Sulfonic acids, derivatives of said acids and pharmaceutical compositions containing them

FIELD: chemistry, pharmaceutics.

SUBSTANCE: described is application of sulfonic acids and their derivatives of formula (I) and pharmaceutically acceptable salts of said compounds (see radical values in invention formula) for obtaining medication for inhibition of human PMN chemotaxis, induced by IL-8 and sulfonic acids and their derivatives of formula (I). Described are three methods of obtaining of the said compounds and pharmaceutical composition based on them.

EFFECT: compounds of formula (I) possess inhibiting activity of human PMN chemotaxis.

11 cl, 2 tbl, 6 ex

 

Brief description of the invention

The present invention relates to sulfonic acids, derivatives of these acids and containing pharmaceutical compositions, which can be used for the prevention and treatment of tissue damage caused by increased recruitment of polymorphonuclear neutrophils (PMN-leukocytes at sites of inflammation.

The level of technology

Separate blood cells (macrophages, granulocytes, neutrophils, polymorphonuclear) respond to chemical stimuli (when stimulated by substances called chemokines) by migration along the concentration gradient of the stimulator through a process called chemotaxis. Main known stimulants or chemokines presents the breakdown products of complement C5a, some N-formylpiperidine resulting from the lysis of the bacterial surface, or peptides synthetic origin, such as formulationacupunture (f-MLP)3, and basically many cytokines, including interleukin-8 (IL-8, also known as CXCL8). Interleukin-8 is an endogenous chemotactic factor produced by most of the nuclear cells, such as fibroblasts and macrophages.

In certain pathological conditions characterized by enhanced recruitment of neutrophils, a large part of tuliposide tissue at the site caused by infiltration of polymorphonuclear cells. Recently it has been demonstrated the value of the activation of neutrophils in the evaluation of disorders associated with post-ischemic reperfusion and pulmonal hyperoxia.

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

Although it is known that the activation of CXCR1 plays a crucial role in mediated IL-8 chemotaxis, it was recently hypothesized that the activation of CXCR2 may play a pathophysiological role in chronic inflammatory diseases such as psoriasis. In fact, the pathophysiological role of IL-8 in psoriatic confirmed the effects of IL-8 on the function of keratinocytes.

Indeed, it was shown that IL-8 is an effective stimulator of proliferation of epidermal cells, and angiogenesis, both of these process are important aspects of psoriatic pathogenesis (A. Tuschil et al. J Invest Dermatol, 99, 294, 1992; Koch AE, et al., Science, 258, 1798,1992).

In addition, the accumulated data suggest that the pathophysiological role of IL-8 in the development of IU the anomalies and metastases may be mediated by activation of CXCR2 (L.R. Bryan et al., Am J Surg, 174, 507, 1997).

Widely disclosed to the potential pathogenic role of IL-8 in lung disease (lung damage, acute respiratory distress syndrome, asthma, chronic pneumonia and cystic fibrosis) and in particular 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).

Research on the contribution of the signal (S)- and (R)-enantiomers of Ketoprofen in anti-inflammatory activity of the racemate and the role of these enantiomers in the modulation of chemokine show (P. Ghezzi et al., J. Exp. Pharm. Ther., 287, 969, 1998)that the two enantiomers and the corresponding salts with chiral not chiral organic bases can inhibit dependent on the dose, the chemotaxis and increase the intracellular concentration of ions of Ca2+induced IL-8 on PMN-leukocytes person (Patent Application US6069172). It was subsequently shown (C. Bizzarri et al., Biochem. Pharmacol. 61, 1429, 2001)that Ketoprofen has the ability to inhibit the biological activity of IL-8 in the presence of other molecules belonging to the class of nonsteroidal anti-inflammatory drugs (NSAID)such as flurbiprofen, ibuprofen, and indomethacin. Inhibitory activity against the enzyme cyclooxygenase (COX), typical NSAID, limits therapeutic use of the decree is the R compounds in relation to the treatment of neutrophil-dependent pathological conditions and inflammatory conditions, such as psoriasis, idiopathic pulmonary fibrosis, acute respiratory failure, disorders caused by reperfusion injury, and glomerulonephritis. Inhibition of prostaglandin synthesis occurring under the influence of the enzyme cyclo-oxygenase, entails an increase in the production of cytokines, which, like TNF-αplay a role in strengthening the unwanted proinflammatory action of neutrophils.

Were discovered new classes of effective and selective inhibitors of the biological activities of IL-8, suitable for administration in vivo. Amides and N-arylsulfonamides R-2-arylpropionic acids are described as effective inhibitors of IL-8 inducing chemotaxis of neutrophils and degranulation (WO 01/58852; WO 00/24710). In addition, recently, as inhibitors of IL-8 have been described new R - and S-2-phenylpropionate acid, completely devoid of unwanted MOR-inhibitory effect (PCT/ER/12939).

Detailed description of the invention

Applicants found that the class of sulfonic acids and their respective derivatives demonstrate ability to effective inhibition of chemotaxis of neutrophils and degranulation induced by IL-8.

Thus, the present invention relates to the use of sulfonic acid and the corresponding derivatives of formula (I):

and pharmaceutically PR is acceptable salts of these compounds,

where

Ar denotes phenyl group, unsubstituted or substituted with one to three substituents, independently selected from the group comprising halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino, C1-C4-acylamino, halogen-C1-C3-alkyl, halogen-(C1-C3-alkoxy, benzoyl, or Ar denotes a substituted or unsubstituted 5-6-membered heteroaryl cycle;

X is or-CH2-or-CH(CH3-group or ethylene group of the formula (II) in the E-configuration, where R' is H or CH3;

Y is selected from O (oxygen), and NH; and

when Y represents O (oxygen), R is H (hydrogen);

when Y represents NH, R is selected from the group including:

- H, C1-C5-alkyl, C1-C5-cycloalkyl, C1-C5alkenyl, C1-C5-acyl;

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

- the remainder 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, means C1-C6-alkyl, C1-C6alkenyl, or, alternatively, Ra and Rb, together with the nitrogen atom to which they PR is connected, form a heterocycle of 3 to 7 members of the formula (III)

where W indicates a simple relationship, CH2, O, S, N-Rc, Rc denotes H, C1-C6-alkyl or C1-C6-alkylphenyl, when getting drugs for inhibition of IL-8-induced chemotaxis of human PMN.

The term "substituted" in the above definition means substituted by a group selected from a range, including C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro or cyano.

Ar denotes a substituted phenyl group selected from the group comprising 3'-benzoylphenyl, 3'-(4-chlorobenzoyl)phenyl, 3'-(4-methylbenzoyl)phenyl, 3'-acetylphenyl, 3'-propionitrile, 3'-isobutylphenyl, 4'-triftoratsetilatsetonom, 4'-benzensulfonamidelor, 4'-triftormetilfullerenov, 4'-benzosulfimide, 4'-benzosulfimide, 4'-acetoxyphenyl, 4'-propionyloxy, 4'-benzyloxyphenyl, 4'-acetylaminophenol, 4'-propionylcarnitine, 4'-benzoylamino, or heteroaromatic cycle selected from pyridine, pyrrole, thiophene, furan, indole.

When Y represents NH, preferred R groups are

- H, C1-C5-alkyl, C1-C5-acyl;

- the remainder of the formula-CH2-CH2-O-(CH2-CH2O)R", where R ' denotes H or C 1-C5-alkyl;

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

The present invention also relates to a new sulfonic acids and related derivatives of the compounds of the above formula (I)selected from the following compounds:

1-(4-isobutylphenyl)econsultancy acid

1-[4-(1-oxo-2-isoindolyl)phenyl]econsultancy acid

2-(4-phenylsulfonyl)econsultancy acid

(1-methyl-5-acetylpyrrole)-1-methanesulfonate acid

2-(3-benzoylphenyl)econsultancy acid

2-(3-isopropylphenyl)econsultancy acid

E-2-(4-isobutylphenyl)Tinsulanonda acid

E-2-(3-benzoylphenyl)Tinsulanonda acid

E-2-(4-methanesulfonylaminoethyl)Tinsulanonda acid

E-2-(4-triftoratsetilatsetonom)Tinsulanonda acid

E-2-(4-isobutylphenyl)atenolole

E-2-(3-benzoylphenyl)atenolole

E-2-[4-(tripterocalyx)phenyl]atenolole

E-2-[4-(methanesulfonamido)phenyl]atenolole

E-2-(4-isobutylphenyl)Aten-N-(N,N-dimethylaminopropyl)sulfonamide

E-2-(3-benzoylphenyl)Aten-N-(N,N-dimethylaminopropyl)sulfonamide

E-2-[4-(triftormetilfullerenov and)phenyl]ethen-N-(N,N-dimethylaminopropyl)sulfonamide

E-2-[4-(methanesulfonamido)phenyl]ethen-N-(N,N-dimethylaminopropyl)sulfonamide

E-2-(4-isobutylphenyl)Aten-N-methylsulfonate

E-2-(3-benzoylphenyl)Aten-N-methylsulfonate

E-2-[4-(tripterocalyx)phenyl]ethen-N-methylsulfonate

E-2-[4-(methanesulfonamido)phenyl]ethen-N-methylsulfonate

E-2-(4-isobutylphenyl)Aten-N-(2"-methoxyethyl)sulfonamide

E-2-(3-benzoylphenyl)Aten-N-(2"-methoxyethyl)sulfonamide

E-2-[4-(tripterocalyx)phenyl]ethen-N-(2"-methoxyethyl)sulfonamide

E-2-[4-(methanesulfonamido)phenyl]ethen-N-(2"-methoxyethyl)sulfonamide

(1-methyl-5-isobutylphenyl)-1-methanesulfonamide

(1-methyl-5-acetylpyrrole)-1-methanesulfonamide

1-(4-isobutylphenyl)econsultant

1-(3-isopropylphenyl)econsultant

1-(4-isobutylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide

1-(3-benzoylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide

1-[4-(tripterocalyx)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide

1-[4-(methanesulfonamido)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide

1-(4-isobutylphenyl)ethane-N-(2-methoxyethyl)sulfonamide

1-(3-benzoylphenyl)ethane-N-(2-methoxyethyl)sulfonamide

1-[4-(tripterocalyx)phenyl]ethane-N-(2-methoxyethyl)sulfonamide

1-[4-(methanesulfonamido)phenyl]ethane-N-(2-methoxyethyl)sulfonamide

1-(4-isobutylphenyl)ethane-N-methylsulfonyl is d

1-(3-benzoylphenyl)ethane-N-methylsulfonate

1-[4-(tripterocalyx)phenyl]ethane-N-methylsulfonate

1-[4-(methanesulfonamido)phenyl]ethane-N-methylsulfonate

1-[4-isobutylphenyl]ethane-N-acetylacetonate

E-2-(3-benzoylphenyl)-2-methylacetophenone

E-2-(3-isopropylphenyl)-2-methylacetophenone

E-2-(4-isobutylphenyl)-2-methylacetophenone

and pharmaceutically acceptable salts of such compounds.

