtain ethyl-2-amino-4-(4-bromophenyl)-thiophene-3-carboxylate. Ethyl-2-amino-4-(4-bromophenyl)-thiophene-3-carboxylate (5 mmol) is treated with 4-tormentilla (5 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 10 hours. The reaction mixture is diluted with 1 N. NaOH (10 ml) and ethyl acetate (15 ml). The layers are separated and the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified on a flash chromatography to obtain ethyl-2-(4-perbenzoic)-4-(bromophenyl)thiophene-3-carboxylate. Ethyl-2-(fermentated)-4-(4-bromophenyl)thiophene-3-carboxylate hydrolyzing under many conditions (e.g., LiOH, water or LiOH, H2O2water; or NaOH, water) to give 2-(4-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid.

Example 2: 2-(4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid (compound 2)

Ethylcyanoacrylate (5 mmol) and p-chloroacetophenone (5 mmol) dissolved in toluene ( ml). Add morpholine (5 mmol), then added activated molecular sieves (4 Å). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is dissolved in toluene (5 ml) and ethanol (5 ml) and add sulfur (0.16 g; 5 mmol). The reaction mixture is heated at 70°C for 12 hours under stirring. The reaction mixture is cooled to room temperature, and evaporated solvents. The residue is purified by HPLC to obtain ethyl-2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate. Ethyl-2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate (5 mmol) is treated with 4-tormentilla (5 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 10 hours. The reaction mixture is diluted with 1 N. NaOH (10 ml) and ethyl acetate (15 ml). The layers separated, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified on a flash chromatography to obtain ethyl-2-(4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylate. Ethyl-2-(fermentated)-4-(4-chlorophenyl)thiophene-3-carboxylate hydrolyzing under many conditions (e.g., LiOH, water, LiOH, H2O2water; or NaOH, water) to give 2-(4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid.

Following the methods described in Example 1 and Example 2 given the following link is:

2-(4-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(2-bromophenyl)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(2-chlorophenyl)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(phenyl)thiophene-3-carboxylic acid; 2-(4-perbenzoic)-4-(4-were)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid; 2-(4-jogesuido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(4-bromophenyl)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(4-bromophenyl)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(4-were)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(4-chlorophenyl)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(4-bromophenyl)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(3,5-dichlorophenyl)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(3-chlorophenyl)thiophene-3-carboxylic acid; 2-(4-brombenzene)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(4-triptoreline)thiophene-3-carboxylic acid; 2-(4-bromobenzene)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(4-bromobenzene is about)-4-(2-bromophenyl)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(3-chlorophenyl)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(4-were)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(2-bromophenyl)thiophene-3-carboxylic acid; 2-(3-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid; 2-(4 chlorobenzamido)-4-(4-were)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(4-triptoreline)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(phenyl)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(2-bromophenyl)thiophene-3-carboxylic acid; 2-(4-chlorobenzamido)-4-(3-chlorophenyl)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(4-chlorophenyl)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(4-were)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(bentot the EN-2-ylamino)-4-(3-chlorophenyl)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(4-triptoreline)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(2-bromophenyl)thiophene-3-carboxylic acid; 2-(bestien-2-ylamino)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(4-chlorophenyl)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(4-were)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(phenyl)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(2-bromophenyl)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(4-forfinal)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(3-chlorophenyl)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(4-triptoreline)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid; 2-(3-methylbenzamide)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid; methyl 2-(4-chlorobenzamido)-4-(4-

forfinal)thiophene-3-carboxylate; ethyl-2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylate; 2-(4-jogesuido)-4-(4-bromophenyl)thiophene-3-carboxylic acid; 4-(2,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid; 4-(3,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid; 4-(3,5-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid; 4-(3-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid; 4-(2-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-CT is about acid; 4-(4-bromophenyl)-2-(2-chloro-4-perbenzoic)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3,4-differentaite)thiophene-3-carboxylic acid; 2-(2-chloro-4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(2-perbenzoic)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3-fluoro-4-methoxybenzamido)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(4-methylbenzamide)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(4-cyanobenzoyl)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(4-ethylbenzamide)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(4-(trifluoromethyl)benzamido)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-

2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid; 4-(4-bromophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid; 4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamide)thiophene-3-carboxylic acid; and 4-(4-chlorophenyl)-2-(3-(4-chlorophenyl)PR is palamida)thiophene-3-carboxylic acid.

Biological examples

In vitro examples

Example 3: In vitro screening for an agent that modulates the level of intracellular calcium

For screening the compounds described herein, such as compounds of formula (I) and formula (II)modulating intracellular calcium, used assays based on fluorescence.

A. Protocol analysis

In cells RBL-2H3, seeded in 384-well plates, within 45 minutes were loaded with FLUO-4-AM (final concentration 2 μm) in HBSS. Cells were washed and placed in a nominally free of CA2+and Mg2+the Hanks solution. After one minute was added to the investigational agent or filler. After an incubation period duration of 15 minutes was added to 1 μm thapsigargin (Tg) for inhibition of ER CA2+-pump and discharge intracellular depot CA2+. 15 minutes after adding Tg depot-driven calcium intake were initiated by addition of exogenous Sa2+to a final concentration of 1.8 mm and cells were observed for a further 10-15 minutes. Monitoring levels of calcium conducted throughout the analysis using FLIPR384(device for reading tablets Molecular Devices with fluorimetric imaging for high-throughput screening).

In an alternative method of screening analysis after one minute after washing the FLUO-4-AM, to the cells SH-SY5Y add the Yali 1 μm Tg. Fifteen minutes after addition of Tg was added to the study compound or medium, then spent another incubation for 15 minutes in a buffer free of Ca2+. Then initiated depot-managed entrance of calcium by the addition of exogenous Ca2+to a final concentration of 1.8 mm and monitored the response for another 10-15 minutes.

A similar screening method of analysis used with cells NECK and RBL-2H3.

Alternatively, the screening method of analysis can be used exogenous VA2+(final concentration 10 mm) instead of exogenous Ca2+. In this case thapsigargin-induced depot-managed sign-VA2+replaces depot-managed sign-Ca2+.

B. data Analysis

Data on the kinetics obtained using FLIPR384analyzed and then stored in a relational database (ActivityBase; IDBS). Then calculate ten quantitative parameters that define various aspects of the response depot-controlled calcium intake. These parameters represent the following.

The average initial value: baseline fluorescence (relative fluorescence units, RFU), averaged over 30 seconds before adding the Ca2+to initiate depot-controlled calcium intake.

The angular coefficient of lift: linear regression of the increase in RFU from 2 to 30 secondphase add Ca 2+.

Constant speed increase (Up To): the rate constant obtained from the Association of the first order RFU from 2 seconds up to the maximum response.

Peak: the maximum RFU (one point), achieved after addition of Ca2+.

Time to peak: the time to reach peak RFU.

Peak/source: the difference between peak and average source RFU.

Angular damping coefficient: linear regression reduce the RFU from the peak to the end of the measurement period.

The rate constant of decay (Decay): the rate constant obtained from the first order decay RFU from the peak to the end of the measurement period.

The area under the curve (AUC): area under the curve from the addition of CA2+the end of the measurement period.

The combination of these parameters used for the description of the compounds of formula (I). Connection re-examined in identical conditions to confirm their activity. Compounds with confirmed activity was then analyzed for subject-dependent concentration effects, and then compounds that demonstrate dependent on the concentration effects, classified as a compound that modulates intracellular calcium.

