2-phenylpropionic acid derivatives and pharmaceutical compositions containing thereof

FIELD: medicine.

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

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

 

The present invention relates to new derivatives of 4-(triftoratsetilatsetonom)propionic acid containing pharmaceutical compositions, which are used as inhibitors of chemotaxis of polymorphonuclear and mononuclear cells, especially in the treatment of neutralization pathologies.

Certain blood cells (macrophages, granulocytes, neutrophils, polymorphonuclear), susceptible to chemical stimulus (when stimulated by chemicals called chemokines), migration along the concentration gradient stimulating agent through a process called chemotaxis. Main known stimulating agents or chemokines presents a decomposition of the complement Sa, some N-formylpiperidine generated as a result of lysis of the bacterial surface, or peptides synthetic origin, such as formyl-methionyl-leucyl-phenylalanine (f-MLP) and mainly by various cytokines, including interleukin-8 (IL-8, have also been identified CXCL8). Interleukin is an endogenous chemotactic factor produced mostly containing the core cells, such as fibroblasts and macrophages.

In certain pathological conditions, marked by a sharp recruitment of neutrophils, more serious damage to the area associated with infiltrat is her neutrophilic cells. Recently was widely shown the role of neutrophil activation when determining damage associated with reperfusion after ischemia and pulmonary hyperoxia.

The biological activity of IL-8 is mediated by the interaction of interleukin membrane receptors CXCR1 and CXCR2, which belong to the family of seven transmembrane receptors expressed by the surface of human neutrophils and some types of T cells (L. Xu et al., J. Leukocyte Biol., 57, 335, 1995). Known selective ligands, which may be different for CXCR1 and CXCR2: GRO-α is an example of CXCR2-selective chemotactic factor.

Broadly described, the potential pathological role of IL-8 in pulmonary diseases (lung damage, acute respiratory distress syndrome, asthma, chronic pulmonary inflammation and fibrosis) and especially in the pathogenesis of COPD (chronic obstructive pulmonary disease) by way of CXCR2 (D. WP Hay and H.M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

Characterized by accumulation of neutrophils occurs in acute and chronic pathological conditions, such as very inflamed and untreatable areas of psoriatic lesions. The neutrophil chemotactic are attracted and activated synergistic action of chemokines, IL-8 and Gro-a released-stimulated keratinocytes, as well as faction Sa/Sa-desag, produced by the activation of alternative complement (T. Terui et al., Exp. Dermatol., 9, 1, 2000).

The authors of the present invention recently described a new class of "omega-aminoalkylation R-2-arylpropionic acids as inhibitors of chemotaxis of polymorphonuclear and mononuclear cells (WO 02/068377). The new class includes compounds that are inhibitors from selective inhibitors Sa to have a dual action inhibitors Sa/IL-8.

In addition, new classes of amides R-2-arylpropionic acids and N-arylsulfonamides described as effective inhibitors of IL-8-induced chemotaxis and degranulation of neutrophils (WO 01/58852; WO 00/24710).

The authors of the present invention discovered a new class of derivatives of 2-(R)-phenylpropionic acids as inhibitors of chemotaxis of polymorphonuclear and mononuclear cells. In particular, the connection of their inventions are potent inhibitors of IL-8-induced chemotaxis of neutrophils and Sa-induced chemotaxis of neutrophils and monocytes with improved pharmacokinetic characteristics and profile of pharmacological activity.

The present invention thus provides derivatives of 2-(R)-phenylpropionic acids of the formula (I):

and their pharmaceutically acceptable salt,

where

R' you are the wounds of

- N., HE,

when R' represents H, R is selected from

- H, C1-C5-alkyl, C3-C6-cycloalkyl,2-C5-alkenyl,1-C5-alkoxy;

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

- amino acid residue, consisting of unbranched or branched C1-C6-alkyl, C3-C6-cycloalkyl,2-C6-alkenyl,1-C6-phenylalkyl substituted one additional carboxypropyl (COOH);

- residue of the formula-CH2-CH2-Z-(CH2-CH2O)nR', where R' represents H or C1-C5-alkyl, n is an integer from 0 to 2 and Z represents oxygen or sulfur;

- residue of the formula -(CH2)n-NRaRb, where n is an integer from 0 to 5 and each of Ra and Rb, which may be the same or different, represents a C1-C6-alkyl, C2-C6alkenyl or, alternatively, Ra and Rb together with the nitrogen atom to which they are bound, form a heterocycle of 3 to 7 members of the formula (II)

where W represents a simple bond, O, S, N-Rc, and Rc represents H, C1-C6-alkyl or C1-C6-alkylphenyl, and n is an integer from 0 to d is 3;

- residue formula SO2Rd, where Rd represents a C1-C6-alkyl, C3-C6-cycloalkyl,2-C6alkenyl, aryl and heteroaryl;

when R' is a HE, R is selected from H, C1-C5-alkyl, C3-C6-cycloalkyl,2-C5-alkenyl.

The present invention further provides the use of compounds of formula (I) as medicines. In particular, these drugs are inhibitors of chemotaxis of polymorphonuclear and mononuclear cells.

The compounds of formula (I), in General, included in the General formula inhibitors of IL-8 and Sa described previously in WO 01/58852, WO 00/24710 and WO 02/068377. Found that the compounds of formula (I) have a significantly advantageous features in comparison with the particularly preferred compounds of the above cited inventions.

Compounds of the invention belong to the chemical class of alltitle. In studies in medicinal chemistry triflate group is considered normal bioisosterism replacement phenolic hydroxyl or metoxygroup; despite the very low efficiency of the corresponding 4-hydroxy - and 4-mutatsionnogo, the compounds of formula (I) unexpectedly turned out to be potent inhibitors of IL-8-induced chemotaxis of human PMN. In addition, triflate group on the phenyl number of the goals specifically gives the high affinity of the receptors CXCR1 and CXCR2, IL-8. The compounds of formula (I), compared with the known inhibitors of IL-8 and/or Sa-induced PMN chemotaxis, as it has been unexpectedly discovered, are very potent inhibitors in the inhibition of GRO-α-induced PMN chemotaxis, indicating a specific effect on R2-mediated path.