Preferably the salt is a sodium salt.

The above econsultancy are chiral compounds, and the invention applies to both the racemic mixture and the individual (+) and (-) enantiomers.

Compounds according to the invention of formula (I), when contain acidic or basic groups can generally be distinguished in the form of the corresponding additive salts with both organic and inorganic pharmaceutically acceptable acids or bases.

Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonate 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), where YR denotes OH, obtained by interaction of the corresponding compounds of the formula (IV), where J denotes H Il is COCH 3with a suitable oxidizing agent such as H2O2, HClO and peroxyacids, preferably m-chloroperbenzoic acid:

The compounds of formula (I)where Y represents NH and X is-CH2-produced by interaction of the respective sulphonylchloride, such as sulphonylchloride, with one or two equivalents of an amine of the formula NH2R in the presence of a suitable organic or inorganic bases, if required.

The compounds of formula (I)where Y represents NH and X is-CH(CN)3-produced by interaction of the corresponding thiols of the formula (IV) with a suitable N-bromamide, such as N-bromophthalimide, and subsequent oxidation of the sulfur atom with subsequent removal of the protection sulfonamidnuyu derived, as described in detail in the examples.

The compounds of formula (I)where Y represents NH, and X represents a group of formula (II), obtained by interaction of the respective sulphonylchloride, such as sulphonylchloride, with an amine of the formula NH2R.

Compounds of the present invention particularly useful as inhibitors of IL-8-induced chemotaxis of human PMN.

The purpose of the present invention consists in obtaining new sulfonic acids and the above-mentioned derivatives of compounds for use as pharmaceuticals.

is soedineniya formula (I) evaluated in vitro for their ability to inhibit chemotaxis of polymorphonuclear leukocytes (hereafter called PMN) and monocytes, induced by fractions of IL-8 and GRO-α. With this purpose, to highlight PMN from heparinised human blood collected from healthy adult volunteers, the mononuclear cells are removed by deposition on the dextran (according to the methodology described W.J. Ming et al., J. Immunol., 138, 1469,1987and the red blood cells with a hypotonic solution. Cell viability is determined by exclusion using Trypanosoma blue, while the proportion of circulating polymorphonuclear cells establish on cytocentrifuged after staining with Diff-Quick.

Recombinant IL-8 person (Pepro Tech) is used as stimulators in experiments on chemotactic activity, obtaining almost identical results: the lyophilized protein is dissolved in a volume of HBSS containing 0.2% albumin calf serum (BSA), to get a basic solution with a concentration of 10-5M, which is diluted with HBSS to a concentration of 10-9M, when tests for chemotactic activity.

During the analysis of chemotactic activity (according to W. Falket et al., J. Immunol. Methods, 33, 239,1980) use do not contain PVP filters with a porosity of 5 μm and microcamera suitable for replication.

The compounds of formula (I) is estimated in the concentration range from 10-6up to 10-10M; with this purpose, these compounds add, the same is concentratie, as at the top of the pores and lower the pores of microcamera. The ability of the compounds according to the invention of formula I to inhibit IL-8-induced chemotaxis of human monocytes produced according to the method described by Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989).

Biological results for some typical compounds obtained in the test for IL-8-induced chemotaxis of PMN in table II (data on inhibition, C = 10-8M).

Particularly preferred compounds of formula (I)where Ar is the group mean of 3'-benzoylphenyl, 3'-(4-chlorobenzoyl)phenyl, 3'-(4-methylbenzoyl)phenyl, 3'-acetylphenyl, 3'-propionitrile, 3'-isobutylphenyl, 4'-triftoratsetilatsetonom, 4'-benzensulfonamidelor, 4'-triftormetilfullerenov, 4'-benzosulfimide, 4'-benzosulfimide, 4'-acetoxyphenyl, 4'-propionyloxy, 4'-benzyloxyphenyl, 4'-acetylaminophenol, 4'-propionylcarnitine, 4'-benzoylamino showing additional capacity for effective inhibition GRO-α-induced PMN chemotaxis; this activity gives the possibility of therapeutic application of these compounds in IL-8-related pathologies, where the path CXCR2 involved specifically or in combination with CXCR1 activation.

Dual inhibitors of IL-8 and GRO-α-induced biological activity in sh is preferred from the viewpoint of the considered therapeutic applications but the described compounds selectively acting on the receptor IL-8 CXCR1 or receptor GRO-α/IL-8 receptor CXCR2 may find useful applications in the treatment described below are the specific pathologies.

The compounds of formula (I), estimated blood ex vivo in whole by the method described Patrignani et al., in J. Pharmacol. .. Ther., 271, 1705,1994, recognized as ineffective as inhibitors of the enzyme cyclooxygenase (COX).

In most cases, the compounds of formula (I) inhibit the production of PGE2induced in macrophages of mice by stimulation with lipopolysaccharide (LPS, 1 μg/ml) in the concentration range from 10-5up to 10-7M. Inhibition of the production of PGE2that can be registered is found mainly within the statistical errors, and often is less than 15-20% of the original level. Reduced effectiveness in the inhibition of CO create advantage for therapeutic use of the compounds according to the invention, since the inhibition of prostaglandin synthesis stimulates cells of the macrophage to extend the synthesis of TNF-α (induced by LPS or hydrogen peroxide), which is an important mediator of neutrophil activation and stimulates the production of the cytokine interleukin-8.

Taking into account discussed above experimental data and the role played by interleukin-8 (IL-8), and the affinity of this is in the processes, including the activation and infiltration of neutrophils, the compounds according to the invention is particularly useful for treatment of diseases, such as psoriasis (R. J. Nicholoff et al., Am. J. Pathol., 138, 129,1991). Other diseases treatable using compounds of the present invention include chronic intestinal inflammatory diseases, such as ulcerative colitis (Y. R. Mahida et al., Clin. Sci., 82, 273,1992and melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463,1981), idiopathic fibrosis (E. J. Miller, cited previously, and P. C. Carré et al., J. Clin. Invest., 88, 1882,1991), glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135,1994), and for the prevention and treatment of damage caused by ischemia and reperfusion.

Inhibitors of activation of CXCR1 and CXCR2 find a useful application, as described in detail above, in particular in the treatment of chronic inflammatory pathologies (e.g., psoriasis), in which, as expected, activation of both receptors IL-8 plays a crucial pathophysiological role in the development of the disease.

Indeed, it is known that activation of CXCR1 is important for IL-8-mediated chemotaxis of PMN (Hammond M et al., J Immunol, 155, 1428, 1995). On the other hand, it is believed that stimulation of the activation of CXCR2 important for IL-8-mediated proliferation of epidermal cells, as well as the angiogenesis in psoriatic patients (Kulke R, et al., J Invest Dermatol, 110, 90, 1998). In addition, selective CXCR2 antagonists are particularly useful in therapeutic applications in the treatment of serious lung diseases such as chronic obstructive pulmonary disease COPD (D. WP Hay and H.M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

Furthermore, in addition to the application of the above compounds, another objective of the present invention is to develop the use of compounds of formula (I) in obtaining medicines used to treat psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous of pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damage caused by ischemia and reperfusion. Pharmaceutical compositions containing a compound according to the invention and a suitable carrier, are also included in the scope of the present invention and attached items.

Compounds according to the invention together with commonly used assistive device, carrier, diluent or excipient can in fact be represented in the form of pharmaceutical compositions and in the relevant standard dosages and in this form can be used in the form of solids, such as tablets or filled capsules, or liquids, such as actuary, suspensions, emulsions, elixirs, or filled with the specified liquid forms capsules, all preparations intended for oral administration or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their corresponding standard dosage forms may include ingredients in conventional proportions, with addition or without addition of additional active compounds or active principles of medicinal substances, and these standard dosage forms may contain any suitable effective amount of the active ingredient, corresponding recommended for use interval daily doses.

When used as a pharmaceutical acid of the present invention is usually administered in the form of pharmaceutical compositions. Such compositions can be obtained well-known in the pharmaceutical field in the manner and contain at least one active connection. Typically, compounds of the present invention is administered in a pharmaceutically effective amount. The real number of input connections is usually set by the attending physician taking into account the specific circumstances, including treatable condition, the chosen route of administration, the actual entered the compound, the age, the weight of the reaction of the individual patient, the severity of symptoms in a patient and the like.

The pharmaceutical compositions according to the invention can be introduced in a variety of ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the chosen method of delivery of the compound is preferably formulated in the form of compositions for injection or for oral administration. Compositions for oral administration can be taken in the form of bulk liquid solutions or suspensions, or bulk powders. However, most often, the compositions are produced in a standard dosage forms, facilitate accurate dosing. The term "standard dosage forms" refers to physically discrete units suitable as single dosages for human patients and other mammals, each unit contains a predetermined quantity of active material calculated to obtain the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical standard dosage forms include pre-filled with pre-measured quantity of ampoules or syringes with liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In the compositions of acidic compounds is predstavlyaet a generally microcomponent (approximately from 0.1 to 50 wt.% or preferably from about 1 to 40 wt.%), the remaining part is composed of various solvents or carriers and processing AIDS for forming the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous and non-aqueous solvent containing buffers suspendresume and dispersing funds, dyes, corrigentov and the like. Liquid forms, including the following compositions for injection, usually stored in the absence of light, in order to avoid a possible catalytic action of light, such as the formation of hydroperoxide or peroxide. Solid forms may include, for example, any of the following ingredients or similar nature connections: binder, such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose, dezintegriruetsja agent, such as alginic acid, Primogel, or corn starch; lubricating substance, such as magnesium stearate; a moving substance, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or corrigent, such as peppermint, methyl salicylate or flavoring additive with orange.