Table a
Typical compounds of formula (I)
No. of connectionsR2-R1-R4% inhibition at 10 µmThe average IC50 (μm) from the angular coefficient in cells RBL-2H3
14-forfinal-N4-bromophenyl>70%2,2
24-forfinal-N4-chlorophenyl-2,3
34-forfinal-N3,4-dichlorophenyl>70%3,3
44-forfinal-H4-triptoreline>70%-
113-forfinal-H4-bromophenyl-0,8
124-chlorophenyl-H4-bromophenyl-1,2
14bestien-2-yl-H4-bromophenyl>70%2,4
153-were-H4-bromophenyl-2,6
164-bromophenyl-H4-were-0,6
174-bromophenyl-H4-chlorophenyl>70%1
184-bromophenyl-H4-bromophenyl>70%1,3
194-bromophenyl-H3,5-dichlorophenyl >70%1,6
204-bromophenyl-H3-chlorophenyl<70%4
214-bromophenyl-H3,4-dimetilfenil>70%4,6
253-forfinal-H4-chlorophenyl-1,3
263-forfinal-H2,4-dichlorophenyl>70%2,1
334-chlorophenyl-H4-chlorophenyl-1
344-chlorophenyl-H4-were-1

35 4-chlorophenyl-N2,4-dichlorophenyl>70%1,6
364-chlorophenyl-N4-forfinal-2,4
374-chlorophenyl-N3,4-dichlorophenyl<70%3
384-chlorophenyl-N3,4-dimetilfenil<70%the 3.8
43bestien-2-yl-N4-chlorophenyl>70%1,0
44bestien-2-yl-N4-were<70%1,3
45bestien-2-yl-N2,4-di is lorgeril >70%2,4
46bestien-2-yl-N3-chlorophenyl>70%10,7
503-were-N4-chlorophenyl-1,2
513-were-N4-were-3
- = not determined

Example 4: Effects of agents that modulates intracellular calcium, degranulation and release of cytokines in cells RBL-2H3 in vitro

To assess degranulation and release of cytokines cells RBL-2H3 were sown and stimulated with 20 nm thapsigargin/20 nm tetradecanoylphorbol (TRA) for 20 hours in the presence or in the absence of the compounds of formula (I) or formula (II). The medium was collected and analyzed for the release of β-hexosaminidase or on the release of the mediator of the inflammatory cytokine TNF-α. Analysis of the enzyme β-hexosaminidase carried out by adding 200 μl of 1 mm p-nitrophenyl acylglycerides substrate (Sigma #N9376) in 0.05 M Na-citrate (pH 4.5) to 50 μl of conditioned medium, incubation for 60 minutes at 37°C, followed by adding 500 μl of 0.05 M Na carbonate, 0.05 M Na bicarbonate, pH of 10.5, thorough mixing and reading the optical density at 405 nm in a spectrophotometer to read the tablets BioRad. Analysis of the release of TNF-α was performed using ELISA kit Rat Tumor Necrosis Factor-α Ultrasensitive ELISA Kit from BioSource.

The results of these analyses are shown in figure 3 and 4.

Example 5: Modulation of intracellular calcium inhibitor of SOCE in cells, sverkhekspressiya STIM1

Depo-managed sign-calcium-sensitive inhibitor 2-aminoethoxyethanol (2-ARV). To study whether the metabolic pathway of entry of CA2+activated by overexpression of STIM1, pharmacologically similar to endogenous SOCE, HEK cells[STIM1] pre-incubated with increasing doses of 2-ARV and measured STIMI-dependent entrance of Ca2+. Mediated thapsigargin depletion depot as control cells HEK-Zeo and HEK cells[STIM1], followed by re-addition of exogenous calcium led to inhibition by 2-ARV with similar values IC50constituting of 11.8 μm and 10.5 μm, respectively. Treatment of HEK cells[STIM1] 2-ARV and the study of calcium intake in the absence of Tg-dependent depletion depot has resulted in a biphasic effect 2-ARV at the entrance of calcium (Fig). The entrance of calcium in this case and what was dotirovala pretreatment of cells free from the Ca 2+the buffer and the input of Ca2+inhibited with the value of the IC50constituting 10.8 microns, similar to the IC50reported for endogenous SOCE in cells NECK. However, at lower concentrations of 2-ARV happened potentiation of calcium intake. The ability to both potentiate and inhibit the entry of calcium is a property of 2-ARV, the existence of which was shown earlier with the use of calcium channels activated by release of calcium (CRAC channels).

The use of compound 1 instead of 2-ARV resulted dependent on the concentration of the inhibition of STIM1-dependent entrance of Ca2+(see Fig).

Thus, overexpression of STIM1 in cells NEC gives CRAC-like property entrance of Ca2+in cells NEK induced effects on cell-free Ca2+buffer without depletion depot thapsigargin. Accordingly, assays for identification of agents that modulates intracellular calcium, may possibly be held in the cells, sverkhekspressiya STIM1, without using standard protocols depletion of intracellular calcium.

Example 6: the Effects of agents that modulates intracellular calcium on the secretion of IL-2 T-Jurkat cells in vitro

For measurement of IL-2 secretion by T-cells Jurkat cells were planted in 96-well plates with a density of 1.5×105the notches on the hole. Cells were stimulated with 2.5 μg/ml of phytohemagglutinin (RNA) lectin + 80 nm TPA for 20 hours in the presence or in the absence of the compounds of formula (I) or formula (II). The medium was then collected and analyzed for levels of IL-2 by ELISA (BioSource) according to the manufacturer's protocols.

The results are shown in Fig.7 and 10.

Example 6A: Effects of agents on the cloned calcium channels, L-type cells SNO in vitro

To prepare the initial solution of the compound in dimethyl sulfoxide (DMSO) and kept them frozen. Fresh concentration of the compound And were prepared daily by dilution of the original solution in a suitable HEPES buffered saline solution. The preparation of each tested compound was treated with ultrasound at room temperature for at least 20 minutes to facilitate dissolution. In enamel 96-well plate for connections made with the appropriate amount of study and control solutions and placed in the hole of the tablet PatchXpress®. Evaluated the effects of five concentrations. Prepared and froze party source solutions positive controls. Fresh concentration of the positive control were prepared daily by dilution of the original solution of HB-PS. The final concentration of DMSO was 0.3%.

Cells were kept in the incubator for tissue cultures ChanTest SOP. To EDI SNO stable was transfusional complementary DNA (cDNA) of a suitable ion channel. Cells were cultured in medium Ham's F-12, supplemented with 10% fetal bovine serum, 100 U/ml of sodium salt of penicillin G, 100 μg/ml streptomycin sulfate, and appropriate antibiotics for selection. Cells in the culture cups washed twice with balanced salt solution Hanks, were treated with trypsin and resuspendable in the culture media before the study. Five concentrations of each tested compound And were applied to intact cells at five-minute intervals. The duration of exposure of each of the studied compound was approximately five minutes.

In the preparation for the session write the intracellular solution was introduced into the intracellular compartments of the flat electrode. After establishing the configuration of the whole cell membrane currents were recorded using a two-channel amplifier with fixation potentials in the system PatchXpress®. Reliable records of whole cells satisfy the following criteria: 1) membrane resistance (Rm)≥MW; 2) leakage current ≤25% of current through the channels. The beginning and stable blockade hCav.1.2/β2/α2δ-channels was measured using a stimulus pattern potential, consisting of a depolarizing test pulse intervals with a duration of 10 seconds from the resting potential, comprising -80 mV. Concentrations of these compounds were applied NAC is pitaniem follows in ascending order without cleaning between applications. Measured maximum current during stage 10 mV. At the end of each experiment were added saturating concentration of nifedipine (10 μm) for blockade hCav1.2-current. Data stored in a computer network ChanTest for analysis. Stationary state was defined as the bounding constant rate of change over time. Stationary state before and after the application of the compounds used to calculate the percentage of current inhibited at each concentration.