It is known that in contrast to the reactive nature of aliphatic triflates, aromatic triflate (artribute) are both chemically and biologically stable. Due to the electron-acceptor properties and lipophilicity triflate group prevents oxidation of the aromatic ring by isozyme of cytochrome P450 systems. Tripleta part helps to increase the metabolic stability of compounds of the formula (I), slowing down the metabolism (hydroxylation of the aromatic ring/Deputy and the subsequent pairing), which usually occurs when the analogues, bearing electron-donating groups, injected in vivo.

In connection with this property, a new class has higher oral bioavailability, more high-t1/2and lower binding protein compared with the classes above cited inventions.

These characteristics provide the best overall pharmacological profile of these medicines and provide the possibility of the activity of therapeutic use them in different chronic or acute pathological conditions.

When R' represents H, preferred groups R are

H, C1-C5-alkyl, C3-C6-cycloalkyl,1-C5-alkoxy, C1-C2-carboxyethyl;

heteroaryl group selected from substituted and unsubstituted pyridine, thiazole, oxazole;

the remainder of the formula-(CH2)n-NRaRb, where n is an integer 2 or 3, more preferably 3, and the group NRaRb is a N,N-dimethylamine, N,N-diethylamine, 1-piperidyl, 1-pyrrolidinyl, 4-morpholyl, 1-pyrrolidyl, 1-piperazinil, 1-(4-methyl)piperazinil;

the remainder of the formula SO2Rd, where Rd represents a C1-C2-alkyl, C3-C6-cycloalkyl.

When R' is a HE, the preferred groups R are H, C1-C5-alkyl, C3-C6-cycloalkyl.

Particularly preferred compounds of the invention are:

1. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonylaminoethyl;

1A. - the sodium salt of R(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonamide;

2. - R(-)-2-[(4'-tripterocalyx)phenyl]propionamide;

3. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-methylpropionamide;

4. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-isopropoxypropylamine;

5. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-cyclopentylpropionate;

p> 6. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide;

6A. - hydrochloride R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide;

7. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide;

7a. - hydrochloride R(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide;

8. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide;

8A. - hydrochloride R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide;

9. - R(+)-2-[(4'-tripterocalyx)phenyl]-N-(2-hydroxyethoxyethyl)propionamide;

10. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(4'-trifluoromethyl)thiazolyl]propionamide;

11. - R(-)-2-[(4'-tripterocalyx)phenyl]-N-methyl-N-hydroxypropionate.

The most preferred compound in the list is the connection 1 and the related sodium salt of 1A.

Compounds of the invention are potent inhibitors of PMN chemotaxis of human-induced IL-8. Compounds of the invention in which R is a residue of formula -(CH2)n-NRaRb, are dual inhibitors of chemotaxis of PMNs induced CA and IL-8.

Compounds of the invention of formula (I) are usually isolated in the form of additive salts with both organic and is Neorganicheskie pharmaceutically acceptable acids or bases. Examples of such acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fumaric acid, citric acid.

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

The compounds of formula (I) receive, from R(-)-2-(4'-triftoratsetilatsetonom)propionic acid, according to the methodology previously described in WO 01/58852, WO 00/24710 and WO 02/068377.

For example, the compounds of formula (I)in which R represents a SO2Rd and Rd represents a C1-C2-alkyl or C3-C6-cycloalkyl, can be obtained by treatment with equimolar amount of R(-)-2-(4'-triftoratsetilatsetonom)propionic acid with equimolar amounts of the appropriate sulfonamida RdSO2NH2in an inert solvent in the presence of equimolar amount or a slight excess of condensing agent such as a carbodiimide (such as dicyclohexylcarbodiimide), soluble carbodiimide (for example, hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide) or 1,1'-carbonyldiimidazole, and protivoiznosnye selected from the group consisting of triethylamine, 4-(N,N-dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.

Compounds of the invention of formula (I) were evaluated in vitro for their Messiah. sposobnosti to inhibit the chemotaxis of polymorphonuclear leukocytes (hereinafter referred to PMNs) and monocytes, induced by fractions of IL-8 and GRO-α and Sa. For this purpose, to highlight PMNs from heparinised human blood collected from healthy adult volunteers, mononuclear cells were removed by means of sedimentation on the dextran (according to the methodology described W.J. Ming et al., J. Immunol., 138, 1469, 1987), and erythrocytes were removed by hypotonic solution. Cell viability was calculated with the exception of Trianon blue, while the proportion of circulating polymorphonuclear cells was evaluated on the centrifuged cells after staining Diff Quick.

In the analysis of induced IL-8 chemotaxis recombinant IL-8 person (Pepro Tech) was used as a stimulating agent in the chemotaxis experiments: liofilizovannye protein was dissolved in a volume of HBSS containing 0.2% bovine serum albumin (BSA)to obtain the initial solution having a concentration of 10-5M, which is dissolved in HBSS to a concentration of 10-9M for the analysis of chemotaxis.

Inhibition of GRO-α-induced chemotaxis was assessed in a similar analysis.

In the analysis Sa-induced chemotaxis faction hr C5a and HrC5a-desid (Sigma) was used as stimulating agents in the chemotaxis experiments, obtaining almost identical results. Liofilizovannye Sa was dissolved in a volume of HBSS containing 0.2% BSA, so to get the original solution with con is entrely 10 -5M, which is dissolved in HBSS to a concentration of 10-9M for the analysis of chemotaxis.

In the experiments of chemotaxis of PMN were incubated with the compounds of the invention of formula (I) for 15' at 37°C in atmosphere containing 5% CO2.