Compositions for injection are usually based on a sterile saline solution for injection or phosphate-buffered physiological RA the creators or other intended for the injection of carriers, known from the prior art. As mentioned above, the acid derivative of the formula I in such compositions is typically a micro-component, frequently ranging from 0.05 to 10 wt.%, the remaining part is suitable for the injection of the carrier, and the like. The average daily dose depends on various factors such as the severity 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) in the day and, optionally, subdivided per multiple techniques. Due to the low toxicity of the compounds according to the invention can also be administered large doses over long periods of time. The above components of the compositions for oral administration or injections are illustrative only. Other materials and methods of processing and the like described in Part 8 of "Remington''s Pharmaceutical Sciences Handbook", 18thEdition, 1990, Mack Publishing Company, Easton, Pennsylvania, is incorporated herein by reference.

Compounds according to the invention can also be entered in the form for slow release or systems deliver drugs through slow release. Description of typical substances for slow release can also be found in the materials included in the above right is CNIC Remington.

The present invention is illustrated by the following examples, which are not considered as limiting the scope of the invention and the attached items.

Example 1

General methods of synthesis uralmetanolgroup acid, 1-arylethanolamine acids of the formula R-Ar-C(CH3)H-SO3H and related enantiomers

To a cooled (T=0-4° (C) to a solution of the substituted benzene (17 mmol) and acetylchloride (18 mmol) in dry CH2Cl2(25 ml) is added in portions, with vigorous stirring, AlCl3(18 mmol). The ice bath is then removed and the solution is heated at the boiling point under reflux until then, until complete disappearance of starting material will not become apparent (2-3 hours). After cooling to room temperature the mixture was poured into a chilled 2N HCl and allowed to mix for 30'. The acid solution is then transferred into a separating funnel and extracted with CH2Cl2(3×20 ml).

The collected organic extracts are washed with saturated NaCl solution (2×25 ml), dried over Na2SO4and evaporated in vacuum, obtaining the net arylation (accounted for 14.45-16,15 mmol) with high yield (85-95%).

To a stirred solution of aryasetiawan (11.5 mmol) in methyl alcohol (40 ml) is added in portions sodium borohydride (17,2 mmol). The mixture is heated when the temperature is ur boiling under reflux until complete disappearance of starting material (3 hours). After cooling to room temperature, to the mixture of 1M HCl and alcohol is separated by distillation. The aqueous phase is extracted with ethyl acetate (3×15 ml) and the collected organic extracts are washed with saturated NaCl solution (2×15 ml), dried over Na2SO4and evaporated in vacuum, obtaining pure 1-arelatively alcohol (yield 75%).

To a stirred solution of 1-arelative alcohol (4.5 mmol) in dry CHCl3(10 ml) add toluxury acid (5,39 mmol) and zinc iodide (2,24 mmol). The reaction mixture is heated at the boiling point under reflux for 3 hours; after cooling to room temperature the mixture was diluted with water (15 ml) and transferred into a separating funnel. The two phases are mixed by shaking and share. The organic phase is washed with a saturated solution of NaHCO3(3×20 ml), then saturated NaCl solution, dried over Na2SO4and evaporated in vacuum, obtaining pure 1-allatectomized (yield 80%).

A solution of 1-abilitytoalert (of 0.91 mmol) in glacial acetic acid (2 ml) was stirred at 60°C and process, adding dropwise, 30% H2O2(4,56 mmol); the resulting solution was stirred at 60°C for 24 hours, then acetic acid is removed by azeotropic distillation with toluene.

The residue was diluted with water (5 ml), 1N NaOH neutralized, washed diet the gross ether (2× 15 ml) and lyophilized, receiving sodium salt of 1-arylethanolamine acid in the form of a white substance, which represents a racemic mixture (yield 90%).

Optical separation

Racemic sodium salt of 1-arylethanolamine acid is filtered through a column filled with resin Amberlite IR-120 (H+ form), elute with water to give the product as a pasty oil. The separation of the two isomers is carried out by crystallization of the corresponding (+) or (-) α-phenylethylamine salts in ethanol solution, as described with respect to the optical separation arylpropionic acids in H. Akgun et al., Arzneim.-Forsch./Drug Res., 46(II), Nr.9, 891-894 (1996). Pure enantiomers isolated in the form of sodium salts.

According to the above method, the following connections:

sodium salt of (-)-1-(4-isobutylphenyl)econsultancy acid (1)

The compound synthesized on the basis of commercial isobutylbenzene.

[a]D = -35 (c=1; H2O)

1H-NMR (DMSO-d6): δ to 7.25 (d, 2H, J=Hz); 7,05 (d, 2H, J=Hz); 3,62 (m, 1H); is 2.37 (d, 2H, J=Hz); to 1.86 (m, 1H); of 1.40 (d, 3H, J=Hz); of 0.91 (d, 6H, J=Hz).

sodium salt of (+)-1-(4-isobutylphenyl)econsultancy acid (2)

The compound synthesized on the basis of commercial isobutylbenzene.

[a]D= +34,5 (c=1; H2O)

1H-NMR (DMSO-d6): δ to 7.25 (d, 2H, J=Hz); was 7.08 (d, 2H, J=Hz); 3,62 (m, 1H); is 2.37 (d, 2H, J=Hz); to 1.86 (m, 1H); 1,4 (d, 3H, J=Hz); of 0.90 (d, 6H, J=Hz).

sodium salt of (-)-1-[4-(1-oxo-2-isoindolyl)phenyl]econsultancy acid (3)

The connection will receive the above method, proceeding from the intermediate 4-(1-oxo-2-isoindolyl)of acetophenone. This intermediate compound is obtained from industrially produced chemicals, phthalaldehyde and 4-aminoacetophenone, based on the techniques described in Ichiro, T. et al., Heterocycles 43:11, 2343-2346 (1996).

[a]D= -52,4 (c=1; H2O)

1H-NMR (DMSO-d6): δ to 7.68 (m, 3H); 7,35 (m, 3H); to 7.15 (d, 2H, J=Hz); and 4.68 (s, 2H); the 3.65 (q, 1H, J1=Hz, J2=3 Hz); of 1.28 (d, 3H, J=Hz).

sodium salt of (+)-1-[4-(1-oxo-2-isoindolyl)phenyl]econsultancy acid (4)

The connection receives the above-described method on the basis of intermediate 4-(1-oxo-2-isoindolyl)of acetophenone. This intermediate compound is obtained from industrially produced chemicals, phthalaldehyde and 4-aminoacetophenone, based on the techniques described in Ichiro, T. et al., Heterocycles 43:11, 2343-2346 (1996).

[a]D= +50 (c=1; H2O)

1H-NMR (DMSO-d6): δ 7,708 (m, 3H); 7,35 (m, 3H); 7.18 in (d, 2H, J=Hz); and 4.68 (s, 2H); the 3.65 (q, 1H, J1=Hz, J2=3 Hz); of 1.30 (d, 3H, J=Hz).

sodium salt of (-)-2-(4-phenylsulfonyl)econsultancy acid (5)

The connection receives the above-described method, based on the intermediate 4-benzosulphochloride obtained from commercial 4-hydroxyacetophenone known for xperimentally methods.

[a]D= -47,5 (c=1; H2O)

1H-NMR (D2O): δ of 7.90 (d, 2H, J=Hz); of 7.70 (t, 1H, J=Hz); at 7.55 (t, 2H, J=Hz); to 7.32 (d, 2H, J=Hz); to 6.95 (d, 2H, J=Hz); to 3.64 (m, 1H); of 1.41 (d, 3H, J=Hz).

sodium salt of (+)-2-(4-phenylsulfonyl)econsultancy acid (6)

The connection will receive the above method, proceeding from the intermediate 4-benzosulphochloride obtained from commercial 4-hydroxyacetophenone using experimental methods.

[a]D= +49 (c=1; H2O)

1H-NMR (D2O): δ to 7.93 (d, 2H, J=Hz); of 7.70 (t, 1H, J=Hz); at 7.55 (t, 2H, J=Hz); to 7.32 (d, 2H, J=Hz); 6,91 (d, 2H, J=Hz); to 3.67 (m, 1H); of 1.41 (d, 3H, J=Hz).

sodium salt of (1-methyl-5-acetylpyrrole)-1-methanesulfonic acid (7)

Synthesis of (7) is effected on the basis of commercial reagent methyl-1-methyl-2-pyrroleacetic that when the acylation according to the method of Friedel-with acetylchloride gives (1-methyl-5-acetylpyrrole)-1-methanizeit. Ester group then hydrolyzing. According to the experimental procedure described in WO 02/0704095 receive related sodium salt (1-methyl-5-acetylpyrrole)-1-methanesulfonic acid.

1H-NMR (DMSO-d6): δ 7,5 (s, 1H); 6,18 (s, 1H); of 3.60 (s, 3H); 3,51 (s, 2H); 2,10 (s, 3H).

sodium salt (±)-2-(3-benzoylphenyl)econsultancy acid (8)

Synthesis of (8) is effected on the basis of a commercial reagent, 3-(1-cyanoethyl)benzoic acid, which acyl is the formation by the method of Friedel-in benzene gives 2-(3'-benzoylphenyl)propionitrile. Following the experimental procedure described in WO 02/0704095 receive related sodium salt of 2-(3'-benzoylphenyl)econsultancy acid.

1H-NMR (D2O): δ 7,80 (d, 2H, J=Hz); of 7.70 (s, 1H); a 7.62 (d, 1H, J=Hz); 7,51 (m, 2H); 7,30 (m, 3H); 3,62 (m, 1H); of 1.40 (d, 3H, J=Hz).

sodium salt (±)-2-(3-isopropylphenyl)econsultancy acid (9)

Synthesis of (9) is effected on the basis of the available reagent, 3-(1-cyanoethyl)of acetophenone, which is by the reaction of Wittig and when recovering methylene group on well-known methods gives 2-(3-isopropylphenyl)propionitrile. Following the experimental procedure described in WO 02/0704095 receive related sodium salt of 2-(3-isopropylphenyl)econsultancy acid.