In vivo examples

Example 7: dose-dependent effects of compound 1, compound 2, cyclosporine A (CSA) or rapamycin with delayed-type hypersensitivity (DTH) on the paws of the mouse

Task: determine dose-dependent effects of the investigated compounds on induced by methylated bovine serum albumin (mBSA) DTH response in the paws with the introduction during the sensitization phase, and phase induction.

Animals: 61 male mice of Swiss Webster weighing approximately 20-25 g at the beginning of the study.

Materials: methylated BSA (Sigma), complete adjuvant's adjuvant (Difco) and incremental N RA M. tuberculosis (Difco).

The General plan of the study

Mice were anestesiologi with isoflurane and produced an intradermal injection of antigen in a dose of 0.1 ml into the tail (0 day (D0), day 7 (D07)). The antigen is purchasing, receiving a solution with a concentration of 4 mg/ml of sterilized the Noi water. Equal volumes of antigen and complete adjuvant's adjuvant, which added to M. tuberculosis (MTB) at a concentration of 4 mg/ml (exposure to ultrasound for 5 minutes after adding the MTB in oil), emuleret manual stirring up until the ball this material will not retain its shape when immersed in water. Introduction the compounds start at 0 day (at intervals of 24 hours) and continued until day 10 when you spend provocation.

10 days in the pad of the right hind paws of the animals injected 20 μl of 10 mg/ml mBSA. Five desensibilisation males mBSA injected into the paw pads. Twenty-four hours (11 days) right and left hind legs cut through the medial and lateral ankles and weigh, and determine the difference in weight is caused by the injection of antigen.

The statistical analysis. Mass paws (mean ± standard error (SE)for each group were analyzed for differences using t-test, t-test or analysis of variance (ANOVA) with subsequent verification of the criterion Dannetta. Statistical significance was p≤0,05.

Table 1
Males from groups introduction
Group NThe introduction of 10 ml/kg daily, oral (p/o)
15Normal controls (without sensitization). Only injection of mBSA in the right paw
28DTH+filler (70% PEG400/30% water)
38DTH+compound 1 (50 mg/kg, oral (p/o), daily)
48DTH+compound 1 (100 mg/kg, p/o, daily)
58DTH+compound 1 (200 mg/kg, p/o, daily)
68DTH+compound 1 (300 mg/kg, p/o, daily)
78DTH+CSA (100 mg/kg, daily, intraperitoneally)
88DTH+rapamycin (5 mg/kg, daily,intraperitoneally)

The study Protocol DTH in mice

The results for compound 1 presented at Fig.

The results for compound 2 is shown in Fig.

Example 7A: Headlamp is cokinetics data connection 1 and connection 2 in rats

Bioavailability and pharmacokinetic properties of the compound 1, administered orally in the filler, representing 70% PEG400/30% H2O in the plasma of rats. Two groups introduction: 1) the group of intravenous (IV) administration at a dose of 2 mg/kg; 2) group oral administration at a dose of 10 mg/kg; male rats Sprague-Dawley (3 rats per group) weighing approximately 250-300 grams. For each group choose up to 8 time points. Typical time points are: before the introduction, 15, 30 minutes, 1, 2, 4, 8 and 24 hours. At each time point up to 300 ál of whole blood is taken through a cannula in the jugular vein. Blood collected in microcentrifuge tubes with anticoagulant and centrifuged at 5000 rpm in microcentrifuge for 5 minutes before transferring the plasma into a clean microcentrifuge tube. Conducted bioanalytical analysis of plasma samples.

A similar method was used to obtain pharmacokinetic data for connection 2.

The results for compound 1 presented at Fig.

The results for compound 2 is shown in Fig.

Example 8: Effect of compound 1 in a rat model of collagen-induced arthritis (CIA)

Objective: to determine the effectiveness of compound 1, administered orally daily in the inhibition of inflammation, destruction of cartilage and bone resorption during development in rats with arthritis induced by collagen type II.

Animals: 44 female Lewis rats (Charles River#7246950), weighing 125-150 g at the beginning of the study. 40 rats were injected with collagen to obtain 40 rats with a strong response to the 10, 11 a day for 4 groups of 10 rats. Four unimmunized animals were used as negative control.

Materials: compound 1 (sodium salt), PEG400 in the form of a liquid, collagen type II, incomplete beta-blockers, acetic acid. Compound 1 prepared in concentrations up to 100 mg/ml in 70% PEG400/30% water. Collagen is purchasing, receiving a solution with a concentration of 4 mg/ml in 0.01 N. acetic acid. Equal volumes of collagen and incomplete adjuvant's adjuvant emuleret manual stirring up until the ball this material will not retain its shape when immersed in water.

General plan of study: animals (10 rats per group for arthritis, 4 rats per group for normal control).

Animals in groups 2-5 anaesthetize with isoflurane and produce collagen injections (0 day (D0)); each animal injected with 300 μl of the mixture in the form of 3 injections under the skin of the back. On the 6th day (D6) animals again anaesthetize and produce the second injection of collagen, as described previously.

Oral administration of compound 1 with intervals of 24 hours (daily) start at 0 day, using input solutions for oral administration of 5 ml/to the. Rats weighed at 0, 3, 6 and 9-17 day arthritis and ankle was measured with a caliper every day since 9 days. The final values of body weight is determined on the 17th day of arthritis. On the 17th day of all animals anaesthetize for the end of blood sampling and then kill. Then the hind legs and knees are removed, the hind legs are weighed and then (knee) was placed in formalin for processing for microscopy. The liver, spleen and thymus, and kidneys are also removed, freed from the outer tissues and weighed. Kidneys retain in formalin for histopathological studies.

The sampling will occur within 1 day and include groups of 2-5 with obtaining samples from all groups. This leads to the fact that the treatment of all animals is the same, and it is important for clinical parameters and final weights of the liver.

The results of the study are shown figure 11.

Example 9: the Effects of compound 1 on colitis induced 2,4-dinitrobenzenesulfonic acid (DNBS), in rats

Method: Male Wistar rats weighing 200±20 g deprived of food for 24 hours before use. Distal colitis induce infusion into the colon DNBS (2,4-dinitrobenzenesulfonic acid, 20 mg in 0.5 ml of 30% ethanol) using a catheter with a length of 12 cm, followed by careful introduction of air (2 ml) through the catheter to ensure the preservation solution in the colon is ISKE. Animals are divided into groups of 5 animals each. The test substance and the filler is administered either once daily or twice a day, by introducing appropriate for 24 hours and 1 hour before infusion DNBS and then for 6 consecutive days. One group of normal control injected only with 0.9% NaCl without the introduction of DNBS. Animals killed 12 hours after the last injection with the introduction of two times a day and 24 hours after the last injection with the introduction of once a day and the colon were removed and weighed. During the experiment, perform daily monitoring of body mass, occult blood in the stool and stool consistency. In addition, at the opening of the abdominal cavity before removing the colon mark adhesions between the colon rectum and other organs, and the presence of ulcerations of the colon after removing and weighing the mass of each colon (score macroscopic damage record in accordance with established scales). Also calculate the ratio of the weight of the colon to body weight according to the formula: weight of the colon (g)/body weight (BW) × 100. "Total" increase of the ratio of the control group filler and groups DNBS relative to the group of filler used as the basis for comparison of individual groups of introducing and expressing as "reduction (%) (% reduction). 30% or more (≥30%) reduction is their ratio of the mass of the colon-to-body weight compared to the control group, which is injected with a filler, is considered as significant.

As standard the investigational agent used sulfasalazin. (Hogaboam CM, et al., An orally active non-selective endothelin receptor antagonist, bosentan, markedly reduces injury in a rat model of colitis. Eur J Pharmacol. 309: 261-269, 1996; Yue G, et al., The 21-aminosteroid tirilazid mesylate can ameliorate inflammatory bowel disease in rats. J Pharmacol Exp Ther. 276: 265-270, 1996.)

The results of the study shown in Fig.