Chemotactic activity Sa evaluated on circulating polymorphonuclear human cells (PMN), resuspending in HBSS at a concentration of 1.5×106PMN in ml.

During the analysis of chemotaxis (according to W. Falket et al., J. Immunol. Methods, 33, 239, 1980) was applied filters without PVP with a porosity of 5 μm and microcamera suitable for replication.

Compounds of the invention of formula (I) was evaluated at concentrations between 10-6and 10-10M; for this purpose they were added at the same concentration as the bottom then the top and pores microcamera. The ability of the compounds of the invention of formula (I) to inhibit the chemotaxis of human monocytes were performed according to the method described by Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989).

The binding protein was determined as follows. Plasma samples of rats in two replicates for each compound at a concentration of 50 μg/ml were incubated at 37°C for 20 minutes with gentle shaking. Then samples were ultrafiltrable through device microsattelite Centrifree® by centrifugation at 1500 g for 15 minutes. Ultrafiltrate was subjected to quantitative analysis of WCE is X-MS/MS (column Luna C18, 150×2 mm EXT. diameter, 5 μm (Phenomenex), mobile phase: eluent A) 0,02M, NSOO-NH4+(pH 4,3 c HCOOH); eluent) CH3IT).

The pharmacokinetic profile (t1/2oral bioavailability and so on) of the claimed compounds was evaluated in male mice after intravenous and oral administration. Pharmacokinetic analysis was performed using the concentration of the compound in plasma at different time. Data were evaluated by Kinetica 2000TMthe version 3.0 software [InnaPhase Corporation, World headquarters, 1700 Race Street, Philadelphia, PA 19103 USA].

Found that the compounds of formula (I), evaluated ex vivo in blood in General accordance with the method described Patrignani et al., in J. Pharmacol. .. Ther., 271, 1705, 1994, are completely ineffective as inhibitors of the enzyme cyclooxygenase (SOH).

In most cases, the compounds of formula (I) inhibit the production of PGE2induced in murine macrophages by stimulation with lipopolysaccharide (LPS, 1 μg/ml), at concentrations between 10-5and 10-7M. Inhibition of the production of PGE2that can be registered, there are, mainly, at the limit of statistical significance, and more often it is below 15-20% of the value. Reduced efficacy in inhibition WITH creates an advantage for therapeutic use the compounds izobreteny is due to the fact, the inhibition of prostaglandin synthesis creates an incentive for cells macrophages to amplify the synthesis of TNF-α (induced by LPS or peroxidation), which is an important mediator atroficescuu activation and stimulus for the production of the cytokine interleukin-8.

Inhibitors of activation XCR1 and CXCR2 find useful application, as described in detail above, particularly in the treatment of chronic inflammatory pathologies (e.g., psoriasis), in which, as expected, activation of both receptors IL-8 plays a critical pathophysiological role in the development of the disease.

Indeed, it is known that activation of CXCR1 is important in IL-mediated the PMN chemotaxis (Hammond M et al., J. Immunol., 155, 142, 1995). On the other hand, it is assumed that the activation of CXCR2 is important for proliferation and angiogenesis IL-mediated epidermal cells of psoriatic patients (Kulke R, et al., J. Invest Dermatol, 110, 90, 1998).

In addition, CXCR2 antagonists are particularly useful in therapeutic applications in the treatment of important pulmonary diseases such as chronic obstructive pulmonary disease COPD (D. WP Hay and H.M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

From the point of view of the experimental evidence discussed above, and the role played by interleukin-8 (IL-8) and agents who have shared with him the origin, the processes that VK is ucaut the activation and infiltration of neutrophils, compounds of the invention are particularly useful in the treatment of diseases such as psoriasis (R. J. Nicholoff et al., Am. J. Pathol., 138, 129, 1991), chronic intestinal inflammatory diseases, such as ulcerative colitis (Y. R. Machida et al., Clin. Sci., 82, 273, 1992), chronic obstructive pulmonary disease (COPD), bullous disease, rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), idiopathic fibrosis (E. J. Miller, previously cited publication and P. C. Carre et al., J. Clin. Invest., 88, 1882, 1991), glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135, 1994).

Compounds of the present invention are also effective for the prevention and treatment of damages caused by ischemia and reperfusion, in particular for protection against functional damage in organ transplantation, especially in kidney transplantation.

In an experimental model of kidney transplantation in rats proved that the compounds of the invention are active in the preservation of renal function immediately after injury due to ischemia/reperfusion that follows isogenic transplantation of kidneys, because they prevent the infiltration of cells in the graft, which takes place after postischemic reperfusion.

Experimental model of kidney transplantation in rats

The study was carried out on the model isogenic transplant kidneys with the use of rats as dvorovi recipients of transplants. Created anastomosis between the renal artery of the recipient and donor, as well as the anastomosis side-to-side renal veins. Vascular clamps were released after 30 minutes (warm ischemia). Native right kidney was then removed. Animals were placed in individual metabolic cages for measurement of daily diuresis as an indicator of recovery of renal function. After 16 and 24 hours renal function was analyzed by measuring the concentration of creatinine in plasma. Twenty-four hours after kidney transplantation the animals were killed. Kidney transplant was removed, did it slices and placed in a solution Dubosq-Brazil for the analysis of conventional histology by light microscope. In addition, additional fragments of the kidney was frozen in liquid nitrogen and used for immunohistochemical analysis of infiltration of inflammatory cells (polymorphonuclear cells, cells positive for MHC class II).

All compounds of the invention showed protection from damage in transplanted rats treated intravenously before kidney transplantation and subcutaneously two hours after transplantation, at a concentration factor of 5 mg/kg to 30 mg/kg

In addition, the compounds of the invention are particularly useful in the treatment of melanoma and angiogenesis.

Activity in vitro on melanoma cells was determined as follows.