1H-NMR (D2O): δ 7,30 (m, 2H); 7,10 (m, 2H); to 3.92 (m, 1H); 3,63 (m, 1H); of 1.42 (d, 3H, J=Hz); of 1.25 (d, 6H, J=8gts).

Example 2

Receive E-unilaterality acids (sodium salts)

Arylethanolamine acid dissolved in thionyl chloride (5 ml) and the solution heated at boiling temperature under reflux overnight. After cooling to room temperature thionyl chloride is evaporated in vacuum and the crude arylethanolamine diluted with dry THF (5 ml) and cooled to T=0°C in a water bath with ice; add 1N aqueous NaOH (0.64 mmol) at T=4°C; water bath with ice is removed and the reaction mixture is left for about 1 hour before is stijene room temperature, thus precipitated white solid. Organic sodium salt is separated by filtration under vacuum, washed with THF and dried in vacuum at 40°C, obtaining the pure sodium salt of E-unilaterality acid (0,32-0.51 mmol) (yield 50-80%) as white solid powder.

According to the method described above the following compounds:

sodium salt of E-2-(4-isobutylphenyl)atenololbuy acid (10)

1H-NMR (D2O): δ of 7.60 (d, 1H, J=8gts); 7,55-to 7.32 (m, 4H); 7,05 (d, 1H, J=Hz); 2,62 (m, 2H); 1,90 (m, 1H); to 0.97 (d, 6H, J=Hz).

sodium salt of E-2-(3-benzoylphenyl)atenololbuy acid (11)

1H-NMR (D2O): δ 7,80 (d, 2H, J=Hz); of 7.70 (s, 1H); the 7.65 (d, 1H, J=8gts); a 7.62 (d, 1H, J=Hz); 7,51 (m, 2H); 7,30 (m, 3H); 7,00 (d, 1H, J=Hz).

sodium salt of E-2-(4-methanesulfonylaminoethyl)atenololbuy acid (12)

1H-NMR (DMSO-d6): δ of 7.60 (d, 1H, J=8gts); to 7.35 (d, 2H, J=8gts); then 7.20 (d, 2H, J=8gts); 7,07 (d, 1H, J=Hz); 6,51 (Sirs, 1H, SO2NH); 3,00 (s, 3H).

sodium salt of E-2-(4-triftoratsetilatsetonom)atenololbuy acid (13)

1H-NMR (CDCl3): δ a 7.62 (d, 1H, J=8gts); 7,50 (d, 2H, J=Hz); to 7.25 (d, 2H, J=Hz); 7,05 (d, 1H, J=Hz).

Example 3

General methods of synthesis of E-arylethanolamine

The solution arylethanolamine acid (0.64 mmol) is dissolved in thionyl chloride (5 ml) and the solution heated at boiling temperature under reflux overnight. After cooling, what about room temperature thionyl chloride is evaporated in vacuum and the crude arylethanolamine diluted with dry THF (5 ml) and cooled to T=0° C in a water bath with ice; add dropwise the selected amine (1.28 mmol). A water bath with ice is removed and the reaction mixture was allowed to stand to reach room temperature. After complete disappearance of the original reagent, the solvent is evaporated in vacuo and to the residue add CHCl3(10 ml) and water (10 ml); the two phases are mixed by shaking and separated, the organic phase is washed with water (3×15 ml), dried over Na2SO4and evaporated in vacuum to give crude product, which was purified flash chromatography. Clean E/Z-arylethanolamine (0,32-0.51 mmol) (yield 50-80%) was isolated as colorless oils.

According to the method described above and using ammonia (0.5 M in 1,4-dioxane) as an amine, the following compounds:

E-2-(4-isobutylphenyl)tinsulanond (14)

1H-NMR (CDCl3): δ at 7.55 (d, 1H, J=Hz); 7,38 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); to 6.88 (d, 1H, J=Hz); 4,75 (Sirs, 2H, SO2NH2); to 2.55 (d, 2H, J=Hz); of 1.94 (m, 1H); of 1.02 (d, 6H, J=Hz).

E-2-(3-benzoylphenyl)tinsulanond (15)

1H-NMR (CDCl3): δ 7,80 (d, 2H, J=Hz); 7,72 (s, 1H); a 7.62 (d, 1H, J=8gts); 7,52 (d, 1H, J=Hz); to 7.50 (m, 2H); 7,30 (m, 3H); to 6.88 (d, 1H, J=Hz); 4,75 (Sirs, 2H, SO2NH2).

E-2-[4-(tripterocalyx)phenyl]tinsulanond (16)

1H-NMR (CDCl3): δ of 7.60 (d, 1H, J=8gts); 7,52 (d, 2H, J=Hz); 7,28 (d, 2H, J=Hz); 7,10 (d, 1H, J=Hz); 4,85 (Sirs, 2H, SO2NH2).

E-2-[4-(IU is unsulfonated)phenyl]tinsulanond (17)

1H-NMR (CDCl3): δ at 7.55 (d, 1H, J=Hz); 7,37 (d, 2H, J=8gts); 7,22 (d, 2H, J=8gts); make 6.90 (d, 1H, J=Hz); 6,45 (Sirs, 1H, SO2NH); 4,80 (Sirs, 2H, SO2NH2); 2,98 (s, 3H).

According to the method described above and using 3-(dimethylamino)Propylamine as an amine, the following compounds:

E-2-(4-isobutylphenyl)Aten-(N,N-dimethylaminopropyl)sulfonamide (18)

1H-NMR (CDCl3): δ was 7.45 (m, 3H); then 7.20 (d, 2H, J=Hz); 6,70 (d, 1H, J=Hz); 6,40 (Sirs, 1H, SO2NH); 3,18 (m, 2H); to 2.55 (m, 4H); 2,30 (s, 6H); of 1.92 (m, 1H); to 1.75 (m, 2H); to 0.97 (d, 6H, J=Hz).

E-2-(3-benzoylphenyl)Aten-N-(N,N-dimethylaminopropyl)sulfonamide (19)

1H-NMR (CDCl3): δ of 7.82 (d, 2H, J=Hz); 7,74 (s, 1H); of 7.60 (d, 1H, J=8gts); 7,50 (d, 1H, J=Hz); was 7.45 (m, 2H); 7,26 (m, 3H); 6,70 (d, 1H, J=Hz); 6,45 (Sirs, 1H, SO2NH); 3.15 in (m, 2H); 2.50 each (m, 4H); to 2.35 (s, 6H).

E-2-[4-(tripterocalyx)phenyl]ethen-(N,N-dimethylaminopropyl)sulfonamide (20)

1H-NMR (CDCl3): δ a 7.62 (d, 1H, J=Hz); of 7.48 (d, 2H, J=Hz); to 7.25 (d, 2H, J=Hz); 7,00 (d, 1H, J=Hz); 6,50 (Sirs, 1H, SO2NH); 3,17 (m, 2H); 2,48 (m, 4H); to 2.35 (s, 6H).

E-2-[4-(methanesulfonamido)phenyl]ethen-(N,N-dimethylaminopropyl)sulfonamide (21)

1H-NMR (CDCl3): δ EUR 7.57 (d, 1H, J=Hz); 7,37 (d, 2H, J=8gts); 7,22 (d, 2H, J=8gts); to 6.75 (d, 1H, J=Hz); 6,50 (Sirs, 2H, SO2NH); 3.15 in (m, 2H); 2,98 (s, 3H); 2.50 each (m, 4H); 2.40 a (s, 6H).

According to the method described above and using methylamine (2M in THF) as an amine, the following compounds:

E-2-(4-isobutyl the Nile)Aten-N-methylsulfonate (22)

1H-NMR (CDCl3): δ at 7.55 (d, 1H, J=Hz); 7,38 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); to 6.88 (d, 1H, J=Hz); 4,80 (Sirs, 1H, SO2NH); a 2.75 (d, 3H, J=4 Hz); to 2.55 (d, 2H, J=Hz); 1,95 (m, 1H); was 1.04 (d, 6H, J=Hz).

E-2-(3-benzoylphenyl)Aten-N-methylsulfonate (23)

1H-NMR (CDCl3): δ 7,81 (d, 2H, J=Hz); of 7.70 (s, 1H); a 7.62 (d, 1H, J=8gts); at 7.55 (d, 1H, J=Hz); was 7.45 (m, 2H); 7,30 (m, 3H); 6.90 to (d, 1H, J=Hz); 4,60 (Sirs, 1H, SO2NH); 2,70 (d, 3H, J=4 Hz).

E-2-[4-(tripterocalyx)phenyl]ethen-N-methylsulfonate (24)

1H-NMR (CDCl3): δ of 7.60 (d, 1H, J=8gts); 7,52 (d, 2H, J=Hz); 7,28 (d, 2H, J=Hz); 7,10 (d, 1H, J=Hz); 4,85 (Sirs, 1H, SO2NH); 2,70 (d, 3H, J=4 Hz).

E-2-[4-(methanesulfonamido)phenyl]ethen-N-methylsulfonate (25)

1H-NMR (CDCl3): δ 7,56 (d, 1H, J=Hz); to 7.35 (d, 2H, J=8gts); then 7.20 (d, 2H, J=8gts); 6,92 (d, 1H, J=Hz); 6,50 (Sirs, 1H, SO2NH); 4,70 (Sirs, 1H, SO2NH); 3,00 (s, 3H), of 2.75 (d, 3H, J=4 Hz).

According to the method described above and using 2-methoxyethylamine as an amine, the following compounds:

E-2-(4-isobutylphenyl)Aten-N-(2-methoxyethyl)sulfonamide (26)

1H-NMR (CDCl3): δ EUR 7.57 (d, 1H, J=Hz); 7,38 (d, 2H, J=Hz); then 7.20 (d, 2H, J=Hz); make 6.90 (d, 1H, J=Hz); 4,80 (Sirs, 1H, SO2NH); 3,74 (m, 2H); 3,55 (m, 2H); of 3.45 (s, 3H); 2,52 (d, 2H, J=Hz); 1,95 (m, 1H); of 1.05 (d, 6H, J=Hz).