Example 10: a Clinical study of the safety and efficacy of compounds of formula (I), (II), (IIA) or (IIB) phase II in patients with active rheumatoid arthritis

The purpose of this phase II study is to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of single and repeat intravenous infusions of compounds of formula (I), (II), (IIA) or (IIB) in patients with active rheumatoid arthritis.

Patients: the appropriate subjects will be men and women aged 18 to 75 years.

Criteria

Inclusion criteria:

- all actors should use appropriate contraception to ensure that no pregnancies during the study and for at least 12 weeks after injection for men and 32 weeks after injection for women;

- body mass index in the range of 18.5-35 kg/m2inclusive, in addition to weight in the range of 55-95 kg;

- the subject must be able to give informer the bath consent and able to follow the requirements and schedule of the study;

- the subject must have a diagnosis of rheumatoid arthritis (RA) in accordance with the revised 1987 criteria of the American College of rheumatology American College of Rheumatology (ACR));

- the subject must have an indicator of disease activity DAS28 over 4.2 screening before treatment;

- the subject must have the level of C-reactive protein (CRP) in serum ≥0.5 mg/DL or the level of erythrocyte sedimentation rate (ESR) 28 mm/h at screening before treatment;

- the subject has not received any biologic therapy in the past, including biological agents for the treatment of rheumatoid arthritis;

- the subject must have the functional hepatic tests, including alanineaminotransferase (ALT) and aspartataminotransferaza (AST), within 1.5 values of the upper limit of normal (ULN) and alkaline phosphatase (ALP) within 3 times ULN at screening; the patient also must have a total bilirubin within ULN at screening;

- the subject must receive methotrexate for at least 3 months and must receive a stable dose of methotrexate (25 mg/week) for at least 8 weeks prior to screening and be ready to change this dose throughout the study;

- if in addition to methotrexate the subject accepts sulfasalazin, it must receive a stable dose for at least 4 weeks before with what rininger and be ready to change this dose throughout the study;

- if in addition to methotrexate the subject accepts hydroxychloroquine or chloroquine, it must receive a stable dose for at least 3 months prior to screening and be ready to change this dose throughout the study;

subjects receiving other oral anti-rheumatic therapy, which may include non-steroidal anti-inflammatory drug (NSAID), inhibitors of cyclooxygenase-2 (MOR-2), glucocorticoids for oral administration, such as prednisolone (approximately 10 mg/day)should follow a stable schemes medication for at least 4 weeks prior to screening and be ready to change this pattern throughout the study;

subjects receiving glucocorticoids for intramuscular injection, such as methylprednisolone (approximately 120 mg/month), should follow a stable regimen of drugs for at least 3 months prior to screening and be ready to change this pattern throughout the study;

- the subject must receive a stable dose of folate in the form of supplements (5 mg/week) for at least 4 weeks before the introduction.

Exclusion criteria:

- any clinically significant deviation from the norm, identified during screening PR the medical evaluation, laboratory examination (for example, gematologicheskii argument is outside the normal range) or electrocardiography (ECG) (12 ECG or Holter);

- the subject is positive for the surface antigen of hepatitis b virus or antibodies to hepatitis C virus screening;

- subject has a history of increased functional liver tests (ALT, AST and ALP > 3 upper limits of normal (ULN); total bilirubin > 1,5 ULN) one or more than once in the last 6 months;

contact or infection with Mycobacterium tuberculosis in the past;

- the subject has an acute infection;

- subject has a history of repeated, chronic or opportunistic infections, which, in the opinion of the investigator and/or medical monitor GSK, put the subject at unacceptable risk if his participation in the study;

- subject has a history of malignancy, except for surgically cured basal cell cancer or women with cured cervical cancer (> 2 years before the study);

- subject has a history of infections caused by human immunodeficiency virus (HIV), or other immunodeficiency diseases;

- the subject whose estimated creatinine clearance less than 50 ml/min;

- the subject has significant cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal condition is tion, which, in the opinion of the investigator and/or medical monitor GSK, put the subject at unacceptable risk if his participation in the study;

- the subject has received cyclosporine, Leflunomide, cyclophosphamide or azathioprine within 1 month before screening; subjects taking cyclosporine, Leflunomide, cyclophosphamide or azathioprine in the past have recovered from all associated with drug adverse events;

the subject took the salts of gold or d-penicillamine within 1 month before screening; subjects who salts of gold or d-penicillamine in the past have recovered from all associated with drug adverse events;

the subject had received glucocorticoids for intraarticular injection within 1 month before screening;

- a recent history of bleeding disorders, anemia, peptic ulcers, vomiting blood or gastrointestinal bleeding;

- subjects with a history of hematologic disease or acquired platelet disorders, including those caused drugs thrombocytopenia, acute idiopathic thrombocytopenia, or disease von Willebrand's disease;

subjects with known risk of intracranial hemorrhage, including surgery on the Central nervous system (CNS) within the last 12 months, and the material of vascular malformations, closed head injury within 6 months or any other event, which is important in the opinion of the investigator and/or medical monitor;

- the subject has a hemoglobin (Hb) < 10 g/deciliter (DL) and platelet count < 150×109per liter (l);

- donation of blood in excess of 500 ml within a period of 56 days before the introduction;

- unwillingness of male subjects to abstain from sexual intercourse with a woman during pregnancy or lactation; or the unwillingness of the male subject to use a condom with spermicide in addition to the use of his female partner other forms of contraception, such as intrauterine device (IUD), diaphragm with spermicide, oral contraceptives, progesterone injection, subcutaneous implants of levonorgestrel or tubal ligation, if a woman can become pregnant for at least 12 weeks after treatment;

- the reluctance of the subject is a female able to get pregnant, to use adequate contraception, as defined in section limitation of the study; if necessary, will be held proof of the impossibility of pregnancy in women (i.e. postmenopausal or surgical infertility, such as tubal ligation or hysterectomy, or bilateral oophorectomy); postmenopausal status will be confirmed the substance of the concentrations of follicle-stimulating (FSH) hormone and estradiol serum screening; surgical infertility will be determined in women with documented hysterectomy, ligation, or bilateral oophorectomy;

- subject has a history of drug abuse within 12 months prior to screening;

- history of regular alcohol consumption exceeding the average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (men), or the average weekly consumption of more than 14 units or an average daily consumption of more than 2 units (women); will also excluded subjects who consume more than 12 units of alcohol for a period of 24 hours; 1 unit is equivalent to half a pint (220 ml) of beer/light beer or 1 (25 ml) unit of alcohol or 1 glass (125 ml) of wine;

- a positive test for pregnancy or lactation at screening;

- participated in the study with any drug undergoing clinical trial within 3 months or 5 elimination half-life (whatever it is longer) before.

The research plan.This study is a randomized, double-blind, placebo-controlled, adaptive research with the selection of doses for the study of safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of single and repeat intravenous infusions soy is inane formula (I), (II), (IIA) or (IIB) in patients with active rheumatoid arthritis. The study is divided into 2 parts. Part a is the adaptive phase with the selection of doses in which the received data on the safety, tolerability, RK and PD single intravenous infusion. Part B is a phase of repeated doses, in which the received data on the safety, tolerability, RK and PD and efficacy of repeated intravenous infusions of the selected level doses.

Primary evaluate results:

- safety and tolerability following single ascending doses of the compounds of formula (I), (II), (IIA) or (IIB) after 1 month and after 3 repeated doses of the compounds of formula (I), (II), (IIA) or (IIB) after 3 months; clinical efficacy scale (DAS28) the compounds of formula (I), (II), (IIA) or (IIB) in 1 month.