About iterate of melanoma cells

Tablets with ninety-six wells containing 2-6×103melanoma cells/well, was pre-treated with selected compounds of the invention, stimulated interleukin-8 (CXCL8) and were cultured for 3-4 days. Then to each well was added bromide 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium (MTT, 400 μg/ml) and the plates were incubated for 2 hours. The medium was removed and lizirovania cells were added to 100 μl of dimethyl sulfoxide. The magnitude of absorption, as determined in the apparatus for reading the microplate was measured changes in cell proliferation.

Analysis of invasion using tablet Matrigel

Melanoma cells were placed in the tablet (5×103cells on sectionone tablets) and gave them the opportunity to attach for 24 hours. After 5 days of treatment selected compounds of the invention the cells were released from the tablets short exposure to a mixture of trypsin-ethylenediaminetetraacetic acid, counted and centrifuged. Camera for invasion Biocoat Matrigel was primiraly according to the manufacturer's instructions. CXCL8, dissolved in serum-free medium, placed in the bottom of the hole to act as chemoattractant and 3×103cells in 500 μl serum-free medium were placed in the upper chamber of the tablet Matrigel and the plate is incubated at 37°C for 22 hours. Cells on the lower surface the displacement of the filter were stained with Diff-Quick and quantitatively determined by the image analyzer, attached to the microscope.

Therefore, the next aim of the present invention is the proposal of using compounds of formula (I) in the manufacture of a medicine for the treatment of psoriasis, ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous bladderworts, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

In table I are listed the biological activity of exemplary compounds of the present invention in comparison with the exemplary compounds of the above-cited patent documents.

Table I
No.% inhibition of PMN migration induced IL-8
(10-9M)
% inhibition of PMN migration induced GRO-α
(10-8M)
% inhibition of PMN migration induced CA
(10-8M)
Inhibitors of IL-8
WO 00/2471050121018 Inactive#
589616Inactive#

WO 01/58852
5712107Inactive#
642613Inactive#
Dual inhibitors of IL-8/C5a

WO 02/068377
4423910556
5212Inactive#6518
51 13Inactive#6710

#Tested at 10-6M

In table II identifies the physico-chemical, pharmacological and pharmacokinetic characteristics of exemplary compounds of formula (I) in comparison with the exemplary compounds of the above-cited patent documents. The compounds of formula (I) exhibit higher oral bioavailability, more high-t1/2and lower binding protein compared with example connections.

Table II
No.Binding protein (50 µg/ml)t1/2(h)Oral bioavailability
Inhibitors of IL-8
of 99.98%0,480%
to 99.00%24,7~100%
98,40% 0,435%
(2)93,80%2,395%
Dual inhibitors of IL-8/C5a
85,00%1,730%
70,36%3,480%
64,07%2,490%

Pharmaceutical compositions comprising a compound of the invention and a suitable carrier are also within the scope of the present invention.

Compounds of the invention together with commonly used assistive device, carrier, diluent or excipient can actually be made in the form of a pharmaceutical composition and their standard dosage forms, and in this form they can be applied in solid form, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with them, all about the and are intended for oral administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their standard dosage forms may include the ingredients in conventional proportions, with an additional active compounds or compound agents or without them, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended range of doses for use.

When used as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. Such compositions can be obtained by a method well known in the pharmaceutical field, they include at least one active connection. The compounds of this invention are usually administered in pharmaceutically effective amounts. The amount of compound injected in fact, usually determined on the basis of acceptable circumstances, including being treated with the state of the chosen route of administration, the actual entered the compound, the age, weight and sensitivity of the individual patient, the severity of the patient's symptoms and the like.

The pharmaceutical compositions of the invention can be administered in a number of ways, including orally, rectally, transdermal, subcutaneous, intravenous, intramuscular or intranasal route. Depending on the intended route of delivery, the connection is preferably made in the form of either injectable or oral compositions. Compositions for oral administration can be in the form of bulk liquid solutions or suspensions, or bulk powders. However more typically, the compositions are in the form of standard dosage forms to facilitate precise dosage. The term "standard dosage forms" refers to physically discrete units suitable as the standard dose for the subject of humans and other mammals, each unit contains a predetermined quantity of active substance calculated to achieve the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Standard dosage forms include pre-filled, containing a pre-measured amount of liquid compositions ampoules or syringes, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the acid compound is usually a smaller component (from about 0.1 to about 50 wt.% or preferably from about 1 to bring the LNA 40 wt.%), and the rest consists of various fillers or carriers and auxiliary means for processing, which helps the formation of the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous filler with buffers, suspendresume and dispersione agents, coloring agents, korrigentami and the like. Liquid formulations, including injectable compositions described below, always store in the absence of light to avoid any catalytic action of light, such as the formation of hydroperoxide or peroxide. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose, disintegrity agent, such as alginic acid, primogel or corn starch; lubricating substance, such as magnesium stearate; a substance giving a slide, such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or corrigent, such as peppermint, methyl salicylate or orange corrigent.

Injectable compositions are usually based on injectable sterile saline, and phosphate buffered saline or other injectable carriers, known in this field. As indicated above, the acid derivative of formula (I) in such compositions is typically a smaller component, often comprising from 0.05 to 10 wt.%, and the rest of the amount is injectable carrier and the like. The average daily dose will depend on various factors such as the seriousness of the disease and the condition of the patient (age, gender and weight). The dose usually ranges from 1 mg or more mg to 1500 mg of the compounds of formula (I), such a dose is not necessarily shared by multiple introductions. Due to the low toxicity of the compounds of the invention can also enter higher doses over extended periods of time. The above-described components for oral input or injectable compositions are merely representative. Additional substances and processing methods and the like described in part 8 of the publication “Remington''s Pharmaceutical Sciences Handbook”, 18thEdition, 1990, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

Compounds of the invention can also be entered in the form for extended release or delivery system for drugs with a long release. Description of representative materials for long-term release can also be found in the included materials in the above directory REM is ngton.