E-2-(3-benzoylphenyl)Aten-N-(2-methoxyethyl)sulfonamide (27)

1H-NMR (CDCl3): δ 7,80 (d, 2H, J=Hz); 7,72 (s, 1H); a 7.62 (d, 1H, J=8gts); at 7.55 (d, 1H, J=Hz); 7,40 (m, 2H); 7,30 (m, 3H); to 6.95 (d, 1H, J=Hz); 4,62 (Sirs, 1H, SO2NH) of 3.75 (m, 2H); 3,50 (m, 2H); 3.40 in (s, 3H).

E-2-[4-(tripterocalyx)phenyl]ethen-N-(2-methoxyethyl)sulfonamide (28)

1H-NMR (CDCl3): δ a 7.62 (d, 1H, J=8gts); 7,50 (d, 2H, J=Hz); 7,30 (d, 2H, J=Hz); to 7.15 (d, 1H, J=Hz); 4,80 (Sirs, 1H, SO2NH); of 3.77 (m, 2H); to 3.52 (m, 2H); 3.40 in (s, 3H).

E-2-[4-(methanesulfonamido)phenyl]ethen-N-(2-methoxyethyl)sulfonamide (29)

1H-NMR (CDCl3): δ 7,58 (d, 1H, J=Hz); to 7.35 (d, 2H, J=8gts); to 7.25 (d, 2H, J=8gts); make 6.90 (d, 1H, J=Hz); 6,52 (Sirs, 1H, SO2NH); 4,75 (Sirs, 1H, SO2NH); 3,70 (m, 2H); 3,50 (m, 2H); 3.40 in (s, 3H); 3,05 (s, 3H).

Example 4

General methods of synthesis of arylethanolamine

(1-Methyl-5-isobutylphenyl)-1-methanesulfonamide (30)

Synthesis of compound (30) is effected on the basis of commercial reagent methyl-1-methyl-2-pyrroleacetic that when the acylation according to the method of Friedel-with isobutyramide gives (1-methyl-5-isobutylphenyl)-1-methanizeit. Ester group then hydrolyzing. According to the experimental procedure described in WO 02/0704095 receive related sodium salt (1-methyl-5-isobutylphenyl)-1-methanesulfonic acid.

The solution of sodium salt of (1-methyl-5-isobutylphenyl)-1-methanesulfonic acid (0.64 mmol) is dissolved in thionyl chloride (5 ml) and the resulting solution is heated at boiling temperature under reflux overnight. After cooling to room temperature thionyl chloride the issue is more in vacuum and the crude (1-methyl-5-isobutylphenyl)-1-methanesulfonate diluted with dry THF (5 ml) and cooled to T=0° C in a water bath with ice; add dropwise a solution of ammonia (1.28 mmol). A water bath with ice is removed and the reaction mixture was allowed to stand to reach room temperature. After complete disappearance of the original reagent, the solvent is evaporated in vacuo and to the residue add CHCl3(10 ml) and water (10 ml); the two phases are mixed by shaking and separated, the organic phase is washed with water (3×15 ml), dried over Na2SO4and evaporated in vacuum to give crude product, which was purified flash chromatography. Net (1-methyl-5-isobutylphenyl)-1-methanesulfonamide (0,60 mmol) (yield 93%) was isolated as a yellow oil.

1H-NMR (DMSO-d6): δ 7,5 (s, 1H); 6,18 (s, 1H); 4,65 (Sirs, 2H, SO2NH2); of 3.60 (s, 3H); 3,51 (s, 2H); to 3.38 (m, 1H); of 1.25 (d, 6H, J=8gts).

According to the method described above and using sodium salt (1-methyl-5-acetylpyrrole)-1-methanesulfonic acid (7) (obtained by the above General method of synthesis uralmetanolgroup acids) obtained the following connection:

(1-methyl-5-acetylpyrrole)-1-methanesulfonamide (31)

1H-NMR (DMSO-d6): δ 7,5 (s, 1H); 6,18 (s, 1H); 4,40 (Sirs, 2H, SO2NH2); of 3.60 (s, 3H); 3,51 (s, 2H); 2,10 (s, 3H).

Enantioselective synthesis of (+) and (-) enantiomers of compounds 32 and 33

Enantioselective synthesis of (+) and (-) enantiomers of 1-(4-isobutylphenyl)acanalonia apolnet, as described in F.A. Davis et al., J. Org. Chem., 58, 4890-4896, (1993). The method includes diastereoselective C-methylation of N-sulfonylation obtained from 4-isobutylmethylxanthine (27) and N,N-aminobutiramida(1S)-(+)-10-camphorsulfonate or N,N-aminobutiramida(1R)-(-)-10-camphorsulfonate. Acid hydrolysis of diastereomers allows you to get the required connections, both in the form of a transparent oil.

(-)-1-(4-Isobutylphenyl)econsultant (32)

[a]D= -8,5 (c=1,2; CHCl3)

1H-NMR (CDCl3): δ 7,30 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); of 4.25 (m, 1H + Sirs SONH2); at 2.45 (d, 2H, J=Hz); to 1.87 (m, 4H); to 0.97 (d, 6H, J=Hz).

(+)-1-(4-Isobutylphenyl)econsultant (33)

[a]D= +15 (c=1; CHCl3)

1H-NMR (CDCl3): δ 7,30 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); of 4.25 (m, 1H + Sirs SONH2); at 2.45 (d, 2H, J=Hz); to 1.87 (m, 4H); to 0.97 (d, 6H, J=Hz).

Example 5

Alternative synthesis of arylethanolamine

Synthesis of (+)-1-(3-isopropylphenyl)acanaloniidae (34)

Specified in the header connection receive on the basis of a commercial reagent, 3-(1-cyanoethyl)benzoic acid, which according to the experimental methods described in K. Kindler et al., Chem. Ber., 99, 226 (1966) and K. Kindler et al., Liebigs Ann. Chem., 26, 707 (1967), gives the intermediate 3-isopropylbenzoic acid. Restoring to a derivative of benzyl alcohol using LiAlH4and the subsequent processing of alcohol thioglucose acid lead promezhutochnogo ethyldiazoacetate. Subsequent hydrolysis of the derivative of the thiol is carried out, as described in E.J. Corey et al., Tet. Lett., 33, 4099 (1992).

To a suspension of 3-isopropylaniline (3,85 g; 23.2 mmol) and tert-butoxide potassium (2.6 g; 23.2 mmol) in CH2Cl2(15 ml) was added 18-Crown-6 (0.6 g; 2.3 mmol). After stirring for 15' at T=0°C-4°C add N-Br-phthalimide (5,24 g; 23.2 mmol). After adding a water bath with ice is removed and the solution allowed to mix at room temperature for 1 h; then the organic phase is washed with water (3×15 ml), dried over Na2SO4and evaporated in vacuum, obtaining an oily residue, which when cleaning flash chromatography gives 3-isopropylbenzylamine (6,05 g; 18,56 mmol) as a pale yellow oil (yield 80%). Subsequent methylation to obtain 1-(3-isopropylphenyl)ethylthiophene perform as described in F.A. Davis et al., J. Org. Chem., 58, 4890-4896, (1993). The target compound, 1-(3-isopropylphenyl)econsultant (31), obtained by oxidation with 3-chloroperbenzoic acid (2 equivalents) and splitting phthalimidopropyl with hydrazine according to well known prior art methods.

1H-NMR (CDCl3): δ 7,28 (m, 2H); 7,05 (m, 2H); 4,40 (Sirs, 2H, SO2NH2); 3,90 (m, 1H); the 3.65 (m, 1H); to 1.35 (d, 3H, J=Hz); of 1.20 (d, 6H, J=8gts).

Alkylation of the corresponding 1-arylethanolamine (obtained by the above method) using 3-dimethylaminopropylamine as the alkylating reagent is carried out in conditions of phase transfer, as described in T. Gajda et al., Synthesis, 1005 (1981) and Burke P.O. et al., Synthesis, 935 (1985). Received the following connections:

(±)-1-(4-isobutylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide (35)

1H-NMR (CDCl3): δ to 7.32 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); 4.26 deaths (m, 1H); 4,10 (Sirs, 1H, SONH); 3,18 (m, 2H); to 2.55 (m, 4H); of 2.45 (d, 2H, J=Hz); 2.40 a (s, 6H); of 1.85 (m, 4H); and 1.00 (d, 6H, J=Hz).

(±)-1-(3-benzoylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide (36)

1H-NMR (CDCl3): δ 7,80 (d, 2H, J=Hz); of 7.70 (s, 1H); a 7.62 (d, 1H, J=Hz); 7,51 (m, 2H); 7,30 (m, 3H); 4,35 (Sirs, 1H, SO2NH); 3,62 (m, 1H); 3,18 (m, 2H); to 2.55 (m, 4H); 2.40 a (s, 6H); of 1.30 (d, 3H, J=Hz).

(±)-1-[4-(tripterocalyx)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide (37)

1H-NMR (CDCl3): δ 7,50 (d, 2H, J=Hz); to 7.25 (d, 2H, J=Hz); 4,30 (Sirs, 1H, SO2NH); of 3.85 (m, 1H); 3,20 (m, 2H); 2,60 (m, 4H); of 2.45 (s, 6H); of 1.25 (d, 3H, J=Hz).

(±)-1-[4-(methanesulfonamido)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide (38)

1H-NMR (CDCl3): δ 7,37 (d, 2H, J=8gts); 7,22 (d, 2H, J=8gts); 6,45 (Sirs, 1H, SO2NH); 4,80 (Sirs, 1H, SO2NH); 3,82 (m, 1H); of 3.25 (m, 2H); 2,98 (s, 3H); to 2.65 (m, 4H); of 2.45 (s, 6H); of 1.05 (d, 3H, J=Hz).