Secondary assessed results:

- weighted average DAS28 after single and repeat intravenous doses;

- parameters RK compounds of formula (I), (II), (IIA) or (IIB) in plasma after single and repeat intravenous doses including the concentration of free and bound compounds of formula (I), (II), (IIA) or (IIB) (serum), AUC(0-∞)Cmax, clearance, volume of distribution and the rate of accumulation;

criteria response DAS28 and EULAR after single and repeat intravenous doses;

response ACR20/ACR50/ACR70 after single and repeated I.V. the dose;

- the number of joints with swelling in assessing 28 joints;

- the number of stressful/painful joints when assessing 28 joints;

subjective assessment of pain;

- General medical assessment of arthritis;

- overall assessment of the arthritis patient;

- index of functional disorders (Health Assessment Questionnaire)

- C-reactive protein (CRP)

the erythrocyte sedimentation rate (ESR)

- General index of fatigue;

- the index of the HAQ disability;

- pharmacodynamic biomarkers after single and repeat intravenous doses;

characteristic AUC50and EC50to change clinical outcome in exposure models in the plasma, as assessed by sigmoid Emaxand models of indirect response PK/PD;

- immunogenicity (human antibodies against the compounds of formula (I), (II), (IIA) or (IIB)).

Example 11: a Clinical study of the safety and efficacy of compounds of formula (I), (II), (IIA) or (IIB) phase II in patients with severe refractory plaque psoriasis

The purpose of this phase II study is to investigate the safety, efficacy and tolerability of the compounds of formula (I), (II), (IIA) or (IIB) in patients with severe refractory plaque psoriasis.

Patients: the appropriate subjects will be men and women aged 18 to 75 years.

Criteria

Inclusion criteria:

- the patient has agely refractory plaque psoriasis and he was ineffective at least 1 systemic therapy (for the purposes of this study, psoralen with ultraviolet radiation type And is considered as a systemic therapy);

- the patient has the psoriatic lesion at least 10% of the body surface (BSA);

- the patient has a score on a scale PSGA 4 or more;

- if the patient is a woman, he has a surgical infertility, or menopause after 2 years or when the possibility of pregnancy, is now applying acceptable from a medical point of view, the method of birth control and agree to continue using this method throughout the study (and for 30 days after participation in the study); acceptable methods of contraception include: abstinence, steroidal contraceptive (oral, transdermal, implant or injection) in combination with a barrier method or intrauterine device (IUD);

the patient, if he is a man who has a surgical infertility or, if he is able to procreate, applies the currently approved method of birth control and agree to continue using this method throughout the study (and for 60 days after the last dose of the compounds of formula (I), (II), (IIA) or (IIB) in view of the possible effects on spermatogenesis);

- it is necessary that the patient was willing and able to comply with the procedures and limitations of the study and agree to return to the clinic for evaluation of long-term results, is it specified in this Protocol.

Exclusion criteria:

the patient received treatment system protivopsoriaticescoe drugs (specifically, retinoids, methotrexate, cyclosporine, etanercept, efalizumab, other biological agents, or other immunomodulators) within 4 weeks or based on ultravioleta radiation (UV-radiation) therapy within 2 weeks, or alefacept within 6 weeks of the planned 1st day of the investigational treatment;

the patient received treatment with strong inhibitors of CYP3A4, including cyclosporine, clotrimazole, fluconazole, Itraconazole, ketoconazole, voriconazole, erythromycin, clarithromycin and troleandomycin, the protease inhibitors of the human immunodeficiency virus (HIV), or nefazodone, within 1 week (7 days) of the planned 1st day of the investigational treatment;

the patient is currently receiving warfarin;

- the patient has hypersensitivity to a compound of formula (I), (II), (IIA) or (IIB) or any component of the compounds of formula (I), (II), (IIA) or (IIB);

- the patient has one or more than one of the following chemical parameters of blood serum, as determined at the screening visit (visit 1):

- levels of bilirubin, more than 2 times the upper limit of normal (ULN);

the levels of ALT or AST more than 2 times the ULN;

levels of serum creatinine, pre is chausie 2 mg/DL;

currently, the patient will need treatment with HIV protease inhibitors;

- the patient receives treatment for the clinical diagnosis of ulcers of the gastrointestinal tract or has a history of melena or bloody vomiting within the previous 3 weeks;

- the patient is a woman in pregnancy or lactation;

the patient received treatment drug undergoing clinical trial within 4 weeks of the planned 1st day of the investigational treatment.

The research plan.This study is a pilot, open, non-randomized study of the efficacy, safety and tolerability of the compounds of formula (I), (II), (IIA) or (IIB) in patients with severe refractory plaque psoriasis with increasing dose.

Example 12: a Clinical study of the safety and efficacy of compounds of formula (I), (II), (IIA) or (IIB) phase II for the prevention of acute rejection after kidney transplantation

Standard immunosuppressive treatment after renal transplantation is a combination of tacrolimus, mycophenolate mofetil and prednisolone. When applying this scheme it is possible to reduce the frequency of acute transplant rejection in the first six months after transplantation to approximately 20%. Currently, the main issue is the improvement of long-term R the results prevention of chronic allograft nephropathy (CAN). Because acute rejection is a major prognostic factor CAN further reduce the frequency of acute rejection may improve long-term survival of the graft. The purpose of this clinical phase II study is to investigate the efficacy and safety of compounds of formula (I), (II), (IIA) or (IIB) for the prevention of acute rejection after renal transplantation.

Patients: the appropriate subjects will be men and women age 18 years and older.

Criteria

Inclusion criteria:

recipient of the transplant kidney;

- signed, dated and witnessed informed consent, approved by the Institute's Supervisory Board (IRB).

Exclusion criteria:

- pregnancy;

- living HLA-identical donor;

- haemolytic uraemic syndrome as the original kidney disease;

- focal segmental glomerulosclerosis that occurred with previous kidney transplant;

more than two unsuccessful previous transplantations, and/or probabilistic risk assessment (PRA) > 85%;

- diabetes mellitus without current insulin treatment;

- the total number of leukocytes < 3000/mm3or the number of platelets < 75000/mm3;

- active infection caused by hepatitis b virus, hepatitis C or HIV;

- tuberculosis in history.

The research plan.Dunn is the first study is a randomized, double-blind, placebo-controlled intervention study the effectiveness and safety of prophylactic use of compounds of formula (I), (II), (IIA) or (IIB). One group will receive a single dose of the compounds of formula (I), (II), (IIA) or (IIB) intravenously at the time of transplantation, and the other group receives a placebo infusion.

Initial results:

- determine the frequency and severity confirmed by biopsy acute rejection in the first six months after transplantation.

Secondary results:

- renal function, as assessed by the clearance of endogenous creatinine 6 months;

the incidence of chronic allograft nephropathy in 6 months;

- cumulative frequency of infections and malignancies in 6 months;

medical costs during the first 6 months after transplantation;

the survival rate of patients and transplant.

Example 13: a Clinical study of the safety and tolerability of the compounds of formula (I), (II), (IIA) or (IIB) phase II in patients with active ulcerative colitis (UC)

The purpose of this phase II study is to investigate the safety, tolerability scheme with the compound of the formula (I), (II), (IIA) or (IIB) in patients with active ulcerative colitis.

Patients: the appropriate subjects will be men and women who s age 18 years and older.