The present invention will be illustrated by the following examples, which shall not be interpreted as limiting the scope of the invention.

EXAMPLES

Examples of abbreviations are: THF for tetrahydrofuran, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene.

All compounds described in the examples, receive, on the basis of R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid, obtained as described previously in WO 03/043625.

Example 1

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-methanesulfonylaminoethyl

1,1'-Carbonyldiimidazole (7,21 g of 44.5 mmol) is added at room temperature to a solution of R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid (13,28 g of 44.5 mmol) in anhydrous CH2Cl2(130 ml). The resulting solution is kept under stirring for 1 hour 30'. Then add methanesulfonamide (to 4.23 g of 44.5 mmol)after 1 hour at room temperature add DBU (6,65 ml of 44.5 mmol). The resulting mixture is left to stir at room temperature over night. The organic phase is washed with 0.5m HCl (2×50 ml), 5% solution of NaH2PO4(3×50 ml) and water until neutrality. After drying over Na2SO4and the solvent is evaporated, the obtained residue is treated with isopropyl simple ether. Formed precipitate was separated by filtration and the mother liquor solutions in arevut under reduced pressure, while receiving the crude solid, which after suspension in n-hexane (50 ml) at room temperature for 2 h gives pure R-(-)-2-[(4'-tripterocalyx)phenyl]-N-methysulfonylmethane (13,2 g to 35.15 mmol) as a white powder (yield 79%).

TPL 98-100°C. [α]D=-49,4 (C=0,5; CH3IT).1H NMR (CDCl3): δ 7,40 (d, 2H, J=7 Hz); 7.23 percent (d, 2H, J=7 Hz); 3,68 (square, 1H, J=7 Hz); 3.15 in (s, 3H); of 1.42 (d, 3H, J=7 Hz).

Example 2A

Sodium salt of R-(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonylaminoethyl

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-methysulfonylmethane (6,89 g, 18,35 mmol) dissolved in ethanol (35 ml) and the solution added dropwise 1M NaOH (volumetric standard) (18,35 ml). The solution is kept stirring for 30' at room temperature. The alcohol is evaporated under reduced pressure and the aqueous solution is frozen and lyophilized during the night. Pure sodium salt obtained as a white powder (7,29 g, 18,35 mmol).

[α]D=-27,2 (C=0,5; CH3IT).

Example 2

R-(-)-2-[(4'-Tripterocalyx)phenyl)]propionamide

Thionyl chloride (4.8 ml, 67 mmol) is added at room temperature to a solution of R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid (10 g, of 33.5 mmol) in anhydrous toluene (10 ml). The solution is refluxed for 2 hours After ohlord is ment to room temperature, the toluene is evaporated under reduced pressure and the crude oily residue was dissolved in CH 2Cl2(25 ml) and the solution for 1 hour bubbled ammonia. The organic solution was washed with water (3×15 ml), dried over Na2SO4and evaporated under reduced pressure, thus obtaining a light brown crude solid, which was purified by suspendirovanie in n-hexane (100 ml) for 2 hours. Pure R-(-)-2-[(4'-tripterocalyx)phenyl]propionamide (8,1 g of 27.2 mmol) was isolated by filtration under vacuum in the form of a white solid (yield 81%).

TPL 67-69°C. [α]D=-12 (C=1; CH3IT).1H NMR (CDCl3): δ of 7.69 (d, 2H, J=7 Hz); 7,22 (d, 2H, J=7 Hz), lower than the 5.37 (user. s, 2H, SOPSH2); 3,63 (square, 1H, J=7 Hz); of 1.53 (d, 3H, J=7 Hz).

Example 3

R-(-)-2-[(4'-Tripterocalyx)phenyl)]-N-methylpropionamide

Thionyl chloride (4 ml) is added at room temperature to a solution of R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid (1 g, 3.35 mmol) in anhydrous toluene (2.5 ml). The solution is refluxed for 2 hours After cooling to room temperature, the toluene is evaporated under reduced pressure and the crude oily residue was dissolved in CH2Cl2(10 ml). The organic solution is added dropwise to a solution of methylamine (0,414 ml, 10,08 mmol) in CH2Cl2(5 ml). The mixture is left to stir at room temperature for 3 hours. The solvent is evaporated under decreased the pressure for the distillation of the excess amine and the crude product is again diluted with CH 2Cl2(10 ml), washed with saturated solution of NaHCO3(2×5 ml) and water (3×15 ml), dried over Na2SO4and evaporated under reduced pressure, thus obtaining the crude residue in the form of an orange oil. The crude oil is purified flash chromatography (eluent: CH2Cl2/CH3HE, 98:2), thus obtaining the pure R-(-)-2-[(4'-tripterocalyx)phenyl]-N-methylpropionamide in the form of a clear oil (0,78 g, 2.51 mmol) (yield 75%).

[α]D=-19 (C=0,5; CH3IT).1H NMR (CDCl3): δ of 7.48 (d, 2H, J=7 Hz); from 7.24 (d, 2H, J=7 Hz); 5,35 (users, 1H, SOPSH); 3,55 (square, 1H, J=7 Hz); 2,72 (d, 3H, J=3 Hz); of 1.55 (d, 3H, J=7 Hz).

Example 4

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-isopropoxypropylamine

To a suspension of the hydrochloride of N-isopropylacrylamide (0.14 g, 1,67 mmol) and NaHCO3(0,19 g, to 3.34 mmol) in anhydrous THF (5 ml) was added R-(-)-2-(4'-triftoratsetilatsetonom)propionate, have been derived from the corresponding acid (0.5 g, 1,67 mmol)as described in example 3 and the solution left to stir at room temperature for 3 hours After evaporation of the solvent the crude product was diluted with CH2Cl2(10 ml), washed with water (2×10 ml), dried over Na2SO4and evaporated under reduced pressure, thus obtaining an oil residue. The crude oil is purified by treatment with n-hexane and formed the I residue after filtration gives pure R-(-)-2-[(4'-tripterocalyx)phenyl]-N-isopropoxypropylamine in the form of a white powder (0.45 g, 1.28 mmol) (yield 77%).