Alkylation of the corresponding 1-arylethanolamine (obtained by the above method) using a simple 2-pomatoleios ether as the alkylating reagent is performed in conditions of phase transfer, as described in T. Gajda et al., Synthesis, 1005 (1981) and Burke P.O. et al., Synthesis, 935 (1985). The following connection is recommended reading:

(±)-1-(4-isobutylphenyl)ethane-N-(2-methoxyethyl)sulfonamide (39)

1H-NMR (CDCl3): δ 7,30 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); of 4.25 (m, 1H); 4.80 to (Sirs, 1H, SO2NH); 3,74 (m, 2H); 3,55 (m, 2H); of 3.45 (s, 3H); of 2.45 (d, 2H, J=Hz); to 1.87 (m, 1H); of 1.65 (d, 3H, J=Hz); to 0.97 (d, 6H, J=Hz).

(±)-1-(3-benzoylphenyl)ethane-N-(2-methoxyethyl)sulfonamide (40)

1H-NMR (CDCl3): δ of 7.82 (d, 2H, J=Hz); of 7.75 (s, 1H); a 7.62 (d, 1H, J=Hz); at 7.55 (m, 2H); 7,30 (m, 3H); 4.25 in (Sirs, 1H, SO2NH); of 3.75 (m, 2H); of 3.60 (m, 1H); 3,55 (m, 2H); of 3.48 (s, 3H); of 1.55 (d, 3H, J=Hz).

(±)-1-[4-(tripterocalyx)phenyl]ethane-N-(2-methoxyethyl)sulfonamide (41)

1H-NMR (CDCl3): δ 7,50 (d, 2H, J=Hz); to 7.25 (d, 2H, J=Hz); 4,30 (Sirs, 1H, SO2NH); of 3.85 (m, 1H); of 3.60 (m, 2H); 3,55 (m, 2H); of 3.48 (s, 3H); to 1.35 (d, 3H, J=Hz).

(±)-1-[4-(methanesulfonamido)phenyl]ethane-N-(2-methoxyethyl)sulfonamide (42)

1H-NMR (CDCl3): δ 7,52 (d, 2H, J=Hz); 7,28 (d, 2H, J=Hz); 6,45 (Sirs, 1H, SO2NH); 4,32 (Sirs, 1H, SO2NH); of 3.85 (m, 1H); 3,62 (m, 2H); 3,55 (m, 2H); of 3.48 (s, 3H); 3,00 (s, 3H); to 1.35 (d, 3H, J=Hz).

Monomethylamine corresponding 1-arylethanolamine (obtained by the above method using diazomethane perform, as described in E. Muller et al., Liebigs Ann. Chem., 623, 34 (1959) and T. Saegusa et al., Tet. Lett., 6131 (1966). Received the following connections:

(±)-1-(4-isobutylphenyl)ethane-N-methylsulfonate (43)

1H-NMR (CDCl3): δ to 7.25 (d, 2H, J=Hz); to 7.18 (d, 2H, J=Hz); 4,80 (Sirs, 1H, SO2NH); 4,20 (m, 1H); 2,70 (d, 3H, J=4 Hz); of 2.45 (d, 2H, J=Hz); 1,87 (who, 1H); of 1.65 (d, 3H, J=Hz); to 0.97 (d, 6H, J=Hz).

(±)-1-(3-benzoylphenyl)ethane-N-methylsulfonate (44)

1H-NMR (CDCl3): δ of 7.82 (d, 2H, J=Hz); of 7.75 (s, 1H); a 7.62 (d, 1H, J=Hz); at 7.55 (m, 2H); 7,30 (m, 3H); 4.25 in (Sirs, 1H, SO2NH); 4,15 (m, 1H); 2,70 (d, 3H, J=4 Hz); of 1.55 (d, 3H, J=Hz).

(±)-1-[4-(tripterocalyx)phenyl]ethane-N-methylsulfonate (45)

1H-NMR (CDCl3): δ 7,52 (d, 2H, J=Hz); 7,28 (d, 2H, J=Hz); 4,10 (Sirs, 1H, SO2NH); of 3.80 (m, 1H); to 2.75 (d, 3H, J=4 Hz); of 1.20 (d, 3H, J=Hz).

(±)-1-[4-(methanesulfonamido)phenyl]ethane-N-methylsulfonate (46)

1H-NMR (CDCl3): δ 7,50 (d, 2H, J=Hz); 7,27 (d, 2H, J=Hz); 6,50 (Sirs, 1H, SO2NH); 4,30 (Sirs, 1H, SO2NH); 3,90 (m, 1H); 3,05 (s, 3H); 2,70 (d, 3H, J=4 Hz); 1.32 to (d, 3H, J=Hz).

(±)-1-(4-isobutylphenyl)ethane-N-acetylacetonate (47)

The compound is synthesized as described above, by acylation with acetylchloride related 1-(4-isobutylphenyl)acanalonia.

1H-NMR (CDCl3): δ 7,28 (d, 2H, J=Hz); then 7.20 (d, 2H, J=Hz); 4,82 (Sirs, 1H, SO2NH); 4,30 (m, 1H); of 2.45 (d, 2H, J=Hz); of 1.85 (m, 1H); of 1.80 (s, 3H); of 1.65 (d, 3H, J=Hz); to 0.97 (d, 6H, J=Hz).

Example 6

General methods of synthesis of E/Z-2-aryl-2-methylethanolamine

The solution of the corresponding aryasetiawan (20 mmol) (obtained by the above method the General approach to the synthesis of 1-arylethanolamine acid) in 10 ml of tert-butyl alcohol is added dropwise over 20 min to a commercial ilide, JOGMEC is centrifugalforce (25 mmol), maintaining the reaction temperature below 25°C, and the resulting mixture is stirred for 4 h at room temperature. At the end of the interaction the mixture is shaken with 50 ml of pentane and 50 ml of water, filtered and the layers separated. The aqueous layer was extracted with 3×50 ml of pentane and dried over sodium sulfate, getting after purification with flash chromatography pure 2-(aryl)propanidid (mixture of E/Z-isomers), (yield 70%). The above rafinirovaniyu by Wittig carbonyl compounds is carried out, as described in Sotaro Miyano et al., Bull. Chem. Soc. J., 1197, 52 (1979).

2-(Aryl)propanidid (2 mmol) dissolved in acetonitrile (5 ml) and added to a solution of thioacetate potassium (4 mmol) in acetonitrile (2 ml) at room temperature; the reaction mixture is stirred for 4 hours. The mixture is quenched with water and extracted with EtOAc; the separated organic layers dried, filtered and concentrated, obtaining 2-arylpropionate (mixture of E/Z-isomers) (almost quantitative yield).

A solution of 2-aryl-2-methylacetoacetate (1.00 mmol) in glacial acetic acid (2 ml) was stirred at 60°C and treated dropwise 30% H2O2(4,56 mmol); the resulting solution was stirred at 60°C for 24 hours, then acetic acid is removed by azeotropic distillation with toluene. The residue was diluted with water (5 ml), neutralized with 1N NaOH, washed with diethyl ether (2 15 ml) and lyophilized, receiving sodium salt of 2-aryl-2-methylaminoethanol acid in the form of a white solid as a mixture of E/Z-isomers (yield 90%).

E/Z-2-aryl-2-methylethanolamine receive the above-described method the General approach to the synthesis of E-arylethanolamine that give E/Z-2-aryl-2-methyl-Tinsulanonda (0,75-0,85 mmol) (yield 85-95%) as colourless oils.

Following the above method, synthesize the following compounds:

E-2-(3-benzoylphenyl)-2-methylacetophenone (48)

1H-NMR (CDCl3): δ to 7.75 (m, 3H); a 7.62 (m, 2H); 7,53 (m, 4H); x 6.15 (d, 1H, J=1,4 Hz), 5,96 (d, 1H, J=1.3 Hz); of 4.38 (Sirs, 2H, SONH2); 2,10 (d, 3H, J=1,4 Hz); 2.0 (d, 3H, J=1,3 Hz).

E-2-(3-isopropylphenyl)-2-methylacetophenone (49)

1H-NMR (CDCl3): δ 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H); x 6.15 (d, 1H, J=1,4 Hz), 5,96 (d, 1H, J=1,3 Hz); of 4.38 (Sirs, 2H, SONH2); 3.15 in (m, 1H); 2,10 (d, 3H, J=1,4 Hz); 2.0 (d, 3H, J=1,3 Hz); of 1.25 (d, 6H, J=Hz).

E-2-(4-isobutylphenyl)-2-methylacetophenone (50)

1H-NMR (CDCl3): δ to 7.32 (d, 2H, J=Hz); of 7.23 (d, 2H, J=Hz); x 6.15 (q, 1H, J=1,4 Hz); 5,96 (kV, 1H, J=1,3 Hz); 4,35 (Sirs, 2H, SONH2); at 2.45 (d, 2H, J=Hz); 2,10 (d, 3H, J=1,4 Hz); 2.0 (d, 3H, J=1,3 Hz); of 1.88 (m, 1H); to 0.97 (d, 6H, J=Hz).

List of chemical names and structures of compounds according to examples 1-6 are presented in table I.