Criteria

Inclusion criteria:

subjects with active UC in the treatment of 5-aminosalicylic acid (5-ASA) and treated with 6-mercaptopurine (6-MP) and/or corticosteroids, or who have previously received treatment with azathioprine (AZA), 6-MP or corticosteroids and were not able to transfer them;

- assessment of Mawa from 6 to 10 points with moderate-severe disease at endoscopy (indicator Mawa at least 2)held within 14 days from the introduction of the investigational medicinal product;

subjects receiving the following drugs may be included in the study, if prior to the introduction of the investigational medicinal product the medication meets the following schemes, and during the studies do not expect any changes:

• prednisolone ≤ 20 mg / day (or equivalent) (dose must be stable for at least 3 weeks before administration of the investigational medicinal product);

• 5-ASA (dose must be stable for at least 4 weeks before administration of the investigational medicinal product);

• AZA or 6-MP (dose must be stable for at least 3 months before the introduction of the investigational medicinal product);

• steroids or 5-ASA rectal administration (must be stable for at least 4 weeks is l before administration of the investigational medicinal product);

subjects using medicines for rectal administration must have a visible lesion at rektoromanoskopii for ≥ 20 cm;

laboratory values at screening must meet certain criteria:

• women should be in menopause (> 12 month absence of menstruation) or have a surgical infertility (for example, hysterectomy, or bilateral oophorectomy), or should use effective contraception (e.g. oral contraceptives, intrauterine device (IUD), double barrier method using a condom and spermicide) for at least 4 weeks before administration of the investigational medicinal product, and must agree to continue contraception during their participation in the study; and

• sexually active male subjects must use a barrier method of contraception throughout the study.

Exclusion criteria:

therapy against tumor necrosis factor (TNF) within 8 weeks before administration of the investigational medicinal product;

any experimental therapy for ≤ 4 weeks before administration of the investigational medicinal product;

- previous treatment with any monoclonal antibody or fused protein on the basis of immunoglobulins at ≤ 8 weeks p is ed investigational treatment;

- the presence of Cushing's syndrome;

- toxic megacolon or fulminant disease in which will probably be required colectomy;

- contraindications to colonoscopy or rektoromanoskopii;

primary or secondary immunodeficiency;

- an autoimmune disease in addition to UC, with the exception of Sjogren syndrome or hypothyroidism;

- malignant disease in history, except for adequately treated basal cell or squamous cell skin cancer or cervical cancer in situ;

- severe mental disease (subjects with stable depression receiving appropriate treatment, will be allowed in the study);

- evidence of acute or chronic infection, confirmed:

a stool culture positive for pathogens and/or toxin Clostridium difficile;

- detection at screening chest x-rays, such as pulmonary infiltration (infiltration) or adenopathy;

- TB treatment, ongoing, clinical or radiographic evidence of active tuberculosis (TB) or, for subjects from North America, the positive reaction to the dry tuberculin, purified from the protein environment (PPD), without prior prophylaxis;

- Herpes zoster for ≤ 3 months before administration of the investigational medicinal product;

- active infection is s disease, when you need intravenous antibiotics within 4 weeks from the investigational treatment or oral administration of antibiotics in the beginning of the study;

- HIV or acquired immunodeficiency syndrome (AIDS);

positive tests for hepatitis b virus (HBV) or hepatitis C virus (HCV), indicating an active or chronic infection;

clinically significant heart disease, in which the necessary medication, unstable angina, myocardial infarction within 6 months, or congestive heart failure;

- arrhythmia that require active therapy, with the exception of clinically insignificant or minor conduction disturbances;

- history of cerebrovascular disease, in which the necessary medication/treatment;

therapy with anticoagulants or set hemorrhagic disorder;

convulsive disorder, which required active therapy;

set the misuse of drugs or alcohol;

- pregnancy or breastfeeding;

any underlying medical condition that, according to lead researcher, will make the investigational medicinal product dangerous to the subject or interfere with the interpretation of the effectiveness or safety of treatment; or

- inability or unwillingness to return for follow-up visits to examine the long-term results and comply with the study Protocol.

Primary evaluate results:

- change indicator Mawa for 57 days compared with screening.

Secondary assessed results:

- frequency of remission.

The research plan.This study is a double blind, placebo-controlled, randomized study of the safety and tolerability of the compounds of formula (I), (II), (IIA) or (IIB) phase II multiple doses in patients with active UC with a sudden exacerbation of the disease. All subjects will have active disease with medication, including 5-ASA, and either accept stable dosvy corticosteroids and/or azathioprine or 6-mercaptopurine, or they have taken these drugs and have not been able to transfer them. A sudden exacerbation of the disease is defined as a record of Mawa from 6 to 10 with moderate-severe disease activity at endoscopy (set by the endoscopic subscale of Mawa at least 2) within 2 weeks before administration of the investigational medicinal product. Dose allowed for simultaneous reception of medicines (corticosteroids, azathioprine (AZA), 6-mercaptopurine (6-MP) and compounds containing 5-am is nonsalicylate (5-ASA)) must not change throughout the study. Subjects will be randomized to receive placebo or the compounds of formula (I), (II), (IIA) or (IIB) intravenously at 1, 15, 29 and 43 days. All subjects will be monitored in the clinic at regular intervals up to 85 days for assessments of safety, efficacy, pharmacokinetics and/or pharmacodynamics. All subjects will be in touch within 70 days after the last injection of the investigational medicinal product. The safety assessment will be carried out through measurement of key indicators of the state of the organism, clinical laboratory tests, physical examinations, assessment of immunogenicity, x-ray examinations of the chest, electrocardiogram and the frequency and severity occurred after the start of treatment adverse events. Primary clinical activity score will determine the change rate of Mawa for 57 days compared with screening. Secondary outcomes include determining the frequency of remission in terms of Mawa for 57 days, the assessment of the healing of the mucosa and the change in the IBDQ compared to the original.

Example 14: a Clinical study of the safety and efficacy of compounds of formula (I), (II), (IIA) or (IIB) phase II in patients with multiple sclerosis

The purpose of this phase II study is to investigate the safety, efficacy and prenovost the compounds of formula (I), (II), (IIA) or (IIB) in patients with recurring-remitting multiple sclerosis.

Patients: the appropriate subjects will be men and women aged 18 to 65 years.

Criteria

Inclusion criteria:

- the availability of accurate diagnosis recurring-remitting multiple sclerosis;

- a history of at least 1 of the following: a) at least 2 relapses of multiple sclerosis (MS) for the last 2 years, but not within 1-month period prior to screening; (b) relapse MS for the last 6 months, but not within 1-month period prior to screening.

Exclusion criteria:

- the presence of diseases of the Central nervous system (CNS) (e.g., CNS lymphoma, systemic lupus erythematosus);

- the presence of significant bulbar lesions of MS or other neurological defects;

- the presence of bedsores;

- immunomodulatory therapy within 3 months before screening.

Primary evaluate results:

- the total number of new Gd-positive T1-positive lesions by magnetic resonance imaging (MRI) of the head up to 23 weeks.

Secondary assessed results:

- the total number of relapses of MS to 23 weeks; change of the indicator Extended scale of disability (Expanded Disability Status Scale (EDSS)) through 23 weeks.

The research plan.This study presented yet a double-blind, placebo-controlled, randomized study of multiple subcutaneous injections of a compound of formula (I), (II), (IIA) or (IIB) phase II with different doses in patients with recurring-remitting multiple sclerosis. Patients will produce subcutaneous injection of compounds of formula (I), (II), (IIA) or (IIB) or placebo on 0, 1, 2, 3, 7, 11, 15 and 19, or 100 week.

The pharmaceutical composition

Parenteral composition

To obtain a parenteral pharmaceutical composition suitable for injection, 100 mg of the compounds of formula (I), (II), (IIA) or (IIB) is dissolved in DMSO and then mixed with 10 ml of 0.9% sterile saline. The mixture include in a standard dosage form suitable for injection.

In another embodiment for obtaining a composition for injection mixing the following ingredients.

IngredientNumber
The compound of formula (I), (II), (IIA) or (IIB)1.2 g
Buffer solution of sodium acetate (0.4 M)2.0 ml
HCl (1 BC) or NaOH (1 M)enough for a suitable pH
Water is (distilled, sterile)a sufficient amount of to 20 ml

All of the above ingredients, except water, are mixed and stirred and, if necessary, slightly warmed up. Then add sufficient amount of water.