[α]D=-24 (C=0,5; CH3IT).1H-NMR (CDCl3): δ 8,15 (users, 1H, CONH); was 7.45 (d, 2H, J=7 Hz); then 7.20 (d, 2H, J=7 Hz); the 3.65 (m, 1H); 3,50 (square, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz); 1,2 (d, 6N, J=7 Hz).

According to the same procedure as described for example 3, was synthesized following amines, proceeding from commercially available amines or amine obtained according to the method described in WO 01/58852; WO 00/24710 and WO 02/068377.

Example 5

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-cyclopentylpropionate

[α]D=-35 (C=1; CH3IT).1H-NMR (CDCl3): δ 7,52 (d, 2H, J=7 Hz); 7,28 (d, 2H, J=7 Hz); 5,55 (users, 1H, CONH); to 3.58 (square, 1H, J=7 Hz); of 3.48 (m, 1H); 2,85 (m, 4H); a 2.36 (m, 4H); was 1.58 (d, 3H, J=7 Hz).

Example 6

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide

[α]D=-26 (C=2; CH3IT).1H-NMR (CDCl3): δ 8,11 (users, 1H, CONH); 7,72 (d, 2H, J=7 Hz); of 7.25 (d, 2H, J=7 Hz); 3,88 (square, 1H, J=7 Hz); 3,55 (m, 2H); 3,30-2,95 (m, 3H); 2,70 (m, 2H); 2,48 (m, 2H); to 2.25 (m, 2H); is 2.05 (m, 2H); 2.00 in total 1.74 (m, 2H); and 1.54 (d, 3H, J=7 Hz).

Example 6A

Hydrochloride R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide (0.15 g, 0.35 mmol) dissolved in CH2Cl2(3 ml). Add 3 N. HCl (0.5 ml) and after stirring at room temperature for 1 h the solvents vepari the try under reduced pressure, and the crude product is diluted with anhydrous ethyl ether (5 ml). Formed precipitate are filtered under vacuum, thus obtaining the pure hydrochloride of R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide in the form of a white powder (0,128 g, 0.28 mmol).

[α]D=-12 (C=2; CH3IT).

Example 7

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide

[α]D=-34 (C=1; CH3IT).1H-NMR (CDCl3): δ 8,65 (users, 1H, CONH); to 7.75 (d, 2H, J=7 Hz); 7,22 (d, 2H, J=7 Hz); was 4.02 (m, 2H); 3,85-3,74 (m, 3H); and 3.31 (m, 2H); 3,0 is 2.80 (m, 2H); 2,41-2,12 (m, 4H); of 1.65 (d, 3H, J=7 Hz).

Example 7a

Hydrochloride R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide

Connection receive according to the method described in example 6A.

[α]D=-22 (C=1; CH3IT).

Example 8

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide

[α]D=-41 (C=1; CH3IT).1H-NMR (CDCl3): δ 8,01 (users, 1H, CONH); a 7.62 (d, 2H, J=7 Hz); to 7.15 (d, 2H, J=7 Hz); 3,80 (square, 1H, J=7 Hz); to 3.52 (m, 2H); and 3.31 (m, 2H); 2.95 and (m, 2H); 2,78 (m, 2H); 2,15-1,90 (m, 6N); of 1.55 (d, 3H, J=7 Hz);

Example 8A

Hydrochloride R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide

Connection receive according to the method described in example 6A.

[α]D=-17 (C=1; CH3IT).

Example 9

R-(+)-2-[(4'-Tripterocalyx)phenyl]-N-(2-hydroxyethoxyethyl)propionamide

A solution of R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid (0,53 g, to 1.79 mmol) in thionyl chloride (1 ml) is refluxed for 2 hours After cooling at room temperature and evaporation under reduced pressure the crude oil residue was dissolved in CH2Cl2(2 ml) and added dropwise to a solution of 2-hydroxyethoxyethyl (0,36 ml, 3.58 mmol) in CH2Cl2(4 ml). The mixture is left to stir at room temperature over night. The solution was washed with water (3×10 ml), dried over Na2SO4and evaporated under reduced pressure, thus obtaining the crude oil residue. The crude substance is distilled processing isopropyl simple ether (over night at room temperature), thus obtaining, after filtration, R-(+)-2-[(4'-tripterocalyx)phenyl]-N-(2-hydroxyethoxyethyl)propionamide in the form of a waxy solid (0,48 g, 1.25 mmol) (yield 70%).

[α]D=+6 (C=1; CH3IT).1H NMR (CDCl3): δ for 7.78 (d, 2H, J=7 Hz); to 6.95 (d, 2H, J=7 Hz); of 5.92 (user. s, 1H, SOPSH); 3,68 (m, 2H); 3,55-3,44 (m, 7H); of 1.52 (d, 3H, J=7 Hz).

Example 10

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[2-(4'-trifluoromethyl)thiazolyl]propionamide

A solution of R-(-)-2-(4'-triftormetilfullerenov the l)propionic acid (1,012 g, 3,39 mmol) in thionyl chloride (2 ml) is refluxed for 2 hours After cooling at room temperature and evaporation under reduced pressure the crude oil residue was dissolved in CH2Cl2(2 ml) and added dropwise to a solution of 2-amino-4-cryptomaterial (1,14 g of 6.78 mmol) in CH2Cl2(4 ml). 2-Amino-4-cryptomaterial receive, as described in M. Moazzam et al., Indian J. Chem., 27B (11), pages 1051-1053 (1988). The resulting mixture is left to stir at room temperature over night. The solution was washed with a saturated solution of NaHCO3(2×5 ml), water (3×10 ml), dried over Na2SO4and evaporated under reduced pressure, thus obtaining the crude oil residue. After treatment of the crude substance isopropyl ether over night at room temperature and filtering the obtained precipitate, emit pure R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(4'-trifluoromethyl)thiazolyl]propionamide in the form of a light brown solid (0,94 g, 2.10 mmol) (yield 62%).