TABLE I
No.NAMEWith RUCTURE
1sodium salt of (-)-1-(4-isobutylphenyl)econsultancy acid
2sodium salt of (+)-1-(4-isobutylphenyl)econsultancy acid
3sodium salt of (-)-1-[4-(1-oxo-2-isoindolyl)phenyl]econsultancy acid
4sodium salt of (+)-1-[4-(1-oxo-2-isoindolyl)phenyl]econsultancy acid
5sodium salt of (-)-2-(4-phenylsulfonyl)econsultancy acid
6sodium salt of (+)-2-(4-phenylsulfonyl)econsultancy acid
7sodium salt of (1-methyl-5-acetylpyrrole)-1-methanesulfonic acid
8sodium salt (±)-2-(3-benzoylphenyl)econsultancy acid
9sodium salt (±)-2-(3-isopropylphenyl)econsultancy acid
10sodium salt of E-2-(4-isobutylphenyl)atenololbuy acid
11sodium salt of E-2-(3-benzoylphenyl)atenololbuy acid
12sodium salt of E-2-(4-methanesulfonylaminoethyl)atenololbuy acid
13sodium salt of E-2-(4-triftoratsetilatsetonom)atenololbuy acid
14E-2-(4-isobutylphenyl)atenolole
15E-2-(3-benzoylphenyl)atenolole
16E-2-[4-(triftoratsetilatsetonom] atenolole
17E-2-[4-(methanesulfonamido)phenyl]atenolole
18E-2-(4-isobutylphenyl)Aten-(N,N-dimethylaminopropyl)sulfonamide
19E-2-(3-benzoylphenyl)the ten-N-(N,N-dimethylaminopropyl)sulfonamide
20E-2-[4-(tripterocalyx)phenyl]ethen-(N,N-dimethylaminopropyl)sulfonamide
21E-2-[4-(methanesulfonamido)phenyl]ethen-(N,N-dimethylaminopropyl)sulfonamide
22E-2-(4-isobutylphenyl)Aten-N-methylsulfonate
23E-2-(3-benzoylphenyl)Aten-N-methylsulfonate
24E-2-[4-(tripterocalyx)phenyl]ethen-N-methylsulfonate
25E-2-[4-(methanesulfonamido)phenyl]ethen-N-methylsulfonate
26E-2-(4-isobutylphenyl)Aten-N-(2-methoxyethyl)sulfonamide
27E-2-(3-benzoylphenyl)Aten-N-(2-methoxyethyl)sulfonamide
28E-2-[4-(tripterocalyx)phenyl]ethen-N-(2-methoxyethyl)sulfonamide
29E-2-[4-(methanesulfonamido)phenyl]ethen-N-(2-methoxyethyl)sulfonamide
30(1-methyl-5-isobutylphenyl)-1-methanesulfonamide
31(1-methyl-5-acetylpyrrole)-1-methanesulfonamide
32(-)-1-(4-isobutylphenyl)econsultant
33(+)-1-(4-isobutylphenyl)econsultant
34(+)-1-(3-isopropylphenyl)econsultant
35(±)-1-(4-isobutylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide
36(±)-1-(3-benzoylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide
37(±)-1-[4-(tripterocalyx)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide
38(±)-1-[4-(methanesulfonamido)f the Nile]ethane-N-(N,N-dimethylaminopropyl)sulfonamide
39(±)-1-(4-isobutylphenyl)ethane-N-(2-methoxyethyl)sulfonamide
40(±)-1-(3-benzoylphenyl)ethane-N-(2-methoxyethyl)sulfonamide
41(±)-1-[4-(tripterocalyx)phenyl]ethane-N-(2-methoxyethyl)sulfonamide
42(±)-1-[4-(methanesulfonamido)phenyl]ethane-N-(2-methoxyethyl)sulfonamide
43(±)-1-(4-isobutylphenyl)ethane-N-methylsulfonate
44(±)-1-(3-benzoylphenyl)ethane-N-methylsulfonate
45(±)-1-[4-(tripterocalyx)phenyl]ethane-N-methylsulfonate
46(±)-1-[4-(methanesulfonamido)phenyl]ethane-N-methylsulfonate
47(±)-1-(4-isobutylphenyl)ethane-N-acetylacetonate
48E-2-(3-benzoylphenyl)-2-methylacetophenone
49E-2-(3-isopropylphenyl)-2-methylacetophenone
50E-2-(4-isobutylphenyl)-2-methylacetophenone

TABLE II

Inhibition (%) of PMN chemotaxis of human induced IL-8 (100 ng/ml)

*Connections tested at s = 10-7

1. The use of sulfonic acid and the corresponding derivatives of formula (I)

and pharmaceutically acceptable salts of these compounds,

where Ar denotes phenyl group substituted by one Deputy, is independently selected from the group comprising From1-C4-alkyl, benzoyl, or Ar means pyrrolyl, replaced by stands and acetyl, or Ar means 4'-triftoratsetilatsetonom;

X means either-CH2-or-CH(CH3)-group, or ethylene group of the formula (II)

in the E-configuration, where R' is H or CH3;

Y is selected from (CIS is oreda) and NH; and

when Y represents O (oxygen), R is H (hydrogen);

when Y represents NH, R is selected from the group comprising H, C1-C5-alkyl, C1-C5-acyl, a residue of the formula-CH2-CH2-Z-(CH2-CH2O)nR", where R" means1-C5-alkyl, n is 0, and Z means oxygen or a residue of formula - (CH2)n-NRaRbwhere n is 0-5 and each of Raand Rbwhich may be identical or different, denote With1-C6-alkyl,

when getting drugs for inhibition of PMN chemotaxis of human-induced IL-8.

2. The use according to claim 1, where Ar denotes a substituted phenyl group selected from the group comprising 3'-benzoylphenyl, 4'-triftoratsetilatsetonom.

3. The use according to claim 1, where YR mean IT.

4. The use according to claim 1, where Y represents NH and R means

H, C1-C5-alkyl, C1-C5-acyl;

the remainder of the formula - (CH2)n-NRaRbwhere n is 3, and the group NRaRbmeans N,N-dimethylamine.

5. Sulfonic acid and derivative compounds of formula (I) according to claim 1, selected from the following compounds:

1-{4-isobutylphenyl)econsultancy acid,

sodium salt of (-)-1-[4-(2-oxopyrrolidin-1-yl)phenyl]econsultancy acid,

sodium salt of (+)-1-[4-(2-who cooperrider-1-yl)phenyl]econsultancy acid,

sodium salt of (+)-1-{4-[(phenylsulfonyl)oxy]phenyl}econsultancy acid,

sodium salt of (-)-1-{4-[(phenylsulfonyl)oxy]phenyl}econsultancy acid,

E-2-(4-isobutylphenyl)Tinsulanonda acid,

E-2-(3-benzoylphenyl)Tinsulanonda acid,

E-2-(4-methanesulfonylaminoethyl)Tinsulanonda acid,

E-2-(4-triftoratsetilatsetonom)Tinsulanonda acid,

E-2-(4-isobutylphenyl)tinsulanond,

E-2-(3-benzoylphenyl)tinsulanond,

E-2-[4-(tripterocalyx)phenyl]tinsulanond,

E-2-[4-(methanesulfonamido)phenyl]tinsulanond,

E-2-(4-isobutylphenyl)Aten-N-(N,N-dimethylaminopropyl)sulfonamide,

E-2-(3-benzoylphenyl)Aten-N-(N,N-dimethylaminopropyl)sulfonamide,

E-2-[4-(tripterocalyx)phenyl]ethen-N-(N,N-dimethylaminopropyl)sulfonamide,

E-2-[4-(methanesulfonamido)phenyl]ethen-N-(N,N-dimethylaminopropyl)sulfonamide,

E-2-(4-isobutylphenyl)Aten-N-methylsulfonate,

E-2-(3-benzoylphenyl)Aten-N-methylsulfonate,

E-2-[4-(tripterocalyx)phenyl]ethen-N-methylsulfonate,

E-2-[4-(methanesulfonamido)phenyl]ethen-N-methylsulfonate,

E-2-(4-isobutylphenyl)Aten-N-(2"-methoxyethyl)sulfonamide,

E-2-(3-benzoylphenyl)Aten-N-(2"-methoxyethyl)sulfo the amide,

E-2-[4-(tripterocalyx)phenyl]ethen-N-(2"-methoxyethyl)sulfonamide,

E-2-[4-(methanesulfonamido)phenyl]ethen-N-(2"-methoxyethyl)sulfonamide,

(1-methyl-5-isobutylphenyl)-1-methanesulfonamide,

(1-methyl-5-acetylpyrrole)-1-methanesulfonamide,

1-(4-isobutylphenyl)econsultant,

1-(3-isopropylphenyl)econsultant,

1-(4-isobutylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide,

1-(3-benzoylphenyl)ethane-N-(N,N-dimethylaminopropyl)sulfonamide,

1-[4-(tripterocalyx)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide,

1-[4-(methanesulfonamido)phenyl]ethane-N-(N,N-dimethylaminopropyl)sulfonamide,

1-(4-isobutylphenyl)ethane-N-(2-methoxyethyl)sulfonamide,

1-(3-benzoylphenyl)ethane-N-(2-methoxyethyl)sulfonamide,

1-[4-(tripterocalyx)phenyl]ethane-N-(2-methoxyethyl)sulfonamide,

1-[4-(methanesulfonamido)phenyl]ethane-N-(2-methoxyethyl)sulfonamide,

1-(4-isobutylphenyl)ethane-N-methylsulfonate,

1-(3-benzoylphenyl)ethane-N-methylsulfonate,

1-[4-(tripterocalyx)phenyl]ethane-N-methylsulfonate,

1-[4-(methanesulfonamido)phenyl] ethane-N-methylsulfonate,

1-[4-isobutylphenyl]ethane-N-acetylacetonate,

E-2-(3-benzoylphenyl)-2-methylacetophenone,

E-2-(3-isopro ylphenyl)-2-methylacetophenone,

E-2-(4-isobutylphenyl)-2-methylacetophenone,

and pharmaceutically acceptable salts of such compounds.

6. Compounds according to claim 5, where connections are

econsultancy as separate (-) or (+) enantiomers.

7. The method of obtaining the compounds according to subparagraph 5 and 6, where YR means IT includes the interaction of the intermediate compounds of formula (IV)

where J denotes H or PINES3with a suitable oxidizing agent such as H2O2, HClO or peroxynitrate, such as m-chloroperbenzoic acid.

8. The method of obtaining the compounds according to subparagraph 5 and 6, where Y represents NH and X is-CH2or ethylene group of the formula (II) in the E-configuration

including the interaction of the corresponding sulphonylchloride, such as sulphonylchloride, with one or two equivalents of an amine of the formula NH2R, where R represents methyl, methoxyethyl or dimethylaminopropyl, or with one equivalent of sodium hydroxide to obtain the corresponding tinsulanond acids.

9. The method of obtaining the compounds according to subparagraph 5 and 6, where Y represents NH and X is-CH(CH3)-including the interaction of the intermediate compounds of formula (IV)

where X represents-CH2 -, J denotes H, with a suitable N-bromamide, such as N-bromophthalimide, and subsequent methylation and oxidation of the sulfur atom with subsequent removal of the protection sulfonamidnuyu derived.