Composition for oral administration

To obtain a pharmaceutical composition for oral delivery, 100 mg of the compounds of formula (I), (II), (IIA) or (IIB) is mixed with 750 mg of starch. The mixture include in unit dosage for oral administration, such as a hard gelatin capsule suitable for oral administration.

In another embodiment, the following ingredients are thoroughly mixed and pressed to obtain tablets with a single notch.

IngredientQuantity per tablet, mg
The compound of formula (I), (II), (IIA) or (IIB)200
Corn starch50
Croscarmellose sodium25
Lactose120
Magnesium stearate5

In yet another embodiment, the following ingred the coefficients thoroughly mixed and introduced into hard gelatin capsule.

IngredientQuantity per tablet, mg
The compound of formula (I), (II), (IIA) or (IIB)200
Lactose, spray dried drying148
Magnesium stearate2

In yet another embodiment for a solution/suspension for oral administration mix the following ingredients.

IngredientNumber
The compound of formula (I), (II), (IIA) or (IIB)1 g
Anhydrous sodium carbonate0.1 g
Ethanol (concentration 200), Pharmacopoeia of the United States of America (USA) (USP)10 ml
Purified water, USP90 ml
Aspartame0.003 g

Composition for sublingual administration (hard bread)

To obtain a pharmaceutical composition for transbukkalno delivery, this is AK solid cake, 100 mg of the compounds of formula (I), (II), (IIA) or (IIB) is mixed with 420 mg of sugar powder, mixed with 1.6 ml of light corn syrup, 2.4 ml distilled water, and 0.42 ml mint extract. The mixture is gently mixed and poured into a mold to obtain a pellet suitable for transbukkalno introduction.

Composition for inhalation

To obtain a pharmaceutical composition for inhalation delivery, 20 mg of the compounds of formula (I), (II), (IIA) or (IIB) is mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% sodium chloride solution. The mixture is included in the device for inhalation delivery, such as a nebulizer, suitable for inhalation.

The composition in gel form for rectal injection

To obtain a pharmaceutical composition for rectal delivery, 100 mg of the compounds of formula (I), (II), (IIA) or (IIB) is mixed with 2.5 g of methylcellulose (1500 MPa), 100 mg of methylparaben, 5 g of glycerin and 100 ml of purified water. The obtained gel mixture is then injected into the device for rectal delivery, such as douche syringes suitable for rectal administration.

The composition is in the form of a suppository

A suppository of total weight 2.5 g is obtained by mixing the compounds of formula (I), (II), (IIA) or (IIB) with Witepsol™ H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and it has the following structure.

IngredientQuantity per suppository mg
The compound of formula (I), (II), (IIA) or (IIB)500
Witepsol® H-15rest

The composition in gel form for topical use

To obtain a pharmaceutical composition in gel form for topical application of 100 mg of the compounds of formula (I), (II), (IIA) or (IIB) is mixed with 1.75 g hydroxypropylcellulose, 10 ml of propylene glycol, 10 ml of isopropylmyristate and 100 ml of purified alcohol USP. The obtained gel mixture was then include in containers, such as tubes, suitable for local administration.

A composition in the form of a solution for ocular injection

To obtain a pharmaceutical composition in the form of a solution for ocular injection of 100 mg of the compounds of formula (I), (II), (IIA) or (IIB) is mixed with 0.9 g of NaCl in 100 ml of purified water and filtered using a 0.2 μm filter. Received isotonic then include devices for ophthalmic delivery, such as a container for eye drops, suitable for ocular administration.

The examples and embodiments described herein are included solely for illustrative purposes, and contents of the description and scope of the attached claims include various modifications or changes, redlagaemye specialists in this field of technology.

1. The compound of formula (I) or its pharmaceutically acceptable salt:

where R1represents hydrogen;
R2represents phenyl, benzothiazol, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OR8With1-C6the alkyl and-N(R9)2;
R4represents phenyl, substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CF3, -OH, -OR8and C1-C6of alkyl;
each R8independently selected from C1-C6of alkyl; and
each R9independently selected from H and C1-C6the alkyl.

2. The compound according to claim 1, where R2represents benzothiazol, possibly substituted by 1 or 2 substituents selected from F, Cl, Br, I, CH3and CN.

3. The compound according to claim 2, where benzothiazyl attached in position 2.

4. The compound according to claim 2, where benzothiazyl attached in position 5.

5. The compound according to claim 1, where R4represents phenyl and substituted by 1 or 2 substituents selected from F, Cl, Br, I, HE, CH3and CF3.

6. Pharmaceutical composition for the modulation of the activity depot-operated calcium channels containing the compound of formula (I) or its pharmaceutically acceptable salt:

where R1represents hydrogen;
R2represents phenyl, benzothiazol, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OR8With1-C6the alkyl or-N(R9)2;
R4represents phenyl, substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CF3, -OH, -OR8and C1-C6of alkyl;
each R8independently selected from C1-C6of alkyl; and
each R9independently selected from H and C1-C6of alkyl;
and pharmaceutically acceptable diluent, excipient or
binder.

7. A compound selected from:
2-(4-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-perbenzoic)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-perbenzoic)-4-(4-triptoreline)thiophene-3-carboxylic acid;
2-(3-perbenzoic)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(bestien-2-ylamino)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamide)-4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzene)-4-(4-were)thiophene-3-carboxylic acid;
2-(4-bromobenzene)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzene)4-(4-bromophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzene)-4-(3,5-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzene)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-bromobenzene)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;
2-(3-perbenzoic)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(3-perbenzoic)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-were)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(4-forfinal)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(3,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(4-chlorobenzamido)-4-(3,4-dimetilfenil)thiophene-3-carboxylic acid;
2-(bestien-2-ylamino)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(bestien-2-ylamino)-4-(4-were)thiophene-3-carboxylic acid;
2-(bestien-2-ylamino)-4-(2,4-dichlorophenyl)thiophene-3-carboxylic acid;
2-(bestien-2-ylamino)-4-(3-chlorophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamide)-4-(4-chlorophenyl)thiophene-3-carboxylic acid;
2-(3-methylbenzamide)-4-(4-were)thiophene-3-carboxylic acid;
4-(2,4-dichlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid
4-(4-chlorophenyl)-2-(3-(3-chlorophenyl)propanamide)thiophene-3-carboxylic acid;
4-(3-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;
4-(2-chlorophenyl)-2-(3-phenylpropanamide)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(2-chloro-4-perbenzoic)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3,4-differentaite)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(2-perbenzoic)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(4-cyanobenzoyl)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(3-forfinal)propanamide)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(2,4-differenl)propanamide)thiophene-3-carboxylic acid;
4-(4-bromophenyl)-2-(3-(3,4-differenl)propanamide)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(4-forfinal)propanamide)thiophene-3-carboxylic acid;
4-(4-chlorophenyl)-2-(3-(4-chlorophenyl)propanamide)thiophene-3-carboxylic acid;
or its pharmaceutically acceptable salt.

8. A method of treating inflammation or disease, disorder or condition of the immune system in a mammal, comprising the introduction of this mammal the compounds of formula (I) or its pharmaceutically acceptable with the and:

where R1represents hydrogen;
R2represents phenyl, benzothiazol, benzofuranyl or the group-CH2CH2is phenyl; where R2possibly substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CN, -NO2, -OR8With1-C6the alkyl and-N(R9)2;
R4represents phenyl, substituted by 1 or 2 substituents, independently selected from F, Cl, Br, I, -CF3, -OH, -OR8and C1-C6of alkyl;
each R8independently selected from C1-C6of alkyl; and
each R9independently selected from N or C1-C6the alkyl.

9. The method of claim 8, where the disease, disorder or condition in a mammal selected from diseases/disorders, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma and multiple sclerosis.