TPL 138-141°C. [α]D=-50 (C=0,5; CH3IT).1H NMR (CDCl3): δ is 10.68 (user. s, 1H, CONH); was 7.45 (d, 2H, J=7 Hz); 7,28 (d, 2H, J=7 Hz), 7,06 (s, 1H); 3,88 (kV, 1H, J=7 Hz); rate of 1.67 (d, 3H, J=7 Hz).

Example 11

R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-methyl-N-hydroxypropionate

A solution of N,N-dimethylformamide (0,42 ml, 5,42 the mol) in CH 2Cl2(4 ml) cooled at T=-20°C and added dropwise a solution of oxalicacid (0.16 ml; to 1.83 mmol) in CH2Cl2(5 ml). At the end of the addition the temperature was raised to 0°C. and after stirring 30' add R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid (0.5 g, 1,67 mmol) and 4-methylmorpholine (0,185 ml, a rate of 1.67 mmol). After stirring at T=0°C for 30' add the hydrochloride of N-methylhydroxylamine (0.27 g, 3.3 mmol) and 4-methylmorpholine (0,73 ml, 6.6 mmol). Temperatures give the opportunity to rise to room temperature and the mixture is left to stir over night. Formed precipitate was separated by filtration and the mother liquor solution evaporated under reduced pressure. The crude oil residue was dissolved in CH2Cl2(5 ml) and the solution washed with 1 N. HCl (2×5 ml), water (2×10 ml), a saturated solution of NaHCO3(2×10 ml), dried over Na2SO4and evaporated under reduced pressure, thus obtaining the crude oil residue. Purification of the crude product flash chromatography (CH2Cl2/CH3HE, 99:1) gives pure R-(-)-2-[(4'-tripterocalyx)phenyl]-N-methyl-N-hydroxypropionate in the form of a light yellow oil (0,355 g at 1.08 mmol) (yield 65%).

[α]D=-23 (C=1,5; CH3IT).1H NMR (DMSO-d6): δ of 10.05 (user. s, 1H, OH); of 7.48 (s, 4H); however, 4.40 (q, 1H, J=7 Hz); 3,10 (s, 3H); of 1.40 (d, 3H, J=7 Hz).

In tablice are chemical names and structural formulas for the compounds of examples 1-11.

ExampleChemical nameThe structural formula
1R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-methanesulfonylaminoethyl
1ASodium salt of R-(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonylaminoethyl
2R-(-)-2-[(4'-Tripterocalyx)phenyl]propionamide
3R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-methylpropionamide
4R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-isopropoxypropylamine
5R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-cyclopentylpropionate
6 R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide
6AHydrochloride R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide
7R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide
7aHydrochloride R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide
8R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide
8AHydrochloride R-(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide
9R-(+)-2-[(4'-Tripterocalyx)phenyl]-N-(2-hydroxyethoxyethyl)propionamide
10R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-[2-(4'-trifluoromethyl)thiazolyl]propionamide
11R-(-)-2-[(4'-Tripterocalyx)phenyl]-N-methyl-N-hydroxypropionate

1. Derivatives of 2-(R)-phenylpropionic acid of the formula (I):

and their pharmaceutically acceptable salts, where
the group R' is selected from
H, HE,
when R' represents H, R is selected from
H, C1-C5-alkyl, C3-C6-cycloalkyl,1-C5-alkoxy;
thiazolyl, substituted CF3,
residue of the formula-CH2-CH2-Z-(CH2-CH2O)nR', where n is equal to 2 and Z represents oxygen;
residue of the formula -(CH2)n-NRaRb, where n is an integer 2 or 3 and Ra and Rb together with the nitrogen atom to which they are bound, form a heterocycle of 5-6 members of the formula (II)

where W represents a simple bond, and n is an integer 1 or 2;
residue of the formula SO2Rd, where Rd represents a C1-C6-alkyl;
when R' is a HE, R is selected from
With1-C5-alkyl.

2. Connect the tion according to claim 1, where,
when R' represents H, R is selected from
H, C1-C5-alkyl, C3-C6-cycloalkyl,1-C6-alkoxy, thiazolyl, substituted CF3;
residue of the formula -(CH2)n-NRaRb, where n is an integer 2 or 3, more preferably 3, and the group NRaRb is a 1-piperidyl, 1-pyrrolidyl;
residue of the formula SO2Rd, where Rd represents a C1-C2-alkyl;
when R' is a HE, R represents a C1-C5-alkyl.

3. Compounds according to claim 1 or 2, selected from:
R(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonamide;
sodium salt of R(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonamide;
R(-)-2-[(4'-tripterocalyx)phenyl]propionamide;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-methylpropionamide;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-isopropoxypropylamine;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-cyclopentylpropionate;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide;
hydrochloride R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-piperidinyl)propyl]propionamide;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide;
hydrochloride R(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(N'-pyrrolidinyl)ethyl]propionamide; R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide;
hydrochloride R(-)-2-[(4'-tripterocalyx)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide;
R(+)-2-[(4'-tripterocalyx)phenyl]-N-(2-hydroxyethoxyethyl)propionamide;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-[2-(4'-trifluoromethyl)thiazolyl]propionamide;
R(-)-2-[(4'-tripterocalyx)phenyl]-N-methyl-N-hydroxypropionate.

4. Compounds according to claim 1, which is R-(-)-2-[(4'-tripterocalyx)phenyl]-N-methanesulfonylaminoethyl and its sodium salt.