10. Pharmaceutical composition having inhibitory action of PMN chemotaxis of human induced IL-8-containing compound according to claim 5 or 6 in a mixture with a suitable carrier.

11. The use according to claims 1 to 4 in order to obtain drugs for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous of pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damage caused by ischemia and reperfusion.



 

Same patents:

The invention relates to pharmaceutical compositions for inhibiting integrase, which contains as active substance a compound of the formula (I)

where X denotes a hydroxy-group; Y represents a group-COORAin which RArepresents hydrogen or ester residue, or denotes a group-CONRINRCin which RINand RCeach independently of one another denotes hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl, and1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or AND1denote optionally substituted indol-3-yl, or contains its tautomer, prodrug, pharmaceutically acceptable salt or hydrate, compounds of formulas I, II

where X, Y described above, AND1- optional replaced heteroaryl; Z1and Z2indicate the relationship; Z2means a connection, (ness.)alkylene, -CH(OH)-, -S-, -SO2-, -O - or-CO; Z4means a connection, (ness.)alkylene, (ness.)albaniles or-CO-; R1means neobyzantine substituted heterocycle, R2denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (ness.)allyloxycarbonyl, optionally substituted aryl, optionally substituted by alloctype, carboxy or halogen; R=0 or 1, with the exception of compounds in which (1) Y and/or AND1denotes optionally substituted indol-3-yl and (2) X denotes a hydroxy-group, Y represents 2-thienyl, AND1denotes a 1H-1,2,4-triazole-3-yl, Z1and Z3each denotes a bond, Z2denotes-NH-, R1denotes phenyl or para-tolyl and p=0; (3) X denotes a hydroxy-group, Y represents 4-methoxyphenyl, or 4-chlorophenyl, AND1means thiazol-5-yl, Z1, Z2, Z3and Z4each represents a bond, R1denotes phenyl, 4-methoxyphenyl or 4-chlorophenyl, R2denotes methyl and p=1; (4) X denotes hydroxyl, Y represents phenyl, 4-were, 4-bromophenyl or 4-chlorophenyl, AND1signifies imidazol-2-yl, Z1and Z3each denotes a bond, Z2denotes methylene, R1denotes phenyl, Z4denotes a bond, R2denotes 4-dimethylaminophenyl or 4-methoxyphenyl, and p=1; (5) X denotes hydroxyl, Y represents phenyl, 4-were-or 4-met is 1 denotes phenyl and p=0; (6) X denotes hydroxyl, Y represents-COORAwhere RAdenotes hydrogen or ethyl, AND1signifies 3-indolyl, imidazo[1,2-a]pyridine-3-yl or imidazo[2,1-b] thiazole-5-yl, Z1, Z2and Z3each represents a bond, R1denotes optionally substituted phenyl, and tautomer, prodrug, pharmaceutically acceptable salt or hydrate; various farmkompanijam, comprising as active ingredient the compound II, the drug compound having anti-HIV activity; the method of obtaining compounds of formula III

as well as the intermediate products of the formula

where Z2denotes a bond, -CO-, -O-, -CH2- or -(CH2)2and R1denotes phenyl, substituted with fluorine, and

where And denotes C-W, where W denotes hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N, Q denotes trail and L denotes ethoxypropan

The invention relates to new derivatives of chloropyridinyl formula I where Het is a group of formula a, b, C, d or e, R1is hydrogen, unsubstituted or substituted C1- C6alkyl, and the substituents selected from the group comprising halogen, phenyl, cyano, C1- C4alkoxy, C1- C4alkylthio,1- C4alkylsulphonyl; C2- C4alkenyl, unsubstituted or substituted C1- C4alkoxygroup; phenyl or unsubstituted or substituted 1 or 21- C4alkoxygroup, n = 1 or 2, and their acid additive salts

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel N-(5-iodo-2-methoxycarbonylphenyl)sulfonylures of the formula (I): wherein R means unsubstituted (C1-C12)-alkyl or substituted with one or more residues from group comprising halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, (C1-C6)-halogenalkoxy-group and unsubstituted phenyl or substituted up to three-fold with similar or different residues chosen from group comprising (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-halogenalkyl, (C1-C4)-halogenalkoxy-group, -CN and nitro-group; or unsubstituted (C3-C12)-cycloalkyl or substituted with one or more residues from group comprising halogen atom, (C1-C4)-alkyl, (C1-C4)-halogenalkyl, (C1-C4)-alkoxy-group, (C1-C4)-halogenalkoxy-group and (C1-C6)-alkylthio-group. Compounds of the formula (I) are intermediate substances used in synthesis of herbicide sulfonylureas that, in turn, show high exploitation indices.

EFFECT: improved method of synthesis, valuable properties of compounds.

12 cl, 2 tbl, 5 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to ortho-substituted arylamides of formula I , wherein J represents phenyl ring or pyrazole ring each substituted with one or two substitutes independently selected from R5; K represents -NR1C(=A)- or -NR1SO2-; L represents -C(=B)NR2-, -SO2NR2- or -C(=B)-; A and B represent O; R1 and R2 represent H; R3 represents C1-C6-alkyl optionally substituted with one or more substitutes, independently selected from group containing CN, NO2, C1-C4-alkylsulfonyl and C2-C6-alkoxycarbonyl; each R4 independently represents C1-C6-alkyl, halogen or CN; each R5 independently represents C1-C6-alkyl, halogen or C1-C4-haloalkoxy or pyridinyl optionally substituted with one substitute independently selected from R9; wherein R9 represents halogen; n = 1-2; with the proviso, that when K represents -NR1C(=A)- L is not -C(=B)NR2-, and salts thereof, method for insect controlling by using abovementioned compounds. Intermediate for synthesis of target compounds having formula 2 also is disclosed.

EFFECT: compounds with insecticide activity, useful in insect controlling.

15 cl, 21 tbl, 9 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

The invention relates to thiosulfonate formulas

< / BR>
< / BR>
or

< / BR>
< / BR>
< / BR>
where R1represents a radical having a length greater than the saturated chain of four carbon atoms, and shorter than the saturated chain from eighteen carbon atoms, and in rotation around the axis passing through the position 1, associated with the SO2and position 4 6-membered ring or through position 1, associated with the SO2group and associated with the Deputy position 3 or 5 of the 5-membered ring, defines a three-dimensional volume, the largest size in which the width is approximately one phenyl ring up to three phenyl rings in a direction transverse to the axis of rotation; R2means hydrido,1-C6alkyl, phenyl-C1-C4alkyl, heteroaryl-C1-C4alkyl, C2-C4alkyl substituted amino; C2-C4alkyl, substituted monosubstituted amino or disubstituted amino, where-C6) alkyl, C5-C8cycloalkyl and C1-C6alkylsulphonyl, or where two of the substituent and the nitrogen to which they are attached, together form pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, and other pyrimidinyl

The invention relates to certain disubstituted acids benzenaminium

The invention relates to new chemical compounds of the class aminomethanesulfonic having bactericidal activity, namely diethylammonium salt N-benzylideneamino-1-phenylmethanesulfonyl acid of the formula (I), and the method of its receipt by the reaction hydrobenzoic with complex diethylamine with sulphurous anhydride and isopropyl alcohol followed by the addition of water at 25oIn the environment of isopropyl alcohol

The invention relates to diethylammonium salt N-methylamino-1-phenylmethanesulfonyl acid of formula 1:

< / BR>
The connection is produced by interaction of benzylideneamino with sulphurous anhydride and diethylamino in the environment of ethyl alcohol in the presence of 5 mol.% triethylmethylammonium followed by the addition of water for 14-16 minutes at 40-50oC

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula I , in which stands for thiophendiyl, phenylene or pyridindiyl; R1 represents alkyl, alkenyl, alkinyl, which optionally contain one or several substitutes, selected from group including halogen, cyano-, nitro- amino group, -NH-alkyl and N(alkyl)2; or -CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-O-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl; or group -NR3R4, in which R3 and R4 independently represent hydrogen; alkyl, alkenyl or alkinyl, which optionally contain one or several substitutes, selected from group including halogen, cyano-, nitro- amino group, -NH-alkyl and N(alkyl) 2; or -CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-(O)-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl; n is 1-6; m is 1-4; and to its pharmaceutically acceptable salts. Invention also relates to medication.

EFFECT: obtaining novel biologically active compounds, intended for inhibition tumor cell proliferation.

25 cl, 6 ex

FIELD: medicine.

SUBSTANCE: invention claims compositions which can include one or several mammary gland tumour proteins, their immunogenic parts or polynucleotides encoding such parts. Alternatively the therapeutic composition can include antigen-presenting cell expressing mammary gland tumour protein, or T-cell specific to cells expressing such protein. These compositions can be applied in prevention and treatment of such diseases as mammary gland cancer. Invention also claims diagnostic methods based on determination of mammary gland tumour protein or mRNA encoding such protein in sample.

EFFECT: use of peptides obtained from protein expressed from mammary gland by tumour in diagnostics and therapy of mammary gland cancer.

37 cl, 6 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns to 3,4-disubstituted tsiklobuten-1,2-diones of the formula I or their pharmaceutically to comprehensible salts or solvates, . A is chosen from the group including

X=-O-, -NH-, -S-,

.

n=1-5

B is chosen from the group including

. The bonds can be used at treatment of mediated chemokine diseases, such as acute both chronic inflammatory diseases and a cancer. The pharmaceutical composition and application of bonds I are also described.

EFFECT: obtaining of bonds which can be used at treatment of mediated chemokine diseases, such as acute both chronic inflammatory diseases and cancer.

50 cl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: antitumoral composition contains taurolipidine, taurultam or their admixture in concentration approximately 0.1-160 mg/ml in combination with biodecomposable adhesive, including the fibrinous hermetic possessing ability to stick to a tissue of a live organism. Invention also concerns a way of processing for the prevention or the inhibition of growth of cancer cells consisting in drawing of an antitumoral composition on certain area of a tissue of a live organism after excising of a tumour. The composition is put on a tissue of an organism by a layer in the thickness from 0.1 to 10 mm.

EFFECT: invention allows preventing with high degree of efficiency repeated development of a tumour after its excising from organism tissues.

18 cl, 1 ex

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