10. The method according to claim 9, where the disease, disorder or condition is a rheumatoid arthritis.

11. The method according to claim 9, where the disease, disorder or condition is a multiple sclerosis.

12. The method according to claim 9, where the disease, disorder or condition is an inflammatory bowel disease.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1,3-disubstituted 4-methyl-1H-pyrrol-2-carboxamides of formula I: wherein the values R1, R2, R3, R4 are presented in cl.1 of the patent claim.

EFFECT: preparing the compounds found to be serotonin-5-HT reuptake inhibitors that enables using them in medicine.

14 cl, 1 dwg

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I, as well as to their physiologically acceptable salts wherein: X means NH; R1 means (C1-C6)-alkyl; R2 means OH; R2' means H; R5' means (C1-C6)-alkylene-O-S(O)2-R6; R3, R3', R4, R4' and R5 independently mean H, OH, (C1-C6)-alkylene-O-S(O)p-R6, O-(CH2)m-phenyl; at least one of the radicals R3, R3', R4, R4' and R5 has the value -O-(CH2)m-phenyl; R6 means OH; m=1; p=2.

EFFECT: compounds can find application in medicine, eg as lipid-lowering agents.

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 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 relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae (1) and (2), where R1 is H or alkyl with 1-6 carbon atoms, R2 is H, alkyl with 1-6 carbon atoms or R1 and R2 together with a nitrogen atom form a saturated or unsaturated 5-, 6- or 7-member ring which can also include one or two heteroatoms independently selected from N, O or S. Said 5-, 6- or 7-member ring is possibly substituted with one or two OH groups or halogen groups, and said 5-, 6- or 7-member ring is possibly condensed with an aromatic or non-aromatic 5- or 6-member ring; R3 is independently selected from H, alkyl with 1-20 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl-alkyl, where the alkyl group has 1-4 carbon atoms, phenyl(hydroxy)alkyl, where the alkyl group has 1-4 carbon atoms, wherein said phenyl groups are possibly substituted with 1-3 groups independently selected from a group comprising halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, or R3 is CO-R7 or CO-O-R7, where R7 is H, alkyl with 1-20 carbon atoms, optionally substituted with a NH2 group or NH-CO alkyl group, where the alkyl group has 1-6 carbon atoms, phenyl or phenyl-alkyl, where the alkyl group has 1-4 carbon atoms, wherein said phenyl groups are possibly substituted with 1-3 groups independently selected from a group comprising halogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, is H, alkyl with 1-6 carbon atoms or CO-R8, where R8 is alkyl with 1-6 carbon atoms; wavy lines denote bonds with carbon atoms, having an R or S configuration; dotted lines denote a bond or absence of a bond provided that the ring containing dotted lines is aromatic; m, n and q are whole numbers independently selected from 0, 1, 2 or 3, provided that the sum of m, n and q equals 2 or 3; s equals 0 or 1; W, X and Y independently denote CH, CR5, CR6 or a heteroatom independently selected from N, O and S, and R5 and R6 are independently selected from H, halogen, alkyl with 1-6 carbon atoms, halogen-substituted alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms and thioxy with 1-3 carbon atoms, phenyl, or R5 and R6 together with atoms to which they are bonded form a carbocyclic ring which has 6 atoms in the ring, or a heterocyclic ring which has 5 or 6 atoms in the ring and 1-3 heteroatoms independently selected from N, O and S. Said carbocyclic or heterocyclic ring, formed jointly by R5 and R6, is possibly substituted with 1-6 R9 groups, where R9 is a halogen.

EFFECT: higher pain-killing and immune-stimulating action.

65 cl, 1 tbl, 256 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

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid, to based pharmaceutical compositions and to their application, for treating spasticity or a spasticity symptom, gastroesophageal reflux disease (GERD), drug addiction, alcohol addiction or alcohol abuse, or cough, or vomiting. Acyloxyalkylcarbamate prodrugs represent a compound of formula (V) or its pharmaceutically acceptable salt where R1 is selected from C1-C6alkyl substituted by C1-C6alkyl, C3-C6cycloalkyl, phenyl, phenyl C1-C6alkyl substituted by phenyl C1-C6alkyl, phenylC2-C6alkenyl, C5-C6heteroaryl containing 1 nitrogen, oxygen or sulphur atom as a heteroatom; R2 and R3 are independently selected from hydrogen, C1-C6alkyl and C3-C6cycloalkyl; R4 is selected from: hydrogen, phenyl, phenyl C1-C6alkyl and C1-C6alkyl and where "substituted" means a group wherein one or two hydrogen atoms are substitute by a substitute which represent C1-C6alkoxy. Also, the invention refers to an intermediate compound of formula (VII) and its pharmaceutically acceptable salt where X represents: fluorine, chlorine, bromine or iodine; R2 and R3 are independently selected from hydrogen and C1-C6alkyl; R4 is selected from: hydrogen, C1-C6alkyl, phenyl and phenyl C1-C6alkyl.

EFFECT: preparation of the acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid which are applicable for the oral introduction and oral introduction with using prolonged release dosage forms.

23 cl, 3 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is 2-alkyl-cycloalk(en)yl-carboxamides of formula

, in which X, s, R1 , L, R2 and A assume values given in the formula of invention, a method of producing said compounds, an agent and use of said compounds against unwanted microorganisms.

EFFECT: higher activity compared to existing compounds, low toxicity and high toleration by plants.

6 cl, 8 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to hot or sweet flavourants in form of a synthetic amide compound or edible salt thereof in amount ranging from approximately 0.001 parts per million to approximately 100 parts per million. The amide compound has formula

where A is a phenyl or a 5- or 6-member heteroaryl ring selected from a group comprising pyridine, pyrazine, pyrazole, thiazole, furan, thiophene, benzofuran and benzothiophene; m equals 1, 2 or 3, each R1 is independently selected from hydroxyl, fluorine, chlorine, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy and isopropoxy, or alternatively two R1 are bonded to form a saturated C1-C3 alkylenedioxy ring on the phenyl; and R2 is a C3-C10 branched alkyl. The amide compound also has formula

in which substitutes A, B, R50, R60, R70, R80, n and m assume values given in the formula of invention. The amide compound is also a specific chemical compound.

EFFECT: obtaining hot and sweet taste modifiers and boosters for food and medicinal products.

39 cl, 7 tbl, 180 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or salts thereof, (1), where R1 denotes a hydrogen atom or a C1-6alkyl group; R2 denotes a hydrogen atom, R3 denotes a hydrogen atom or a C1-6alkyl group when R4 and R5 denote hydrogen atoms, R6 denotes a hydrogen atom or a cyano group, or in >C(R6) C(R5)(R4) - denotes a double bond, R4 and R6 are absent, and R5 denotes a hydrogen atom; or R4 denotes a hydrogen atom and R5 denotes a hydroxy group or a halogen atom, R6 denotes a hydrogen atom or a cyano group, R7 denotes one or two substitutes selected from a group comprising a hydrogen atom, a halogen atom, a nitro group and C1-6alkoxy group, A denotes a 5-member or a 6-member non-aromatic heterocyclic ring which contains one sulphur atom (the sulphur atom can form an oxide), W denotes an oxo group, two hydrogen atoms, two fluorine atoms or a combination of a hydrogen atom and a hydroxy group, and X denotes an oxygen atom or a sulphur atom.

EFFECT: medicinal agent based on these compounds have inhibitory action on production of prostaglandin E2 and can be used in medicine to treat urological diseases.

5 cl, 7 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: there are presented drug derivatives wherein said derivatives contain a H2S-releasing fragment of 4-hydroxythiobenzamide which is either covalently bond with the drug, or forms a pharmaceutically acceptable salt with the antilipidemic drug.

EFFECT: compounds show higher activity, or reduced side effects.

5 cl, 26 ex, 22 dwg

Up!