5. Compounds according to claim 1 for use as pharmaceuticals for the treatment of psoriasis, ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous bladderworts, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

6. The use of compounds according to any one of claims 1 to 4 for the manufacture of drugs for the treatment of psoriasis, ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous bladderworts, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages, calling the R ischemia and reperfusion.

7. Pharmaceutical composition for the treatment of psoriasis, ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous bladderworts, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion, which includes the compound according to any one of claims 1 to 4 in a mixture with a suitable carrier.

8. The method of obtaining compounds of formula (I) according to claim 1, in which R' represents H, and R is the SO2Rd, where Rd represents a C1-C2alkyl, which includes the processing of R-(-)-2-(4'-triftoratsetilatsetonom)propionic acid with a suitable sulfonamide RdSO2NHz, where Rd represents a C1-C2-alkyl, in the presence of a condensing agent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry, medicine.

SUBSTANCE: in the general formula (I): X is oxygen atom; R1 is C1-10-alkyl , substituted if necessary by phenyl or thienyl group; or R1 is C3-7-cycloalkyl, thienyl, pyridinyl; the thienyl groups can be substituted if necessary by 1-2 C1-3-alkyl groups; phenyl can be substituted if necessary by 1-2 halogen atoms; R2 is C1-6-alkyl; or R2 is C3-7-cycloalkyl, phenyl or pyridinyl; phenyl if necessary can be substituted by one or more halogen atoms or by the CN, C1-3-alkyl, C1-3-alkoxyl, C1-3-fluoroalkyl groups; R3 is C1-6-alkyl; R4 is hydrogen atom or C1-6-alkyl; R5 and R5' are independently of each other the hydrogen atom, hydroxyl; or R5 and R5' form together the oxo-group; n is integer value in the range from 0 to 3; R6 is independently of each other hydrogen atom, halogen atom, C1-3-alkyl, C1-3-alkoxyl.

EFFECT: compounds of present invention can find application as pharmaceutical for pathology treatment where the inhibitor of β-amiloyd peptide β-A4 is useful.

8 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel compounds N(1,3-tiazol-2-yl)amides of 2-diphenylmethylenehydrazono-5,5-dimethyl-2,4-diooxohexane acid of formula (Ia, b): demonstration anti-inflammatory and analgetic activity. Invention also relates to method of their obtaining.

EFFECT: obtaining novel compounds.

2 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry.

SUBSTANCE: invention describes novel substituted benzoylcyclohexenones of the general formula (I): wherein values Q, Y, Z, R1-R5 and their possible tautomeric forms and their possible salts given in the invention claim. Invention proposes substituted benzoylcyclohexenones of the general formula (I) that possess the herbicide activity.

EFFECT: valuable property of compounds.

2 cl, 10 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-heterocyclyl-1,2-ethanediol carbamates of the formula (I) , their enantiomers, enantiomeric mixtures or pharmaceutically acceptable salts wherein A means a heterocyclic fragment chosen from the following group:

B1 and B2 mean independently hydroxy-group or -OCONR1R2 under condition that B1 and B2 don't mean hydroxy-group simultaneously; R1 and R2 mean hydrogen atom; R3, R4 and R5 mean alkyl, halogen atom, trihalogenmethyl, trialkylmethyl, -NO2, -CN and phenyl. These compounds can be used in treatment of the central nervous system disorders being especially as anticonvulsants and anti-epileptic agents. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of General formula

where X1-X5denote SN2or one of them denotes NH, and the other X1-X5are CH2; k is 0 or 1, R1is1-8the alkyl, C1-8hydroxyalkoxy; t is 0, 1 or 2; And represents phenyl or pyridinyl; R2is H, hydroxyl, halogen or1-6the alkyl, C1-6alkoxygroup; n is 0, 1-4; p is 0 or an integer from 1 to 5, Y is-C(O)-; Z is CH2or their pharmaceutically acceptable salts

The invention relates to compounds of formula (I), their stereochemical isomeric forms, their salts obtained by the joining of acid or base, their N-oxides or Quaternary ammonium derivative, where the dotted line represents an optional bond; X is absent when the dotted line represents a bond, or X is a hydrogen or a hydroxy-group, when the dotted line is not a bond, R1, R2, R5and R6each independently selected from hydrogen, halogen, hydroxy-group, WITH1-4of alkyl, C1-4alkoxygroup, SO3N and the like; R3and R4each independently selected from hydrogen, halogen, hydroxy-group, WITH1-4of alkyl, C1-4alkoxygroup, nitro, amino, ceanography, trifloromethyl or cryptometer;represents a radical of the formula (a-1), (a-2), (a-3), (a-4), (a-5), (6), (7), (8), (9), (10), where a1represents a direct bond or C1-6alcander; AND2represents a C2-6alcander; R7- R11represents hydrogen, C1-6alkyl, amino1-6alkyl and the like, provided that when L is Soboh the

The invention relates to a new specified in the title of a chemical compound, which are presented below, and to methods for the treatment of painful conditions, modulating allergic, inflammatory or cholinergic activity in mammals, using the new mentioned above in the title of chemicals

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

The invention relates to new derivatives of 4-hydroxypiperidine General formula (I), where X denotes-O-, -NH-, -CH2-, -CH= , -CO2-, -SOP(lower alkyl) -, or-CONH-, R1- R4independently from each other, is hydrogen, hydroxy, nitro-group, a lower alkylsulfonyl, 1 - or 2-imidazolyl, 1-(1,2,4-triazolyl), R5and R6independently from each other, is hydrogen, lower alkyl, hydroxy - or oxoprop, R7- R10independently from each other, is hydrogen, lower alkyl, halogen, trifluoromethyl or lower alkoxygroup, n = 0 or 1, or their pharmaceutically acceptable acid additive salts

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

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